NZ732527B2 - Pyridazinone macrocycles as irak inhibitors and uses thereof - Google Patents

Abstract

The present invention relates to compounds of Formula (I) and pharmaceutically acceptable compositions thereof, useful as IRAK inhibitors. Ring A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; which is optionally substituted. ed.

Description

PYRIDAZINONE MACROCYCLES AS IRAK INHIBITORS AND USES THEREOF RELATED APPLICATIONS This application claims the benefit of US. Provisional ation number 62/112,793, filed on February 6, 2015, the contents of which are hereby incorporated by reference in its ty.

TECHNICAL FIELD OF THE INVENTION The present invention provides for nds of Formula (I) as IRAK tors and their use in the treatment of cancer, and other diseases related to IRAK pression, including rheumatoid arthritis, systemic lupus erythematosus or lupus nephritis.

BACKGROUND OF THE INVENTION Kinases ze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites and play key roles in all aspects of eukaryotic cell physiology. ally, protein kinases and lipid kinases participate in the signaling events which control the activation, growth, differentiation and survival of cells in response to ellular mediators or stimuli such as growth factors, nes or chemokines. In general, protein kinases are classified in two , those that preferentially phosphorylate tyrosine residues and those that preferentially phosphorylate serine and/or threonine residues.

Kinases are important therapeutic targets for the development of anti-inflammatory drugs (Cohen, 2009. Current Opinion in Cell Biology 21, 1-8), for example kinases that are involved in the orchestration of adaptive and innate immune ses. Kinase targets of particular interest are members of the IRAK family.

The interleukin—l receptor-associated kinases (IRAKs) are critically involved in the tion of intracellular signaling networks controlling inflammation ood and Li, 2008.

Cytokine 42, 1-7). IRAKs are expressed in many cell types and can mediate signals from various cell receptors including toll—like receptors (TLRs). IRAK4 is thought to be the initial protein kinase activated downstream of the interleukin-1 (IL—1) receptor and all toll-like-receptors (TLRs) except TLR3, and initiates signaling in the innate immune system via the rapid activation of IRAKl and slower activation of IRAK2. lRAKl was first identified h biochemical purification of the IL-1 dependent kinase ty that unoprecipitates with the IL-1 type 1 receptor (Cao et a1., 1996. Science 271(5252): 1128-31). IRAK2 was identified by the search of the human expressed sequence tag (EST) database for sequences homologous to IRAKI (Muzio et al., 1997. Science 278(5343): 1612-5). IRAK3 (also called IRAKM) was identified using a murine EST sequence encoding a polypeptide with significant homology to IRAKl to screen a human phytohemagglutinin—activated peripheral blood leukocyte (PBL) cDNA library (Wesche et a1., 1999. J. Biol. Chem. 274(27): 19403-10). IRAK4 was identified by database searching for ike ces and PCR of a universal cDNA library (Li et a1., 2002. Proc.

Natl. Acad. Sci. USA 99(8):5567—5572).

Mice that express a catalytically inactive mutant of IRAK4 instead of the wild-type kinase are completely resistant to septic shock triggered by several TLR agonists and are impaired in their response to IL—1. Children who lack IRAK4 activity due to a genetic defect suffer from recurring infection by pyogenic ia. It appears that ependent TLRs and IL—1Rs are vital for childhood immunity against some ic bacteria but play a redundant role in protective immunity to most infections in adults. Therefore IRAK4 inhibitors may be useful for the treatment of chronic inflammatory diseases in adults without making them too susceptible to bacterial and viral infections (Cohen, 2009. Current Opinion in Cell Biology 21, 1- 8). Potent IRAK4 inhibitors have been developed (Buckley et a1., 2008. Bioorg Med Chem Lett. 18(12):3656-60). IRAKl is essential for the TLR7 -mediated and TLR9—mediated tion of IRF7 and the production of interferon- alpha (IFN-a) suggesting that IRAKl inhibitors may be useful for the treatment of ic lupus erythematosus (SLE). IRAK2 is activated downstream of IRAK4 and plays a role in proinflammatory cytokine production. Therefore IRAK2 tors may be useful for inflammatory diseases.

SUMMARY OF THE ION In one aspect, the invention provides compounds of Formula (I): and pharmaceutically acceptable derivatives, solvates, salts, hydrates and stereoisomers thereof. [0007a] In particular the present invention es a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: Ring A is pyrazolyl; which is ally substituted; X is absent, or ; Y is an optionally substituted C1–6 tic; Z is –O-, N N N NN N N N N or ; W is CH or N; each R is independently hydrogen, C1–6 aliphatic, C3–10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms ndently selected from en, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or (followed by 3A) two R groups on the same atom are taken together with the atom to which they are attached to form a C3–10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; each R1 is independently -R, halogen, -OR, –SR, –CN, – NO2, -SO2R, -SOR, -C(O)R, -CO2R, -C(O)N(R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or –N(R)2; R2 is hydrogen; R4 is hydrogen; and n is 0, 1, 2, 3, 4, or 5; and wherein "optionally substituted" means groups that are unsubstituted or substituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with one or more substituents selected from the group consisting of: -F, -Cl, -Br, -I, deuterium, - OH, alkoxy, oxo, -NO2, -CN, CF3, -NH2, -NH alkyl, kenyl, -NH-alkynyl, -NH- cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-heterocyclic, -dialkylamino, lamino, - diheteroarylamino, -O-alkyl, -O-alkenyl, ynyl, loalkyl, -O-aryl, -O-heteroaryl, - O-heterocyclic, -C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)-carbocyclyl, -C(O)-aryl, - C(O)-heteroaryl, -C(O)-heterocyclyl, -CONH2, -CONH-alkyl, -CONH-alkenyl, -CONH- alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl, - NHC(O)-alkyl, -NHC(O)-alkenyl, )-alkynyl, -NHC(O)-carbocyclyl, -NHC(O)-aryl, - NHC(O)-heteroaryl, -NHC(O)-heterocyclyl, -CH2NH2, 2CH3, -alkyl, -alkenyl, - alkynyl, -aryl, lkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, - carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, and – methoxyethoxy. [0007b] r provided herein is a pharmaceutical ition comprising a compound of formula I or a pharmaceutically acceptable salt f, and a pharmaceutically acceptable adjuvant, r, or vehicle. (followed by 3B) In another aspect, the invention provides compounds of Formula (I) which are suitable for the treatment and/or prevention of ers related to IRAK1 and IRAK4. In another aspect, the invention provides compounds which are able to modulate, especially inhibit the activity or function of IRAK1 and IRAK4 in disease states in mammals. [0008a] In a still further aspect the t invention provides the use of a compound of formula (I), or a pharmaceutically able salt thereof, in the manufacture of a ment for ng an IRAK-mediated disorder, for example Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel Disease (Cronh’s Disease and Ulcerative Colitis), mmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated periodic syndromes, Schnitzler's syndrome, Systemic juvenile thic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, sclerosis, Celiac disease, DIRA (Deficiency of IL-1 Receptor Antagonist), Alzheimer’s disease, Parkinson’s disease, and Cancer, in a patient in need thereof.

According to another aspect the invention provides methods for the treatment and/or prevention of disorders selected from auto-immune, matory disorders, vascular diseases, neurodegenerative ers, bacterial and viral infections, allergy, asthma, pancreatitis, multi-organ failure, kidney diseases, platelet aggregation, cancer, transplantation, sperm motility, erythrocyte deficiency, graft rejection, lung injuries, respiratory diseases and ischemic conditions.

In certain embodiments, the present ion provides compounds of Formula (I) which are selective for IRAK-4 and/or IRAK-1. In certain embodiments, the present invention es nds of a (I) which are selective for IRAK-4 and IRAK-1. (followed by 3C) ED DESCRIPTION OF CERTAIN EMBODIMENTS 1. General Description of Compounds of the Invention In certain aspects, the present invention provides for inhibitors of IRAK. In some ments, such compounds include those of the formulae described , or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein. 2. Compounds and Definitions (followed by 4) Compounds of this invention e those described generally above, and are r illustrated by the classes, subclasses, and species disclosed herein. As used , the following definitions shall apply unless otherwise ted. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75‘h Ed. onally, general principles of organic try are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March’s Advanced c Chemistry", 5‘h Ed., Ed.: Smith, MB. and March, J ., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

The term "aliphatic" or "aliphatic group", as used herein, means a ht—chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of ration, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle:9 6Lcycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain l-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain l-5 tic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups n 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some ments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a clic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C1-C8 alkyl, C2-C3 alkenyl, C2—C3 alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term "lower alkyl" refers to a C1.4 straight or branched alkyl group. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and teIt-butyl.

The term "lower haloalkyl" refers to a C14 straight or branched alkyl group that is substituted with one or more halogen atoms.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, or orus (including, any oxidized form of nitrogen, sulfur, or phosphorus; the quatemized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4— dihydro—2H—pyrrolyl), NH (as in pyrrolidinyl) or NR+ (as in tituted pyrrolidinyl)).

The term urated", as used herein, means that a moiety has one or more units of unsaturation.

As used herein, the term "bivalent C1—8 (or C1—6) saturated or unsaturated, straight or branched, hydrocarbon chain", refers to bivalent alkylene, lene, and alkynylene chains that are straight or branched as defined herein.

According to the invention, bivalent groups include substitution in both directions, and when inserted between any two , (e.g., the group "-OC(O)-" or "C02" inserted O O X\JL JL/Y between X and Y), includes both 0 Y and X 0 The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., —(CH2)n—, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

The term "alkenylene" refers to a bivalent 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 a substituted tic group.

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

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and n each ring in the system ns three to seven ring members. The term "aryl" is used interchangeably with the term "aryl ring". In certain ments of the present invention, "aryl" refers to an ic ring . Exemplary aryl groups are , biphenyl, naphthyl, anthracyl and the like, which optionally includes one or more substituents. Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non—aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, thridinyl, or tetrahydronaphthyl, and the like.

The terms oaryl" and "heteroar—", used alone or as part of a larger moiety, e. g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 TC electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five atoms. The term "heteroatom" refers to nitrogen, oxygen, or , and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, t limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, nyl, indolizinyl, purinyl, yridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar—", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, liphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.

Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, nolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H—quinolizinyl, olyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3—b]—l,4—oxazin— 3(4H)—one. A heteroaryl group is optionally mono— or bicyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5— to 7—membered monocyclic or 7—lO—membered bicyclic cyclic moiety that is either saturated or partially rated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a ted or partially unsaturated ring having 0—3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen is N (as in 3,4—dihydro— rolyl), NH (as in idinyl), or +NR (as in N—substituted pyrrolidinyl), A heterocyclic ring 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 tuted. es of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, ydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, zinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", ocyclyl ring’ 7 7 , "heterocyclic group’, "heterocyclic ", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a cyclyl ring is fused to one or more aryl, heteroaryl, or liphatic rings, such as indolinyl, 3Hiindolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group is optionally mono— or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a cyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term ally unsaturated" is intended to ass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein d.

As described , certain compounds of the invention contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogens that are either | —R1 explicit or implicit from the structure (e.g., refers to at least ; and NH N/ NH NH refers to at least R1 R1 Or R1 Unless , 9 . otherwise indicated, an "optionally substituted" group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a specified group, the substituent is either the same or different at every position. Combinations of substituents oned by this 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 d when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently deuterium; halogen; —(CH2)MR°; —(CH2)040R°; -O(CH2)0_ 4R0, —O—(CH2)04C(O)OR°; —(CH2)04CH(OR°)2; —(CH2)043R°; —(CH2)MPh, which are optionally tuted with R°; —(CH2)MO(CH2)(HPh which is optionally tuted with R°; — CH=CHPh, which is ally substituted with R°; —(CH2)04O(CH2)(H—pyridyl which is optionally substituted with R0; —NOz; —CN; —N3; -(CH2)04N(RO)2; —(CH2)04N(R°)C(O)R°; — N(R°)C(S)R°; —(CH2)0—4N(R°)C(O)NR°2; —N(R°)C(S)NR°2; d4N(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)04C(O)OR°; —(CH2)04C(O)SR°; -(CH2)MC(O)OSiR°3; —(CH2)MOC(O)R°; — OC(O)(CH2)04$R°, SC(S)SRO; —(CH2)04$C(O)R°; —(CH2)04C(O)NR°2; —C(S)NR°2; —C(S)SRO; —SC(S)SR°, -(CH2)0—40C(O)NR°2; -C(O)N(OR°)R°; —C(O)C(O)R°; H2C(O)R°; — )R°; -(CH2)04$SR°; 04$(O)2R°; —(CH2)04$(O)2OR°; —(CH2)MOS(O)2R°; — S(O)2NR°2; '(CH2)0_4$(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; —(C14 straight or branched alkylene)O— N(R°)2; 0r —(C14 straight or branched alkylene)C(O)O—N(R°)2, wherein each R° is optionally tuted as defined below and is independently hydrogen, C176 aliphatic, *CHzPh, )(L 1Ph, —CH2-(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 definition above, two independent occurrences of R°, taken together with their ening atom(s), form a embered saturated, partially unsaturated, or aryl mono— or bicyclic ring having 0—4 heteroatoms ndently selected from en, oxygen, or sulfur, which is optionally substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently deuterium, halogen, —(CH2)0,2R', —(haloR'), —(CH2)(HOH, —(CH2)(}20R°, —(CH2)072CH(OR°)2; oR'), —CN, —N3, —(CH2)(%2C(O)R., —(CH2)072C(O)OH, —(CH2)d2C(O)OR°, —(CH2)d2$R', —(CH2)(LZSH, —(CH2)(LzNH2, —(CH2)&2NHR°, —(CH2)(HNR°2, —N02, —SiR°3, —OSiR°3, -C(O)SR', —(C14 straight or ed alkylene)C(O)OR', or —SSR' wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently selected from C14 aliphatic, —CH2Ph, —O(CH2)(HPh, or a n1bered 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 2S.

Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, —0(C(R*2))z,3o—, or —S(C(R*i))2,3s—, wherein each independent occurrence of R’k is selected from hydrogen, C14 aliphatic which is substituted as defined below, or an unsubstituted 5—6—n1en1bered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from en, oxygen, or . Suitable divalent substituents that are bound to Vicinal substitutable carbons of an "optionally substituted" group include: —O(CR*2)2,3O—, wherein each independent occurrence of R* is selected from en, C14 tic which is optionally substituted as defined below, or an tituted 5—6— membered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen, —R', -(haloR°), —OH, —OR', —O(haloR'), —CN, —C(O)OH, —C(O)OR°, —NH2, —NHR', —NR'2, or —NOz, n each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C14 aliphatic, —CH2Ph, —O(CH2)(HPh, or a 5—6—rnernbered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur. le substituents on a tutable en of an "optionally substituted" group e —Rl, —NRl2, —C(O)Rl, —C(O)0Rl, —C(O)C(O)Rl, —C(O)CH2C(O)Rl, —S(O)2Ri, —S(O)2NRT2, —C(S)NRT2, —C(NH)NRT2, or —N(Rl)S(O)2Rl; wherein each RT is independently hydrogen, C14 aliphatic which is optionally substituted as defined below, unsubstituted —OPh, or an unsubstituted 5—6—n1en1bered saturated, partially unsaturated, or aryl ring having 0—4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur, or, hstanding the definition above, two independent occurrences of R], taken together with their intervening atoni(s) form an unsubstituted 3—12—n1en1bered ted, lly unsaturated, or aryl rnono— or bicyclic ring having 0—4 heteroatoms independently ed from nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of RT are independently halogen, —R', —(haloR'), —OH, —OR', —O(haloR'), —CN, —C(O)OH, —C(O)OR°, —NH2, —NHR', —NR°2, or -N02, wherein each R' is unsubstituted or where preceded by "halo" is substituted only with one or more halogens, and is independently C14 aliphatic, *CHzPh, 70(CH2)(HPh, or a 576i membered ted, partially unsaturated, or aryl ring having 0—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In n embodiments, the terms "optionally substituted", "optionally substituted alkyl," "optionally substituted "optionally substituted alkenyl," nally substituted alkynyl", "optionally substituted carbocyclic,39 4:optionally substituted aryl", H optionally substituted heteroaryl," nally substituted heterocyclic," and any other optionally substituted group as used herein, refer to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the en atoms thereon with typical substituents including, but not limited to: -F, —Cl, -Br, —I, deuterium, -OH, protected hydroxy, alkoxy, oxo, thiooxo, -NOz, —CN, CF3, N3, -NH2, protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, —NH cycloalkyl, -NH - aryl, -NH -heteroaryl, -NH ocyclic, -dialkylamino, -diarylamino, -diheteroarylamino, alkyl, alkenyl, -O- l, -O- lkyl, -O-aryl, -O-heteroaryl, -O- heterocyclic, -C(O)- alkyl, -C(O)- alkenyl, -C(O)- alkynyl, -C(O)- carbocyclyl, -C(O)-aryl, -C(O)- heteroaryl, -C(O)-heterocyclyl, -CONH2, -CONH— alkyl, —CONH— alkenyl, —CONH— alkynyl, -CONH-carbocyclyl, - CONH—aryl, heteroaryl, -CONH-heterocyclyl, -OCOz- alkyl, -OCOz- alkenyl, -OC02- alkynyl, -OCOz- carbocyclyl, -OCOz-aryl, - OCOz-heteroaryl, -OCOz-heterocyclyl, —OCONH2, —OCONH— alkyl, - alkenyl, - OCONH— alkynyl, -OCONH— carbocyclyl, -OCONH— aryl, -OCONH- heteroaryl, —OCONH- heterocyclyl, -NHC(O)- alkyl, -NHC(O)- alkenyl, —NHC(O)- alkynyl, —NHC(O)- carbocyclyl, - NHC(O)—aryl, —NHC(O)-heteroaryl, —NHC(O)-heterocyclyl, —NHCOz— alkyl, —NHCOz- alkenyl, — NHCOz- alkynyl, -NHC02 - carbocyclyl, -NHC02- aryl, -NHC02- heteroaryl, -NHC02- heterocyclyl, —NHC(O)NH2, —NHC(O)NH— alkyl, —NHC(O)NH— alkenyl, —NHC(O)NH— l, — NHC(O)NH- carbocyclyl, —NHC(O)NH—aryl, —NHC(O)NH-heteroaryl, -NHC(O)NH— heterocyclyl, NHC(S)NHz, -NHC(S)NH- alkyl, -NHC(S)NH- alkenyl, -NHC(S)NH- alkynyl, - NHC(S)NH— carbocyclyl, —NHC(S)NH—aryl, —NHC(S)NH—heteroaryl, —NHC(S)NH—heterocyclyl, —NHC(NH)NH2, —NHC(NH)NH— alkyl, -NHC(NH)NH- -alkenyl, —NHC(NH)NH— alkenyl, - NHC(NH)NH- carbocyclyl, —NHC(NH)NH—aryl, H)NH-heteroaryl, —NHC(NH)NH— heterocyclyl, —NHC(NH)— alkyl, —NHC(NH)— l, —NHC(NH)— l, —NHC(NH)— carbocyclyl, —NHC(NH)-aryl, -NHC(NH)-heteroaryl, —NHC(NH)-heterocyclyl, -C(NH)NH- alkyl, -C(NH)NH- alkenyl, -C(NH)NH- alkynyl, -C(NH)NH- carbocyclyl, - H—aryl, —C(NH)NH—heteroaryl, —C(NH)NH—heterocyclyl, -S(O)- alkyl, - S(O)— l, - S(O)- alkynyl, — S(O)- carbocyclyl, - ryl, - S(O)- heteroaryl, - S(O)-heterocyclyl -SOzNH2, -SOzNH- alkyl, -SOzNH- alkenyl, -SOzNH- alkynyl, - SOzNH— carbocyclyl, —SOzNH— aryl, —SOzNH— heteroaryl, —SOzNH— heterocyclyl, -NHSOz— alkyl, -NHSOz— alkenyl, — NHSOz- alkynyl, -NHSOz— carbocyclyl, -NHSOz- aryl, -heteroaryl, -NHSOz-heterocyclyl, -CH2NH2, -CH2802CH3, , di-, or tri-alkyl silyl, -all As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound l judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are 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, l—l9, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those d from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, romic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.

Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, ate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, oate, hexanoate, odide, 27hydroxyiethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3—phenylpropionate, phosphate, pivalate, nate, stearate, ate, sulfate, tartrate, thiocyanate, pitoluenesulfonate, undecanoate, valerate salts, and the like.

Salts d from appropriate bases e alkali metal, alkaline earth metal, ammonium and N+(C14alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts e, when appropriate, nontoxic um, quaternary ammonium, and amine cations formed using rions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., omeric, reomeric, and geometric (or conformational» forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless ise stated, all tautomeric forms of the nds of the ion are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically ed atoms.

For example, compounds having the present structures including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C- or 14C—enriched carbon are within the scope of this invention. In some embodiments, the group comprises one or more deuterium atoms.

Deuterium (2H) can also be orated into a compound of the formula I for the purpose in order to manipulate the oxidative lism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic , which in turn is caused by the change in ground state energies necessary for covalent bond ion after this isotopic exchange.

Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a ion in the rate in rate—limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi— product reaction, the product distribution ratios can be altered ntially. For explanation: if deuterium is bonded to a carbon atom at a non—exchangeable position, rate differences of kM/kD = 2-7 are typical. If this rate difference is successfully applied to a com-pound of the formula I that is susceptible to oxidation, the profile of this compound in vivo can be drastically modified and result in improved pharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilled in the art is able to ze pharmacokinetic parameters while retaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative lism. In vitro liver microsomal assays tly available provide valuable information on the course of oxidative lism of this type, which in turn permits the rational design of deuterated compounds of the formula I with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic es of compounds of the formula I are thereby obtained, and can be expressed quantitatively in terms of increases in the in vivo half-life (t/2), concentration at m therapeutic effect (Cum), area under the dose response curve (AUC), and F; and in terms of reduced clearance, dose and materials costs.

As used herein, the term "modulator" is defined as a compound that binds to and /or inhibits the target with measurable affinity. In certain embodiments, a tor has an ICso and/or binding constant of less about 50 "M, less than about 1 uM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

The terms "measurable affinity" and "measurably inhibit," as used herein, means a measurable change in IRAK activity between a sample comprising a nd of the present invention, or composition thereof, and IRAK, and an equivalent sample comprising IRAK, in the absence of said compound, or ition thereof.

Combinations of substituents and variables envisioned by this invention are only those that result in the formation of stable nds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e. g., therapeutic or prophylactic administration to a subject).

The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The tion of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or ns thereof. 3. Descriytion of Exemplary Comyounds According to one aspect, the present invention provides a compound of formula I, R2 o | NJR I I—R4 /W NY O NH i n(R1 > or a pharmaceutically acceptable salt thereof, wherein: Ring A is a 5-6 ed monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; which is optionally substituted; X is , —O-, —S-, -SOz-, -SO-, -C(O)-, -COz-, -C(O)N(R)—, —OC(O)N(R)—, —NRC(O)-, —NRC(O)N(R)-, -NRSOz—, or —N(R)—; or X is (CRR)m—O-, —(CRR)mS-, mSOz-, mSO-, —(CRR)mC(O)-, —(CRR)mCOz—, —(CRR)mC(O)N(R)—, -(CRR)mOC(O)N(R)—, - NRC(O)-, -(CRR)mNRC(O)N(R)—, —(CRR)mNRSOz-, or —(CRR)mN(R)-; Y is an optionally substituted C14 aliphatic; Z is absent, a divalent C3710 aryl, a divalent 3-8 membered saturated or partially unsaturated carbocyclic ring, a divalent 3—7 ed heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a nt 5—6 membered clic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or Z is —O-, —S—, —SOz—, —SO—, , —COz—, —C(O)N(R)—, —OC(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —NRSOz-, or , N(R)-; W is CR or N; each R is independently hydrogen, C176 aliphatic, C3710 aryl, a 3—8 ed saturated or partially unsaturated carbocyclic ring, a 3—7 membered heterocylic ring having 1-4 heteroatoms independently selected from en, oxygen, or sulfur, or a 5-6 membered monocyclic aryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or two R groups on the same atom are taken together with the atom to which they are attached to form a C3710 aryl, a 3—8 membered saturated or partially unsaturated carbocyclic ring, a 3—7 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms ndently selected from nitrogen, oxygen, or sulfur; each of which is optionally tuted; each R1 is independently -R, halogen, -OR, —SR, —CN, —N02, -SOzR, -SOR, —C(O)R, -C02R, —C(O)N(R)2, —NRC(O)R, -NRC(O)N(R)2, —NRSOzR, or —N(R)2; R2 is —R, halogen, -OR, —SR, —CN, —N02, -SOzR, —SOR, -C(O)R, —C02R, —C(O)N(R)2, - NRC(O)R, -NRC(O)N(R)2, —NRSOzR, or ; R4 is -R, halogen, -OR, —SR, —CN, —NOz, -SOzR, -SOR, -C(O)R, —COzR, -C(O)N(R)2, - NRC(O)R, -NRC(O)N(R)2, -NRSOzR, or —N(R)2; each m is independently l or 2; and n is 0,1, 2, 3, 4, or 5.

In certain embodiments, Ring A is furanyl, furazanyl, imidazolidinyl, imidazolinyl, olyl, isothiazolyl, isoxazolyl, oxadiazolyl, 1,2,3—oxadiazolyl, l,2,4-oxadiazolyl;- 1,2,5— zolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H—pyrrolyl, pyrrolyl, lyl, l, thienothiazolyl, thienooxazolyl, WO 27024 thienoimidazolyl, enyl, triazinyl, 1,2,3—triazolyl, triazolyl, 1,2,5—triazolyl, or l,3,4—triazolyl; each of which is optionally substituted.

In n ments, Ring A is pyrazolyl; which is optionally substituted.

In certain embodiments, Ring A is «EAX?§A§A:N~4,0 f In certain embodiments, X is .

