IRAK Degrader and its Use

Abstract

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

Description

[Technical Field]

[0001] REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 267,372, filed January 31, 2022, U.S. Provisional Patent Application No. 63 / 268,341, filed February 22, 2022, U.S. Provisional Patent Application No. 63 / 269,581, filed March 18, 2022, U.S. Provisional Patent Application No. 63 / 363,687, filed April 27, 2022, U.S. Provisional Patent Application No. 63 / 365,741, filed June 2, 2022, and U.S. Provisional Patent Application No. 63 / 374,297, filed September 1, 2022, each of which is incorporated by reference in its entirety.

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

[0003] The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes, and its deficiency or imbalance can lead to the pathogenesis of various diseases. The covalent attachment of ubiquitin to specific protein substrates is activated through the action of E3 ubiquitin ligases.

[0004] There are over 600 E3 ubiquitin ligases that promote the ubiquitination of various proteins in vivo, which can be classified into four families: HECT-domain E3s, U-box E3s, monomeric ring E3s, and multisubunit E3s. In general, Li et al. (PLOS One, 2008, 3, 1487), entitled "Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling."; Berndsen et al. (Nat.Struct.Mol.Biol., 2014, 21, 301-307), entitled "New insights into ubiquitin E3 ligase mechanism"; Deshaies et al. (Ann.Rev.Biochem.,2009,78,399-434), title "RING domain E3 ubiquitin ligases."; Spratt et al. (Biochem.2014,458,421-437), title "RBR E3 ubiquitin ligases:new structures,new insights,new questions."; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347), entitled "Roles of F-box proteins in cancer."

[0005] The UPP plays a vital role in the degradation of short-lived regulatory proteins that are important in various fundamental cellular processes, including the cell cycle, cell surface receptor regulation, and the control of ion channels and antigen presentation. This pathway has been implicated in the pathogenesis of several genetic disorders (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and muscle wasting pathology, as well as in several malignant forms. Many diseases are associated with abnormal UPP, negatively affecting cell cycle and division, cellular responses to stress and extracellular regulators, neuronal network morphogenesis, cell surface receptor regulation, ion channels, secretory pathways, DNA repair, and organelle biogenesis.

[0006] Defects in this process have recently been linked to the pathology of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) those that result from loss of function, resulting in the stabilization of certain proteins, and (b) those that result from gain of function, i.e., the aberrant or accelerated degradation of protein targets. UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthesize small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consist of a target protein-binding ligand and an E3 ubiquitin ligase ligand, which induces proteasome-mediated degradation of selected proteins via their recruitment to E3 ubiquitin ligase, followed by ubiquitination. These drug-like molecules offer the possibility of temporal control over protein expression. Such compounds can induce the inactivation of proteins of interest upon addition to cells or administration to animals or humans, and may be useful as biochemical reagents, leading to a new paradigm for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46). [Prior art documents] [Non-patent literature]

[0007] [Non-Patent Document 1] Crews C,Chemistry&Biology,2010,17(6):551-555;Schnnekloth JS Jr.,Chembiochem,2005,6(l):40-46 Summary of the Invention [Problem to be solved by the invention]

[0008] There is a continuing need in the art for effective treatments for diseases, particularly inflammatory diseases. However, nonspecific 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. As such, small molecule therapeutics that exploit E3 ligase-mediated proteolysis of target proteins, such as interleukin-1 receptor-associated kinase ("IRAK"), hold promise as therapeutic agents. Therefore, there is a need to identify compounds that are IRAK degraders useful as therapeutic agents. [Means for solving the problem]

[0009] The present application relates to novel bifunctional compounds that function to recruit IRAK kinase to E3 ubiquitin ligases for degradation, as well as methods for their preparation and use. In particular, the present disclosure provides bifunctional compounds that have utility as modulators of targeted ubiquitination of IRAK kinase, which is subsequently degraded and / or otherwise inhibited by bifunctional compounds as described herein. An advantage of the compounds provided herein is that they are capable of a wide range of pharmacological activity consistent with degradation / inhibition of IRAK kinase. Additionally, the present disclosure provides methods of using an effective amount of the compounds described herein for the treatment or amelioration of disease states, such as cancer or inflammatory disorders.

[0010] It has now been found that compounds of the present invention and pharmaceutically acceptable compositions thereof are effective in modulating targeted ubiquitination. Such compounds have the formula Ia to I-ii: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

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

[0012] The compounds provided by this invention are also useful for studying the IRAK enzyme in biological and pathological phenomena; studying intracellular signal transduction pathways occurring in body tissues; and for the comparative evaluation of novel IRAK inhibitors or IRAK degraders or other modulators of kinases, signaling pathways, and cytokine levels in vitro or in vivo. DETAILED DESCRIPTION OF THE INVENTION

[0013] 1. General Description of Certain Embodiments of the Invention: The compounds of the present invention and compositions thereof are useful as degraders and / or inhibitors of one or more IRAK protein kinases. In some embodiments, 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 exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Furthermore, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

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

[0016] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or monovalent bonds connecting two bridgeheads, and a "bridgehead" is any skeletal atom of the ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In some embodiments, bridged bicyclic groups have 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 connected to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents, such as those shown for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Representative bridged bicyclic groups include: [ka]

[0017] The term "lower alkyl" refers to a C1-4 straight or branched alkyl group. Representative lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0018] The term "lower haloalkyl" refers to a C1-4 straight or branched alkyl group substituted with one or more halogen atoms.

[0019] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocycle, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl)).

[0020] The term "unsaturated," as used herein, means that a moiety has one or more units of unsaturation.

[0021] As used herein, the term "divalent C1-8 (or C1-6) saturated or unsaturated, straight or branched, hydrocarbon chain" refers to divalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

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

[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 with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

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

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

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

[0027] "Heteroaryl" and "heteroar-," used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy," refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in the cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. As used herein, the terms "heteroaryl" and "heteroar-" also include groups in which a heteroaromatic ring is fused to one or more aryl, alicyclic, or heterocyclyl rings, and the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. Heteroaryl groups can be monocyclic or bicyclic. The 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 "heteroaromatic ring," any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently are optionally substituted.

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

[0029] A heterocycle can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocycle 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, phenanthridinyl, or tetrahydroquinolinyl. Heterocyclyl groups can be monocyclic, bicyclic, bridged bicyclic, or spirocyclic. Heterocycles can 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 portions independently are optionally substituted.

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

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

[0032] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH2)O-4R°; -(CH2)O-4OR°; -O(CH2)O-4Ro, -O-(CH2)O-4C(O)OR°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CH2)O-4Ph (which may be substituted by R°); -(CH2)O-4O(CH2)O-1Ph (which may be substituted by R°); -CH=CHPh (which may be substituted by R°); -(CH2) O-4O(CH2)O-1-pyridyl (which may be substituted by R°); -NO2; -CN; -N3; ​​-(CH2)O-4N(R°)2; -(CH2)O-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)O-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)O-4N(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)O-4C(O)R°; -C(S)R°;-(CH2)0~4C(O)OR°;-(CH2)0~4C(O)SR°;-(CH2)0~4C(O)OSiR°3;-(CH2)0~4OC(O)R°;-OC(O)(CH2)0~4SR-, SC(S)SR°;-(CH2)0~4 SC(O)R°;-(CH2)0~4C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°,-(CH2)0~4OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°; -C(NOR°)R°;-(CH2)0~4SSR°;-(CH2)0~4S(O)2R°;-(CH2)0~4S(O)2OR°;-(CH2)0~4OS(O)2R°;-S(O)2NR°2;-(CH2)0~4S(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;-(C1~4 linear or branched alkylene)ON(R°)2;or -(Ci-4 straight or branched alkylene)C(O)ON(R°)2, where each R° may be substituted as defined below and is independently hydrogen, Ci-6 aliphatic, -CH2Ph, -O(CH2)o-1Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R°, taken together with their intervening atoms, form a 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below;

[0033] Suitable monovalent substituents on R° (or the ring formed by two independent occurrences of R° taken together with their intervening atoms) are independently halogen, -(CH2)0-2R●, -(haloR●), -(CH2)0-2OH, -(CH2)0-2OR●, -(CH2)0-2CH(OR●)2; -O(haloR●), -CN, -N3, -(CH2)0-2C(O)R●, -(CH2)0-2C(O)OH, -(CH2)0-2C(O)OR●, -(CH2)0-2SR●, -(CH2)0-2SH, -(CH2)0-2NH2, - (CH2)0-2NHR●, —(CH2)0-2NR●2, —NO2, —SiR●3, —OSiR●3, —C(O)SR●, —(C1-4 straight or branched alkylene)C(O)OR●, or —SSR●, where each R● is unsubstituted or, if preceded by “halo”, substituted only with one or more halogens, independently selected from C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0034] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2-3O-, or -S(C(R*2))2-3S-, where each independent occurrence of R* is selected from hydrogen, a C1-6 aliphatic group which may be substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include: -O(CR*)O-, where each independent occurrence of R* is selected from hydrogen, a C1-6 aliphatic, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

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

[0036] Suitable substituents on a substitutable nitrogen of an "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†; each R† independently is hydrogen, a C1-6 aliphatic (which may be substituted as defined below), an unsubstituted or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R† taken together with their intervening atoms form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] Suitable substituents on an aliphatic group of R† are independently 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, when preceded by “halo”, substituted only with one or more halogens, and is independently a C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0038] As used herein, the term "provided compounds" refers to any genus, subgenus, and / or species set forth herein.

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is within the scope of sound medical judgment, is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, and the like. Examples of the salts include sulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0040] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N(Ci_4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include amine cations, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates, formed where appropriate, using counterions such as non-toxic ammonium, quaternary ammonium, and halides.

[0041] Unless otherwise specified, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E stereoisomers. Thus, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the present compounds are within the scope of the present invention. Furthermore, unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures containing the replacement of a hydrogen by deuterium or tritium, or the replacement of a carbon by a C- or C-enriched carbon are within the scope of the present invention. Such compounds are useful, for example, as analytical tools, probes in biological assays, or 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 with measurable affinity. In certain embodiments, an inhibitor has an IC50 and / or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[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 measurable affinity, resulting in ubiquitination and subsequent degradation of the IRAK kinase. In certain embodiments, the degrader has a DC50 of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, less than about 10 nM, or less than about 1 nM.

[0044] The compounds of the present invention can be tethered to a detectable moiety. It will be appreciated that such compounds are useful as imaging agents. Those skilled in the art will recognize that the detectable moiety can be linked to the provided compounds via a suitable substituent. As used herein, the term "suitable substituent" refers to a moiety that can be covalently bound to the detectable moiety. Such moieties are well known to those skilled in the art and include groups containing, for example, a carboxylate moiety, an amino moiety, a thiol moiety, or a hydroxyl moiety, to name just a few. It will be recognized that such moieties can be linked to the provided compounds directly or via a tethering group, such as a bivalent saturated or unsaturated hydrocarbon chain. In some embodiments, such moieties can be linked via click chemistry. In some embodiments, such moieties can be linked via 1,3-cycloaddition of an azide with an alkyne, optionally in the presence of a copper catalyst. Methods using click chemistry are known in the art and include those described by Rostovtsev et al., Angew. Chem. Int. Ed. 2002, 41, 2596-99 and Sun et al., Bioconjugate Chem., 2006, 17, 52-57.

[0045] As used herein, the term "detectable moiety" is used interchangeably with the term "label" and refers to any moiety that can be detected, such as primary and secondary labels. Primary labels, such as radioisotopes (e.g., tritium, P, P, S, or C), mass tags, and fluorescent labels, are signal-generating reporter groups that can be detected without further modification. Detectable moieties also include luminescent and phosphorescent groups.

[0046] The term "secondary label," as used herein, refers to moieties such as biotin and various protein antigens that require the presence of a second intermediate for the generation of a detectable signal. For biotin, the secondary intermediate may include a streptavidin enzyme conjugate. For antigen labels, the secondary intermediate may include an antibody-enzyme conjugate. Some fluorescent groups act as secondary labels because they transfer energy to another group in the process of non-radioactive fluorescence resonance energy transfer (FRET), and the second group generates the signal that is detected.

[0047] The terms "fluorescent label," "fluorochrome," and "fluorophore," as used herein, refer to a moiety that absorbs light energy at a defined excitation wavelength and emits light energy at a different wavelength. Examples of fluorescent labels include, but are not limited to, Alexa Fluor dyes (Alexa Fluor 350, Alexa Fluor 488, Alexa Fluor 532, Alexa Fluor 546, Alexa Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, and Alexa Fluor 680), AMCA, AMCA-S, BODIPY dyes (BODIPY FL, BODIPY R6G, BODIPY TMR, BODIPY TR, BODIPY 530 / 550, BODIPY 558 / 568, BODIPY 564 / 570, BODIPY 576 / 589, BODIPY 581 / 591, BODIPY 630 / 650, BODIPY 650 / 665), carboxyrhodamine 6G, carboxy-X-rhodamine (ROX), Cascade Blue, Cascade Yellow, Coumarin 343, cyanine dyes (Cy3, Cy5, Cy3.5, Cy5.5), Dansyl, Dapoxyl, dialkylaminocoumarin, 4',5'-dichloro-2',7'-dimethoxy-fluorescein, DM-NERF, eosin, erythrosine, fluorescein, FAM, hydroxycoumarin, IRDyes (IRD40, IRD700, IRD800), JOE, Lissamine rhodamine B, Marina Blue, methoxycoumarin, naphthofluorescein, Oregon Green 488, Oregon Green 500, Oregon Green 514, Pacific Blue, PyMPO, pyrene, rhodamine B, rhodamine 6G, rhodamine Green, rhodamine Red, Rhodol Green, 2',4',5',7'-tetra-bromosulfone-fluorescein, tetramethyl-rhodamine (TMR), carboxytetramethylrhodamine (TAMRA), Texas Red, Texas Red-X.

[0048] The term "mass tag," as used herein, refers to any moiety that can be uniquely detected by its mass using mass spectrometry (MS) detection techniques. Examples of mass tags include electrophoretic release tags, such as N-[3-[4'-[(p-methoxytetrafluorobenzyl)oxy]phenyl]-3-methylglyceronyl]isonipecotic acid, 4'-[2,3,5,6-tetrafluoro-4-(pentafluorophenoxyl)]methylacetophenone, and derivatives thereof. The synthesis and utility of these mass tags are described in U.S. Patent Nos. 4,650,750, 4,709,016, 5,360,8191, 5,516,931, 5,602,273, 5,604,104, 5,610,020, and 5,650,270. Other examples of mass-tags include, but are not limited to, nucleotides, dideoxynucleotides, oligonucleotides of various lengths and basic compositions, oligopeptides, oligosaccharides and other synthetic polymers of various lengths and monomer compositions. A wide variety of organic molecules, both neutral and charged (biomolecules or synthetic compounds), in the appropriate mass range (100-2000 daltons) can also be used as mass-tags.

[0049] The terms "measurable affinity" and "measurably inhibit," as used herein, refer to a measurable change in IRAK protein kinase activity between a sample containing a compound of the present invention or a composition thereof and IRAK protein kinase and an equivalent sample containing IRAK protein kinase in the absence of said compound or composition thereof.

[0050] 3. Description of Representative Embodiments: As noted above, in certain embodiments, the present invention provides compounds of formula Ia-I-ii: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, X is a divalent moiety selected from -CH- or -C(O)-; Y is nitrogen or CH; Ring A is phenylenyl, naphthylenyl, pyridinylenyl, [ka] is a ring selected from Ring B is a fused ring selected from benzo or 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; Each of R1, R2 and R3 independently represents hydrogen, R A, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -CR2N(R)C(O)R, -CR2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), - OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C (O)NR2, -N(R)S(O)2R, -N(R)P(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R; each R is independently hydrogen or an optionally substituted group selected from a C1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same carbon or nitrogen optionally together with their intervening atoms form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R A is independently an optionally substituted group selected from a C aliphatic, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5 is hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl or C3-6 cycloalkyl; or two R5 groups on the same carbon atom combine to form, together with the carbon atom to which the two R5 groups are attached, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R5 groups on two different carbon atoms combine to form, together with the intervening atom connecting the two R5 groups, a 3- to 7-membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each of rings C and D is independently a ring selected from phenyl or a 5- to 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. or a pharmaceutically acceptable salt thereof.

[0051] As defined above and described herein, X is a divalent moiety selected from -CH2- and -C(O)-.

[0052] In some embodiments, X is -CH2-. In some embodiments, X is -C(O)-.

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

[0054] As defined above and as described herein, Y is a nitrogen atom or CH.

[0055] In some embodiments, Y is a nitrogen atom. In some embodiments, Y is CH.

[0056] In some embodiments, Y is selected from those shown in Table 1 below.

[0057] As defined above and as described herein, Ring A can be selected from phenylenyl, naphthylenyl, pyridinylenyl, [ka] is a ring selected from:

[0058] In some embodiments, Ring A is phenylenyl. In some embodiments, Ring A is naphthylenyl. In some embodiments, Ring A is pyridinylenyl. 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] In some embodiments, ring A is [ka] In some embodiments, ring A is [ka] is.

[0059] In other embodiments, Ring A is a 6-10 membered monocyclic or bicyclic heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0060] In some embodiments, ring A is selected from those shown in Table 1 below.

[0061] As defined above and described herein, Ring B is a fused ring selected from benzo or 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0062] 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.

[0063] In some embodiments, ring B is selected from those shown in Table 1 below.

[0064] 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] is.

[0065] As defined above and as described herein, each of Ring C and Ring D is independently a ring selected from phenyl or a 5-9 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments, ring C is phenyl. In some embodiments, ring C is a 5- to 9-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 6-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ring C is a 9-membered heteroaryl ring having 2 nitrogens. In some embodiments, ring C is a 9-membered heteroaryl ring having 3 nitrogens.

[0067] 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.

[0068] 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] is.

[0069] 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 nitrogens. In some embodiments, ring D is a 9 membered heteroaryl ring having 3 nitrogens.

[0070] 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 pyrrolo[1,2-a]pyrimidine.

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

[0072] In some embodiments, ring C and ring D are selected from those shown in Table 1 below.

[0073] As defined above and as described herein, each of R, R, and R is independently hydrogen, R, halogen, —CN, —NO, —OR, —SR, —NR, —SiR, —S(O)R, —S(O)NR, —S(O)R, —C(O)R, —C(O)OR, —C(O)NR, —C(O)N(R)OR, —C(R)N(R)C(O)R, —C(R)N(R)C(O)NR, —CFR, —CFR, —CF, —CR(O R), -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.

[0074] In some embodiments, one or more of R1, R2, and R3 are hydrogen. In some embodiments, one or more of R1, R2, and R3 are deuterium. In some embodiments, one or more of R1, R2, and R3 are R-A. In some embodiments, one or more of R1, R2, and R3 are halogen. In some embodiments, one or more of R1, R2, and R3 are R-A. In some embodiments, one or more of R1, R2, and R3 are -CN. In some embodiments, one or more of R1, R2, and R3 are -NO. In some embodiments, one or more of R1, R2, and R3 are -OR. In some embodiments, one or more of R1, R2, and R3 are -Si(OH)R. In some embodiments, one or more of R1, R2, and R3 are -Si(OH)R. In some embodiments, one or more of R1, R2, and R3 are -SR. In some embodiments, one or more of R1, R2, and R3 is -NR2. In some embodiments, one or more of R1, R2, and R3 is -SiR3. In some embodiments, one or more of R1, R2, and R3 is -S(O)2R. In some embodiments, one or more of R1, R2, and R3 is -S(O)2NR2. In some embodiments, one or more of R1, R2, and R3 is -S(O)R. In some embodiments, one or more of R1, R2, and R3 is -C(O)R. In some embodiments, one or more of R1, R2, and R3 is -C(O)OR. In some embodiments, one or more of R1, R2, and R3 is C(O)NR2. In some embodiments, one or more of R1, R2, and R3 is -C(O)N(R)OR. In some embodiments, one or more of R1, R2, and R3 is -CR2N(R)C(O)R. In some embodiments, one or more of R1, R2, and R3 is -CR2N(R)C(O)NR2. In some embodiments, one or more of R1, R2, and R3 is -CFR2. In some embodiments, one or more of R1, R2, and R3 is -CF2R. In some embodiments, one or more of R1, R2, and R3 is -CF3. In some embodiments, one or more of R1, R2, and R3 is -CR2(OR).In some embodiments, one or more of R1, R2, and R3 is -CR2(NR2). In some embodiments, one or more of R1, R2, and R3 is -OC(O)R. In some embodiments, one or more of R1, R2, and R3 is -OC(O)NR2. In some embodiments, one or more of R1, R2, and R3 is -OP(O)R2. In some embodiments, one or more of R1, R2, and R3 is -OP(O)(OR)2. In some embodiments, one or more of R1, R2, and R3 is -OP(O)(OR)NR2. In some embodiments, R2 is independently -OP(O)(NR2)2-. In some embodiments, one or more of R1, R2, and R3 is -N(R)C(O)OR. In some embodiments, one or more of R1, R2, and R3 is -N(R)C(O)R. In some embodiments, one or more of R1, R2, and R3 is -N(R)C(O)NR2. In some embodiments, one or more of R1, R2, and R3 is -N(R)P(O)R2. In some embodiments, one or more of R1, R2, and R3 is -N(R)P(O)(OR)2. In some embodiments, one or more of R1, R2, and R3 is -N(R)P(O)(OR)NR2. In some embodiments, one or more of R1, R2, and R3 is -N(R)P(O)(NR2). In some embodiments, one or more of R1, R2, and R3 is -N(R)S(O)R.

[0075] In some embodiments, R1 is fluoro. In some embodiments, R1 is chloro. In some embodiments, R1 is C1-6 alkyl. In some embodiments, R1 is methyl. In some embodiments, R1 is -C(OH)Me2. In some embodiments, R1 is -CHF2. In some embodiments, R1 is -CF3. In some embodiments, R1 is -OC1-6 alkyl. In some embodiments, R1 is -OMe. In some embodiments, R1 is [ka] In some embodiments, R is [ka] In some embodiments, R is [ka] is.

[0076] In some embodiments, R2 is fluoro. In some embodiments, R2 is chloro. In some embodiments, R2 is C1-6 alkyl. In some embodiments, R2 is methyl. In some embodiments, R3 is -C(OH)Me2. In some embodiments, R2 is -CHF2. In some embodiments, R3 is -CF3. In some embodiments, R2 is -OC1-6 alkyl. In some embodiments, R2 is -OMe.

[0077] In some embodiments, R3 is fluoro. In some embodiments, R3 is chloro. In some embodiments, R3 is -CN. In some embodiments, R3 is C1-6 alkyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl. In some embodiments, R3 is isopropyl. In some embodiments, R3 is t-butyl. In some embodiments, R3 is -CH2OMe. In some embodiments, R3 is -C(OMe)Me2. In some embodiments, R3 is -C(CN)Me2. In some embodiments, R3 is C3-6 cycloalkyl. In some embodiments, R3 is cyclopropyl. In some embodiments, R3 is cyclobutyl. In some embodiments, R3 is -CHF2. In some embodiments, R3 is -CF3. In some embodiments, R3 is -OCF3. In some embodiments, R3 is -OCHF2. In some embodiments, R3 is -OC1-6 alkyl. In some embodiments, R3 is -OiPr. In some embodiments, R3 is -OC3-6cycloalkyl. In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is -OMe. In some embodiments, R3 is -NMe2. In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is [ka] In some embodiments, R3 is -SMe. In some embodiments, R3 is -SCF3. In some embodiments, R3 is -SOCF3. In some embodiments, R3 is -SO2CF3.

[0078] In some embodiments, R1, R2, and R3 are selected from those shown in Table 1 below.

[0079] As defined above and as described herein, R4 is hydrogen, C1-5 alkyl, or C3-6 cycloalkyl.

[0080] In some embodiments, R4 is hydrogen. In some embodiments, R4 is C1-5 alkyl. In some embodiments, R4 is C3-6 cycloalkyl.

[0081] In some embodiments, R4 is methyl. In some embodiments, R4 is ethyl. In some embodiments, R4 is cyclopropyl.

[0082] In some embodiments, R4 is selected from those shown in Table 1 below.

[0083] As defined above and as described herein, R5 is hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl or C3-6 cycloalkyl, and two R5 groups on the same carbon atom combine to form, together with the carbon atom to which the two R5 groups are linked, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or two R5 groups on two different carbon atoms combine with the intervening atom linking the two R5 groups to form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0084] In some embodiments, R5 is hydrogen. In some embodiments, R5 is halo. In some embodiments, R5 is -CN. In some embodiments, R5 is -OR. In some embodiments, R5 is oxo. In some embodiments, R5 is C1-6 alkyl. In some embodiments, R5 is -CR2OR. In some embodiments, R5 is -O-C1-6 alkyl. In some embodiments, R5 is C1-6 haloalkyl. In some embodiments, R5 is -O-C1-6 haloalkyl. In some embodiments, R5 is C3-6 cycloalkyl. In some embodiments, two R5 groups on the same carbon atom, together with the carbon atom to which the two R5 groups are attached, combine to form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R5 groups on two different carbon atoms combine, together with the intervening atom connecting the two R5 groups, to form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0085] In some embodiments, R5 is fluoro. In some embodiments, R5 is geminal difluoro. In some embodiments, R5 is methyl. In some embodiments, R5 is —OH. In some embodiments, R5 is —OMe. In some embodiments, R5 is —CMe2OH. In some embodiments, R5 is —CF3. In some embodiments, R5 is —CHF2. In some embodiments, R5 is —CH2CF3. In some embodiments, R5 is —CH2CHF2.

[0086] In some embodiments, two R5 groups on two different carbon atoms combine to form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring, -R5-, having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, where -R5- is -CH2-, -O-, -CH2CH2-, -CHO-, or -CHOCH2-. In some embodiments, two R5 groups on two different carbon atoms combine to form a bridged bicyclic ring, e.g., [ka] ) to form -R5-.

[0087] In some embodiments, [ka] teeth, [ka] is.

[0088] In some embodiments, [ka] teeth, [ka] is.

[0089] In some embodiments, R5 is selected from those shown in Table 1 below.

[0090] As defined above and described herein, each R is independently an optionally substituted group selected from hydrogen or a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from C1-6 aliphatic, phenyl, nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or two R groups on the same carbon or nitrogen optionally join together with their intervening atoms to form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged 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 attached.

[0091] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted C1-6 aliphatic. In some embodiments, R is C1-6 alkyl (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R is C1-6 haloalkyl (e.g., -CF3, CHF2, etc.). In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, two R groups on the same carbon or nitrogen optionally join together with their intervening atoms to form an optionally substituted 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic, or spirocyclic carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0092] In some embodiments, R is selected from those shown in Table 1 below.

[0093] As defined above and described herein, each R A is independently an optionally substituted group selected from C aliphatic, phenyl, a 4-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0094] In some embodiments, R A is an optionally substituted C1-6 aliphatic. In some embodiments, R A is a C1-6 alkyl (e.g., methyl, ethyl, isopropyl, etc.). In some embodiments, R A is a C1-6 haloalkyl (e.g., —CF3, CHF2, etc.). In some embodiments, R A is an optionally substituted phenyl. In some embodiments, R A is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R A is an optionally substituted 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R A is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0095] In some embodiments, RA is selected from those shown in Table 1 below.

[0096] As defined above and as described herein, each of m, n, p, and q is independently 0, 1, 2, 3, or 4.

[0097] In some embodiments, one or more of m, n, p, and q is 0. In some embodiments, one or more of m, n, p, and q is 1. In some embodiments, one or more of m, n, p, and q is 2. In some embodiments, m is 3. In some embodiments, one or more of m, n, p, and q is 4.

[0098] In some embodiments, m, n, p, and q are selected from those shown in Table 1 below.

[0099] In some embodiments, -(C1-6 aliphatic)- in Formulae Is-Iu is -CH2-, -CH2CH2-, -CH2CH2CH2-, [ka] is.

[0100] In some embodiments, -(C1-6 aliphatic)- in Formulae Is-It is selected from those shown in Table 1 below.

[0101] In some embodiments, the present invention provides compounds of formula Ia, where m is 1 and R2 is -OC1-6alkyl, as shown, and the compound of formula Ia-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, n, p, and q is as defined above and described in the embodiments herein, both alone and in combination.

[0102] In some embodiments, the present invention provides compounds of formula Ia, where m is 1 and R2 is halo, as shown, and the compound has formula Ia-2: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, n, p, and q is as defined above and described in the embodiments herein, both alone and in combination.

[0103] In some embodiments, the present invention provides compounds of formula Ia, where q is 1 and R5 is C1-6 alkyl, as shown, and the compound has formula Ia-3: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0104] In some embodiments, the present invention provides compounds of formula Ib, where m is 1 and R2 is -OC1-6alkyl, as shown, and the compound has formula Ib-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, n, p, and q is as defined above and described in the embodiments herein, both alone and in combination.

[0105] In some embodiments, the present invention provides compounds of formula Ib, where m is 1 and R2 is halo, as shown, and the compound has formula Ib-2: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, n, p, and q is as defined above and described in the embodiments herein, both alone and in combination.

[0106] In some embodiments, the present invention provides compounds of formula Ib, where q is 1 and R5 is C1-6 alkyl, as shown, and the compound has formula Ib-3: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0107] In some embodiments, the present invention provides compounds of formula Ic, where m is 1 and R2 is -OC1-6alkyl, as shown, and the compound has formula Ic-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in embodiments herein, both alone and in combination.

[0108] In some embodiments, the present invention provides compounds of formula Ic, where m is 1 and R2 is halo, as shown, and the compound has formula Ic-2: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in embodiments herein, both alone and in combination.

[0109] In some embodiments, the present invention provides compounds of formula Ic, where q is 1 and R5 is C1-6 alkyl, as shown, and the compound of formula Ic-3: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0110] In some embodiments, the present invention provides compounds of formula Ic, where q is 1 and R5 is halo, as shown, and the compound has formula Ic-4: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0111] In some embodiments, the present invention provides compounds of formula Ic, where the ring is phenylenyl as shown, and formula Ic-5: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, R5, Ring C, Ring D, X, Y, m, n, p, and q is as defined above and described in the embodiments herein, both alone and in combination.

[0112] In some embodiments, the present invention provides compounds of formula Ic, where the ring is phenylenyl, p is 1, and R3 is [ka] and formula Ic-6: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring C, Ring D, X, Y, m, n, p, and q is as defined above and described in the embodiments herein, both alone and in combination.

[0113] In some embodiments, the present invention provides compounds of formula Id, where m is 1 and R2 is -OC1-6alkyl, as shown, and the compound has formula Id-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0114] In some embodiments, the present invention provides compounds of formula Id, where m is 1 and R2 is halo, as shown, and the compound has formula Id-2: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0115] In some embodiments, the present invention provides compounds of formula Id, where q is 1 and R5 is C1-6 alkyl, as shown, and the compound has formula Id-3: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0116] In some embodiments, the present invention provides compounds of formula Id, where q is 1 and R5 is halo, as shown, and the compound has formula Id-4: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R3, Ring A, Ring C, Ring D, X, Y, m, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0117] In some embodiments, the present invention provides compounds of formula Ih, where m is 1 and R2 is -OC1-6alkyl, as shown, and the compound has formula Ih-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, n, p, and q is as defined above and described in the embodiments herein, both alone and in combination.

[0118] In some embodiments, the present invention provides compounds of formula Ih, where m is 1 and R2 is halo, as shown, and the compound has formula Ih-2: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, n, p, and q is as defined above and described in the embodiments herein, both alone and in combination.

[0119] In some embodiments, the present invention provides compounds of formula Ir, where q is 1-2 and R5 is halo, as shown, and the compounds of formula Ir-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0120] In some embodiments, the present invention provides compounds of formula Ir, where R5 is geminal difluoro, as shown, and formula Ir-2: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0121] In some embodiments, the present invention provides compounds of formula Ir, where q is 1-2 and ring C is [ka] and R5 is halo, and the compound of formula Ir-3: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0122] In some embodiments, the present invention provides compounds of formula Ir, where q is 1-2 and ring C is [ka] and R5 is geminal difluoro, and has the formula Ir-4: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0123] In some embodiments, the present invention provides compounds of formula Iq, where q is 1-2 and R5 is halo, as shown, and the compound has formula Iq-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0124] In some embodiments, the present invention provides compounds of formula Iu, wherein, as shown, -(C1-6 aliphatic)- is [ka] and formula Iu-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, R5, Ring A, Ring C, Ring D, X, Y, n, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0125] In some embodiments, the present invention provides compounds of formula Iw, where q is 1-2 and R5 is halo, as shown, and the compound has formula Iw-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0126] In some embodiments, the present invention provides compounds of formula Iw, where q is 1-2 and R5 is halo, as shown, and the compound of formula Iw-2: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0127] In some embodiments, the present invention provides compounds of formula Iw, where R5 is geminal difluoro, as shown, and formula Iw-3: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0128] In some embodiments, the present invention provides compounds of formula Iw, where q is 1-2 and ring C is [ka] and R5 is halo, and the compound of formula Iw-4: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R3, ring A, ring D, X, Y, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0129] In some embodiments, the present invention provides compounds of formula Iw, wherein ring C is: [ka] and R5 is geminal difluoro, and has the formula Iw-5: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R3, ring A, ring D, X, Y, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0130] In some embodiments, the present invention provides compounds of formula Iw, where R5 is fluoro, as shown, and formula Iw-6: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0131] In some embodiments, the present invention provides compounds of formula Iy, wherein, as shown, C1-6 aliphatic is: [ka] wherein q is 1 to 2, R5 is halo, and the compound of formula Iy-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0132] In some embodiments, the present invention provides compounds of formula Iz, where q is 1-2, R5 is halo, and the compound has formula Iz-1: [ka] or a pharmaceutically acceptable salt thereof, wherein each of R1, R3, Ring A, Ring C, Ring D, X, Y, n, m, and p is as defined above and described in the embodiments herein, both alone and in combination.

[0133] Representative compounds of the present invention are shown in Table 1 below.

[0134] [Table 1-1]

[0135] [Table 1-2]

[0136] [Table 1-3]

[0137] [Table 1-4]

[0138] [Table 1-5]

[0139] [Table 1-6]

[0140] [Table 1-7]

[0141] [Table 1-8]

[0142] [Table 1-9]

[0143] [Table 1-10]

[0144]

Table 1-11

[0145]

Table 1-12

[0146]

Table 1-13

[0147]

Table 1-14

[0148]

Table 1-15

[0149]

Table 1-16

[0150]

Table 1-17

[0151]

Table 1-18

[0152]

Table 1-19

[0153]

Table 1-20

[0154]

Table 1-21

[0155]

Table 1-22

[0156]

Table 1-23

[0157]

Table 1-24

[0158]

Table 1-25

[0159]

Table 1-26

[0160]

Table 1-27

[0161]

Table 1-28

[0162]

Table 1-29

[0163]

Table 1-30

[0164]

Table 1-31

[0165]

Table 1-32

[0166]

Table 1-33

[0167]

Table 1-34

[0168]

Table 1-35

[0169]

Table 1-36

[0170]

Table 1-37

[0171]

Table 1-38

[0172]

Table 1-39

[0173]

Table 1-40

[0174]

Table 1-41

[0175]

Table 1-42

[0176]

Table 1-43

[0177]

Table 1-44

[0178]

Table 1-45

[0179]

Table 1-46

[0180]

Table 1-47

[0181]

Table 1-48

[0182]

Table 1-49

[0183]

Table 1-50

[0184]

Table 1-51

[0185]

Table 1-52

[0186]

Table 1-53

[0187]

Table 1-54

[0188]

Table 1-55

[0189]

Table 1-56

[0190]

Table 1-57

[0191]

Table 1-58

[0192]

Table 1-59

[0193]

Table 1-60

[0194]

Table 1-61

[0195]

Table 1-62

[0196]

Table 1-63

[0197]

Table 1-64

[0198]

Table 1-65

[0199]

Table 1-66

[0200]

Table 1-67

[0201]

Table 1-68

[0202]

Table 1-69

[0203]

Table 1-70

[0204]

Table 1-71

[0205]

Table 1-72

[0206]

Table 1-73

[0207]

Table 1-74

[0208]

Table 1-75

[0209]

Table 1-76

[0210]

Table 1-77

[0211] Table 1-78

[0212]

Table 1-79

[0213]

Table 1-80

[0214]

Table 1-81

[0215]

Table 1-82

[0216]

Table 1-83

[0217]

Table 1-84

[0218]

Table 1-85

[0219]

Table 1-86

[0220]

Table 1-87

[0221] Table 1-88

[0222]

Table 1-89

[0223]

Table 1-90

[0224]

Table 1-91

[0225]

Table 1-92

[0226]

Table 1-93

[0227]

Table 1-94

[0228]

Table 1-95

[0229]

Table 1-96

[0230]

Table 1-97

[0231]

Table 1-98

[0232]

Table 1-99

[0233]

Table 1-100

[0234]

Table 1-101

[0235]

Table 1-102

[0236]

Table 1-103

[0237]

Table 1-104

[0238]

Table 1-105

[0239]

Table 1-106

[0240]

Table 1-107

[0241]

Table 1-108

[0242]

Table 1-109

[0243]

Table 1-110

[0244]

Table 1-111

[0245]

Table 1-112

[0246]

Table 1-113

[0247]

Table 1-114

[0248]

Table 1-115

[0249]

Table 1-116

[0250]

Table 1-117

[0251]

Table 1-118

[0252]

Table 1-119

[0253]

Table 1-120

[0254]

Table 1-121

[0255]

Table 1-122

[0256]

Table 1-123

[0257]

Table 1-124

[0258]

Table 1-125

[0259]

Table 1-126

[0260]

Table 1-127

[0261] Table 1-128

[0262]

Table 1-129

[0263] Table 1-130

[0264]

Table 1-131

[0265] Table 1-132

[0266]

Table 1-133

[0267] Table 1-134

[0268] Table 1-135

[0269]

Table 1-136

[0270]

Table 1-137

[0271]

Table 1-138

[0272]

Table 1-139

[0273] Table 1-140

[0274]

Table 1-141

[0275] Table 1-142

[0276] [Table 1-143]

[0277] [Table 1-144]

[0278] In some embodiments, the present invention provides a compound shown in Table 1 above, or a pharmaceutically acceptable salt thereof.