In certain embodiments, X is —O-, —S—, -SOz-, —SO—, -C(O)-, -COz-, -C(O)N(R)-, —OC(O)N(R)—, —NRC(O)-, )N(R)-, -NRSOz-, or —N(R)—; or X is -(CRR)m—O-, — (CRR)mS-, -(CRR)mSOz-, -(CRR)mSO-, -(CRR)mC(O)-, —(CRR)mCOz—, —(CRR)mC(O)N(R)-, —(CRR)mOC(O)N(R)—, -(CRR)mNRC(O)—, —(CRR)mNRC(O)N(R)-, —(CRR)mNRSOz-, or — (CRR)mN(R)-.

In certain embodiments, X is -C(O)-, -COz-, —C(O)N(R)-, -OC(O)N(R)-, —NRC(O)-, —NRC(O)N(R)-, or -NRSOz—; or X is -(CRR)mC(O)-, —(CRR)mC02—, —(CRR)mC(O)N(R)-, —(CRR)mOC(O)N(R)—, —(CRR)mNRC(O)-, -(CRR)mNRC(O)N(R)—, or —(CRR)mNRSOz-.

In certain embodiments, X is -C(O)N(R)-, or -(CRR)mC(O)N(R)-, wherein m is l.

O o In certain embodiments, X is In certain embodiments, Y is methylene, ethylene, ene, i—propylene, butylene, s—butylene, straight or branched pentylene, or straight or branched hexylene; each of which is optionally substituted.

In n embodiments, Y is methylene, ethylene, propylene, i—propylene, ne, or lene; each of which is optionally substituted.

In certain embodiments, Z is absent.

In certain embodiments, Z is a divalent C3710 aryl, a divalent 3-8 membered saturated or partially unsaturated carbocyclic ring, a divalent 3—7 membered heterocylic ring having 1-4 atoms independently selected from nitrogen, oxygen, or sulfur, or a divalent 5-6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or Z is —O—, —S—, —SOz—, —SO—, —C(O)—, —C02-, (R)-, -OC(O)N(R)-, -NRC(O)—, )N(R)-, -NRSOz—, or —N(R)-.

In certain embodiments, Z is a a divalent C3710 aryl or 3-7 membered heterocylic ring having 1—4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a divalent 5— 6 membered monocyclic heteroaryl ring having 1—4 heteroatoms independently ed from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or Z is —O-, —S—, -SOz—, -SO-, —OC(O)N(R)—, —NRC(O)—, —NRC(O)N(R)—, —NRSOz—, or 7N(R)—.

In certain embodiments, Z is a divalent C3710 aryl or 5—6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from en, oxygen, or , which is optionally substituted; or Z is 70—.

In certain embodiments, Z is —O-, Q/ 6N Nfi/ (5 /IN /| N/l % ‘s: "a: z: 12‘ am in In n embodiments, Z is —O-, 2) / / N—N | \ N \ A: "‘a E N In certain embodiments, W is CH.

In certain embodiments, W is N.

In certain embodiments, each of Ring A, W, X, Y, Z, R, R1, R2, R4, m, and n, is as defined above and described in embodiments, s and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound of formula La, |\ N /W [{1\| O NH or a pharmaceutically acceptable salt thereof, wherein each of Ring A, W, X, Y, Z, R, and m, is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention provides a compound of formula I-b, l | O NH ,Z or a pharmaceutically able salt thereof, wherein each of Ring A, X, Y, Z, R, and m, is as d above and described in embodiments, classes and subclasses above and herein, singly or in combination.

In certain embodiments, the present invention es a compound of formula 1-0, |\ N /N |\|]\| O NH ,Z or a pharmaceutically acceptable salt thereof, wherein each of Ring A, X, Y, Z, R, and m, is as defined above and described in embodiments, classes and subclasses above and herein, singly or in combination.

In certain embodiments, the invention es a compound selected from Table 1: Table 1 13 14 15 In some embodiments, the present invention es a compound selected from those depicted above, or a pharmaceutically acceptable salt thereof.

Various structural ions may show a atom without an attached group, l, charge, or counterion. Those of ordinary skill in the art are aware that such depictions are meant to indicate that the heteroatom is attached to hydrogen (e.g., 11/ is understood to be E/OH ).

In n ments, the compounds of the invention were synthesized in accordance with the schemes provided in the Examples below. 4. Uses, Formulation and Administration Pharmaceutically Acceptable Compositions According to another embodiment, the invention provides a composition comprising a nd of this invention or a pharmaceutically acceptable derivative thereof and a ceutically able carrier, adjuvant, or vehicle. The amount of compound in itions of this invention is such that is effective to measurably t IRAK, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this invention is such that is effective to measurably t IRAK, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition of this invention is formulated for administration to a patient in need of such composition.

The term "patient" or "subject", as used herein, means an animal, preferably a mammal, and most preferably a human.

The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non— toxic carrier, adjuvant, or vehicle that does not y the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that are used in the compositions of this invention include, but are not limited to, ion exchangers, a, 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 ate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, nyl pyrrolidone, cellulose—based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene— polyoxypropylene-block polymers, polyethylene glycol and wool fat.

A "pharmaceutically acceptable tive" means any non—toxic salt, ester, salt of an ester or other derivative of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active lite or residue thereof.

Compositions of the present invention are administered , parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.

The term "parenteral" as used herein includes subcutaneous, enous, uscular, intra— articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or enously. Sterile injectable forms of the compositions of this invention include aqueous or oleaginous suspension. These suspensions are 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 l,3-butanediol.

Among the acceptable es and solvents that are employed are water, Ringer’s on and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

For this e, any bland fixed oil employed includes synthetic mono- or di- glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural ceutically—acceptable oils, such as olive oil or castor oil, ally in their polyoxyethylated versions. These oil ons or suspensions also n a long-chain alcohol diluent or dispersant, such as carboxymethyl ose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, , or other dosage forms are also be used for the purposes of formulation.

Pharmaceutically acceptable compositions of this invention are orally administered in any orally able dosage form. ary oral dosage forms are capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents are optionally also added.

Alternatively, pharmaceutically acceptable compositions of this ion are administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non—irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

Pharmaceutically acceptable compositions of this invention are also administered topically, especially when the target of treatment includes areas or organs readily accessible by l application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable l formulations are readily prepared for each of these areas or organs.

Topical ation for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches are also used.

For topical applications, ed pharmaceutically acceptable compositions are formulated in a le ointment ning the active component suspended or ved in one or more carriers. Exemplary carriers for l administration of compounds of this aremineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active ents suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable rs include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Pharmaceutically acceptable compositions of this ion are optionally administered by nasal aerosol or inhalation. Such compositions are ed according to ques well-known in the art of pharmaceutical formulation and are prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

Most preferably, pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food.

In some embodiments, pharmaceutically able itions of this invention are administered without food. In other embodiments, pharmaceutically acceptable compositions of this invention are administered with food.

The amount of compounds of the present invention that are optionally 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. Preferably, provided compositions should be formulated so that a dosage of between 0.01 - 100 mg/kg body weight/day of the compound can be administered to a patient receiving these compositions.

It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, ing the activity of the specific compound employed, 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 ty of the particular disease being treated. The amount of a nd of the present invention in the composition will also depend upon the particular nd in the composition.

Uses of Coonunds and Pharmaceutically Accthable Compositions The t invention rmore relates to a method for treating a subject suffering from an IRAK related disorder, comprising administering to said subject an ive amount of a compound of formula I and related formulae.

The present invention preferably relates to a method, n the IRAK associated disorder is an autoimmune disorder or condition associated with an overactive immune response or cancer. The present invention furthermore relates to a method of ng a t suffering from an immunoregulatory abnomality, sing stering to said subject a compound of formula (I), and related formulae in an amount that is effective for treating said immunoregulatory abnormality.

The present invention preferably relates to a method wherein the immunoregulatory abnormality is an autoimmune or chronic inflammatory disease selected from the group consisting of: allergic diseases, ophic lateral sclerosis (ALS), systemic lupus erythematosus, c rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune is, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy and asthma.

The present invention furthermore s to a method wherein the immunoregulatory abnormality is bone marrow or organ transplant rejection or graft—versus—host disease.

The present invention furthermore relates to a method wherein the regulatory abnormality is selected from the group consisting of: transplantation of organs or tissue, graft- versus—host es brought about by transplantation, mune syndromes including rheumatoid arthritis, systemic lupus matosus, Hashimoto's ditis, multiple sclerosis, ic sclerosis, myasthenia gravis, type I es, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post—infectious autoimmune es including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, t dermatitis, eczematous dermatitis, hoeic dermatitis, lichen planus, gus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, l cornea, dystrophia epithelialis corneae, corneal a, ocular pemphigus, Mooren's ulcer, scleritis, ' opthalmopathy, Vogt—Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or inveterate asthma, late asthma and airway hyper-responsiveness, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and osis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal burns, coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture's syndrome, hemolytic—uremic syndrome, diabetic nephropathy, multiple myositis, Guillain-Barre me, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's e, pure red cell a, aplastic anemia, hypoplastic anemia, idiopathic ocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis, scleroderma, Wegener’s granuloma, Sjogren's syndrome, adiposis, eosinophilic fascitis, lesions of gingiva, periodontium, alveolar bone, substantia ossea , glomerulonephritis, male pattern alopecia or alopecia senilis by preventing epilation or providing hair ation and/or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary's syndrome, n's disease, ia—reperfusion injury of organs which occurs upon preservation, transplantation or ischemic disease, endotoxin-shock, pseudomembranous colitis, colitis caused by drug or ion, ischemic acute renal insufficiency, chronic renal insufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer, pulmonary emphysema, cataracta, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, corneal alkali burn, dermatitis erythema multiforme, linear IgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis of carcinoma and hypobaropathy, disease caused by histamine or leukotriene—C4 release, Behcet's disease, autoimmune hepatitis, y biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver is, necrosis caused by toxin, viral hepatitis, shock, or anoxia, s hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure, ant hepatic failure, late-onset hepatic e, —on-chronic" liver failure, tation of chemotherapeutic effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile ia, parkison diseases,trauma, and chronic bacterial infection.

In certain embodiments, disorders associated with IRAK are selected from Rheumatoid Arthritis, Psoriatic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, sing Spondylitis, Osteoporosis, Systemic sclerosis, le Sclerosis, Psoriasis, Type I diabetes, Type II diabetes, Inflammatory Bowel e (Cronh’s Disease and Ulcerative Colitis), Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin— associated periodic syndromes, zler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman’s disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, DIRA ( Deficiency of IL-l Receptor Antagonist), Alzheimer’s disease, Parkinson’s disease, and Cancer.

In certain embodiments, the cancer is selected from carcinoma, lymphoma, blastoma ding medulloblastoma and retinoblastoma), a (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including oid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More ular examples of such s include squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small—cell lung cancer (SCLC), non—small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer ding metastatic breast cancer), colon , rectal cancer, ctal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal , prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, testicular , esophageal cancer, tumors of the biliary tract, as well as head and neck cancer.

In certain embodiments, the cancer is brain, lung, colon, epidermoid, squamous cell, bladder, gastric, pancreatic, breast, head, neck, renal, kidney, liver, ovarian, te, colorectal, uterine, rectal, oesophageal, testicular, gynecological, thyroid , melanoma, hematologic malignancies such as acute myelogenous leukemia, multiple myeloma, chronic myelogneous leukemia, myeloid cell leukemia, glioma, Kaposi’s sarcoma, or any other type of solid or liquid tumors. In some embodiments, the cancer is metastatic . In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is colon cancer.

In various embodiments, compounds of formula (I), and related formulae exhibit a ICSO for the binding to IRAK of less than about 5 uM, preferably less than about 1 HM and even more preferably less than about 0.100 HM.

The method of the invention can be performed either in-vitro or o. The susceptibility of a particular cell to treatment with the compounds according to the invention can be ularly ined by in-vitro tests, whether in the course of research or clinical application. Typically, a culture of the cell is combined with a compound according to the invention at various concentrations for a period of time which is sufficient to allow the active agents to inhibit IRAK activity, usually between about one hour and one week. In—vitro treatment can be carried out using cultivated cells from a biopsy sample or cell line.

The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; s; horses, cows, dogs, cats, etc. Animal models are of interest for experimental igations, providing a model for treatment of human disease.

For identification of a signal transduction y and for detection of interactions between various signal transduction pathways, various ists have developed suitable models or model systems, for example cell culture models and models of transgenic animals. For the determination of certain stages in the signal transduction cascade, interacting compounds can be utilized in order to modulate the . The compounds according to the invention can also be used as reagents for testing IRAK-dependent signal uction pathways in animals and/or cell culture models or in the clinical es mentioned in this application.

Moreover, the uent teaching of the present specification concerning the use of the compounds according to formula (I) and its derivatives for the production of a medicament for the lactic or therapeutic treatment and/or monitoring is considered as valid and applicable without restrictions to the use of the compound for the inhibition of IRAK activity if expedient.