[0279] 4. Uses, Formulations and Administration Pharmaceutically acceptable compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is such that it is effective to measurably degrade and / or inhibit IRAK protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the amount of compound in the composition of the present invention is such that it is effective to measurably degrade and / or inhibit IRAK protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0280] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0281] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological properties of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can 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, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial 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, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0282] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, the compound of the invention or an inhibitory or degradatively active metabolite or residue thereof.

[0283] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of IRAK protein kinase or a mutant thereof.

[0284] As used herein, the term "degradatively active metabolite or residue thereof" means that the metabolite or residue thereof is also a degrader of IRAK protein kinase or a mutant thereof.

[0285] The compositions of the present invention may be administered orally, parenterally, 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, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, 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. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0286] For this purpose, any sterile, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0287] The pharmaceutically acceptable composition of the present invention can be orally administered 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 cornstarch.Lubricants such as magnesium stearate are also commonly added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents.If necessary, certain sweeteners, flavorings or coloring agents can also be added.

[0288] Alternatively, the pharmaceutically acceptable compositions of the present invention can 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, thereby melting in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0289] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0290] Topical application for the lower intestinal tract may suitably be effected in a rectal suppository formulation (see above) or in a suitable enema formulation, or topically-transdermal patches may also be used.

[0291] For topical application, the provided pharmaceutically acceptable composition can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.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 wax and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated in a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0292] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline or, preferably, as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment, such as petrolatum.

[0293] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques well known in the art of pharmaceutical formulation, using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants, and may be prepared as a solution in saline.

[0294] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can 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.

[0295] The amount of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0296] It should also 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, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in the composition will also depend on the particular compound in the composition.

[0297] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for degrading and / or inhibiting the kinase activity of one or more enzymes.

[0298] Examples of kinases that may be 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 mutants thereof. Li et al., "IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase," PNAS 2002, 99(8), 5567-5572; Flannery et al., "The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signaling," Biochem Pharm 2010, 80(12), 1981-1991 (incorporated by reference in their entireties).

[0299] The activity of the compounds utilized in the present invention as degraders and / or inhibitors of IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of either the phosphorylation activity and / or subsequent functional consequences or the ATPase activity of activated IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof. An alternative in vitro assay quantifies the ability of an inhibitor to bind to IRAK-1, IRAK-2, and / or IRAK-4. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / IRAK-1, inhibitor / IRAK-2, or inhibitor / IRAK-4 complex, and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by performing competition experiments in which new inhibitors are incubated with IRAK-1, IRAK-2, and / or IRAK-4 bound to known radioligands.Representative in vitro and in vivo assays useful in assaying IRAK-4 inhibitors are described, for example, in Kim et al., "A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity," J. Exp. Med. 2007, 204(5), 1025-1036; Lebakken et al., "A Fluorescence Lifetime Based Binding Assay to Characterize Kinase Inhibitors," J. Biomol. Screen. 2007, 12(6), 828-841; Maschera et al., "Overexpression of an enzymatically inactive interleukin-1-receptor-associated kinase activates nuclear factor-κB," Biochem. J. 1999, 339, 227-231; and Song et al., "The kinase activities of interleukin-1 receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human "IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof, including those described and disclosed in "IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof," Mol. Immunol. 2009, 46, 1458-1466, each of which is incorporated by reference herein in its entirety. Detailed conditions for assaying the compounds utilized in the present invention as degraders and / or inhibitors of IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof, are set forth in the Examples below.

[0300] The best-characterized member of the IRAK family is the serine / threonine kinase IRAK-4, which is involved in signaling innate immune responses from Toll-like receptors (TLRs) and Toll / IL-1 receptors (TIRs).

[0301] Innate immunity detects pathogens through the recognition of pathogen-associated molecular patterns by TLRs, which then link to adaptive immune responses. 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.

[0302] TLRs mediate innate immune responses by upregulating the expression of inflammatory genes in multiple target cells. See, e.g., Sen et al., "Transcriptional signaling by double-stranded RNA: role of TLR3," Cytokine & Growth Factor Rev. 2005, 16, 1-14 (incorporated by reference in its entirety). While TLR-mediated inflammatory responses are critical for innate immunity and host defense against infection, uncontrolled inflammation is harmful to the host and leads to sepsis and chronic inflammatory diseases such as chronic arthritis, atherosclerosis, multiple sclerosis, cancer, autoimmune disorders such as rheumatoid arthritis, lupus, asthma, psoriasis, and inflammatory bowel disease.

[0303] Upon ligand binding, most TLRs recruit the adaptor molecule MyD88 through their TIR domains, which mediates MyD88-dependent pathways. MyD88 then recruits IRAK-4, which participates in the nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinase, and interferon-regulatory factor (IL-reg) cascades, leading to the induction of proinflammatory cytokines. NF-κB activation results in the induction of proinflammatory 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 an important role in TLR-mediated immune and inflammatory responses. IRAK4 is a key mediator of innate immune responses orchestrated by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-like receptors (TLRs). Inactivation of IRAK-1 and / or IRAK-4 activity has been shown to result in reduced cytokine and chemokine production in response to IL-1 and TLR ligand stimulation. See, for example, Picard et al., "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency," Medicine (Baltimore), 2010, 89(6), 043-25; Li, "IRAK4 in TLR / IL-1R signaling: Possible clinical applications," Eur. J. Immunology 2008, 38:614-618; Cohen et al., "Targeting protein kinases for the development of anti-inflammatory drugs," Curr. Opin. Cell Bio. 2009, 21:317-324; Flannery et al., "The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signaling," Biochem. Pharm.2010,80(12),1981-1991;Gottipati et al.,“IRAK1:A critical signaling mediator of innate immunity,”Cellular Signaling 2008,20,269-276;Kim et al.,“A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity,”J.Exp.Med.2007 204(5),1025-1036;Koziczak-Holbro et al.,“IRAK-4 Kinase Activity Is Required for Interleukin-1(IL-1)Receptor- and Toll-like Receptor 7-mediated Signaling and Gene Expression,”J.Biol.Chem.2007,282(18),13552-13560;Kubo-Murai et al.,“IRAK-4-dependent Degradation of IRAK-1 is a Negative Feedback Signal for TLR-mediated NF-κB Activation,”J.Biochem.2008,143,295-302;Maschera et al.,“Overexpression of an enzymatically inactive interleukin-1-receptor-associated kinase activates nuclear factor-κB,”Biochem.J.1999,339,227-231;Lin et al.,“Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR / IL-1R signalling,”Nature 2010,465(17),885-891;Suzuki et al.,“IRAK-4 as the central TIR signaling mediator in innate immunity,”TRENDS in Immunol.2002,23(10),503-506;Suzuki et al.,“Severe impairment of interleukin-1 and Toll-like receptor signaling in mice lacking IRAK-4,”Nature 2002,416,750-754;Swantek et al.,“IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin,”J.Immunol.2000,164,4301-4306;Hennessy,E.,et al.,Targeting Toll-like receptors:emerging therapeutics?”Nature Reviews,vol.9,pp:293-307(2010);Dinarello,C.“Interleukin-18 and the Pathogenesis of Inflammatory Diseases,”Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007) (each of which is incorporated herein by reference in its entirety). Indeed, knockdown mice expressing catalytically inactive mutant IRAK-4 proteins are completely resistant to septic shock and exhibit impaired IL-1 activity. Furthermore, these mice are resistant to joint and bone inflammation / destruction in an arthritis model, suggesting that IRAK-4 may be targeted to treat chronic inflammation. Furthermore, as shown by one study in which patients over the age of 14 lacking IRAK-4 activity did not develop invasive infections, IRAK-4 appears to be important for childhood immunity against some pyogenic bacteria, while it has been shown to play a redundant role in protective immunity against most infections in adults. Cohen et al., "Targeting protein kinases for the development of anti-inflammatory drugs," Curr. Opin. Cell Bio. 2009, 21: 317-324; Ku et al.,“Selective predisposition to bacterial infections in IRAK-4-deficient children:IRAK-4-dependent TLRs are otherwise redundant in protective immunity,”J.Exp.Med.2007,204(10),2407-2422;Picard et al.,“Inherited human IRAK-4 deficiency:an update,”Immunol.Res.2007,38,347-352;Song et al.,“The kinase activities of interleukin-e receptor associated kinase(IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells,”Mol.Immunol.2009,46,1458-1466;Rokosz,L.et al.,“Kinase inhibitors as drugs for chronic inflammatory and immunological diseases:progress and challenges,”Expert Opinions on Therapeutic Targets,12(7),pp:883-903(2008);Gearing,A.“Targeting toll-like receptors for drug development:a summary of commercial approaches,”Immunology and Cell Biology,85,pp:490-494(2007);Dinarello,C."IL-1: Discoveries, controversies and future directions," European Journal of Immunology, 40, pp:595-653 (2010) (each of which is incorporated by reference in its entirety). Because TLR activation elicits IRAK-4 kinase activity, IRAK-4 inhibition provides an attractive target for treating the underlying causes of inflammation in a myriad of diseases.

[0304] Representative IRAK-4 inhibitors include, for example, those described in Buckley et al. Bioorg.Med.Chem.Lett. 2008, 18, 3211-3214; Buckley et al. Bioorg.Med.Chem.Lett. 2008, 18, 3291-3295; Buckley et al. Bioorg.Med.Chem.Lett. 2008, 18, 3656-3660; Powers et al., "Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4," Bioorg.Med.Chem.Lett. 2006, 16, 2842-2845; Wng et al., "IRAK-4 Inhibitors for Inflammation," Curr. Topics in Med. Chem. 2009, 9, 724-737 (each of which is incorporated by reference herein in its entirety).

[0305] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0306] The provided compounds are degraders and / or inhibitors of one or more of IRAK-1, IRAK-2, and / or IRAK-4 and are therefore useful for treating one or more disorders associated with the activity of one or more of IRAK-1, IRAK-2, and / or IRAK-4. Accordingly, in certain embodiments, the present invention provides a method for treating an IRAK-1-mediated, IRAK-2-mediated, and / or IRAK-4-mediated disorder, comprising administering a compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0307] As used herein, the terms "IRAK-1-mediated," "IRAK-2-mediated," and / or "IRAK-4-mediated" disorders, diseases, and / or conditions, as used herein, refer to any disease or other deleterious condition in which IRAK-1, IRAK-2, and / or IRAK-4, or one or more mutants thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which IRAK-1, IRAK-2, and / or IRAK-4, or one or more mutants thereof, are known to play a role.

[0308] In some embodiments, the present invention provides methods for treating one or more disorders, diseases and / or conditions, wherein the disorder, disease or condition is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a genetic disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, a liver disease, a pathological immune condition including T-cell activation, a cardiovascular disorder or a CNS disorder.

[0309] Diseases and conditions that can be treated according to the methods of the present invention include cancer (e.g., Ngo, V. et al., "Oncogenically active MYD88 mutations in human lymphoma," Nature, vol. 000, pp: 1-7 (2010); Lust, J. et al., "Induction of a chronic disease state in patients with smoldering of indolent multiple myeloma by targeting interleukin 1β-induced interleukin 6 production and the myeloma proliferative component," Mayo Clinic Proceedings, 84(2), pp: 114-122 (2009)), diabetes, cardiovascular disease, viral disease, autoimmune diseases such as lupus (e.g., Dinarello, C., "Interleukin-18 and the pathogenesis of inflammatory diseases," Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007); Cohen, J. et al., "Induction of a chronic disease state in patients with smoldering of indolent multiple myeloma by targeting interleukin 1β-induced interleukin 6 production and the myeloma proliferative component," Mayo Clinic Proceedings, 84(2), pp: 114-122 (2009)), and other conditions. et al., "Targeting protein kinases for the development of anti-inflammatory drugs," Curr. Opin. Cell Bio. 2009, 21:317-324) and rheumatoid arthritis (see, e.g., Geyer, M. et al., "Actual status of antiinterleukin-1 therapies in rheumatic diseases," Current Opinion in Rheumatology, 22, pp:246-251 (2010)), autoinflammatory syndromes (see, e.g., Hoffman, H. et al., "Efficacy and Safety of Rilonacept (Interleukin-1 Trap) in Patients with Cryopyrin-Associated Periodic Syndromes," Arthritis & Rheumatism, vol. 58, no. 8, pp: 2443-2452 (2008)), atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease (see, e.g., Cario, E. "Therapeutic Impact of Toll-Like Receptors on Inflammatory Bowel Diseases: A Multiple-edged Sword," Inflamm. Bowel Dis., 14, pp: 411-421 (2008)), inflammation (see, e.g., Dinarello, C. "Interleukin 1 and Interleukin 18 as Mediators of Inflammation and the Aging Process," The American Journal of Clinical Nutrition, 83, pp:447S-455S (2006)), acute and chronic gout and gouty arthritis (e.g., Terkeltaub, R. "Update on gout: new therapeutic strategies and options," Nature, vol. 6, pp:30-38 (2010); Weaver, A. "Epidemiology of gout," Cleveland Clinic Journal of Medicine, vol. 75, suppl. 5, pp:S9-S12 (2008); Dalbeth, N. et al., "Hyperuricemia and gout: state of the art and future perspectives," Annals of Rheumatic Diseases, 69, pp:1738-1743 (2010); Martinon, F. et al., "Gout-associated uric acid crystals activate the NALP3 inflammasome," Nature, vol.440, pp:237-241(2006);So,A.et al.,“A pilot study of IL-1 inhibition by anakinra in acute gout,”Arthritis Research&Therapy,vol.9,no.2,pp:1-6(2007);Terkeltaub,R.et al.,“The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis:results of a Placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study,”Annals of Rheumatic Diseases,68,pp:1613-1617(2009);Torres, R. et al.,“Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis,”Annals of Rheumatic Diseases, 68, pp:1602-1608 (2009)), neurological disorders, metabolic syndrome (see, for example, Troseid, M. "The role of interleukin-18 in the metabolic syndrome," Cardiovascular Diabetology, 9:11, pp:1-8 (2010)), immunodeficiency disorders such as AIDS and HIV (see, for example, Iannello, A. et al., "Role of Interleukin-18 in the Development and Pathogenesis of AIDS," AIDS Reviews, 11, pp:115-125 (2009)), destructive bone disorders (see, for example, Hennessy, E., et al., “Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews, vol. 9, pp: 293-307 (2010)), osteoarthritis, proliferative disorders, Waldenstroem's macroglobulinemia (see, e.g., Treon, et al., “Whole genome sequencing reveals a widely expressed mutation (MYD88 L265P) with oncogenic activity in Waldenstroem's macroglobulinemia,” 53rd ASH Annual Meeting; Xu, et al., “A somatic variant in MYD88 (L256P) revealed by whole genome sequencing differentiates lymphoplasmacytic lymphoma from marginal zone lymphomas,” 53rd ASH Annual Meeting; Yang et al., “Disruption of MYD88 pathway signaling leads to loss of constitutive IRAK1, NK-kB, and JAK / STAT signaling and induces apoptosis of cells expressing the MYD88 L265P mutation in Waldenstroem's Macroglobulinemia”53rd ASH Annual Meeting;Iriyama et al.See, "Clinical Significance of Genetic Mutations of CD79B, CARD11, MYD88, and EZH2 Genes in Diffuse Large B-Cell Lymphoma Patients," 53rd ASH Annual Meeting; infectious diseases, conditions associated with cell death, pathological immune conditions involving T cell activation, and CNS disorders in patients. In one embodiment, a human patient is treated with a compound of the invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound is present in an amount that measurably degrades and / or inhibits IRAK-1 alone, IRAK-2 alone, IRAK-4 alone, and / or IRAK1 and IRAK4 kinase activity.

[0310] The compounds of the present invention may be used to treat benign or malignant tumors of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, stomach tumors, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid, solid tumors, carcinomas, sarcomas, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, in particular colon cancer or colorectal adenoma, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia Neoplasms of epithelial origin, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's, breast cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorders, MyD88-driven disorders, smoldering low-grade multiple myeloma or hematologic malignancies (leukemia, diffuse large B-cell lymphoma (DLBCL), ABC and malignant lymphoma (MLBCL), chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, MDS.

[0311] In some embodiments, the proliferative disease that can be treated according to the methods of the invention is a MyD88-driven disorder. In some embodiments, the MyD88-driven disorder that can be treated according to the methods of the invention is selected from ABC DLBCL, primary CNS lymphoma, primary extranodal lymphoma, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

[0312] In some embodiments, the proliferative disease that can be treated according to the methods of the present invention is an IL-1 driven disorder, hi some embodiments, the IL-1 driven disorder is smoldering low-grade multiple myeloma.

[0313] The compounds according to the present invention are useful for treating inflammatory or obstructive airway diseases, resulting in, for example, reduced tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of all types and origins, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis 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, those under the age of 4 or 5, who present with symptoms of wheezing and have been or can be diagnosed as "wheezing infants," an established patient category of major medical interest, currently often identified as having primary or early-phase asthma.

[0314] The compounds according to the present invention are useful in the treatment of heteroimmune diseases, including, but not limited to, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, house dust mite, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0315] Prophylactic efficacy in the treatment of asthma is evidenced by a reduction in the frequency or severity of symptomatic attacks, e.g., acute asthma or bronchoconstrictor attacks, improved lung function, or improved airway hyperresponsiveness. This may further be evidenced by a reduction in the need for other symptomatic treatments, such as anti-inflammatory or bronchodilator treatments, such as treatments aimed at limiting or interrupting symptomatic attacks as they occur. The prophylactic benefit in asthma may be particularly evident in subjects prone to "morning dip." "Morning dip" is a recognized asthmatic syndrome common to a significant percentage of cases, characterized by asthmatic attacks and asthma attacks, e.g., around 4:00-6:00 a.m., typically a time away from substantially any previously administered symptomatic asthma treatment.

[0316] The compounds of the present invention may be used for other inflammatory or obstructive airway diseases and conditions for which the present invention is applicable, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung disease (COPD, COAD or COLD), including chronic bronchitis or its associated dyspnea, emphysema and exacerbations of airway hyperresponsiveness to other medications, particularly other inhaled medications. The present invention is also applicable to the treatment of bronchitis of any type or genesis, including, but not limited to, acute, arachidonic, catarrhal, croupus, chronic or tuberculoid bronchitis. Further inflammatory or obstructive airway diseases to which the present invention is applicable include pneumoconiosis (inflammatory diseases of the lungs, usually occupational, frequently associated with airway obstruction and caused by repeated inhalation of dust, whether chronic or acute), whatever the type or origin, such as aluminum lung disease, anthracosis, asbestosis, copper lung disease, feather lung disease, siderosis, silicosis, tobacco disease and byssinosis.

[0317] With regard to their anti-inflammatory activity, in particular with regard to the inhibition of eosinophil activation, the compounds of the invention are also useful in the treatment of eosinophil-associated disorders, such as eosinophilia, particularly affecting the airways and / or lungs, and therefore eosinophil-associated disorders of the airways including hypereosinophilia (e.g. including pathological eosinophilic infiltration of lung tissue) and eosinophil-associated disorders of the airways resulting from or occurring concomitantly with, for example, Loeffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD and eosinophil-associated disorders affecting the airways caused by drug reactions.

[0318] The compounds of the invention are also useful in the treatment of 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, epidermolysis bullosa acquisita, acne vulgaris, hidradenitis suppurativa, Sweet's syndrome, pyoderma gangrenosum and other inflammatory or allergic conditions of the skin.

[0319] The compounds of the invention may also be used in the treatment of other diseases or conditions, such as diseases or conditions which have an inflammatory component, for example, the treatment of diseases and conditions of the eye such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases which involve an autoimmune reaction or have an autoimmune component or etiology, such as autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, severe rheumatoid arthritis, and the like. 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, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic fever syndrome, nephritis, Vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, including e.g. idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle fatigue, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis and exercise) induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, nasal sinusitis, eye allergies, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or reduction of disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,Cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, spinal cord It may also be used to treat meningitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, interstitial pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0320] In some embodiments, the inflammatory disease that can be treated according to the methods of the present invention is a disease of the skin, hi some embodiments, the inflammatory disease of the skin is 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, epidermolysis bullosa acquisita, hidradenitis suppurativa, and other inflammatory or allergic conditions of the skin.

[0321] In some embodiments, inflammatory diseases that may 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.

[0322] In some embodiments, the inflammatory disease that can be treated according to the methods of the invention is a TH17-mediated disease, hi some embodiments, the TH17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0323] In some embodiments, inflammatory diseases that can be treated according to the methods of the present invention are selected from Sjogren's syndrome, allergic disorders, osteoarthritis, eye allergies, eye conditions such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).

[0324] In some embodiments, the present invention provides a method of treating hidradenitis suppurativa in a patient in need thereof, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0325] In some embodiments, the present invention provides a method of treating atopic dermatitis in a patient in need thereof, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0326] In some embodiments, the present invention provides a method of treating rheumatoid arthritis in a patient in need thereof, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0327] Cardiovascular diseases that may be treated according to the methods 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 aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, and deep vein thrombosis.

[0328] In some embodiments, neurodegenerative diseases that may 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.

[0329] Loss of IRAK4 function resulted in reduced 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 altered gene expression patterns associated with changes in microglial phenotype, linked to increased expression of IRF transcription factors that govern the microglial phenotype. Furthermore, loss of IRAK4 function, including increased expression of insulin-degrading enzymes, promoted amyloid clearance mechanisms. Finally, blocking IRAK function restored olfactory behavior (Cameron et al. "Loss of Interleukin Receptor-Associated Kinase 4 Signaling Suppresses Amyloid Pathology and Alters Microglial Phenotype in a Mouse Model of Alzheimer's Disease" Journal of Neuroscience (2012) 32(43), 15112-15123).

[0330] In some embodiments, the present invention provides methods for treating, preventing, and reducing the severity of Alzheimer's disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt or composition thereof.

[0331] In some embodiments, the present invention provides methods of treating disease conditions commonly associated with transplantation, hi some embodiments, the disease or condition commonly associated with transplantation is selected from organ transplantation, organ transplant rejection, and graft-versus-host disease.

[0332] In some embodiments, the present invention provides methods of treating a metabolic disease, hi some embodiments, the metabolic disease is selected from type 1 diabetes, type 2 diabetes, metabolic syndrome, and obesity.

[0333] In some embodiments, the present invention provides methods of treating a viral disease, hi some embodiments, the viral infection is an HIV infection.

[0334] Furthermore, the present invention provides the use of a compound as defined herein or a pharmaceutically acceptable salt or hydrate or solvate thereof for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive ventilatory disease, a cardiovascular disease, a metabolic disease, a neurological disease, a neurodegenerative disease, a viral disease or a disorder commonly occurring in association with transplantation.

[0335] Combination therapy Depending on the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition are administered in combination with the compounds and compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate" for the disease, or condition, being treated.

[0336] In certain embodiments, provided combinations or compositions thereof are administered in combination with another therapeutic agent.

[0337] In some embodiments, the present invention provides methods of treating a disclosed disease or condition, the methods comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of a disclosed compound and an additional therapeutic agent or agents acts synergistically.

[0338] Examples of drugs in the combinations of the present invention may be combined with, but are not limited to, treatments for Alzheimer's disease, such as Aricept® and Excelon®; treatments for HIV, such as ritonavir; treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, lopinrol, pramipexole, bromocriptine, pergolide, trihexefendil, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma, such as albuterol and Singulair®; drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory drugs, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulatory and immunosuppressive drugs such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and antiparkinsonian drugs; drugs for treating cardiovascular diseases such as β-blockers, ACTH E inhibitors, diuretics, nitrates, calcium channel blockers, and statins; drugs for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; drugs for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; drugs that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and drugs for treating immune deficiency disorders, such as gamma globulins.

[0339] In certain embodiments, a combination therapy of the invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapy.

[0340] These additional drugs can be administered separately from the provided combination therapy as part of multiple dose regimens.Alternatively, these drugs can be part of a single dosage form, mixed together with the compound of the present invention in a single composition.When administered as part of multiple dose regimens, the two active drugs can be administered simultaneously, consecutively, or within a certain time from each other, usually within 5 hours from each other.

[0341] As used herein, the terms "combination," "adjusted," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a combination of the present invention may be administered together, simultaneously or sequentially, in separate unit dosage forms or in a single unit dosage form with another therapeutic agent.

[0342] The amount of additional therapeutic agent present in the compositions of the invention will not exceed the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0343] One or more other therapeutic agents may be administered separately from the compound or composition of the present invention as part of a multiple dose regimen. Alternatively, one or more other therapeutic agents may be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as a multiple dose regimen, one or more other therapeutic agents and the compound or composition of the present invention may be administered simultaneously, sequentially, or within a certain time period from each other, 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 compound or composition of the present invention are administered as a multiple dose regimen within a time period of more than 24 hours per part.

[0344] In one embodiment, the present invention provides a composition comprising a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. The therapeutic agents may be administered together with a provided compound or a pharmaceutically acceptable salt thereof, or may be administered before or after administration of a provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further detail below. In certain embodiments, a provided compound or a pharmaceutically acceptable salt thereof may be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, can 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.

[0345] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), and the like; corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like; probenecid; allopurinol; febuxostat (Ultramarin); oric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Dep en® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®) and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), trademark), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), "anti-IL-6" agents,for example tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab, anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopen ex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate (Beclovent®), ®), Qvar® and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®) and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®,Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®) and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®) and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), proteases enzyme inhibitors, such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptiv®); s®), 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 any combination thereof.

[0346] In another embodiment, the present invention provides a method of treating gout, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, and febuxostat (Uloric®).

[0347] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof a compound or a 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, hydrocortisone, sulfasalazine (Azulfidine®); antimalarials, such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®); gold salts, such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®); D-penicillamine (Depen® or Cuprimine®); azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), etc., and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), (R) and adalimumab (Humira®), "anti-IL-1" agents, such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies, such as rituximab (Rituxan®), "anti-T cell" agents, such as abatacept (Orencia®), and "anti-IL-6" agents, such as tocilizumab (Actemra®).

[0348] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies, such as tanezumab.

[0349] In some embodiments, the present invention provides a method of treating lupus, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0350] In some embodiments, the present invention provides a method of treating inflammatory bowel disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as flagyl or ciprofloxacin.

[0351] In some embodiments, the present invention provides a method of treating asthma, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, as well as anti-IL-33 antibodies such as REGN3500 (SAR440340) or CNTO7160, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids, and the like. and administering one or more additional therapeutic agents selected from steroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthemanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0352] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and beta-2 agonists such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo and one or more additional therapeutic agents selected from inhaled corticosteroids, such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, such as benzodiazepines (BQ-24®) and aminophylline; and in some embodiments, the present invention provides a method of treating eosinophilic COPD, comprising administering to a patient in need thereof one or more additional therapeutic agents selected from a provided compound or a pharmaceutically acceptable salt thereof and an anti-IL-33 antibody, such as REGN3500 (SAR440340) or CNTO7160.In some embodiments, the present invention provides a method of treating eosinophilic asthma, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from an anti-IL-33 antibody, such as REGN3500 (SAR440340) or CNTO7160.

[0353] In some embodiments, the present invention provides a method of treating HIV by administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, as well as a nucleoside reverse transcriptase inhibitor, such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine, or a combination thereof. non-nucleoside reverse transcriptase inhibitors, such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®), such as fluvirin (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®); nucleotide reverse transcriptase inhibitors, such as tenofovir (Viread®), protease inhibitors, such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®) and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), and combinations thereof.

[0354] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (hydroxydaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0355] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (hydroxydaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0356] In another embodiment, the present invention provides a method of treating a hematological tumor, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological tumor is DLBCL (Ramirez et al., "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0357] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (hydroxydaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0358] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound 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.

[0359] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a rituximab / bendamustine chemotherapy regimen.

[0360] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor (e.g., ibrutinib).

[0361] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and an anti-CD20 antibody (e.g., rituximab).

[0362] In some embodiments, the invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and an anti-CD79B ADC (e.g., polatuzumab).

[0363] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor (e.g., venetoclax).

[0364] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and lenalidomide or pomalidomide.

[0365] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g., umbralisib).

[0366] In some embodiments, the present invention provides a method of treating a T-cell disease or disorder described herein, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g., umbralisib).

[0367] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a proteasome inhibitor (e.g., bortezomib).

[0368] In some embodiments, the present invention provides a method of treating a T-cell disease or disorder described herein, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and a proteasome inhibitor (e.g., bortezomib).

[0369] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from bortezomib (Velcade®) and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor (in combination with lenalidomide (Revlimid®)).

[0370] In another embodiment, the present invention provides a method of treating Waldenstrom's macroglobulinemia, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0371] In some embodiments, the one or more other therapeutic agents are hedgehog pathway antagonists. Approved hedgehog pathway inhibitors that may be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for the treatment of basal cell carcinoma.

[0372] In some embodiments, the one or more other therapeutic agents is a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0373] In some embodiments, the one or more other therapeutic agents is a histone deacetylase (HDAC) inhibitor. In some embodiments, the HDAC inhibitor is selected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0374] In some embodiments, the one or more other therapeutic agents is a CDK inhibitor, such as a CDK4 / CDK6 inhibitor. 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).

[0375] In some embodiments, the one or more other therapeutic agents is a folate inhibitor. Approved folate inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[0376] In some embodiments, the one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. Tested CCR4 inhibitors that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0377] In some embodiments, the one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. Tested IDH inhibitors that may be useful in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0378] In some embodiments, the one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors that can be used in the present invention and that have been tested include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being tested in phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndromes (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0379] In some embodiments, the one or more other therapeutic agents are glutaminase inhibitors. Tested glutaminase inhibitors that can be used in the present invention include CB-839 (Calithera Biosciences).

[0380] In some embodiments, the 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 that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0381] In some embodiments, the one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Tested topoisomerase inhibitors that may be useful in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0382] In some embodiments, the 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 targeting apoptotic proteins that are undergoing clinical trials and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0383] In some embodiments, the 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 (degalarix, Firmagon®, Ferring Pharmaceuticals).

[0384] In some embodiments, the one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0385] In some embodiments, the 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, preventing it from binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediate bone pathology in solid tumors with bone metastasis. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[0386] In some embodiments, the one or more other therapeutic agents are inhibitors of the interaction between two major p53 suppressor proteins, MDMX and MDM2. Tested inhibitors of p53 suppressor proteins that may be used in the present invention include ALRN-6924 (Aileron), a leading peptide that equipotently binds to and disrupts the interaction of MDMX and MDM2 with 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).

[0387] In some embodiments, the one or more other therapeutic agents are inhibitors of transforming growth factor beta (TGF-beta or TGFβ). Tested inhibitors of TGF-beta proteins that can be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody being tested in clinical trials for the treatment of various cancers, including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and renal cancer (NCT02947165). In some embodiments, the TGF-beta protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being tested for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Furthermore, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as those described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. 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 trap compound (NCT02699515); and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ "trap."

[0388] In some embodiments, the one or more other therapeutic agents are selected from glembatumumab vedotin-monomethylauristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody linked to a cytotoxic MMAE (CR011). gpNMB is a protein overexpressed by multiple tumor types that is associated with the metastatic potential of cancer cells.

[0389] In some embodiments, one or more other therapeutic agents are antiproliferative compounds, such as aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic antimetabolites, platin compounds, compounds that target / reduce protein or lipid kinase activity and additional anti-angiogenic compounds, compounds that target, reduce or inhibit the activity of protein or lipid phosphatases, gonadorelin agonists, antiandrogens, methionine aminopeptidase inhibitors, matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 and leucovorin from Pfizer, but are not limited to these.

[0390] In some embodiments, the present invention provides a method of treating Alzheimer's disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0391] In some embodiments, the one or more other therapeutic agents are taxane compounds, which cause disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compounds are selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0392] In some embodiments, the one or more other therapeutic agents are nucleoside inhibitors or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0393] In some embodiments, the nucleoside inhibitor is trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (a prodrug for the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolite cytidine analog, Pfizer); lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource) Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (a protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an enzyme for asparagine deficiency, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (anti-microtubule agent, tubulin-based mitotic inhibitor, Halaven®, Eisai); cabazitaxel (anti-microtubule agent, tubulin-based mitotic inhibitor, Jevtana®, Sanofi-Aventis); capacetrin (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, thought to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva); ixabepilone (semi-synthetic analogue of epothilone B, anti-microtubule agent, tubulin-based mitotic inhibitor, Ixempra®, Bristol-Myers Squibb);Selected from nelarabine (prodrug of a deoxyguanosine analog, a nucleoside metabolism inhibitor, Arranon®, Novartis); chlorafavine (prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology);

[0394] In some embodiments, the one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include bevacizumab (Avastin®, Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody, and ziv-aflibercept, also known as VEGF trap (Zaltrap®; Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer). AG and Onyx; dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariadne) Pharmaceuticals; Her2 and EGFR inhibitors such as 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, such as cabozantinib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); certinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[0395] Other kinase inhibitors and VEGF-R antagonists under development that may be used in the present invention include tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovinitinib (TKI258, Novartis); tiauanib (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 Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0396] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0397] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor, wherein the disease is selected from the group consisting of inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, Sjogren's syndrome, multiple sclerosis, systemic thyroiditis, and rheumatoid arthritis. Neuropathic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's 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 universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous nephropathy, endometriosis, interstitial cystitis, and urinary tract infections. Pemphigus vulvodynia, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immune deficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mite or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis inflammation, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, interstitial pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis,Rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, 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, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenström hypergammaglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma Bone and joint diseases including, but not limited to, large cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer or cancer of mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, rheumatoid arthritis, seronegative spondyloarthropathy (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis Transplantation, thromboembolic disorders (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass, restenosis after aortocoronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, photodermatitis, sinusitis, interstitial pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue grafts Rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura,Selected from Waldenstrom's hypergammaglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, osteoarthritis, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0398] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0399] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or gastrointestinal The cancer is selected from cancer, in particular colon carcinoma or colorectal adenoma or tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, neoplasms of epithelial phenotype, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, or leukemia, and the disease is selected from Cowden syndrome, Lhermitte-Duclos disease, and Banayan-Zonana syndrome, or a disease in which the PI3K / PKB pathway is abnormally activated. asthma of any type or origin, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic bronchitis or associated respiratory distress (COPD, COAD or COLD), emphysema and exacerbation of airway hyperresponsiveness as a result of other medications, especially other inhaled medications, acute, arachidonic bronchitis of any type or origin, including, but not limited to, catarrhal, croupus, chronic or tuberculous bronchitis, pneumoconiosis of any type or origin (inflammatory disease of the lungs, usually occupational, frequently associated with airway obstruction, caused by repeated inhalation of dust, whether chronic or acute), including aluminum lung, anthracosis, asbestosis, copper lung, feather lung, siderosis, silicosis, tobacco disease and byssinosis, Löffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis,inflammatory diseases involving an autoimmune response or having an autoimmune component or cause, including polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granulomas and eosinophil-related disorders affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpes dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemfis, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, Myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine eye diseases, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and glomerulonephritis (with and without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and neurodegenerative diseases caused by cerebral ischemia and traumatic injury, glutamate neurotoxicity, and hypoxia.

[0400] In some embodiments, the one or more other therapeutic agents is a phosphatidylinositol 3-kinase (PI3K) inhibitor. In some embodiments, the PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0401] In some embodiments, the present invention provides a method of treating AML, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from a FLT3 inhibitor; a targeted agent, such as an IDH inhibitor, an anti-CD33 ADC (e.g., Mylotarg), a BCL2 inhibitor, and a hedgehog inhibitor; and a chemotherapeutic agent, such as AraC, daunorubicin, etoposide, methotrexate, fludarabine, mitoxantrone, azacitidine, and a corticosteroid.

[0402] In some embodiments, the present invention provides a method of treating MDS, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from azacitidine, decitabine, and Revlimid.

[0403] In some embodiments, the present invention provides a method of treating an inflammatory skin condition, such as hidradenitis suppurativa, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from an anti-TNF drug.

[0404] In some embodiments, the present invention provides a method of treating an inflammatory skin condition, such as atopic dermatitis, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from an IL-4 / IL-13 targeted agent, such as dupilumab.