The invention also relates to the use of compounds ing to formula (1) and/or physiologically acceptable salts thereof for the prophylactic or therapeutic ent and/or monitoring of diseases that are caused, mediated and/or propagated by IRAK activity.

Furthermore, the invention relates to the use of compounds ing to formula (1) and/or physiologically acceptable salts thereof for the production of a medicament for the prophylactic or therapeutic treatment and/or monitoring of es that are caused, mediated and/or propagated by IRAK activity. In certain embodiments, the invention provides the use of a compound according to formula I or physiologically able salts thereof, for the production of a medicament for the prophylactic or therapeutic ent of a IRAK -mediated disorder.

Compounds of formula (1) and/or a physiologically acceptable salt thereof can furthermore be employed as ediate for the preparation of further medicament active ingredients. The medicament is preferably prepared in a non-chemical manner, e. g. by combining the active ingredient with at least one solid, fluid and/or semi—fluid carrier or excipient, and optionally in conjunction with a single or more other active nces in an appropriate dosage form.

The compounds of formula (1) according to the invention can be administered before or following an onset of disease once or several times acting as therapy. The aforementioned compounds and medical products of the inventive use are particularly used for the therapeutic treatment. A therapeutically relevant effect relieves to some extent one or more symptoms of a disorder, or returns to normality, either partially or completely, one or more physiological or biochemical parameters associated with or causative of a e or pathological condition.

Monitoring is considered as a kind of treatment provided that the compounds are administered in distinct intervals, e.g. in order to boost the response and eradicate the ens and/or symptoms of the disease completely. Either the cal compound or different nds can be applied. The methods of the ion can also be used to reduce the likelihood of developing a disorder or even prevent the initiation of disorders associated with IRAK activity in advance or to treat the g and continuing symptoms.

] In the meaning of the invention, prophylactic ent is advisable if the subject possesses any ditions for the aforementioned physiological or pathological conditions, such as a familial disposition, a genetic defect, or a usly incurred disease.

The invention furthermore relates to a medicament comprising at least one compound according to the invention and/or ceutically usable tives, salts, solvates and stereoisomers thereof, including mixtures thereof in all ratios. In n embodiments, the invention relates to a medicament comprising at least one compound according to the invention and/or physiologically acceptable salts thereof.

A "medicament" in the meaning of the invention is any agent in the field of medicine, which comprises one or more compounds of formula (I) or preparations thereof (e.g. a pharmaceutical composition or pharmaceutical formulation) and can be used in prophylaxis, therapy, follow-up or aftercare of patients who suffer from diseases, which are associated with IRAK activity, in such a way that a pathogenic modification of their overall ion or of the condition of particular regions of the organism could establish at least temporarily.

In various embodiments, the active ingredient may be administered alone or in combination with other treatments. A synergistic effect may be achieved by using more than one compound in the pharmaceutical composition, i.e. the compound of formula (I) is combined with at least another agent as active ingredient, which is either r compound of formula (I) or a compound of different structural scaffold. The active ingredients can be used either simultaneously or sequentially.

Included herein are methods of treatment in which at least one chemical entity provided herein is administered in combination with an nflammatory agent. Anti— atory agents include but are not limited to NSAIDs, non-specific and COX-2 ic cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants and methotrexate. es of NSAIDs include, but are not limited to, ibuprofen, rofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, ac, fenoprofen calcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium, and hydroxychloroquine.

Examples of NSAIDs also include COX—2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib dnd/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include by are not limited to acetylsalicylic acid or aspirin, sodium salicylate, and e and magnesium salicylates.

The nflammatory agent may also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium ate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compound such as gold sodium thiomalate or auranofin.

The invention also es embodiments in which the anti-inflammatory agent is a metabolic inhibitor such as a dihydrofolate reductase inhibitor, such as methotrexate or a dihydroorotate dehydrogenase inhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which at least one anti—inflammatory compound is an anti—monoclonal antibody (such as umab or pexelizumab), a TNF antagonist, such as entanercept, or infliximab, which is an anti-TNF alpha monoclonal antibody.

Still other embodiments of the invention pertain to combinations in which at least one active agent is an immunosuppressant compound such as an immunosuppressant nd chosen from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

The disclosed compounds of the formula I can be administered in ation with other known eutic agents, including anticancer agents. As used here, the term "anticancer agent" relates to any agent which is administered to a t with cancer for the purposes of treating the cancer.

The anti—cancer treatment defined above may be applied as a monotherapy or may involve, in addition to the herein disclosed compounds of formula 1, conventional surgery or radiotherapy or medicinal therapy. Such medicinal therapy, e.g. a chemotherapy or a targeted therapy, may include one or more, but preferably one, of the following umor agents: Alkylating : such as altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, ine, ranimustine, temozolomide, thiotepa, treosulfan, mechloretamine, uone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, TH—3024, VAL—0834; um Compounds: such as carboplatin, tin, eptaplatin, miriplatine hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin; DNA ng agents: such as amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine1’3; Topoisomerase Inhibitors: such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, belotecan, inium e, voreloxin; Microtubule modifiers: such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel; Antimetabolites: such as asparaginase3 , azacitidine, calcium levofolinate, capecitabine, cladribine, cytarabine, enocitabine, idine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; ridine, elacytarabine, raltitrexed, tabine, tegafur2’3, trimetrexate; Anticancer antibiotics: such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, ozocin, valrubicin, zinostatin, cin, daunurobicin, ycin; aclarubicin, peplomycin, pirarubicin; Hormones/Antagonists: such as abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, lstilbestrol; acolbifene, danazol, deslorelin, stanol, orteronel, enzalutamide1’3; Aromatase inhibitors: such as aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane; Small molecule kinase inhibitors: such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, nib, fenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, aXitinib; afatinib, alisertib, dabrafenib, dacomitinib, clib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tipifarnib, tivantinib, tivozanib, inib, pimasertib, brivanib alaninate, cediranib, apatinib4, cabozantinib S-malate1’3, ibrutinib1’3, icotinib4, buparlisibz, cipatinib4, cobimetinib1’3, idelalisib1’3, fedratinibl, XL-6474; ensitizers: such as methoxsalen3; porfimer , talaporfin, temoporfin; Antibodies: such as alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab2’3; catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, mumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, mumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, mab, dalotuzumab1’2’3, onartuzumab1’3, racotumomabl, tabalumab1’3, EMD-5257974, nivolumab1’3; Cytokines: such as aldesleukin, interferon alfaz, interferon alfa2a3, interferon alfa2b2’3; celmoleukin, tasonermin, teceleukin, oprelvekin1’3, recombinant interferon beta- la4; Drug Conjugates: such as denileukin diftitox, ibritumomab an, iobenguane 1123, prednimustine, trastuzumab emtansine, ustine, gemtuzumab, ozogamicin, cept; cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab1’3, Vintafolide1’3; Vaccines: such as sipuleucelg; Vitespen3, emepepimut—S3, oncoVAX4, rindopepimut3, troVaXA, MGN—16014, MGN—17034; and Miscellaneous: alitretinoin, bexarotene, omib, everolimus, ibandronic acid, imiquimod, domide, lentinan, metirosine, mifamurtide, pamidronic acid, pegaspargase, tatin, sipuleucel3, sizofiran, tamibarotene, temsirolimus, thalidomide, oin, Vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxil, iniparib, ixazomib, lonidamine, zole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, stat, trabedersen, ubenimex, valspodar, gendicine4, picibanil4, reolysin4 , retaspimycin hydrochloride", trebananib2’3, virulizin4, carfilzomib1’3, endostatin4, immucothel4, belinostat3, MGN—l7034. (1 Prop. INN (Proposed International Nonproprietary Name); 2Rec. INN mended International Nonproprietary Names); 3 USAN (United States Adopted Name); 4 no INN).

] In another aspect, the ion provides for a kit consisting of separate packs of an effective amount of a compound according to the invention and/or pharmaceutically acceptable salts, derivatives, solvates and isomers thereof, including mixtures f in all ratios, and optionally, an effective amount of a further active ingredient. The kit comprises suitable ners, such as boxes, individual bottles, bags or ampoules, The kit may, for example, comprise separate ampoules, each containing an effective amount of a compound ing to the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios, and an effective amount of a further active ingredient in dissolved or lyophilized form.

As used , the terms "treatment," "treat," and "treating" refer to reversing, ating, ng the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment is administered after one or more symptoms have ped. In other embodiments, treatment is administered in the absence of symptoms. For example, treatment is administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a y of symptoms and/or in light of genetic or other susceptibility factors). Treatment is also continued after symptoms have resolved, for example to prevent or delay their recurrence.

The compounds and compositions, according to the method of the present invention, are administered using any amount and any route of administration effective for treating or lessening the severity of a disorder provided above. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the ty of the ion, the particular agent, its mode of administration, and the like.

Compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression "dosage unit form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be tood, however, that the total daily usage of the compounds and itions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the er being treated and the ty of the disorder; the activity of the specific compound ed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of ion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

Pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, erally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, nts, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the nds of the invention are administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 100 mg/kg and preferably from about 1 mg/kg to about 50 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired eutic effect.

In certain embodiments, a therapeutically effective amount of a compound of the formula (I), and related formulae and of the other active ingredient depends on a number of factors, including, for example, the age and weight of the animal, the precise disease condition which requires treatment, and its severity, the nature of the formulation and the method of stration, and is ultimately determined by the treating doctor or vet. However, an effective amount of a compound is generally in the range from 0.1 to 100 mg/kg of body weight of the recipient (mammal) per day and particularly typically in the range from 1 to 10 mg/kg of body weight per day. Thus, the actual amount per day for an adult mammal ng 70 kg is usually between 70 and 700 mg, where this amount can be administered as an individual dose per day or usually in a series of part-doses (such as, for example, two, three, four, five or six) per day, so that the total daily dose is the same. An effective amount of a salt or solvate or of a physiologically functional derivative thereof can be determined as the fraction of the effective amount of the compound per se.

In n embodiments, the pharmaceutical formulations can be administered in the form of dosage units, which comprise a predetermined amount of active ingredient per dosage unit. Such a unit can comprise, for example, 0.5 mg to l g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of a compound according to the invention, depending on the disease condition treated, the method of administration and the age, weight and condition of the patient, or pharmaceutical formulations can be stered in the form of dosage units which comprise a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those which comprise a daily dose or part—dose, as indicated above, or a corresponding fraction thereof of an active ingredient. Furthermore, ceutical formulations of this type can be prepared using a process, which is lly known in the pharmaceutical art.

Liquid dosage forms for oral administration e, but are not limited to, pharmaceutically able emulsions, microemulsions, ons, suspensions, syrups and s. In addition to the active nds, the liquid dosage forms optionally contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, ene glycol, tylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures f. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions are formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation are also a sterile injectable solution, suspension or emulsion in a ic parenterally able diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this e any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the ation of injectables. lnjectable 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 e injectable medium prior to use.

In order to prolong the effect of a compound of the present invention, it is often ble to slow the absorption of the compound from subcutaneous or intramuscular ion.

This is lished by the use of a liquid suspension of lline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered nd form is accomplished by dissolving or suspending the compound in an oil vehicle. lnjectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of compound to r and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers e poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also ed by entrapping the compound in liposomes or mulsions that are compatible with body tissues.

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

Solid dosage forms for oral administration include capsules, s, 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 ate and/or a) fillers or extenders such as starches, lactose, sucrose, e, mannitol, and silicic acid, b) binders such as, for example, ymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and , c) humectants such as glycerol, (1) disintegrating agents such as agar——agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, WO 27024 cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) ants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form also optionally comprises buffering agents.

Solid compositions of a similar type are also employed as fillers in soft and hard— filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical ating art. They optionally n opacifying agents and can also be of a composition that they release the active ient(s) 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 r type are also employed as fillers in soft and hard—filled gelatin capsules using such excipients as e or milk sugar as well as high molecular weight polethylene glycols and the like.

] The active compounds can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, s, capsules, pills, and granules can be prepared with gs and shells such as enteric coatings, e controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms also se, as is normal ce, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms optionally also comprise buffering agents. They optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, ally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or s. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention.

Additionally, the present invention contemplates the use of transdermal patches, Which have the added advantage of providing controlled ry of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. tion enhancers can also be used to increase the flux of the compound across the skin. The rate can be lled by either providing a rate controlling membrane or by dispersing the compound in a r matrix or gel. ing to one embodiment, the ion relates to a method of inhibiting IRAK activity in a biological sample comprising the step of ting said biological sample with a compound of this invention, or a composition comprising said compound.

According to r embodiment, the invention relates to a method of inhibiting IRAK, or a mutant thereof, activity in a biological sample in a positive manner, comprising the step of contacting said biological sample with a compound of this invention, or a composition sing said compound.