[0405] In some embodiments, the present invention provides a method of treating an inflammatory skin condition, such as psoriasis, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-17 and anti-IL-23 antibodies.

[0406] The compounds and compositions according to the methods of the present invention can be administered in any amount and using any route of administration effective to treat or reduce 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 subject's species, age, and general condition, the severity of the infection, the specific drug, its mode of administration, and the like. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form," as used herein, refers to a physically discrete unit of drug appropriate for the patient to be treated. However, it will 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 scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used, and factors well known in the medical arts.

[0407] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (such as by powder, ointment, or drops), bucally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally, one or more times daily, at dosage levels of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg of subject body weight per day, to achieve the desired therapeutic effect.

[0408] 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, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (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 of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweeteners, flavorings, and perfumes.

[0409] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any sterile, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0410] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0411] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the rate of polymer formation of the compound and the properties of the particular polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0412] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present invention with a suitable non-irritating excipient or carrier which is solid at ambient temperature but liquid at body temperature, such as cocoa butter, polyethylene glycol or a suppository wax, and thus will melt in the rectum or vaginal cavity and release the active compound.

[0413] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, jasmine, and the like. They are mixed with potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, etc., e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, etc., and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain buffering agents.

[0414] Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. These may optionally contain opacifying agents and may also be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0415] The active compound may also be in microencapsulated form with one or more excipients, as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells, such as enteric coatings, release-controlling 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. As is common practice, such dosage forms may also contain additional 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 forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0416] Dosage forms for topical or transdermal administration of a compound of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as required. Ophthalmic formulations, ear drops, and eye drops are also contemplated as being within the scope of the present invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0417] According to one embodiment, the present invention relates to a method of inhibiting protein kinase activity or degrading protein kinases in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention or a composition comprising said compound.

[0418] 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 mutants thereof in a biological sample, comprising the step of contacting said biological sample with a compound of the present invention or a composition comprising said compound.

[0419] The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, stool, semen, tears or other bodily fluids or extracts thereof.

[0420] Inhibition and / or degradation of protein kinases or protein kinases selected from IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof, activity in biological samples is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0421] Another embodiment of the invention relates to a method of degrading protein kinases and / or inhibiting protein kinase activity in a patient, comprising administering to said patient a compound of the invention or a composition comprising said compound.

[0422] According to another embodiment, the present invention relates to a method for inhibiting the degradation and / or activity of IRAK-1, IRAK-2, and / or IRAK-4 or one or more mutants thereof in a patient, comprising the step of administering to said patient a compound of the present invention or a composition comprising said compound. In other embodiments, the present invention provides a method for treating a disorder mediated by one or more IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof in a patient in need thereof, comprising the step of administering to said patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0423] Depending on the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as appropriate for the disease, or condition, being treated.

[0424] The compounds of the present invention may also be used to advantage in combination with other antiproliferative compounds, such as aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, compounds with microtubule activity, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-tumor antimetabolites, platin compounds, compounds that target / inhibit protein or lipid kinase activity and further anti-angiogenic compounds, compounds that target, decrease or inhibit the activity of protein or lipid phosphatases, gonadorelin agonists, antiandrogens, and methionine aminopeptidase inhibitors. ;matrix metalloproteinase inhibitors;bisphosphonates;biological response modifiers;antiproliferative antibodies;heparanase inhibitors;inhibitors of Ras oncogenic isoforms;telomerase inhibitors;proteasome inhibitors;compounds used in the treatment of hematological malignancies;compounds that target, decrease or inhibit the activity of Flt-3;Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010, Conforma Therapeutics; temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZD6244 from AstraZeneca, PD181461 and leucovorin from Pfizer, and the like.

[0425] The term "aromatase inhibitor," as used herein, refers to a compound that inhibits estrogen production, such as 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 formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. Combinations of the present invention which include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors, such as tumors of the breast.

[0426] In some embodiments, the one or more other therapeutic agents is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0427] In some embodiments, the one or more other therapeutic agents is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca), and letrozole (Femara®, Novartis).

[0428] The term "antiestrogen," as used herein, refers to a compound that counteracts 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 commercially available under the trade name Nolvadex™. Raloxifene hydrochloride is commercially available under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combinations of the present invention that include chemotherapeutic agents that are antiestrogens are particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0429] The term "antiandrogen," 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 "gonadorelin agonist," as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0430] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Irinotecan is commercially available, for example, under the trade name Camptosar™ and may be administered in that form. Topotecan is commercially available under the trade name Hycamptin™.

[0431] The term "topoisomerase II inhibitors," as used herein, includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations, e.g., Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, anthraquinones, mitoxantrone, losoxantrone, and podophyllotoxin, etoposide, and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0432] The term "microtubule active agent" includes, but is not limited to, microtubule stabilizing, microtubule destabilizing compounds and microtubulin 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; discodermolide; coticin and epothilones and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0433] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0434] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0435] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

[0436] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0437] The term "Bcl-2 inhibitor" as used herein includes, but is not limited to, ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitor Ascenta, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), genasense (G3139), HA14-1 (and analogs thereof; see WO 2008 / 118802, U.S. Patent Application Publication No. 2010 / 0197686), navitoclax (and analogs thereof; see U.S. Patent Application Publication No. 7,390,799), NH-1 (Shenayng Pharmaceutical In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0438] The term "compounds which target / reduce protein or lipid kinase activity; or protein or lipid phosphatase activity; or further anti-angiogenic compounds", as used herein, refers to protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFR), such as compounds which target, reduce or inhibit the activity of PDGFR, in particular compounds which inhibit PDGF receptors, such as N-phenyl-2-pyrimidine-amine derivatives, e.g. imatinib, SU101, SU6668 and GFB-111; b) compounds which target, reduce or inhibit the activity of fibroblast growth factor-receptors (FGFR); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds which target, reduce or inhibit the activity of IGF-IR d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib;i) Compounds that target, decrease or inhibit the activity of c-Abl family members, their gene-fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target, decrease or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; PD173955 from ParkeDavis; or dasatinib ( BMS-354825), etc.; j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of 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), including staurosporine derivatives, such as midostaurin; further examples of compounds include, but are not limited to, compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, 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), including staurosporine derivatives, such as midostaurin; k) compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, e.g. UCN-01, safingol, BAY43-9006, bryostatin 1, perifosine; lurmofosine; RO318220 and RO320432; GO6976; lsis3521; LY333531 / LY379196; isothiinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); or compounds that inhibit the ATP-dependent ATP synthesis, such as imatinib mesylate (Gleevec™) or tryphostins, such as tryphostin A23 / RG-50810; AG99; tryphostin AG213; tryphostin AG1748; tryphostin AG490; tryphostin B44; tryphostin B44 (+) enantiomer; tryphostin AG555; AG494; tryphostin AG556, AG957, and adafostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adafostin);l) Compounds which target, decrease or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1, ErbB2, ErbB3, ErbB4, as homo- or heterodimers) and mutants thereof, such as compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family, in particular compounds which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4, or which inhibit EGF or EGF-related ligands. m) compounds, proteins or antibodies that bind to the c-Met receptor, CP358774, ZD1839, ZM105180; 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, decrease or inhibit the activity of the c-Met receptor n) compounds that inhibit one or more JAK family members (JAK1 / JAK2), including, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds which target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib;and q) compounds that target, decrease or inhibit the signaling effects of the Hedgehog (Hh) or Smoothened receptor (SMO) pathways, including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (salidegib);

[0439] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0440] In some embodiments, the one or more other therapeutic agents are growth factor antagonists, such as antagonists of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR). 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); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targets activated EGFR, Tagrisso®, AstraZeneca).

[0441] The term "PI3K inhibitor", as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, 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, pictelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0442] The term "BTK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0443] The term "SYK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Exelair, PRT-062607, and fostamatinib.

[0444] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO 2008 / 039218, U.S. Patent Application Publication Nos. 2008 / 0108636 and WO 2011 / 090760, and U.S. Patent Application Publication No. 2010 / 0249092, each of which is incorporated by reference in its entirety.

[0445] Further examples of SYK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the present invention can be found in WO 2003 / 063794, U.S. Patent Application Publication No. 2004 / 0029902, WO 2005 / 007623, U.S. Patent Application Publication No. 2005 / 0075306 and WO 2006 / 078846, U.S. Patent Application Publication No. 2006 / 0211657, each of which is incorporated by reference in its entirety.

[0446] Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the invention are described in WO 2004 / 019973, U.S. Patent Application Publication No. 2004 / 0106569, WO 2004 / 089925, U.S. Patent Application Publication No. 2004 / 0242631, U.S. Patent Application Publication No. 8,138,347, WO 2002 / 088112, U.S. Patent Application Publication No. 2004 / 0116421, WO 2004 / 0242631, and WO 2004 / 0242631, each of which is incorporated by reference in its entirety. No. 2007 / 084786, U.S. Patent Application Publication No. 2010 / 0249126, WO 2007 / 129161, U.S. Patent Application Publication No. 2008 / 0076768, WO 2006 / 122806, U.S. Patent Application Publication No. 2008 / 0194579, WO 2005 / 113554, U.S. Patent Application Publication No. 2008 / 0275067 and WO 2007 / 044729, U.S. Patent Application Publication No. 2010 / 0087440.

[0447] Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of the invention can be found in WO 2009 / 114512, U.S. Patent Application Publication No. 2009 / 0233903, WO 2008 / 109943, U.S. Patent Application Publication No. 2010 / 0197671, WO 2007 / 053452, U.S. Patent Application Publication No. 2007 / 0191405, WO 2001 / 0142246, U.S. Patent Application Publication No. 2001 / 0053782 and WO 2007 / 070514, U.S. Patent Application Publication No. 2007 / 0135461, each of which is incorporated by reference herein in its entirety.

[0448] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, eg, unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0449] Examples of proteasome inhibitors useful in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0450] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as, eg, okadaic acid or a derivative thereof.

[0451] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0452] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acids such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0453] The term "bisphosphonate" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and that retain antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0454] The term "heparanase inhibitor" as used herein refers to a compound that targets, decreases or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferon.

[0455] The term "inhibitors 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 inhibitors," 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 particularly compounds that inhibit the telomerase receptor, such as telomestatin.

[0456] The term "methionine aminopeptidase inhibitors," as used herein, refers to compounds that target, decrease or inhibit the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[0457] The term "proteasome inhibitor," as used herein, refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decreases, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN341.

[0458] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors)" as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogues marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B, or AAJ996.

[0459] 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, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0460] Compounds that target, decrease or inhibit the activity of the FLT-3R-like tyrosine kinase receptor are 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.

[0461] The term "HSP90 inhibitor," as used herein, includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that target, reduce, or inhibit the degradation of HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90 are, 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; radicicol, and HDAC inhibitors.

[0462] 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 refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0463] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly in combination with therapies used for the treatment of AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412.

[0464] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogues hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease 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 compounds disclosed in U.S. Pat. No. 6,552,065, including, but not limited to, MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, particularly the lactate salt. As used herein, somatostatin receptor antagonist refers to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and below means ionizing radiation that occurs as any electromagnetic ray (such as X-rays and gamma rays) or particle (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy, which is known in the art. See Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4th Edition, Vol. 1, pp. 248-275 (1993).

[0465] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binder" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to a pyrimidine or purine nucleoside analog, including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0466] Also included are compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers, such as Macgon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiozyme (RPI4610) and bevacizumab (Avastin™).

[0467] Photodynamic therapy, as used herein, refers to a treatment that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0468] Angiogenic antisteroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0469] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0470] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0471] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other active ingredients, such as anti-inflammatory, bronchodilatory, or antihistamine active ingredients, particularly in the treatment of obstructive or inflammatory airway diseases, such as those mentioned above, for example, as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or mitigating potential side effects of such drugs. The compounds of the present invention can be mixed with the other active ingredients in a fixed pharmaceutical composition, or they can be administered separately, before, simultaneously with, or after the other active ingredients. Thus, the present invention includes combinations of the compounds of the present invention with anti-inflammatory, bronchodilatory, antihistamine, or anti-tussive active ingredients, as described above, wherein the compounds of the present invention and the active ingredients are in the same or different pharmaceutical compositions.

[0472] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, SB209247, and the like; LTD4 antagonists such as montelukast and zafirlukast, and the like; PDE4 inhibitors such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allofilin (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ 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 bronchodilator drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts, and CHF4226 (Chiesi), and glycopyrrolate.

[0473] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0474] Other useful combinations of compounds of the invention with anti-inflammatory agents are with 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, CXCR5, in particular 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]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0475] The structures of active compounds identified by code number, generic name or trade name can be obtained from book editions of standard catalogs "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0476] The compounds of the present invention can also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0477] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can be in the form of a fixed combination, or the administration of the compounds of the present invention and one or more other therapeutic compounds can be staggered or given independently of each other, or the combined administration of a fixed combination and one or more other therapeutic compounds.The compounds of the present invention can also or additionally be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention or a combination thereof, particularly for tumor treatment.Long-term treatment is equally possible as adjuvant therapy in the context of other treatment strategies, as described above.Other possible treatments are, for example, treatments to maintain the patient's condition after tumor regression or even chemopreventive therapy in at-risk patients.

[0478] These additional drugs can be administered separately from the composition containing the compound of the present invention as part of a multiple dose regimen.Alternatively, these drugs can be part of a single dosage form, mixed together with the compound of the present invention in a single composition.When administered as part of a multiple dose regimen, the two active drugs can be presented simultaneously, sequentially, or within a certain time from each other, usually within 5 hours from each other.

[0479] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or in a single unit dosage form. Thus, the present invention provides a unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0480] The amounts of both the compounds of the invention and additional therapeutic agent (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compound of the invention can be administered.

[0481] In compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dose of 0.01 to 1,000 μg / kg body weight / day of the additional therapeutic agent may be administered.

[0482] The amount of one or more other therapeutic agents present in the compositions of the invention may be an amount not exceeding the amount typically administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of one or more other therapeutic agents in the compositions disclosed herein ranges from about 50% to 100% of the amount typically administered in a composition comprising that agent as the only therapeutically active agent. In some embodiments, the one or more other therapeutic agents are administered at a dosage 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" refers to the amount of an FDA-approved therapeutic agent approved for administration according to the FDA label insert.

[0483] The compounds of the present invention or pharmaceutical compositions thereof can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of thrombus formation 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.

[0484] Representative tumor immunotherapy drugs In some embodiments, the one or more other therapeutic agents are tumor immunotherapeutic agents. As used herein, the term "tumor immunotherapeutic agent" refers to an agent that is effective for enhancing, stimulating, and / or upregulating immune responses in a subject. In some embodiments, the administration of a tumor immunotherapeutic agent with a compound of the present invention has a synergistic effect in the treatment of cancer.

[0485] The tumor immunotherapeutic agent can be, for example, a small molecule drug, an antibody, or a biological or small molecule. Examples of biological tumor immunotherapeutics 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.

[0486] In some embodiments, the tumor immunotherapeutic is (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including costimulatory) signal in T cells, both of which result in the amplification of antigen-specific T cell responses.

[0487] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory 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 costimulatory or costimulatory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, 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, and 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.

[0488] In some embodiments, the tumor immunotherapeutic 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.

[0489] In some embodiments, the combination of a compound of the present invention and a tumor immunotherapeutic agent may stimulate a T cell response. In some embodiments, the tumor immunotherapeutic is (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0490] In some embodiments, the tumor immunotherapeutic is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells, hi some embodiments, the tumor immunotherapeutic is an antagonist of a KIR, such as lirilumab.

[0491] In some embodiments, the tumor immunotherapeutic agent is a CSF-1R antagonist, such as RG7155 (see WO 2011 / 070024, U.S. Patent Application Publication No. 2011 / 0165156, WO 2011 / 0107553, U.S. Patent Application Publication No. 2012 / 0329997, WO 2011 / 131407, U.S. Patent Application Publication No. 2013 / 0005949, WO 2013 / 087699, U.S. Patent Application Publication No. 2014 / 0336363, WO 2013 / 1 and agents that inhibit or deplete macrophages or monocytes, including, but not limited to, CSF-IR antagonist antibodies, including FPA-008 (WO 2011 / 140249, US 2011 / 0274683; WO 2013 / 169264; WO 2014 / 036357, US 2014 / 0079699).

[0492] In some embodiments, the tumor immunotherapeutic agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling through inhibitory receptors, one or more agents that systemically increase the frequency of antagonistic and anti-tumor T cells, agents that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), 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 exhaustion), and agents that initiate innate immune activation and / or inflammation at the tumor site.

[0493] In some embodiments, the tumor immunotherapeutic 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.

[0494] In some embodiments, the tumor immunotherapeutic is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the tumor immunotherapeutic is an antibody or antigen-binding portion thereof 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; WO 2012 / 145493). In some embodiments, the tumor immunotherapeutic can be pidilizumab (CT-011). In some embodiments, the tumor immunotherapeutic is a recombinant protein called AMP-224, which is composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0495] In some embodiments, the tumor immunotherapeutic 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; WO 2010 / 077634, U.S. Patent Application Publication No. 2010 / 0203056), durvalumab (MEDI4736), BMS-936559 (WO 2007 / 005874, U.S. Patent Application Publication No. 2009 / 0055944), or MSB0010718C (WO 2013 / 079174, U.S. Patent Application Publication No. 2014 / 0341917).

[0496] In some embodiments, the tumor immunotherapeutic agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG-3 antibody is BMS-986016 (WO 2010 / 019570, U.S. Patent Application Publication No. 2010 / 0150892, WO 2014 / 008218, U.S. Patent Application Publication No. 2014 / 0093511) or IMP-731 or IMP-321 (WO 2008 / 132601, U.S. Patent Application Publication No. 2010 / 0233183, WO 2009 / 044273, U.S. Patent Application Publication No. 2011 / 0008331).

[0497] In some embodiments, the tumor immunotherapeutic is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO 12 / 32433).

[0498] In some embodiments, the tumor immunotherapeutic is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO 2006 / 105021, U.S. Patent Application Publication No. 2007 / 0098719, WO 2009 / 009116, U.S. Patent Application Publication No. 2009 / 0136494), or MK-4166 (WO 2011 / 028683, U.S. Patent Application Publication No. 2012 / 0189639).

[0499] In some embodiments, the tumor immunotherapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is 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); an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO 2009 / 073620, U.S. Patent Application Publication No. 2011 / 053941, WO 2009 / 132238, U.S. Patent Application Publication No. 2011 / 136796, WO 2011 / 056652, U.S. Patent Application Publication No. 2012 / 277217, WO 2012 / 142237, U.S. Patent Application Publication No. 2014 / 066625).

[0500] In some embodiments, the tumor immunotherapeutic is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0501] In some embodiments, the tumor immunotherapeutic 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 (WO 2006 / 029879, U.S. Patent Application Publication No. 7,501,496).

[0502] In some embodiments, the tumor immunotherapeutic is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the tumor immunotherapeutic 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.

[0503] In some embodiments, the tumor immunotherapeutic agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0504] In some embodiments, the tumor immunotherapeutic is MGA271 (against B7H3) (WO 2011 / 109400, US 2013 / 0149236).

[0505] In some embodiments, the tumor immunotherapeutic is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab, mafenatox, apolizumab, atezolimumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, alatumumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0506] In some embodiments, the tumor immunotherapeutic agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis have been shown in clinical trials to be able to deregulate activated tumor-reactive T cells and induce durable anti-tumor responses, enhancing many tumor histologies, including some tumor types not traditionally considered sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (OPDIVO®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown potential to improve overall survival in RCC patients who have experienced disease progression during or after prior antiangiogenic therapy.

[0507] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis in tumor cells. Approved immunomodulatory therapeutics that may be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[0508] In some embodiments, the tumor immunotherapeutic agent is a cancer vaccine, which is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-resistant) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions of melanoma.In some embodiments, the tumor immunotherapeutic agent is an oncolytic virotherapy, e.g., pexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF; Reolysin®, Oncolytics, in 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), a variant of the respiratory enteric orphan virus (reovirus) that does not replicate in cells without RAS activation; enadenotsileb (NG-348, formerly known as PsiOxus, ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, 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); and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF; GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux), an adenovirus engineered to express GM-CSF. GmbH), a vaccinia virus modified to express beta-galactosidase (beta-gal) / beta-glucuronidase or beta-gal / human sodium iodide symporter (hNIS), respectively; peritoneal carcinomatosis (NCT01443260); fallopian tube and ovarian cancers (NCT02759588); or bladder cancer (NCT02365818); CG0070 (Cold Genesys), an adenovirus modified to express GM-CSF.

[0509] In some embodiments, the tumor immunotherapeutic is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus modified to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutics targeted against difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), a modified adenovirus called Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) modified to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which may be further modified to express antigens designed to generate antigen-specific CD8+ T cell responses.

[0510] In some embodiments, the tumor immunotherapeutic is a T cell engineered to express a chimeric antigen receptor, or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

[0511] CARs are constructed from a binding domain, which may be derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen fused to an endodomain, which is the functional end of a T cell receptor (TCR), such as the CD3-zeta signaling domain from the TCR, which can generate an activation signal in T lymphocytes. Upon antigen binding, such CARs connect to endogenous signaling pathways in effector cells, generating activation signals similar to those initiated by the TCR complex.

[0512] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Patent No. 8,906,682, the entire contents of which are incorporated herein by reference, which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3-zeta). When expressed in T cells, the CAR 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 are currently underway using CAR-T in a wide variety of applications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1]

[0513] In some embodiments, the immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as innate immune cell subpopulations that express IL-17, 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).

[0514] In some embodiments, the immunostimulatory agent is a Toll-like receptor (TLR) agonist or activator. Suitable TLR activators include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that has been tested against B-cell, follicular, and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which has been tested against squamous cell carcinoma of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[0515] Other tumor immunotherapeutic agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; and MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0516] In some embodiments, the immunostimulant is selected from elotuzumab, mifamurtide, agonists or activators of Toll-like receptors, and activators of RORγt.

[0517] In some embodiments, the Immunostimulating Therapeutic Agent is recombinant human interleukin-15 (rhIL-15). rhIL-15 is being tested in medical centers as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the Immunostimulating Agent is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 conjugated to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which is being 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, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0518] In some embodiments, the tumor immunotherapeutic agent is selected from those described in Jerry L. Adams ET.AL., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, pages 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapeutic agent is selected from the examples described in Table 1 of Jerry L. Adams ET.AL. In some embodiments, the tumor immunotherapeutic agent is a small molecule that targets an immune-cancer target selected from those listed in Table 2 of Jerry L. Adams ET.AL. In some embodiments, the tumor immunotherapeutic agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams ET.AL.

[0519] In some embodiments, the tumor immunotherapeutic agent is selected from small molecule tumor immunotherapeutic agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapeutic agent is an agent that targets a pathway as described in Peter L. Toogood.

[0520] In some embodiments, the tumor immunotherapeutic is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BiTE(Registered Trademark)) antibody constructs can mediate bystander tumor cell killing," PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapeutic 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, the bispecific T cell engager (BiTE®) antibody construct activates T cells, resulting in induction of bystander cell lysis. In some embodiments, the bystander cells are solid tumors. In some embodiments, the bystander cells being lysed are in proximity to the BiTE®-activated T cells. In some embodiments, the bystander cells comprise tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, the tumor immunotherapeutic is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the tumor immunotherapeutic is ex vivo expanded tumor-infiltrating T cells.In some embodiments, the tumor immunotherapeutic is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly links T cells to a tumor-associated surface antigen (TAA).

[0521] Representative immune checkpoint inhibitors In some embodiments, the tumor immunotherapeutic is an immune checkpoint inhibitor as described herein.

[0522] The term "checkpoint inhibitor" as used herein refers to a drug that is useful for preventing cancer cells from evading the patient's immune system.One of the main mechanisms of anti-tumor immune destruction is also known as "T cell exhaustion", which occurs as a result of chronic exposure to antigens, which leads to the upregulation of inhibitory receptors.These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0523] PD-1 and its co-inhibitory receptors, such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B- and T-lymphocyte attenuator (BTLA; CD272), T-cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte activation gene-3 (Lag-3; CD223), are often referred to as checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular signals to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0524] In some embodiments, the immune checkpoint inhibitor is an antibody against PD-1, which binds to the programmed cell death 1 receptor (PD-1) and prevents the receptor from binding to the inhibitory ligand PDL-1, thus abolishing the tumor's ability to suppress the host anti-tumor immune response.

[0525] In one aspect, the checkpoint inhibitor is a biotherapeutic or a small molecule. In another aspect, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In a further aspect, 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, a B-7 family ligand, or a combination thereof. In one aspect, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In a further aspect, the interleukin is IL-7 or IL-15. In a particular aspect, the interleukin is glycosylated IL-7. In a further aspect, the vaccine is a dendritic cell (DC) vaccine.

[0526] Checkpoint inhibitors include any agent that statistically significantly blocks or inhibits an inhibitory pathway of the immune system. Such inhibitors may include small molecule inhibitors, or may include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary checkpoint molecules that can be targeted for blockage or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (which belongs to the CD2 family of molecules and is expressed on all NK, gamma delta, and memory CD8+ (alpha beta) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. 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. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (a CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (a PD-1 blocker), nivolumab (an anti-PD1 antibody), CT-011 (an anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (an anti-PDL1 antibody), BMS-936559 (an anti-PDL1 antibody), MPLDL3280A (an anti-PDL1 antibody), MSB0010718C (an anti-PDL1 antibody), and ipilimumab (an anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0527] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the 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).

[0528] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, rilumab, IPH2101, pembrolizumab (Keytruda®), and tremelimumab.

[0529] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron), an anti-PD-1 antibody being studied in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck), 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), an inhibitory antibody that binds to PD-1, in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced or metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that 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 cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic histopathological 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).

[0530] In some embodiments, the checkpoint inhibitor is an inhibitor of T-cell immunoglobulin mucin-containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody being tested in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody being tested in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody being tested in advanced malignancies (NCT02608268).

[0531] In some embodiments, the checkpoint inhibitor is an inhibitor of a T cell immunoreceptor having Ig and ITIM domains or an inhibitor of TIGIT, an immunoreceptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0532] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte-activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being tested in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron), also an anti-LAG-3 antibody, is being tested in malignant tumors (NCT03005782). IMP321 (Immutep SA), an LAG-3-Ig fusion protein, is being tested in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0533] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being tested in clinical trials include PF-04518600 / PF-8600 (Pfizer), an agonistic anti-OX40 antibody, in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck), an agonistic anti-OX40 antibody, in a Phase 1 cancer trial (NCT02528357); MCT02318394 and NCT02705482, in advanced solid tumors. EDI0562 (Medimmune / AstraZeneca), an agonistic anti-OX40 antibody; MEDI6469, an agonistic 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 agonistic anti-OX40 antibody, in advanced cancer (NCT02737475).

[0534] Checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists being tested in clinical trials include utomilumab (PF-05082566, Pfizer), an agonistic anti-CD137 antibody, in diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); and urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0535] The checkpoint inhibitors that can be used in the present invention include CD27 agonists.CD27 agonists that have been tested in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics), an agonistic anti-CD27 antibody, in squamous cell head and neck cancer, ovarian carcinoma, colorectal cancer, renal cell carcinoma, and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0536] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists being tested in clinical trials include TRX518 (Leap Therapeutics), an agonistic anti-GITR antibody, in malignant melanoma and other solid tumors (NCT01239134 and NCT02628574); solid tumors and lymphomas (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody, in advanced cancers (NCT02740270); INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody, in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck), an agonistic anti-GITR antibody, in solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgG1 Fc domain, in advanced solid tumors (NCT02583165).

[0537] The checkpoint inhibitor that can be used in the present invention includes inducible T cell costimulator (ICOS, also known as CD278) agonist.The ICOS agonist that has been tested in clinical trials includes MEDI-570 (Medimmune), an agonistic anti-ICOS antibody, in lymphoma (NCT02520791);GSK3359609 (Merck), an agonistic anti-ICOS antibody, in phase 1 trial (NCT02723955);JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody, in phase 1 trial (NCT02904226).

[0538] Checkpoint inhibitors that may be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being tested in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to the three domains of the long cytoplasmic tail (KIR3DL2), in lymphoma (NCT02593045).

[0539] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors being tested in clinical trials include ALX-148 (Alexo Therapeutics), an antagonistic variant of (SIRPa) that binds to CD47 and prevents CD47 / SIRPa-mediated signaling, in a Phase 1 study (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created 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). These include: CC-90002 (Celgene), an anti-CD47 antibody that acts by preventing it from delivering the "eat" signal and is in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody, in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.) in colorectal neoplasia and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0540] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors being tested in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody in solid tumors (NCT02754141).

[0541] Checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). STING agonists being tested in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide in Phase 1 trials (NCT02675439 and NCT03172936).

[0542] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors being tested in clinical trials include pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710), and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); and pexidartinib (PLX3397, Plexxikon), a CSF1R small molecule inhibitor, in pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT03153410). These include IMC-CS4 (LY3022855, Lilly), an anti-CSF-1R antibody, in advanced solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis), an orally available inhibitor of CSF1R, in advanced solid tumors (NCT02829723).

[0543] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors being tested in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0544] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. [Example]

[0545] Synthesis method The following examples are intended to illustrate the present invention and should not be construed as limiting it. Temperatures are given in degrees Celsius. Unless otherwise stated, all evaporations were carried out under reduced pressure, preferably between about 15 mmHg and 100 mmHg (=20-133 mbar). The structures of final products, intermediates, and starting materials were confirmed by standard analytical methods, such as microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are conventional in the art.

[0546] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention were either commercially available or could be made by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Additionally, the compounds of the present invention can be made by organic synthesis methods known to those skilled in the art, as shown in the examples below.

[0547] Intermediates: (E)-4-Ethoxy-1,1-difluorobut-3-en-2-one (Intermediate CJB) [ka] A solution of (2,2-difluoroacetyl) 2,2-difluoroacetate (7.50 g, 43.0 mmol, CAS#401-67-2) was dissolved in MTBE (100 mL) at 0 °C. Then, a solution of vinyloxyethane (3.11 g, 43.0 mmol, CAS#109-92-2) in pyridine (3.75 g, 47.4 mmol) was added to the mixture at 0 °C. The resulting mixture was stirred at 20 °C for 12 h. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (2 × 80 mL). The combined organic layers were washed with brine (80 mL), dried over Na SO , filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10:1 to 5:1) to give the title compound (3.00 g, 46% yield) as a yellow liquid. 1H NMR(400MHz,CDCl3)δ 7.85(d,J=12.0Hz,1H),5.90(d,J=4.0Hz,1H),5.87-5.58(m,1H),4.07(q,J=8.0Hz,2H),1.40(t,J=8.0Hz,3H).

[0548] 4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexanol (Intermediate CJC) [ka] Step 1 - Methyl 2-(4-(benzyloxy)cyclohexyl)hydrazinecarboxylate. To a mixture of methyl N-aminocarbamate (2.48 g, 19.5 mmol, HCl, CAS#2987-06-6) in DCM (60 mL) was added TEA (3.96 g, 39.1 mmol) at 25 °C until the pH stabilized at 8. The mixture was stirred at 20 °C for 0.5 h, and then HOAc (2.35 g, 39.1 mmol) was added to the solution at 20 °C until the pH stabilized at 5-6. The mixture was cooled to 0 °C. Next, 4-benzyloxycyclohexanone (4.00 g, 19.5 mmol, CAS#6294-89-9) was added, and the mixture was stirred for 2 h. Next, NaBH(OAc)3 (8.30 g, 39.1 mmol) was added in one portion. The resulting reaction mixture was stirred at 20° C. for 12 hours. Upon completion, the reaction mixture was quenched with water (4 mL), diluted with water (80 mL), and extracted with DCM (60 mL×2). The combined organic phase was washed with saturated sodium chloride solution (60 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate=1:1 to 1:2) to give the title compound (5.20 g, 95% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ 8.62-8.39(m,1H),7.38-7.35(m,1H),7.32(s,2H),7.29-7.23(m,1H),4.48(d,J=6.4Hz,1H),4.46-4.43(m,2H) ),3.55(s,3H),3.51-3.45(m,1H),3.40-3.21(m,1H),2.86-2.71(m,1H),1.83-1.74(m,2H),1.49-1.40(m,6H).

[0549] Step 2 - 1-(4-(benzyloxy)cyclohexyl)-3-(difluoromethyl)-1H-pyrazole. To a solution of methyl N-[(4-benzyloxycyclohexyl)amino]carbamate (4.50 g, 16.1 mmol) in toluene (50 mL) was added TFA (2.03 g, 17.7 mmol) under N. The mixture was stirred at 20 °C for 20 min, then (E)-4-ethoxy-1,1-difluoro-but-3-en-2-one (2.91 g, 19.4 mmol, Intermediate CJB) was added in one portion. The mixture was then stirred at 20 °C for 12 h. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (2 × 80 mL). The combined organic layers were washed with brine (100 mL), dried with NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 10:1 to 5:1) to give the title compound as a yellow oil (4.00 g, 80% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.91-7.86 (m, 1H), 7.39-7.24 (m, 5H), 7.10-6.79 (m, 1H), 6.48 (d, J = 0.8 Hz, 1H), 4.55-4.47 (m, 2H), 4.31-4.21 (m, J = 4.0, 7.6, 11.2 Hz, 1H), 3.66 (d, J = 2.8 Hz, 1H), 2.11-1.94 (m, 4H), 1.85-1.73 (m, 2H), 1.65-1.53 ​​(m, 2H).

[0550] Step 3 - 4-(3-(Difluoromethyl)-1H-pyrazol-1-yl)cyclohexanol. To a solution of 1-(4-benzyloxycyclohexyl)-3-(difluoromethyl)pyrazole (4.00 g, 13.0 mmol) in THF (40 mL) was added H2 (26.3 mg, 13.0 mmol) (15 psi) and Pd / C (1.20 g, 3.92 mmol). The mixture was stirred at 25 °C for 12 h. Upon completion, the reaction mixture was diluted with water (100 mL) and extracted with EA (100 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 1:5 to 1:1) to give the title compound (1.98 g, 70% yield) as a colorless oil. 1H NMR(400MHz,DMSO-d6)δ 7.87(d,J=2.0Hz,1H),7.09-6.80(m,1H),6.49-6.46(m,1H),4.84-4.67(m,1H),4.23-4.13(m, J=4.0,12.0Hz,1H),3.54-3.42(m,1H),2.02-1.86(m,5H),1.83-1.69(m,3H),LC-MS(ESI+)m / z 217.0(M+H)+.

[0551] Step 4 - 4-(3-(Difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclohexyl 2,2,2-trifluoroacetate. To a solution of 4-[3-(difluoromethyl)pyrazol-1-yl]cyclohexanol (1.98 g, 9.16 mmol) in TFAA (15 mL) was added HNO3 (1.41 g, 14.1 mmol) at 0 °C. The mixture was then stirred at 25 °C for 12 h. Upon completion, the reaction mixture was poured into ice water (100 mL) and aqueous NaHCO3 was added at 25 °C until the pH stabilized at 7, then the mixture was extracted with 160 mL of EA (2 × 80 mL). The organic layer was washed with saturated brine (2 × 80 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5:1 to 1:1) to give the title compound (2.80 g, 85% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.31 (t, J = 5.6 Hz, 1H), 5.08-4.98 (m, J = 4.0, 12.0 Hz, 1H), 4.50-4.40 (m, J = 4.0, 12.0 Hz, 1H), 4.06-4.06 (m, 1H), 2.16 (d, J = 12.0 Hz, 4H), 2.05-1.92 (m, 2H), 1.78-1.64 (m, 2H). LC-MS (ESI+) m / z 357.9 (M+H)+.

[0552] Step 5 - 4-(3-(Difluoromethyl)-4-nitro-1H-pyrazol-1-yl)cyclohexanol. To a solution of [4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]cyclohexyl] 2,2,2-trifluoroacetate (2.80 g, 7.84 mmol) in EtOH (15 mL) was added K2CO3 (2.17 g, 15.6 mmol). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (2.00 g, 97% yield) as a yellow liquid. LC-MS (ESI+) m / z 261.9 (M+H)+.

[0553] Step 6 - 4-(4-amino-3-(difluoromethyl)-1H-pyrazol-1-yl)cyclohexanol. To a solution of 4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]cyclohexanol (2.00 g, 7.66 mmol) in THF (40 mL) was added H2 (15.4 mg, 7.66 mmol) (15 psi) and Pd / C (600 mg, 2.30 mmol). The mixture was stirred at 25 °C for 12 h. Upon completion, the reaction mixture was diluted with water (60 mL) and extracted with EA (80 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (60 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give a residue. The residue was purified by column chromatography (SiO2, ethyl acetate / petroleum ether = 1:5 to 1:1) to give the title compound (1.70 g, 99% yield) as a colorless oil. LC-MS(ESI+)m / z 232.0(M+H)+.