The compounds of the invention are useful in-vitro as unique tools for understanding the biological role of IRAK, including the evaluation of the many factors thought to influence, and be influenced by, the production of IRAK and the ction of IRAK. The present compounds are also useful in the development of other compounds that interact with IRAK since the present compounds provide important structure-activity relationship (SAR) information that facilitate that development. Compounds of the t invention that bind to IRAK can be used as reagents for detecting IRAK in living cells, fixed cells, in biological fluids, in tissue nates, in purified, natural biological materials, etc. For example, by labeling such compounds, one can identify cells expressing IRAK. In addition, based on their ability to bind IRAK, compounds of the present invention can be used in in—situ staining, FACS (fluorescence— activated cell sorting), sodium dodecyl e polyacrylamide gel electrophoresis (SDS-PAGE), ELISA (enzyme-linked immunoadsorptive assay), etc., enzyme purification, or in purifying cells expressing IRAK inside permeabilized cells.The compounds of the invention can also be utilized as commercial research reagents for various medical research and diagnostic uses. Such uses can include but are not d to: use as a calibration standard for quantifying the activities of ate IRAK inhibitors in a variety of functional assays; use as blocking reagents in random nd screening, i.e. in looking for new families of IRAK ligands, the compounds can be used to block recovery of the presently claimed IRAK compounds; use in the co—crystallization with IRAK enzyme, i.e. the compounds of the present invention will allow formation of ls of the compound bound to IRAK, enabling the determination of enzyme/compound structure by x—ray llography; other research and diagnostic applications, wherein IRAK is preferably activated or such activation is conveniently calibrated t a known quantity of an IRAK inhibitor, etc.; use in assays as probes for determining the expression of IRAK in cells; and developing assays for detecting compounds which bind to the same site as the IRAK binding ligands.

The compounds of the invention can be d either themselves and/or in combination with al measurements for stics of treatment effectiveness.

Pharmaceutical compositions containing said compounds and the use of said compounds to treat IRAK-mediated conditions is a promising, novel approach for a broad spectrum of therapies causing a direct and immediate improvement in the state of health, whether in human or in . The orally bioavailable and active new chemical entities of the invention improve convenience for patients and compliance for physicians.

The compounds of formula (1), their salts, isomers, tautomers, enantiomeric forms, diastereomers, tes, derivatives, prodrugs and/or lites are terized by a high specificity and stability, low manufacturing costs and convenient handling. These features form the basis for a reproducible action, wherein the lack of cross-reactivity is ed, and for a reliable and safe interaction with the target structure.

The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Modulation of IRAK, or a mutant thereof, activity in a ical sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, ical specimen storage, and biological assays.

EXEMPLIFICATION As depicted in the Examples below, in n exemplary embodiments, compounds are prepared according to the following general procedures. It will be appreciated that, although the general methods depict the synthesis of certain compounds of the present invention, the following general methods, and other methods known to one of ordinary skill in the art, can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

The symbols and conventions used in the ing descriptions of processes, schemes, and examples are tent with those used in the porary scientific literature, for example, the Journal of the American Chemical Society or the l of Biological Chemistry.

Unless otherwise indicated, all temperatures are expressed in 0C (degrees Centigrade).

All reactions were conducted at room temperature unless ise noted. All compounds of the present invention were synthesiszed by processes ped by the ors.

Compound numbers utilized in the Examples below correspond to compound numbers set forth supra.

The ing abbreviations refer to the iations used below: Ac (acetyl), BlNAP (2,2’—bis(disphenylphosphino)-l,l’-binaphthalene), dba (dibenzylidene acetone), Bu ), tBu (tert-Butyl), DCE (dichloroethane), DCM (Dichloromethane), 6 (chemical shift), DIEA (di-isopropyl ethylamine), DMA (dimethyl acetamide), DMSO (Dimethyl Sulfoxide), DMF (N,N—Dimethylformamide), Dppf (l,l’-bis (diphenyl phosphine ferrocene)), EtOAc (Ethyl e), EtOH (Ethanol), eq (equivalent), g (gram), cHex hexane), HATU (N-[(Dimethylamino)(3H-[ l ,2,3]triazolo[4,5-b]pyridin yloxy)methylene]—N—methylmethanaminiumhexafluoro phosphate), HPLC (High Performance Liquid Chromatography), h , LDA (lithium diisopropyl amine), LiHMDS (lithium bis(trimethylsilyl)amide), MHz (Megahertz), MeOH (Methanol), min (minute), mL (milliliter), mmol (millimole), mM (millimolar), mp (melting point), MS (Mass Spectrometry), MW (microwave ), NMR (Nuclear Magnetic Resonance), O/N (overnight), PBS (Phosphate Buffered Saline), RT (room temperature), TEA (Triethyl amine), TFA (Trifluoroacetic acid), THF (Tetrahydrofuran), TLC (Thin Layer tography).

In general, the compounds according to Formula (I) and related formulae of this invention can be prepared from readily available starting materials. If such starting materials are not commercially ble, they may be prepared by standard synthetic techniques. In general, the sis pathways for any individual compound of Formula (I) and related formulae will depend on the specific substituents of each molecule, such factors being appreciated by those of ordinary skilled in the art. The following l methods and procedures described hereinafter in the examples may be employed to prepare compounds of Formula (I) and related formulae.

Reaction conditions ed in the following schemes, such as temperatures, solvents, or co- reagents, are given as examples only and are not restrictive. It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents etc.) are given, other experimental conditions can also be used unless otherwise stated.

Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine sation procedures. For all the protection and ection methods, see Philip J. Kocienski, in "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994 and, Theodora W. Greene and Peter G. M. Wuts in ctive Groups in Organic Synthesis", Wiley lnterscience, 3r01 Edition 1999. 1H NMR was recorded on a Bruker 400 MHz spectrometer or Varian 500 MHz spectrometer, using al signal of deuterated solvent as internal reference. Chemical shifts (5) are reported in ppm relative to the residual t signal (5 = 2.49 ppm for 1H NMR in DMSO-d6). 1H NMR data are reported as follows: chemical shift plicity, ng constants, and number of hydrogens). Multiplicity is abbreviated as follows: s et), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad).

LCMS-Analysis was performed under the following conditions: Method : A: 0.1 % formic acid in H20, B: ACN: Runtime: 6.5 min Flow Rate: 1.0 mL/min Gradient: 5-95% B in 4.5 min, wavelength 254 and 215 nM.

Column: Waters Sunfire C18, 3.0x50mm, 3.5um, +ve mode Mass Scan: 100-900 Da.

Example 1 Scheme 1 E‘r/\/\N/ Wb N OH H N ' I N | N‘ N/ 052003, DMF \ THFH2,0 40 so I I MeO O N \ —> 0 o 100 00, 1h Cs23,00 DMF rt ON OK—>o HN \ boo/NH \boc boc 1a 1b 1c 0 O MZMHN l‘ | I '1" I '1" | LiOH N\ N\ HCI MeOH THFH20 4000 BOP, DMF , O —> O —b HN O HN O BOP-0| 0 o DIEA DCM / / / / Me Me NH2 /N — _N 0 NH2 N N LP /N H 1d 1e 1f 1 Synthesis of compound 1a: carbamic acid tert-but l ester: A reaction mixture of Pyridazine-3,6-diol (2000.0 mg; 17.84 mmol; 1.0 eq.), cesium carbonate (5813.7 mg; 17.84 mmol; 1.0 eq.) and 3—bromo-propyl— carbamic acid tert-butyl ester (4248.8 mg; 17.84 mmol; 1.0 eq.) in DMF (20ml) was stirred at 100 °C for 1h. After cooling to rt, the reaction mixture was poured into water, and extracted with ethyl acetate. The combined c phases were washed with brine twice, dried and trated to yield the crude, which was then treated with small amount of ethyl acetate. The collected white solid was the pure title compound (3200.0 mg; yield: 67%). LC-MS (M+H)+: Synthesis of compound 1b: 3—|3—13—tert—Butoxycarbonylamino-propoxygoxo—6H— pyridazin-l-ylmethyl -benzoic acid methyl ester: A reaction mixture of [3-(6-oxo-l,6-dihydro- zin—3—yloxy)—propyl]—carbamic acid tert—butyl ester (2000.0 mg; 7.43 mmol; 1.00eq.), cesium ate (2419.7 mg; 7.43 mmol; 1.0 eq.) and 3—bromomethyl-benzoic acid methyl ester (1701.2 mg; 7.43 mmol; 1.0 eq.) in DMF (10 ml) was d at It overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried and concentrated to give the crude, which was purified by prep HPLC (30-70% ACN in water containing 0.1% NH4OH) to afford the pure title compound as colorless stick oil: (2680.0 mg; yield: 86%). LC—MS (M—Boc+H) +: 318.

WO 27024 Synthesis of compound 1c: 3—|3—13—tert—Butoxycarbonylamino—propoxy2—6—oxo—6H— pyridazin-l-ylmethyl -benzoic acid lithium salt: A mixture of 3—[3—(3-tert— Butoxycarbonylamino-propoxy)oxo-6H-pyridazinylmethyl]-benzoic acid methyl ester (1580.0 mg; 3.78 mmol; 1.0 eq.) and lithium hydroxide monohydrate (317.6 mg; 7.57 mmol; 2.0 eq.) in THF (5 ml) and water (5 ml) was stirred at 40°C for 2 hr. After cooling to rt, the reaction mixture was concentrated to dryness to afford the title compound as an off-white solid (1600.0 mg; Yield: 103%). LC—MS (M+Na) +: 426.

Synthesis of compound 1d: 4-i 3—| 3—13—tert—Butoxycarbonylamino-propoxy2oxo— 6H- ridazin-l- lmeth l-benzo lamino meth l-1H- razolecarbox lic acid meth lester: To a stirred solution of 3—[3—(3—tert—Butoxycarbonylamino—propoxy)—6—oxo—6H—pyridazin—1— ylmethyl]—benzoic acid (300.0 mg; 0.74 mmol; 1.0 eq.) and 4-aminomethyl-1H-pyrazole-3— carboxylic acid methyl ester (230.8 mg; 1.49 mmol; 2.0 eq.) in DCM (3 ml), was added ethyldiisopropy—amine (0.26 ml; 1.49 mmol; 2.0 eq.), and then oxo—3—oxazolidinyl) phosphinic chloride (397.5 mg; 1.56 mmol; 2.1 eq.). The resulting mixture was stirred at rt for 3h. The reaction mixture was diluted with ethyl acetate and washed with brine, citric acid solution and brine, dried and concentrated to give the title compound as an off-white solid (400 mg: Yield: 100%), which was used for the next step without further purification. LC-MS (M+Na) +2 563. sis of nd 1e: 4- 3- 3- 3-Amino- ro ox oxo-6H- ridazin-l- ylmethyll—benzoylamino[—1—methyl—1H—pyrazolecarboxylic acid methyl ester: To a stirred solution of 4-{3-[3-(3-tert-Butoxycarbonylamino-propoxy)oxo-6H-pyridazinylmethyl]- benzoylamino}methyl-1H-pyrazolecarboxylic acid methyl ester (520.0 mg; 0.96 mmol; 1.0 eq.) in methanol (3 ml), was added the solution of 4 M HCl in dioxane (1.92 ml; 7.7 mmol; 8.0 eq.). The mixture was stirred at RT for 3 hr. The reaction mixture was concentrated to yield a yellow solid residue. The residue was dissolved in 5 ml of water, was neutralized with sodium carbonate (305.8 mg; 2.89 mmol; 3.0 eq.) to pH > 9, which was extracted with DCM twice. The combined organic layers were washed with brine, dried and concentrated to s to afford the title product (360.0 mg; Yield: 85%) as light yellow solid. LC-MS (M+H) +: 441. sis of compound 1f: 4— 3- 3- 3—Amino— ro ox —6—oxo-6H— ridazin-l— lmeth l —benzo lamino —1—meth l—lH— carbox lic acid lithium salt: A e of 4— { 3-[3-(3-Amino-propoxy)oxo-6H-pyridazinylmethyl]-benzoylamino}methyl-1H- pyrazole—3—carboxylic acid methyl ester (360.0 mg; 0.82 mmol; 1.00 eq.) and lithium hydroxide monohydrate (68.6 mg; 1.63 mmol; 2.0 eq.) in THF (2ml) and water (2ml) was d at 40 0C for 2 hr. The reaction mixture was concentrated to dryness to afford the title compound as an off- white solid (260.0 mg; Yield: 73%). LC—MS (M+H) +: 427.

Synthesis of compound 1: 12-meth loxa-1 9 12 13 16 25-hexaazatetrac clo 19.3.1.13’7.01°’" sa-3 5 7 26 10 13 2 22-heptaene-8 15,24-trione A mixture of 4—{3-[3-(3-Amino—propoxy)—6—oxo-6H-pyridazin—1—ylmethyl]—benzoylamino}-1— methyl-1H-pyrazolecarboxylic acid lithium salt (220.0 mg; 0.51 mmol; 1.0 eq.), (benzotriazolyloxy)-tris(dimethylamino)-phosphonium hexafluorophosphate (278.41 mg; 0.61 mmol; 1.2 eq.) and ethyldiisopropylamine (0.13 ml; 0.76 mmol; 1.5 eq.) in DMF (10 ml) was stirred at rt ght. The reaction mixture was concentrated and the residue was purified by prep HPLC (20—60% ACN in water containing 0.1% NH4OH) to yield the title compound as a white solid (58.0 mg; yield: 28%). LC-MS (M+H) +: 409. 1H NMR (400 MHz, DMSO-d6) 10.46 (s, 1H), 8.75 (t, J: 6.3 Hz, 1H), 8.22 (d, J: 1.1 Hz, 1H), 7.95 (s, 1H), 7.87 — 7.80 (m, 1H), 7.71 — 7.63 (m, 1H), 7.55 (t, J: 7.7 Hz, 1H), 7.26 (dd, J = 9.8, 1.2 Hz, 1H), 6.93 (dd, J: 9.8, 1.2 Hz, 1H), 5.10 (s, 2H), 4.30 (t, J: 6.3 Hz, 2H), 3.92 (s, 3H), 3.46 (m, 2H), 1.91 (m, 2H).