[0554] 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate CJD) [ka] Step 1—5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-(4-hydroxycyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. To a solution of 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.13 g, 4.32 mmol, intermediate AEH) in DMF (12 mL) was added HATU (2.14 g, 5.62 mmol) and DIEA (1.68 g, 12.9 mmol) dropwise at 25° C. over 30 min. Next, 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexanol (1.00 g, 4.32 mmol, Intermediate CJC) was added, and the mixture was stirred at 60 °C for 12 h. Upon completion, the residue was diluted with water (60 mL) and extracted with EA (2 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5:1 to 1:1) to give the title compound (1.80 g, 90% yield) as a yellow oil. H NMR (400 MHz, DMSO-d) δ 9.54-9.46(m,1H),8.78(d,J=8.0Hz,1H),8.38(d,J=4.0Hz,1H),8.25(d,J=5.6Hz,1H),7. 30-6.93(m,1H),6.88-6.42(m,1H),4.77(d,J=17.2Hz,1H),4.69-4.47(m,1H),4.27-4.15( m,1H),3.87-3.77(m,2H),3.76-3.61(m,1H),3.54-3.42(m,1H),3.17(d,J=5.6Hz,2H),2. 04-1.88(m,4H),1.79-1.69(m,3H),1.63-1.52(m,1H),1.31-1.21(m,2H),LC-MS(ESI+)m / z 474.2(M+H)+.

[0555] Step 2 - 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-(4-oxocyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. To a solution of N-[3-(difluoromethyl)-1-(4-hydroxycyclohexyl)pyrazol-4-yl]-5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (900 mg, 1.90 mmol) in DCM (10 mL) was added DMP (1.05 g, 2.47 mmol). The mixture was stirred at 40 °C for 3 h. Upon completion, the reaction mixture was quenched with NaSO (20 mL) and NaHCO (20 mL) at 25 °C, then extracted with 50 mL of DCM (25 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (25 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (790 mg, 88% yield) as a yellow solid. LC-MS (ESI+) m / z 472.0 (M+H)+.

[0556] [(5R)-5-(5-bromo-6-methoxy-indazol-2-yl)tetrahydropyran-2-yl]methanol (Intermediate CJG) [ka] Step-1—Tert-butyl-(3,4-dihydro-2H-pyran-2-ylmethoxy)-diphenyl-silane. To a solution of 3,4-dihydro-2H-pyran-2-ylmethanol (10.0 g, 87.6 mmol, CAS#3749-36-8) in DMF (200 mL) was added imidazole (11.9 g, 175 mmol) and TBDPSCl (28.9 g, 105 mmol). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was diluted with EA (60 mL) and washed with water (3 × 10 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was then purified by column chromatography (SiO, petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to give the title compound (51 g, 83% yield) as a colorless oil. 1H NMR(400MHz,CDCl3)δ 7.58(t,J=1.6Hz,4H)7.23-7.30(m,6H)6.23(d,J=6.0Hz,1H)4.50-4.55(m,1H)3.81(t,J=2.0Hz,1H)3 .66-3.72(m,1H)3.55-3.60(m,1H)1.89-1.98(m,1H)1.78-1.87(m,2H)1.54-1.65(m,1H)0.96(s,9H).

[0557] Step 2 - 6-[[Tert-butyl(diphenyl)silyl]oxymethyl]tetrahydropyran-3-ol. To a solution of tert-butyl-(3,4-dihydro-2H-pyran-2-ylmethoxy)-diphenyl-silane (10.0 g, 28.3 mmol) in THF (100 mL) was added 9-BBN (1 M, 141 mL) dropwise at 0 °C. After the addition, the mixture was brought to 25 °C and the reaction was continued at 25 °C for 14 h. The reaction mixture was then oxidized with NaOH (3 M, 56.7 mL) and HO (259 mmol, 26.7 mL, 28% solution), and the reaction was maintained at 55 °C for 1 h. KCO (784 mg, 5.67 mmol) was then added at 0 °C, and the mixture was stirred for 1 h. Upon completion, the reaction mixture was diluted with HO (200 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The aqueous phase was quenched by the addition of NaSO (2000 mL). The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give the title compound as a colorless oil (10.1 g, 96% yield). 1H NMR(400MHz,CDCl3)δ 7.72(d,J=6.8Hz,4H)7.39-7.46(m,6H)4.16(q,J=7.2Hz,1H)4.01(d,J=7.2Hz,1H)3.77(d,J=5.2Hz,1H)3.68(t,J=5.2Hz,1H)3.57(s,1H) )3.37-3.44(m,1H)3.12(t,J=10.4Hz,1H)2.34(s,1H)2.09-2.18(m,1H)1.82-1.90(m,1H)1.36-1.48(m,2H)1.11(s,9H).LC-MS(ESI+)m / z 393.0(M+H)+.

[0558] Step 3—[6-[[Tert-butyl(diphenyl)silyl]oxymethyl]tetrahydropyran-3-yl]methanesulfonate. To a solution of 6-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydropyran-3-ol (5.22 g, 14.0 mmol) in DCM (50 mL) was added TEA (2.85 g, 28.1 mmol) and methylsulfonyl methanesulfonate (3.68 g, 21.1 mmol). The mixture was stirred at 0° C. for 2 h. Upon completion, the residue was diluted with HO (12 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound. LC-MS (ESI+) m / z 466.2 (M+H)+.

[0559] Step 4—[(5R)-5-(5-Bromo-6-methoxy-indazol-2-yl)tetrahydropyran-2-yl]methanol. To a solution of [6-[[tert-butyl(diphenyl)silyl]oxymethyl]tetrahydropyran-3-yl]methanesulfonate (3.00 g, 6.69 mmol) in DMF (5 mL) was added 5-bromo-6-methoxy-2H-indazole (759 mg, 3.34 mmol, CAS#152626-78-3) and CsCO (2.18 g, 6.69 mmol). The mixture was stirred at 80 °C for 16 h. Upon completion, the residue was diluted with HO (5 mL) and extracted with EA (3 × 10 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25mm*10um; mobile phase: [water (FA)-ACN]; B%: 20% to 50%, 10.5 min) to give the title compound (80 mg, 7% yield) as a yellow solid. 1H NMR(400MHz,CDCl3)δ 8.30(s,1H)7.90(s,1H)7.03(s,1H)4.57-4.66(m,2H)4.07(d,J=2.4Hz,1H)3.95(s,3H)3 .58-3.70(m,3H)2.47-2.57(m,1H)2.15-2.23(m,1H)1.76-1.87(m,1H)1.41-1.52(m,2H).

[0560] 6-(1-Fluoro-1-methyl-ethyl)-N-[2-[(3R,6R)-6-formyltetrahydropyran-3-yl]-6-methoxy-indazol-5-yl]pyridine-2-carboxamide (Intermediate CJH) [ka] Step 1 - 6-(1-Fluoro-1-methyl-ethyl)-N-[(2S)-2-[6-(hydroxymethyl)tetrahydropyran-3-yl]-6-methoxy-indazol-5-yl]pyridine-2-carboxamide. A mixture of [(5R)-5-(5-bromo-6-methoxy-indazol-2-yl)tetrahydropyran-2-yl]methanol (80 mg, 230 μmol, Intermediate CJG), 6-(1-fluoro-1-methyl-ethyl)pyridine-2-carboxamide (51.2 mg, 281 μmol, CAS#152626-78-3), Pd(dba) (21.4 mg, 23.4 μmol), Xantphos (13.5 mg, 23.4 μmol), and CsCO (152 mg, 468 μmol) in dioxane (5 mL) was degassed and purged with N three times. The mixture was then stirred at 80 °C under a N atmosphere for 16 h. Upon completion, the residue was diluted with HO (5 mL) and extracted with EA (3 × 10 mL). The combined organic layer was washed with brine (2 × 9 mL), dried over NaSO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase: [water (FA)-ACN]; B%: 37% to 67%, 10 min) to obtain the title compound (75 mg, 70% yield) as a white solid. 1H NMR(400MHz,CDCl3)δ 10.85(s,1H)8.85(s,1H)8.32(s,1H)8.21(d,J=7.6Hz,1H)7.95(t,J=7.6Hz,1H)7.76(d,J=7.6Hz,1H)7.06(s,1H)4.60-4.67(m,2H)4. 00-4.08(m,4H)3.63-3.71(m,3H)2.54(d,J=14.0Hz,1H)2.15-2.21(m,1H)1.80-1.87(m,6H)1.63(s,2H)1.50(s,1H).LC-MS(ESI+)m / z 443.0(M+H)+.

[0561] Step 2 - 6-(1-Fluoro-1-methyl-ethyl)-N-[2-[(3R,6R)-6-formyltetrahydropyran-3-yl]-6-methoxy-indazol-5-yl]pyridine-2-carboxamide. To a solution of 6-(1-fluoro-1-methyl-ethyl)-N-[2-[(3R,6R)-6-(hydroxymethyl)tetrahydropyran-3-yl]-6-methoxy-indazol-5-yl]pyridine-2-carboxamide (75.0 mg, 169 μmol) in DCM (1 mL) was added DMP (143 mg, 339 μmol). The mixture was stirred at 25 °C for 2 h. Upon completion, the residue was diluted with HO (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were washed with brine (2 x 6 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound. LC-MS (ESI+) m / z 459.1 (M+H)+.

[0562] 5-Fluoro-N-[2-(4-formylcyclohexyl)-6-methoxy-indazol-5-yl]pyridine-3-carboxamide (Intermediate CJI) [ka] Step 1—5-Fluoro-N-[2-[4-(hydroxymethyl)cyclohexyl]-6-methoxy-indazol-5-yl]pyridine-3-carboxamide. A mixture of 5-fluoropyridine-3-carboxamide (107 mg, 766 μmol, CAS#70-58-6), [4-(5-bromo-6-methoxy-indazol-2-yl)cyclohexyl]methanol (200 mg, 589 μmol, synthesized via Steps 1–3 of Intermediate ATE), BrettPhos Pd G3 (53 mg, 58 μmol), and Cs2CO3 (576 mg, 1.77 mmol) in dioxane (3 mL) was degassed and purged with N2 three times, then the mixture was stirred at 90 °C for 16 h under a N2 atmosphere. Upon completion, the mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give the title compound (164 mg, 62% yield) as a white solid. LC-MS (ESI+) m / z 399.0 (M+H)+.

[0563] Step 2 - 5-Fluoro-N-[2-(4-formylcyclohexyl)-6-methoxy-indazol-5-yl]pyridine-3-carboxamide. To a solution of 5-fluoro-N-[2-[4-(hydroxymethyl)cyclohexyl]-6-methoxy-indazol-5-yl]pyridine-3-carboxamide (104 mg, 261 μmol) in DCM (1 mL) was added DMP (132 mg, 313 μmol). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was quenched by the addition of NaSO (1 mL) and NaHCO (1 mL). The reaction mixture was filtered and concentrated in vacuo. The residue was diluted with DCM (20 mL) and NaHCO (20 mL). The mixture was filtered and concentrated to give a residue. The filtrate was concentrated, and the mixture was extracted with DCM (10 mL × 3). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was then purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give the title compound (96 mg, 85% yield) as a brown solid. LC-MS (ESI+) m / z 396.9 (M+H)+.

[0564] 5-(1-piperidyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (intermediate CJJ) [ka] Step 1 - Ethyl 5-(1-piperidyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate. A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (800 mg, 3.55 mmol, CAS# 1224944-77-7), piperidine (603 mg, 7.09 mmol, CAS# 110-89-4), and DIEA (916 mg, 7.09 mmol) in ACN (12 mL) was degassed and purged with N2 three times. The mixture was then stirred at 60 °C under a N2 atmosphere for 2 h. Upon completion, the reaction mixture was concentrated in vacuo. The mixture was then diluted with HO (30 mL) and extracted with EA (20 mL x 3). The combined organic layers were washed with saturated NaCl (20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (950 mg, 97% yield) as a yellow solid. H NMR (400 MHz, DMSO-d) δ 8.65 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 4.18-4.15 (m, 2H), 3.75-3.72 (m, 4H), 1.67-1.54 (m, 6H), 1.27 (t, J = 7.2 Hz, 3H). LC-MS (ESI+) m / z 275.1 (M+H)+.

[0565] Step 2 - 5-(1-piperidyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. To a solution of ethyl 5-(1-piperidyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (800 mg, 2.92 mmol) in MeOH (8 mL) and HO (2 mL) was added LiOH.HO (367 mg, 8.75 mmol). The mixture was stirred at 50 °C for 16 h. Upon completion, the reaction mixture was concentrated in vacuo. Next, HCl (3 M) was added to the mixture to adjust the pH to 6, and the mixture was then filtered to give the title compound (600 mg, 83% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 12.13-10.76(m,1H),8.64(d,J=8.0Hz,1H),8.15(s,1H),6.82(d,J=8.0Hz,1H),3.74-3.70(m,4H),1.67-1.53(m,6H).LC-MS(ESI+)m / z 247.0(M+H)+.

[0566] 3-[4-[3-[4-[[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methyl]piperazin-1-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate CJK) [ka] Step 1—Tert-butyl N-[3-(difluoromethyl)-1-[4-[[4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]piperazin-1-yl]methyl]cyclohexyl]pyrazol-4-yl]carbamate. To a mixture of 3-[3-methyl-2-oxo-4-(3-piperazin-1-ylprop-1-ynyl)benzimidazol-1-yl]piperidine-2,6-dione (721 mg, 1.46 mmol, TFA, Intermediate CBD) in THF (10 mL) was added TEA (200 μL) to adjust the pH to 8, and then the mixture was stirred at −20° C. for 0.5 h. Next, tert-butyl N-[3-(difluoromethyl)-1-(4-formylcyclohexyl)pyrazol-4-yl]carbamate (500 mg, 1.46 mmol, Intermediate ABM) and HOAc (80 uL) were added to adjust the pH to 5, and the mixture was then stirred at −20° C. for 1 h. Finally, NaBH(OAc) (339 mg, 1.60 mmol) was added, and the mixture was stirred at −20° C. for 1 h. Upon completion, the reaction mixture was quenched with water (0.5 mL) and concentrated in vacuo to give a residue. The residue was then diluted with HO (100 mL) and extracted with EA (100 mL × 3). The combined organic layers were washed with saturated NaCl (30 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO2, DCM:MeOH=40:1 to 10:1) to give the title compound (700 mg, 68% yield) as a yellow solid.1H NMR(400MHz,DMSO-d6)δ 11.11(s,1H),8.91(s,1H),7.87(s,1H),7.19-7.10(m,2H),7.05-6.99(m,1H),6.91-5.67(m,1 H),5.40(dd,J=5.6,12.4Hz,1H),4.12(t,J=10.4Hz,1H),3.65(s,3H),3.13-3.06(m,1H),2.94- 2.84(m,2H),2.78-2.59(m,6H),2.05-1.95(m,4H),1.93-1.84(m,3H),1.79-1.66(m,3H),1.44 (s,9H),1.23(s,1H),1.20-1.14(m,2H),1.13-1.10(m,2H),0.88-0.78(m,1H);LC-MS(ESI+)m / z 709.3(M+H)+.

[0567] Step 2 - 3-[4-[3-[4-[[4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methyl]piperazin-1-yl]prop-1-ynyl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione. To a mixture of tert-butyl N-[3-(difluoromethyl)-1-[4-[[4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynyl]piperazin-1-yl]methyl]cyclohexyl]pyrazol-4-yl]carbamate (300 mg, 423 μmol) in DCM (5 mL) was added TFA (2 mL), and the mixture was stirred at 20 °C for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (305 mg, 99% yield, TFA) as a brown liquid. LC-MS (ESI+) m / z 609.3 (M+H)+.

[0568] 5-Pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate CJL) [ka] Step 1—Ethyl 5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxylate. A mixture of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (1.20 g, 5.32 mmol, CAS# 1224944-77-7), DIEA (1.85 mL), and pyrrolidine (756.50 mg, 10.6 mmol) in ACN (5 mL) was degassed and purged with N three times. The mixture was then stirred at 60 °C for 2 h under a N atmosphere. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with HO (50 mL) and extracted with DCM (100 mL × 3). The combined organic layers were washed with saturated NaCl (20 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, DCM:MeOH = 50:1 to 20:1) to give the title compound (1.00 g, 72% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.30-8.15 (m, 2H), 6.19 (d, J = 7.6 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.80 (s, 2H), 3.47 (s, 2H), 2.14-1.93 (m, 4H), 1.39 (t, J = 7.2 Hz, 3H); LC-MS (ESI+) m / z 261.2 (M+H)+.

[0569] Step 2 - 5-Pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid. A mixture of ethyl 5-pyrrolidin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxylate (840 mg, 3.23 mmol) and LiOH.HO (406 mg, 9.68 mmol) in MeOH (10 mL) and HO (2 mL) was stirred at 60 °C for 2 h. Upon completion, the reaction mixture was filtered to afford the title compound (700 mg, 93% yield) as a white solid. 1H NMR (400 MHz, DO) δ 8.07 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 6.09 (d, J = 8.0 Hz, 1H), 3.63-3.18 (m, 4H), 1.94 (s, 4H).

[0570] 5-(Azetidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Intermediate CJM) [ka] Step 1—Ethyl 5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate. To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (500 mg, 2.22 mmol) and azetidine (253 mg, 4.43 mmol) in ACN (10 mL) was added DIEA (572 mg, 4.43 mmol), and the mixture was stirred at 60° C. for 2 h. Upon completion, the reaction mixture was concentrated in vacuo to give a residue. The residue was diluted with water (20 mL) and extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (400 mg, 73% yield) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.66(d,J=7.6Hz,1H),8.17(s,1H),6.31(d,J=7.6Hz,1H),4.21-4.13(m,6H),2.37(t,J=7.6Hz,2H),1.27(t,J=7.2Hz,3H).LC-MS(ESI+)m / z 246.7(M+H)+.

[0571] Step 2 - 5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a solution of ethyl 5-(azetidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 812 μmol) in MeOH (2 mL) and HO (0.5 mL) was added LiOH.HO (68.1 mg, 1.62 mmol), and the mixture was stirred at 60 °C for 2 h. Upon completion, the reaction mixture was concentrated in vacuo to remove MeOH and then acidified with hydrochloric acid (1 M) to pH = 5-6. The mixture was then concentrated in vacuo to afford the title compound (150 mg, 84% yield) as a yellow oil. 1H NMR(400MHz,DMSO-d6)δ 8.61(d,J=7.6Hz,1H),8.04(s,1H),6.21(d,J=7.6Hz,1H),4.19(t,J=7.2Hz,4H),2.34(t,J=7.6Hz,2H).

[0572] 4-Chloro-1-methyl-pyrazole-3-carboxylic acid (CAS#84547-85-3) (Intermediate CJN) [ka] 3-[4-[9-[[4-(5-amino-6-methoxy-indazol-2-yl)cyclohexyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (Intermediate CJO) [ka] Step 1—Tert-butyl N-[2-[4-[[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]cyclohexyl]-6-methoxy-indazol-5-yl]carbamate. To a solution of 3-[4-(3,9-diazaspiro[5.5]undecan-3-yl)-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione (205 mg, 390 μmol, TFA, Intermediate BXR) in DMF (2 mL) and THF (4 mL) was added TEA (39.4 mg, 390 μmol, 54.3 μL), and the mixture was stirred at −10° C. for 10 minutes. Next, tert-butyl N-[2-(4-formylcyclohexyl)-6-methoxy-indazol-5-yl]carbamate (145 mg, 390 μmol, Intermediate BGT) and AcOH (46.8 mg, 780 μmol, 44.6 μL) were added to the mixture, and the mixture was stirred at −10° C. for 20 minutes. Next, NaBH(OAc) (107 mg, 507 μmol) was added to the mixture, and the mixture was stirred at −10° C. for 1 hour. Upon completion, the reaction mixture was quenched with HO (1 mL) and concentrated in vacuo to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 20%-50%, 15 min) to give the title compound (280 mg, 93% yield) as a white solid.1H NMR(400MHz,DMSO-d6)δ 11.10(s,1H),8.18(s,1H),7.89(s,1H),7.80(s,1H),7.00-6.95(m,3H),6.92-6.81(m,1H), 5.35(dd,J=5.6,12.8Hz,1H),4.41-4.30(m,1H),3.85(s,3H),3.63(s,3H),2.95-2.82(m,6H ),2.75-2.65(m,2H),2.65-2.56(m,2H),2.52-2.51(m,4H),2.17-2.09(m,2H),2.04-1.83(m ,6H),1.82-1.68(m,3H),1.63-1.50(m,4H),1.46(s,9H),1.24-1.09(m,2H),LC-MS(ESI+)m / z 769.5(M+H)+.

[0573] Step 2 - 3-[4-[9-[[4-(5-amino-6-methoxy-indazol-2-yl)cyclohexyl]methyl]-3,9-diazaspiro[5.5]undecan-3-yl]-3-methyl-2-oxo-benzimidazol-1-yl]piperidine-2,6-dione. To a solution of tert-butyl N-[2-[4-[[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-3,9-diazaspiro[5.5]undecan-9-yl]methyl]cyclohexyl]-6-methoxy-indazol-5-yl]carbamate (55.0 mg, 71.5 μmol) in DCM (1 mL) was added HCl / dioxane (3 M, 2 mL). The mixture was stirred at 25 °C for 2 h. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (50.0 mg, 99% yield) as a yellow solid; LC-MS (ESI+) m / z 669.4 (M+H)+.

[0574] 3-[3-methyl-2-oxo-4-[4-(4-piperidyloxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate CJP) [ka] Step 1 – Tert-butyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]oxy]piperidine-1-carboxylate. A mixture of tert-butyl 4-(4-piperidyloxy)piperidine-1-carboxylate (500 mg, 1.76 mmol, CAS# 845305-83-1), 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (805 mg, 1.76 mmol, synthesized via Steps 1-4 of Intermediate HP), CsCO (1.72 g, 5.27 mmol), and 1,3-bis[2,6-bis(1-propylbutyl)phenyl]-4,5-dichloro-2H-imidazol-1-ium-2-ide; 3-chloropyridine; dichloropalladium (85.5 mg, 87.9 μmol) in dioxane (12 mL) was degassed and purged with N three times. The mixture was then stirred at 100° C. under a N atmosphere for 16 h. Upon completion, the reaction mixture was concentrated in vacuo. The mixture was diluted with H O (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with saturated NaCl with H O (10 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO , PE:EA=50:1 to 1:1) to give the title compound (320 mg, 27% yield) as a yellow solid. H NMR (400 MHz, DMSO-d) δ 7.21(d,J=8.4Hz,2H),6.98-6.82(m,4H),6.80-6.68(m,1H),5.57-5.43(m, 1H),4.79-4.75(m,2H),3.73(s,3H),3.71-3.58(m,6H),3.58-3.44(m,1H), 3.35(s,2H),3.12-2.99(m,4H),2.89-2.64(m,4H),1.99(s,3H),1.81-1.73 (m,2H),1.63-1.53(m,1H),1.40(s,9H),1.36-1.27(m,2H).LC-MS(ESI+)m / z 662.2(M+H)+.

[0575] Step 2 - 3-[3-Methyl-2-oxo-4-[4-(4-piperidyloxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione. To a solution of tert-butyl 4-[[1-[1-[1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]oxy]piperidine-1-carboxylate (250 mg, 377 μmol) in TFA (1 mL) was added TfOH (0.2 mL). The mixture was stirred at 70 °C for 2 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (205 mg, 97% yield, TFA) as a yellow oil. LC-MS (ESI+) m / z 442.0 (M+H)+.

[0576] Step 3—Tert-butyl 4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]oxy]piperidine-1-carboxylate. To a solution of 3-[3-methyl-2-oxo-4-[4-(4-piperidyloxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione (200 mg, 360 μmol, TFA) in DCM (3 mL) was added (Boc)O (117 mg, 540 μmol) and TEA (109 mg, 1.08 mmol). The mixture was stirred at 25° C. for 16 h. Upon completion, the reaction mixture was concentrated in vacuo. The mixture was diluted with HO (5 mL) and extracted with EA (5 mL × 3). The combined organic layers were washed with saturated NaCl (5 mL) along with HO, dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE:EA = 50:1 to 0:1) to give the title compound (190 mg, 97% yield) as a yellow solid. H NMR (400 MHz, DMSO-d) δ 11.08 (s, 1H), 7.00-6.93 (m, 1H), 6.92-6.82 (m, 2H), 5.34-5.30 (m, 1H), 4.03-3.98 (m, 1H), 3.69-3.64 (m, 2H), 3.62 (s, 3H), 3.56-3.47 (m, 1H), 3.14-3.06 (m, 4H), 3.0 5-2.96(m,2H),2.77-2.57(m,4H),2.00-1.98(m,1H),1.98-1.95(m,1H),1.81-1.7 3(m,2H),1.68-1.51(m,2H),1.44-1.38(m,9H),1.36-1.27(m,2H).LC-MS(ESI+)m / z 542.1(M+H)+.

[0577] Step 4 - 3-[3-Methyl-2-oxo-4-[4-(4-piperidyloxy)-1-piperidyl]benzimidazol-1-yl]piperidine-2,6-dione. To a solution of tert-butyl 4-[[1-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]-4-piperidyl]oxy]piperidine-1-carboxylate (100 mg, 184 μmol) in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at 25 °C for 1 h. Upon completion, the reaction mixture was concentrated in vacuo to afford the title compound (100 mg, 97% yield, TFA) as a yellow oil. LC-MS (ESI+) m / z 442.0 (M+H)+.

[0578] 5-Methylsulfonylpyridine-3-carboxylic acid (Intermediate CJQ) [ka] Step 1 - Methyl 5-methylsulfanylpyridine-3-carboxylate. To a solution of 5-methylsulfanylpyridine-3-carboxylic acid (300 mg, 1.77 mmol, CAS#74470-28-3) in CHOH (0.5 mL) was added thionyl chloride (421 mg, 3.55 mmol) at 0 °C. The mixture was then stirred at 70 °C for 2 h. Upon completion, the mixture was concentrated to a residue. The mixture was diluted with DCM (10 mL) and quenched with NaHCO (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (300 mg, 92% yield) as a yellow oil. LC-MS (ESI+) m / z 184.2 (M+H)+.

[0579] Step 2 - Methyl 5-methylsulfonylpyridine-3-carboxylate. To a solution of methyl 5-methylsulfanylpyridine-3-carboxylate (50 mg, 272 μmol) in DCM (0.5 mL) was added m-CPBA (294 mg, 1.36 mmol, 80% solution). The mixture was stirred at 25 °C for 0.5 h. Upon completion, the mixture was diluted with DCM (2 mL) and quenched with NaSO (1 mL) and NaHCO (1 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to give the title compound (40 mg, 67% yield) as a white solid. LC-MS (ESI+) m / z 215.8 (M+H)+.

[0580] Step 3 - 5-Methylsulfonylpyridine-3-carboxylic acid. To a solution of methyl 5-methylsulfonylpyridine-3-carboxylate (40 mg, 185 μmol) in MeOH (0.5 mL) and HO (0.1 mL) was added LiOH.HO (23.4 mg, 557 μmol). The mixture was stirred at 25 °C for 1 h. Upon completion, the mixture was concentrated to give a residue. To the mixture was then added HCl (3 M) (0.5 mL) at 25 °C until the pH stabilized at 2-3. The mixture was filtered, and the filter cake was dried under vacuum to give the title compound (27 mg, 72% yield) as a white solid. LC-MS (ESI+) m / z 202.0 (M+H)+.

[0581] 5-Methylsulfinylpyridine-3-carboxylic acid (Intermediate CJR) [ka] Step 1—Methyl 5-methylsulfinylpyridine-3-carboxylate. To a solution of methyl 5-methylsulfanylpyridine-3-carboxylate (100 mg, 545 μmol, synthesized via Step 1 of Intermediate CJQ) in DCM (2 mL) was added m-CPBA (129 mg, 600 μmol) at 0 °C. The mixture was then stirred at 0 °C for 0.5 h. Upon completion, the mixture was quenched with saturated NaSO (5 mL) and saturated NaHCO (5 mL) at 25 °C and then stirred for 30 min. The mixture was then extracted with DCM (2 × 15 mL). The combined organic layers were then washed with NaHCO (2 × 15 mL) and saturated brine (2 × 15 mL). The combined organic layers were dried over NaSO, filtered, and the filtrate was concentrated in vacuo to provide a residue. The residue was purified by column chromatography (SiO, PE:EA = 5:1 to PE:EA = 0:1, PE:EA = 0:1, P1: Rf = 0.14) to give the title compound as a white solid (65 mg, 59.7% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.19 (d, J = 2.0 Hz, 1H), 9.08 (d, J = 2.0 Hz, 1H), 8.56 (t, J = 2.0 Hz, 1H), 3.93 (s, 3H), 2.91 (s, 3H); LC-MS (ESI+) m / z 199.9 (M+H)+.

[0582] Step 2 - 5-Methylsulfinylpyridine-3-carboxylic acid. To a solution of methyl 5-methylsulfinylpyridine-3-carboxylate (65 mg, 326 μmol) in HO (0.4 mL) and MeOH (2 mL) was added LiOH.HO (41.0 mg, 978 μmol). The mixture was then stirred at 25 °C for 1 h. Upon completion, the reaction mixture was adjusted to pH = 3 and concentrated in vacuo to afford the title compound (50 mg, 83% yield) as a yellow solid. LC-MS (ESI+) m / z 186.2 (M+H)+.

[0583] Tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate (Intermediate CJS) [ka] Step 1—Tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate. To a solution of benzyl 4-formylpiperidine-1-carboxylate (4.5 g, 18.2 mmol, CAS# 138163-08-3), tert-butyl piperazine-1-carboxylate (4.07 g, 21.8 mmol, CAS# 143238-38-4) in THF (80 mL) was added HOAc (1.09 g, 18.2 mmol), and the mixture was stirred at 0° C. for 30 min. Next, NaBH(OAc) (7.71 g, 36.4 mmol) was added, and the mixture was stirred at 0° C. for 1.5 h. Upon completion, the reaction was diluted with water (80 mL) and extracted with EA (100 mL × 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO, PE / EA = 2 / 1 to 1 / 1) to give the title compound (5.5 g, 72% yield) as a colorless oil. 1H NMR(400MHz,CDCl3)δ 7.32-7.18(m,5H),5.04(s,2H),4.08(d,J=11.2Hz,2H),3.34(s,4H),2.69(t,J=11.2Hz,2H), 2.27(s,4H),2.11(s,2H),1.73-1.52(m,3H),1.38(s,9H),1.13-0.93(m,2H).LC-MS(ESI+)m / z 418.5(M+H)+.

[0584] Step 2—Tert-butyl 4-(4-piperidylmethyl)piperazine-1-carboxylate. To a solution of tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)methyl]piperazine-1-carboxylate (1.5 g, 3.59 mmol) in THF (15 mL) was added Pd / C (500 mg, 10 wt%) under Ar. The suspension was degassed under vacuum, purged with H three times, and then stirred under H atmosphere (15 psi) at 20° C. for 1 h. Upon completion, the reaction was filtered to obtain the filtrate, which was then concentrated in vacuo to afford the title compound (1.0 g, 98% yield) as a colorless oil. 1H NMR(400MHz,CDCl3)δ 3.45-3.36(m,3H),3.11(d,J=12.4Hz,2H),2.74-2.4...

Claims

1. Formulae I-a to I-ii: 【Chemical 450】 【Chemistry 451】 【Chemistry 452】 【Chemistry 453】 【Chemistry 454】 【Chemistry 455】 【Chemistry 456】 【Chemistry 457】 (In the formula, X is a divalent moiety selected from -CH- or -C(O)-; Y is nitrogen or CH; Ring A is phenylenyl, naphthienyl, pyridinylenyl, 【Chemistry 458】 is a ring selected from Ring B is a fused ring selected from benzo or 5-6 membered heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R4 is hydrogen, C1-5 alkyl or C3-6 cycloalkyl; Each of R1, R2, and R3 is independently hydrogen, RA, halogen, -CN, -NO2, -OR, -SR, -NR2, -SiR3, -S(O)2R, -S(O)2NR2, -S(O)R, -C(O)R, -C(O)OR, -C(O)NR2, -C(O)N(R)OR, -C(R)2N(R)C(O)R, -C(R)2N(R)C(O)NR2, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2). , -OC(O)R, -OC(O)NR2, -OP(O)R2, -OP(O)(OR)2, -OP(O)(OR)NR2, -OP(O)(NR2)2, -N(R)C(O)OR, -N(R)C(O)R, -N(R) C(O)NR2, -N(R)S(O)2R, -N(R)P(O)R2, -N(R)P(O)(OR)2, -N(R)P(O)(OR)NR2, -N(R)P(O)(NR2)2 or -N(R)S(O)2R; each R is independently an optionally substituted group selected from hydrogen or a C1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same carbon or nitrogen optionally together with their intervening atoms form a 4-11 membered saturated or partially unsaturated monocyclic, bicyclic, bridged bicyclic or spirocyclic carbocyclic or heterocyclic ring having, in addition to the carbon or nitrogen to which the two R groups are attached, from 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur; each RA is independently an optionally substituted group selected from a C1-6 aliphatic, phenyl, 4-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; R5 is hydrogen, halo, -CN, -OR, oxo, C1-6 alkyl, -CR2OR, -OC1-6 alkyl, C1-6 haloalkyl, -OC1-6 haloalkyl or C3-6 cycloalkyl; or two R5 groups on the same carbon atom combine to form, together with the carbon atom to which the two R5 groups are attached, a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; or two R5 groups on two different carbon atoms combine together with the intervening atom connecting said two R5 groups to form a 3-7 membered saturated or partially unsaturated carbocyclic or heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; Each of rings C and D is independently a ring selected from phenyl or a 5-9 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and Each of m, n, p and q is independently 0, 1, 2, 3 or 4. or a pharma- ceutically acceptable salt thereof.

2. The formula: 【Chemistry 459】 2. The compound according to claim 1, which is a compound selected from any one of the following:

3. The formula: 【Chemistry 460】 2. The compound according to claim 1, which is a compound selected from any one of the following:

4. The formula: 【Chemistry 461】 【Chemistry 462】 2. The compound according to claim 1, which is a compound selected from any one of the following:

5. The formula: 【Chemistry 463】 2. The compound according to claim 1, which is a compound selected from any one of the following:

6. The formula: 【Chemistry 464】 【Chemistry 465】 2. The compound according to claim 1, which is a compound selected from any one of the following:

7. The formula: 【Chemistry 466】 【Chemistry 467】 【Chemistry 468】 2. The compound according to claim 1, which is a compound selected from any one of the following:

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

9. 9. The compound according to any one of claims 1 to 8, wherein m is 1 and R2 is hydrogen, RA, halogen, -CN, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R or -OC(O)NR2.

10. 10. The compound of claim 1, wherein p is 1 and R3 is hydrogen, RA, halogen, -CN, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -CFR2, -CF2R, -CF3, -CR2(OR), -CR2(NR2), -C(O)R, -C(O)OR, -C(O)NR2, -C(S)NR2, -C(O)N(R)OR, -OC(O)R or -OC(O)NR2.

11. The compound according to any one of claims 1 to 10, wherein ring C and ring D are independently selected from 5-9 membered heteroaryl rings having 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

12. 12. The compound according to any one of claims 1 to 11, selected from any one of the compounds shown in Table 1, or a pharma- ceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12 and a pharma- ceutically acceptable carrier, adjuvant or vehicle.

14. 14. The pharmaceutical composition of claim 13, further comprising an additional therapeutic agent.

15. A method for degrading IRAK4 protein kinase in a patient or biological sample, comprising administering to said patient or contacting said biological sample with a compound according to any one of claims 1 to 12 or a pharmaceutical composition thereof.

16. 13. A method of treating an IRAK4-mediated disorder, disease or condition in a patient, comprising administering to said patient a compound according to any one of claims 1 to 12 or a pharmaceutical composition thereof.

17. 17. The method of claim 16, further comprising administration of an additional therapeutic agent.

18. 13. A method of treating an autoimmune disease, an inflammatory disorder, or an immune deficiency disorder in a patient, comprising administering to said patient a compound according to any one of claims 1 to 12 or a pharmaceutical composition thereof.

19. The disease or disorder includes 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, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis. , systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, optionally including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic, non-allergic, mild, moderate, severe, bronchitis or exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, nasal sinusitis, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or reduction in disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation 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, bursitis, cervicitis, bile duct inflammation, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, small intestine colitis, epicondylitis, epididymitis, fasciitis, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schonlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis,19. The method of claim 18, which is vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, herpes dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndrome, adult-onset Still's disease, macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis, familial Mediterranean fever, NLRP12 autoinflammatory syndrome, or osteoarthritis.

20. The disease or disorder may be ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, chronic rhinosinusitis with nasal polyps (CRSwNP), hemolytic anemia, aplastic anemia, pure red cell aplasia, idiopathic thrombocytopenia, eosinophilia, hypereosinophilia, Löffler's syndrome, eosinophilic pneumonia, tropical eosinophilia, bronchopulmonary aspergillosis, polyarteritis nodosa, Churg-Strauss syndrome, eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD, psoriasis, generalized pustular psoriasis, psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis, herpetiform, scleroderma, vitiligo, 19. The method of claim 18, which is hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, 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 syndrome, adult-onset Still's disease, macrophage activation syndrome, primary and secondary hemophagocytic lymphohistiocytosis, familial Mediterranean fever, or NLRP12 autoinflammatory syndrome.

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