Example 2 Scheme 2 1) NaH, DMF OH 0‘ Br [1‘ 1 I \ N/ N‘ boc~N I\ I H_,‘ O OH / DIPEA ACN rl K2300 Pd(32PBut) o o /, / CI I N—N N—N 2) LIOH Dioxane-H 2,O 100C THF-H2O, 40 0C /‘/ boc~N 2b 2c I | LiOH \ BOP,D|EA HCI MeOHH THF-HO 40 QCHN DMF \\ ognuN \ HN O / BOP DIEA MO \ o DMF Mo ‘2" MO/ N’N / / /N- /fi>—< ZNH2 N-N O N—N A / LI4 2 / H [NH NH2 2d 2e 2f 2 Synthesis of compound 23: 3— 3-Chlorooxo-6H— acid methyl ester: The reaction mixture of 6-chloro—2H-pyridazin—3—one 0 mg; 51.43 mmol; 1.0 eq.), 3-bromomethyl-benzoic acid methyl ester (12145.0 mg; 51.43 mmol; 1.0 eq.) and DIEA (12.8 ml; 77.14 mmol; 1.5 eq.) in MeCN (40 ml) was stirred at rt overnight. The precipitate was filtered and washed with ACN to yield the title compound as an ite solid (13000.0 mg; yield: 91%). LC-MS (M+H)+: 279. sis of compound 2b: 3— 6—Oxo 1H— razol 1 —6H— ridazin-l- lmeth l — benzoic acid methyl esterzTo a degassed mixture of 3—(3-chloro—6—oxo-6H-pyridazin—1— ylmethyl)-benzoic acid methyl ester (500.0 mg; 1.79 mmol; 1.0 eq.), 1-Boc-pyrazoleboronic acid pinacol ester (598.4 mg; 1.97 mmol; 1.1 eq.), potassium carbonate (272.7 mg; 1.97 mmol; 1.1 eq.) in 10 ml of dioxane and 1 ml of water, was added palladium tritert—butylphosphane (27.51 mg; 0.05 mmol; 0.03 eq.). The on mixture was stirred at 100 °C overnight. The off- white precipitate formed in the reaction mixture was filtered and washed with water to yield the title compound (400 mg, yield: 72%). LC-MS (M+H)+: 311.

Synthesis of compound 2c: 3- 3- 1- 2-tert-Butox carbon lamino-eth l-1H- razol- 4-yl]—6—oxo-6H-pyridazin—1—ylmethyl}—benzoic acid: To a solution of 3—[6—oxo(1H—pyrazol—4— yl)—6H—pyridazin—1—ylmethyl]—benzoic acid methyl ester (230.0 mg; 0.74 mmol; 1.0 eq.) in DMF (4 ml), was added sodium hydride (32.61 mg; 0.82 mmol; 1.1 eq.). After stirring at rt for 15 min, 2-(Boc—amino) ethylbromide (199.3 mg; 0.89 mmol; 1.2 eq.) was added. The ing mixture was stirred at RT overnight. The reaction e was poured into water, acidified to pH 2 with citric acid and then extracted with ethyl e. The combined c phased was concentrated and then ted to lithium hydroxide monohydrate (62.2 mg; 1.48 mmol; 2.0 eq.) in THF (2ml) and water (2m1). The resulting mixture was stirred at 40 0C for 2h. The reaction mixture was 10% ied with citric acid to pH 2 and extracted with ethyl acetate twice. The combined combined organic phases were washed with samll amount of brine and concentrated to yield the title compound as white solid (325 mg; yield: 100%). LC—MS (M+H) +: 440.

Synthesis of compound 2d: 4—13—{3—l1—12—tert—Butoxycarbonylamino-ethyl)—1H— razol loxo-6H- n-l- lmeth l -benzo lamino meth l-1H- razole carboxylic acid methyl ester: A mixtue of 3—{3—[1—(2—tert—Butoxycarbonylamino—ethyl)—1H— pyrazolyl]oxo—6H—pyridazin—1-ylmethyl}—benzoic acid (325.00 mg; 0.74 mmol; 1.0 eq.), (benzotriazolyloxy)tris(dimethylamino)phosphonium hexafluorophosphate (375.6 mg; 0.89 mmol; 1.2 eq.) and ethyldiisopropylamine (0.20 ml; 1.11 mmol; 1.5 eq.) in DMF (4 ml) was stirred at rt for 4h. The reaction mixture was poured into water and extracted with ethyl acetate, washed with brine and concentrated to give the crude title compound, which was used for next step without further purification. (400 mg; Yield: 69%). LC-MS (M-Boc+H) +: 477.

Synthesis of compound 2e: 4— 3— 3— 1— 2—Amino-eth 1 -1H- a stirred solution of crude 4-(3-{3-[1-(2-tert-Butoxycarbonylamino-ethyl)-1H-pyrazolyl] oxo—6H—pyridazin—1—ylmethyl}—benzoylamino)—1—methyl-1H-pyrazole—3-carboxylic acid methyl ester (400.00 mg; 0.69 mmol; 1.0 eq.) in methanol (2 ml), was added 4.0M HCl in dioxane (1.73 ml; 6.94 mmol; 10.0 eq.). The resulting mixture was stirred at RT for 5h. The reaction mixture was concentrated to a yellow solid residue, which was purified by Prep-HPLC % ACN in water containing 0.1% NH4OH) to yield the title compound as white solid (230.0 mg; Yield: 70%). LC-MS (M+H) +: 477.

Synthesis of compound 2f: 4— 3— 3— 1— 2—Amino-eth 1 -1H- razol l oxo—6H— ridazin-l- lmeth l -benzo lamino meth l-lH— razolecarbox lic acid lithium salt: A mixture of 4-(3-{3-[1-(2-Amino-ethyl)-1H-pyrazolyl]oxo-6H-pyridazinylmethyl}- benzoylamino)—1-methyl—1H—pyrazolecarboxylic acid methyl ester (230.00 mg; 0.48 mmol; 1.0 eq.) and lithium hydroxide monohydrate (40.5 mg; 0.97 mmol; 2.0 eq.) in 3 ml of THF and 3 ml of water was stirred at 40 0C for 1.5 hr. The reaction mixture was concentrated to dryness to yield the title compound as a white solid (240.0 mg; Yield: 106%). LC—MS (M+H)+: 463.

] Synthesis of compound 2: HN o // WMO N—N / H 12-meth l-4 5 8 11 12 15 23 27-octaaza entac clo 21.3.1.12 5.117 21.010 14 nonacosa-l 27 2 29 3 10 13 17 28 18 20 25-nonaene-9 16 24-trione A mixtue of 4-(3-{3—[l-(2-Amino-ethyl)—1H—pyrazolyl]—6—oxo-6H-pyridazin—1—ylmethyl}— lamino)methyl-1H-pyrazolecarboxylic acid lithium salt (240.00 mg; 0.51 mmol; 1.0 eq.), (benzotriazol—1—yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (280.35 mg; 0.61 mmol; 1.2 eq.) and ethyldiisopropylamine (0.13 ml; 0.77 mmol; 1.5 eq.) in DMF (10 ml) was stirred at rt for 4h. After the l of DMF, the residue was purified by Prep-HPLC (20- 60% ACN in water containing 0.1% NH4OH) to yield the title compound as a white solid (25.0 mg; Yield: 12%). LC—MS (M+H) +: 445. 1H NMR (500 MHz, DMSO-d6) 6 10.75 (s, 1H), 8.83 (t, J = 6.4 Hz, 1H), 8.82 (s, 1H), 8.23 (s, 1H), 7.96 (d, J: 1.9 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J: 7.9 Hz, 1H), 7.80 (d, J: 9.6 Hz, 1H), 7.71 (d, J: 7.5 Hz, 1H), 7.55 (t, J: 7.7 Hz, 1H), 6.92 (d, J = 9.3 Hz, 1H), 5.29 (s, 2H), 4.39 — 4.31 (m, 2H), 4.04 (d, J = 8.0 Hz, 2H), 3.89 (s, 3H).

Example 3 Scheme 3 HO\B,OH [l] | LiOH \ THF--H20 40 "C DIPEA ACN rtM K2COS P0""3%) O (f / Dioxane-H2,O 100C N‘ HN\b°° 22 3b g] | LiOH BOPDIEA HCI MeOH THF-H20 40 c‘CN DMF N —>N HN O / BOPDIEA M0 0 DMF // Mo// /N/0 N/ O N—N O NH N—N O NH /— / boc / / 2 / Lit /N_N H 3'1 3e 3f 3 Synthesis of compound 3b: 3- 3— 5— tert—Butox carbon lamino—meth l- ridin—3— l —6—oxo-6H— ridazin-l— lmeth l -benzoic acid meth l ester: To a degassed e of 3-{3— [5-(tert-Butoxycarbonylamino-methyl)-pyridin-3 -yl] oxo-6H-pyridazinylmethyl } -benzoic acid methyl ester (460.0 mg; 1.0 mmol), [5-[(tert-butoxycarbonylamino)methyl]—3— pyridyl]boronic acid (497.4 mg; 1.97 mmol; 1.1 eq.), potassium carbonate (272.7 mg; 1.97 mmol; 1.1 eq.) in 10 ml of dioxane and 1 ml of water, was added palladium tritert— butylphosphane (27.51 mg; 0.05 mmol; 0.03 eq.). The on mixture was stirred at 100 0C for 4h. After cooling to RT, the on mixture was diluted with ethyl acetate, washed with brine and concentrated. The crude was purified by pre-HPLC to yield the title compound as a white solid (460.00 mg; yield: 57%). LC-MS (M+H) +: 451.

Synthesis of compound 3c: 3-i 3—|5—1tert—Butoxycarbonylamino—methylg-pyridin-3— loxo-6H- ridazin-l- lmeth l -benzoic acid m salt: A mixture of 3-{3-[5-(tert— Butoxycarbonylamino-methyl)—pyridin—3-yl]—6—oxo-6H-pyridazin-1—ylmethyl}-benzoic acid methyl ester (450.0 mg; l. 00 mmol; 1.0 eq.) and lithium hydroxide monohydrate (83.84 mg; 2.00 mmol; 2.0 eq.) in 5 ml of THF and 5 ml of water was stirred at 40 0C for 2h. The on mixture was concentrated to dryness to yield the title compound as a white solid (440.0 mg; yield: 100%). LC-MS (M+H)+: 437.

Synthesis of compound 3d: 4- 3- 3- 5- tert—Butox carbon lamino-meth l - ridin l—6—oxo—6H— n—l— lmeth l —benzo lamino —l—meth l—lH— —3—carbox lic acid methyl ester: A mixture of 3-{3—[5-(tert-Butoxycarbonylamino—methyl)-pyridinyl]oxo—6H— pyridazin—l—ylmethy1}—benzoic acid lithium salt (240.0 mg; 0.54 mmol; 1.0 eq.), (benzotriazol— 1-yloxy)tris(dimethylamino)-phosphonium hexafluorophosphate (321.5 mg; 0.71 11111101; 1.3 eq.) and ethyldiisopropylamine (0.14 ml; 0.81 mmol; 1.5 eq.) in DMF (3 ml) was stirred at It for 4h.

The reaction e was poured into water and extracted with ethyl acetate, washed with brine and concentrated to yield the crude title compound as off—white solid (310.0 mg; yield: 100%), which was used for next step without further purification. LC-MS (M+H)+: 574.

Synthesis of compound 3e: 4— 3— 3— 5—Aminometh 1— the stirred solution of crude 4-(3-{3-[5-(tert-Butoxycarbonylamino-methyl)-pyridiny1]oxo- 6H—pyridazin—1—y1methy1}—benzoylamino)—1—methyl—1H—pyrazole—3—carboxylic acid methyl ester (300 mg; 0.52 mmol; 1.0 eq.) in methanol (2 ml), was added 4.0M HCl in dioxane (1.3 ml; 5.22 mmol; 10.0 eq.). The resulting mixture was d at RT for 5h. The reaction mixture was concentrated to a yellow solid residue, which was purified by PLC (10—50 % ACN in water containing 0.1% NH4OH) to yield the title compound as white solid (170.0 mg; Yield: 69%). LC—MS (M+H) +: 474.

Synthesis of compound 3f: 4- 3- 3- ometh l- ridin 1 oxo-6H- ridazin-l- lmeth 1-benzo lamino meth 1-1H— carbox 1ic acid lithium salt: A mixture of 4- { 3-[3-(5-Aminomethyl-pyridin-3 -yl)oxo-6H-pyridazin- l -ylmethyl] - lamino}methy1—1H-pyrazolecarboxylic acid methyl ester (160.00 mg; 0.34 mmol; 1.0 eq.) and lithium hydroxide monohydrate (28.3 mg; 0.68 mmol; 2.0 eq.) in 2 m1 of THF and 2 ml of water was d at RT for 1.5 hr. The reaction mixture was concentrated to dryness to yield the title compound as a white solid (180.00 mg; Yield: 107%). LC-MS (M+H) +: 460.

Synthesis of compound 3: 17-methyl-6;14.17,l8,21,25,29-heptaazapentacyclo 21.3.1.12,6.18,12.015,19|nonacosa-lg27);2g29). 3,8,10,12128g;15,18,23,25-decaene-5,13,20-trione A mixtue of 4- { 3-[3-(5-aminomethyl-pyridin-3 -yl)oxo-6H-pyridazinylmethyl]— benzoylamino}methyl-1H-pyrazolecarboxylic acid lithium salt (180.0 mg; 0.39 mmol; 1.0 eq.), triazolyloxy)tris(dimethylamino)phosphonium orophosphate (211.62 mg; 0.46 mmol; 1.2 eq.) and ethyldiisopropylamine (0.10 ml; 0.58 mmol; 1.5 eq.) in DMF (10 ml) was stirred at rt for 4h. After the removal of DMF, the e was purified by Prep HPLC (20— 60% ACN in water containing 0.1% NH4OH) to yield the title compound as a white solid (62.0 mg; Yield: 36%). LC-MS (M+H)+: 442. 1H NMR (400 MHz, DMSO-d6) 8 10.79 (s, 1H), 9.27 (t, J: 6.0 Hz, 1H), 9.23 (s, 1H), 9.01 (d, J: 2.2 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.19 (d, J: 9.2 Hz, 2H), 8.10 (s, 1H), 7.92 (d, J: 7.8 Hz, 1H), 7.75 (d, J: 7.6 Hz, 1H), 7.57 (t, J: 7.7 Hz, 1H), 7.04 (d, J: 9.6 Hz, 1H), 5.40 (s, 2H), 4.50 (d, J = 6.1 Hz, 2H), 3.89 (s, 3H).

Example 4 gNfijNIIO o NH 12-meth loxa-1 9 12 13 16 24-hexaazatetrac clo 18.3.1.13 7.010 14 entacosa- 3 5 7 25 10 13 20 24 21-he taene-8 15 23-trione 4 Compound 4 was prepared by the similar procedure as described in the synthesis of compound 1 using (2-bromoethyl)-carbamic acid tert-butyl ester as the starting material. The d compound was obtained by Prep—HPLC purification (20—60% ACN in water ning 0.1% NH4OH) as a white solid (12.0 mg; yield: 10%). LC-MS (M+H) +: 395. 1H NMR (400 MHz, DMSO—d6) 5 9.92 (s, 1H), 8.56 (d, J = 5.7 Hz, 1H), 8.16 (s, 1H), 7.79 (s, 1H), 7.72 (d, J = 7.7 Hz, 1H), 7.61 (d, J: 7.6 Hz, 1H), 7.50 (t, J: 7.6 Hz, 1H), 7.31 (d, J: 9.8 Hz, 1H), 6.96 (d, J = 9.8 Hz, 1H), 5.16 (s, 2H), 4.72 (s, 2H), 3.88 (s, 3H), 3.60 (q, J = 5.0 Hz, 2H).

Example 5 O NHO / N 12-meth loxa-1 9 12 13 16 26-hexaazatetrac clo 20.3.1.13 7.010 14 he tacosa- 3 5 7 27 10 13 22 26 23-he taene-8 15 25-trione 5 ] nd 5 was prepared by the similar procedure as described in the synthesis of compound 1 using (4-bromobutyl)—carbamic acid tert-butyl ester as the starting material. The desired compound was ed by PrepHPLC purification (20-60% ACN in water containing 0.1% NH4OH) as a white solid (30.0 mg; yield: 16%). LC-MS (M+H) +: 423. 1H NMR (400 MHz, DMSO—d6) 5 11.54 (s, 1H), 8.72 (t, J: 6.3 Hz, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.87 (d, J: 7.5 Hz,1H), 7.69 (d, J: 7.5 Hz,1H), 7.55 (t, J: 7.5 Hz,1H), 7.16 (d, J: 9.8 Hz,1H), 6.88 (d, J = 9.7 Hz, 1H), 5.14 (s, 2H), 4.59 (d, J: 5.9 Hz, 2H), 3.93 (s, 3H), 3.48—3.39 (m, 2H), 1.77-1.69 (m, 4H).

O M é N-N H 12- oxan l oxa-1 9 12 13 16 25-hexaazatetrac clo 19.3.1.13 7.010 14 hexacosa- 3 5 7 26 10 13 21 25 22-he taene-S 15 24-trione 6 Compound 6 was prepared by the similar ure as described in the synthesis of compound 1 using 4-amino(tetrahydro-pyranyl)-1H-pyrazolecarboxylic acid methyl ester as the starting material. The desired compound was obtained by Prep HPLC purification (20—60% ACN in water containing 0.1% NH4OH) as a white solid (20.0 mg; yield: 11%). LC— MS (M+H)+: 479. 1H NMR (400 MHz, DMSO-d6) 6 10.43 (s, 1H), 8.66 (t, J: 6.4 Hz, 1H), 8.26 (s, 1H), 7.96 (t, J = 1.7 Hz, 1H), 7.83 (dt, J = 7.8, 1.5 Hz, 1H), 7.67 (dt, J = 7.6, 1.4 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 9.7 Hz, 1H), 6.93 (d, J = 9.8 Hz, 1H), 5.10 (s, 2H), 4.56 — 4.48 (m, 1H), 4.31 (t, J : 6.2 Hz, 2H), 4.01 (t, J = 3.3 Hz, 1H), 3.98 (t, J : 3.2 Hz, 1H), 3.55 — 3.40 (m, 4H), 2.06 - 1.99 (m, 4H), 1.94 (d, J = 7.2 Hz, 2H).

Nil). | M05/HN O / 7 Example 8 12-meth loxa-1 9 12 13 16 25 26-he taazatetrac clo 19.3.1.13 7.010 14 hexacosa- 3 5 7 26 10 13 21 25 22-he taene-8 15 24-trione 8 nd 8 was prepared by the similar procedure as described in the synthesis of compound 1 using 6-chloromethyl-pyridinecarboxylic acid methyl ester as the starting material. The desired compound was obtained by prep HPLC purification (10—50% ACN in water containing 0.1% NH4OH) as a white solid (23.0 mg; yield: 17%). LC—MS (M+H) +: 410. 1H NMR (500 MHz, DMSO-d6) 6 10.99 (s, 1H), 8.54 (t, J = 6.4 Hz, 1H), 8.31 (s, 1H), 8.08 — 7.96 (m, 2H), 7.75 (d, J = 7.5 Hz, 1H), 7.28 (d, J: 9.8 Hz, 1H), 6.88 (d, J: 9.7 Hz, 1H), 5.14 (s, 2H), 4.24 (t, J: 5.8 Hz, 2H), 3.89 (s, 3H), 3.43 — 3.40 (m, 2H), 1.83 — 1.80 (m, 2H).

Example 9 12- - l oxa-1 9 12 13 16 25 26-he taazatetrac clo 19.3.1.13 7.010 14 hexacosa- 3 5 7 26 10 13 21 25 22-he taene-8 15 24-trione 9 Compound 9 was prepared by the similar procedure as described in the synthesis of compound 1 using 6-chloromethyl-pyridinecarboxylic acid methyl ester and 4-amino hydro-pyran-4—yl)-1H-pyrazole-3—carboxylic acid methyl ester as the starting materials. The desired nd was ed by Prep HPLC purification (10-50% ACN in water containing 0.1% NH4OH) as a white solid (66.0 mg; yield: 37%). LC-MS (M+H) +: 480. 1H NMR (500 MHz, DMSO—d6) 5 10.98 (s, 1H), 8.48 —8.43 (m, 1H), 8.35 (s, 1H), 8.14 — 7.85 (m, 2H), 7.75 (d, J = 7.5 Hz, 1H), 7.28 (d, J = 9.6 Hz, 1H), 6.88 (d, J: 9.7 Hz, 1H), 5.15 (s, 2H), 4.59 — 4.40 (m, 1H), 4.27 —4.21 (m, 2H), 3.97 (d, J = 11.3 Hz, 2H), 3.58 _ 3.38 (m, 4H), 2.01 _ 1.96 (m, 4H), 1.88 4 1.80 (m, 2H).

Example 10 99\ N O HN O ‘AN—N N 12-tert-butyloxa-1,9,12,13,16,25,26-heptaazatetracyclo[19.3.1.13,7.01°,14]hexacosa- 3 5 7 26 10 13 21 25 22-h6 taene-8 15 24-trion6 10 Compound 10 was ed by the similar procedure as described in the synthesis of compound 1 using 6-chloromethy1-pyridinecarboxylic acid methyl ester and 4-aminotert— butyl-1H—pyrazolecarboxylic acid methyl ester as the starting materials. The desired compound was obtained by Prep HPLC purification % ACN in water containing 0.1% NH4OH) as a white solid (118.0 mg; yield: 59%). LC-MS (M+H) +: 451. 1H NMR (500 MHz, DMSO-d6) 6 10.97 (s, 1H), 8.38 (t, J = 6.4 Hz, 1H), 8.34 (s, 1H), 8.05 (t, J = 7.6 Hz, 1H), 7.99 (d, J = 7.7 Hz, 1H), 7.75 (d, J: 7.6 Hz, 1H), 7.28 (d, J = 9.8 Hz, 1H), 6.89 (d, J: 9.7 Hz, 1H), .15 (s, 2H), 4.25 (t, J: 5.7 Hz, 2H), 3.51 — 3.38 (m, 2H), 1.87- 1.81 (m, 2H), 1.56 (s, 9H).

Example 11 Nil)' | HN o mo 0" NN— N 18-h drox oxan l oxa-1 9 12 13 16 25-hexaazatetrac clo 19.3.1.13 7.010 14 a- 3 5 7 26 10 13 21 25 22-he taene-8 15 24-trione 11 Compound 11 was ed by the similar procedure as described in the synthesis of compound 1 using (3-chloro-2—hydroxy-propyl)-carbamic acid tert-butyl ester and 4-amino (tetrahydro-pyranyl)-1H-pyrazolecarboxylic acid methyl ester as the ng materials. The desired compound was obtained by PLC purification (10-50% ACN in water containing 0.1% NH4OH) as a white solid (13.0 mg; yield: 14%). LC-MS (M+H) +: 495. 1H NMR (500 MHZ, DMSO—d6) 5 10.37 (s, 1H), 8.61 (t, J: 6.4 Hz, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.83 (d, J: 7.7 Hz, 1H), 7.66 (d, J: 7.5 Hz, 1H), 7.53 (t, J: 7.6 Hz, 1H), 7.21 (d, J: 9.6 Hz, 1H), 6.90 (d, J = 9.7 Hz,1H), 5.24 (d, J: 5.4 Hz,1H), 5.18 (d, J = 13.9 Hz, 1H), 5.02 (d, J: 13.8 Hz,1H), 4.53 —4.47 (m, 1H), 4.29 (dd, J = 11.1, 3.6 Hz, 1H), 4.11 (dd, J = 11.2, 6.4 Hz, 1H), 3.99 -3.91 (m, 2H), 3.87 -3.83 (m, 1H), 3.59 (dt, J = 13.4, 8.0 Hz, 1H), 3.45 (td, J = 11.3, 3.5 Hz, 2H), 3.25 (ddd, J: 13.4, 5.9, 2.5 Hz, 1H), 2.06 — 1.96 (m, 4H).

Example 12 gr"?NI | HN O /N—N N 18-h drox meth loxa-l 9 12 13 16 25-hexaazatetrac clo 19.3.1.13 7.010 14 hexacosa- 3 5 7 26 10 13 21 25 22-he taene-8 15 24-trione 12 WO 27024 Compound 12 was prepared by the similar ure as described in the synthesis of compound 1 using (3—chlorohydroxy-propyl)-carbamic acid tert-butyl ester as the starting material. The desired compound was obtained by Prep-HPLC purification (10—50% ACN in water containing 0.1% NH4OH) as a white solid (18.0 mg; yield: 27%). LC—MS (M+H) +: 425. 1H NMR (400 MHz, DMSO—d6) 6 10.40 (s, 1H), 8.69 (t, J: 4.0 Hz, 1H), 8.21 (s, 1H), 7.98 (t, J = 1.7 Hz, 1H), 7.85 (dt, J = 7.8, 1.5 Hz, 1H), 7.67 (dt, J = 7.6, 1.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.23 (d, J: 9.7 Hz, 1H), 6.92 (d, J = 9.8 Hz, 1H), 5.22 (d, J: 8.0 Hz, 1H), 5.19 (d, J: 13.0 Hz, 1H), 5.04 (d, J = 13.9 Hz, 1H), 4.30 (dd, J = 11.2, 3.5 Hz, 1H), 4.13 (dd, J = 11.2, 6.3 Hz, 1H), 3.92 (s, 3H), 3.86 — 3.80 (m, 1H), 3.67 — 3.55 (m, 1H), 3.28 — 3.18 (m, 1H).

Example 13 17-meth l-6 14 17 18 21 24 29-he taaza entac clo 21.3.1.12 6.18 12.015 19 nonacosa- l 27 2 29 3 8 10 12 28 15 18 23 25-decaene-5 l3 20-trione l3 Compound 13 was prepared by the similar procedure as described in the synthesis of compound 3 using [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolanyl)-pyridinylmethyl]- carbamic acid tert-butyl ester as the starting material. The d compound was obtained by PLC purification (20-60% ACN in water containing 0.1% NH4OH) as a white solid (35.0 mg; yield: 17%). LC—MS (M+H)+: 442. 1H NMR (500 MHz, 6) 5 10.78 (s, 1H), 9.41 (s, 1H), 8.84 (s, 1H), 8.56 (d, J = 5.3 Hz, 1H), 8.19 (s, 1H), 8.15 — 8.03 (m, 2H), 7.92 (d, J: 7.7 Hz, 1H), 7.76 (d, J = 6.5 Hz, 2H), 7.57 (t, J = 7.9 Hz, 1H), 7.05 (d, J = 9.7 Hz, 1H), 5.40 (s, 2H), 4.72 — 4.51 (m, 2H), 3.88 (s, 3H).

Example 14 WO 27024 HN O Né— N / H 17-meth l-6 14 17 18 21 30-hexaaza entac clo 22.3.1.12 6.18 12.015 19 triaconta-l 28 2 30 3 8 12 29 15 18 24 26-decaene-5 13 20-trione 14 Compound 14 was prepared by the similar procedure as described in the synthesis of compound 3 using {2-[3-(4,4,5,5—Tetramethyl—[1,3,2]dioxaborolanyl)-phenyl]—ethyl}— carbamic acid tert-butyl ester as the starting material. The desired nd was obtained by Prep-HPLC purification (20-60% ACN in water containing 0.1% NH4OH) as a white solid (120.0 mg; yield: 53%). LC—MS (M+H) +: 455. 1H NMR (500 MHZ, 6) 6 11.17 (s, 1H), 8.66 (t, J: 5.9 Hz, 1H), 8.32 (q, J = 1.8 Hz, 2H), 8.17 (s, 1H), 8.04 (q, J: 1.8 Hz, 2H), 7.98 (d, J = 9.8 Hz, 1H), 7.81 (ddt, J = 15.1, 7.6, 1.4 Hz, 2H), 7.62 - 7.52 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.25 (dt, J = 7.8, 1.3 Hz, 1H), 7.03 (d, J = 9.7 Hz, 1H), 5.38 (s, 2H), 3.89 (s, 3H), 3.83 — 3.72 (m, 3H), 3.02 (t, J: 6.1 Hz, 2H).

Example 15 Scheme 4 DIPEA ACN rt K2003 PO""311% (1 M900 e-H2,0 40 0C OH 40 2a 4b /NH SnClz LiOH EtOH-H20 60 0C THF-H2.0 rt NaH DMFN05: ’N é:/|\]‘ 4d 4e 4f 15 Synthesis of compound 4b: 3— 3- 3- 2—H drox —eth l- hen l—6—oxo-6H- ridazin— l- lmeth l -benzoic acid meth l ester: To a degassed mixture of 3—(3—chlorooxo—6H— pyridazin-l-ylmethyl)-benzoic acid methyl ester (640.0 mg; 2.3 mmol; 1.0 eq.), [3-(2— hydroxyethyl)phenyl]boronic acid (438.3 mg; 2.6 mmol; 1.15 eq.) and potassium carbonate (634.7 mg; 4.5 mmol; 2.0 eq.) in 10 ml of dioxane and 1 ml of water, was added palladium tritert-butylphosphane (117.36 mg; 0.23 mmol; 0.10 eq.). The reaction e was stirred at 40 OC overnight. After cooling to rt, the on mixture was diluted with ethyl acetate, washed with brine and concentrated. The white solid was percipitated out, filtered and washed with ether to yield the title compound as a white solid (510.0 mg; yield: 61 %). LC-MS (M+H) +: 365.

] Synthesis of compound 4c: 3—1 3— 3—12—Methanesulfonyloxy—ethylj—phenyl —6—oxo—6H— pyridazin-l-ylmethyl{-benzoic acid methyl ester: To a solution of 3-{3-[3-(2-Hydroxy-ethyl)— phenyl]oxo-6H-pyridazin-l-ylmethyl}-benzoic acid methyl ester (510.00 mg; 1.4 mmol; 1.0 eq.) in 5 ml of THF, was added diisopropylethylamine (0.63 ml; 3.5 mmol; 2.5 eq.), followed by methanesulfonyl chloride (0.14 ml; 1.75 mmol; 1.25 eq.). The resulting mixture was stirred at rt for 4 h. The reaction mixture was diluted with ethyl acetate and washed with samll amount of brine. The organic layer was dried over magnesium e and trated to dryness to yield the crude title compound as ite solid (400.0 mg; yield: 65 %), which was used for the next step without further purification. LC-MS (M+H)+: 443.

Synthesis of compound 4d: phenyl{—6-oxo—6H-pyridazin—1—ylmethylg-benzoic acid methyl ester: To a solution of 3—methyl— -nitro-1H-pyrazole (229.80 mg; 1.8 mmol; 2.0 eq.) in 12 ml of DMF, was added sodium hydride (90.4 mg; 2.26 mmol; 2.5 eq.). After stirring at rt for 10 min, 3—(2— Methanesulfonyloxy—ethyl)-phenyl]—6—oxo-6H-pyridazin—1—ylmethyl}—benzoic acid methyl ester (400.0 mg; 0.9 mmol; 1.0 eq.) was added. The resulting mixture was stirred at It for 24 h. After removal of the solvent, the crude was purified by prep HPLC (20—80% ACN in water ning 0.1% NH4OH) to yield the title compound (68.0 mg; yield: 16%). LC-MS (M+H)+: 474.

Synthesis of compound 4e: 3- 3- 3- 2- ometh l- razol-l- l -eth l - phenyl{—6—oxo—6H—pyridazin—1—ylmethylj—benzoic acid methyl ester: The reaction mixture of 3— (3-{ 3-[2-(3-Methylnitro—pyrazolyl)—ethyl]-phenyl}oxo-6H—pyridazinylmethyl)— benzoic acid methyl ester (68.0 mg; 0.14 mmol; 1.0 eq.) and dichlorotin (136.2 mg; 0.72 mmol; .0 eq.) in 5 ml of EtOH and 2.5 ml of water was stirred at 60 0C for 6 h. After cooling to rt, the reaction mixture was quenched with 1 ml of ammonia on and the stirred for 10 min. After removal of the solvents, the residue was disloved in 3 ml of DMSO and filtered through a celite pad. The filtrate was ted to prep HPLC purification to afford the title compound (40.0 mg; yield: 63%). LC-MS (M+H) +: 444.

Synthesis of compound 4f: 3- 3- 3- 2- 5-Aminometh l- razol-l- l -eth l - hen l -6H- ridazin-l- lmeth l -benzoic acid lithium salt: A mixture of 3-(3-{3-[2—(5- aminomethyl-pyrazolyl)-ethyl]—phenyl}-6—oxo-6H-pyridazinylmethyl)-benzoic acid methyl ester (35.0 mg; 0.08 mmol; 1.0 eq.) and lithium hydroxide monohydrate (13.2 mg; 0.32 mmol; 4.0 eq.) was stirred in 1 ml of THF and 1 ml of water at rt for 4 h. The reaction mixture was concentrated to dryness to yield the title compound (40.0 mg; yield: 113%). LC-MS (M+H) +2 430. sis of compound 15: WO 27024 17-meth l-6 14 18 19 28- entaaza entac clo 20.3.1.12 6.18 12.015 19 octacosa- l 26 2 28 3 8 10 12 27 15 17 22 24-decaene—5 l3-dione 15 A mixtue of 3-(3-{3-[2-(3-aminomethyl-pyrazol-l-yl)-ethyl]-phenyl}oxo-6H- pyridazin-l-ylmethyl)-benzoic acid lithium (40.0 mg; 0.09 mmol; 1.0 eq.), (benzotriazol-l- yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (81.2 mg; 0.18 mmol; 2.0 eq.) and ethyldiisopropylamine (0.02 ml; 0.1 mmol; 1.05 eq.) in DMF (5 ml) was stirred at rt for l h.

After the l of DMF, the residue was purified by Prep HPLC (20-80% ACN in water ning 0.1% NH4OH) to yield the title compound as a White solid (8.0 mg; Yield: 22%). LC— MS (M+H)+: 412. 1H NMR (400 MHz, DMSO-d6) 6 10.02 (s, 1H), 8.12 — 8.01 (m, 2H), 7.76 (s, 1H), 7.63 — 7.57 (m, 2H), 7.48 — 7.43 (m, 4H), 7.08 — 7.05 (m, 2H), 5.23 (s, 2H), 4.79 (bs, 2H), 4.05 (bs, 2H), 3.04 (s, 3H).

Example 16: enzymatic assays IRAKl enzymatic assay IRAK4 is a human purified inant enzyme EV—IRAK4 (l—460)).

In this assay, IRAK4 hydrolyses ATP, autophosphorylates and phosphorylates a Serine/Threonine generic peptidic substrate (STK: 6lSTlBLC from CisBio International).

Measurement of IRAK—4 inhibition is performed in 384—well format based on a scence assay (ADP-GloTM Kinase Assay from Promega). Purified human recombinant IRAK4 (0.3ug/ml) and serial diluted compounds in DMSO (range of concentration from lOuM to 0.5nM) or controls (1% DMSO) are incubated for 15 minutes at RT in assay buffer containing 50 mM Hepes pH 7.0, Fatty acid—free BSA 0.1%, threitol (DTT) 2mM, MgCl2 lOmM, EGTA 0.5mM, Triton X-100 0.01%, MnCl2 5mM. The kinase reaction is then initiated by the addition of ATP (2uM) and the peptidic substrate STKl—biotin peptide (300nM). After 2 hours of incubation at RT, the reaction is stopped and the unconsumed ATP ed by the on of ADP—GloTM Reagent according to supplier instructions. After 40 minutes of incubation at RT, the Kinase Detection Reagent is then added to the assay plate according to supplier instructions.

After 20 minutes of incubation at RT, the luminescence signal is ed with a plate—reading meter nElmer Envision or equivalent reader).

IRAKl enzymatic assay: lRAKl is a human purified recombinant enzyme (His-TEV—IRAKl (194-712)) In this assay, IRAKl hydrolyses ATP and autophosphorylates. Measurement of IRAK-l inhibition is performed in 384-Well format based on luminescence assay (ADP-G10TM Kinase Assay from Promega). Purified human recombinant IRAKl (0.3ug/ml) and serial diluted compounds in DMSO (range of tration from 10uM to 0.5nM) or ls (1% DMSO) are incubated for 15 s at RT in assay buffer containing 50 mM Hepes pH 7.0, Fatty acid—free BSA 0.1%, Dithiothreitol (DTT) 2mM, MgC12 10mM, EGTA 0.5mM, Triton X-100 0.01%. The kinase reaction is then initiated by the addition of ATP at a concentration of luM. After 2 hours of incubation at RT, the reaction is stopped and the unconsumed ATP depleted by the addition of ADP—GloTM Reagent according to supplier instructions. After 40 minutes of incubation at RT, the Kinase ion Reagent is then added to the assay plate according to supplier instructions.

After 20 minutes of incubation at RT, the luminescence signal is measured with a luminometer (PerkinElmer Envision or equivalent reader).

Results are given in the following table.

* IC50 > 5 uM ** IC50 ranges from 1 uM — 5 uM *** IC50 ranges from 100 nM - 1.0 11M **** IC50 < 100 nM NT Not Tested Compound IRAKl IRAK4 1C50 1C50 WO 27024 **** **** *** **** *** *** *** **** *** **** ** 11 *** **** 12 ** **** 13 *** **** 14 *** **** Example 17. Pharmaceutical preparations (A) Injection vials: A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogen phosphate in 3 l of bidistilled water is adjusted to pH 6.5 using 2 N hydrochloric acid, sterile ed, transferred into injection vials, is lyophilized under sterile conditions and is sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soy lecithin and 1400 g of cocoa , is poured into moulds and is allowed to cool. Each suppository contains 20 mg of active ingredient.

(C) Solution: A on is prepared from 1 g of an active ingredient according to the invention, 9.38 g of 4 - 2 H20, 28.48 g of NazHPO4 - l2 H20 and 0.1 g of benzalkonium chloride in 940 ml of bidistilled water. The pH is ed to 6.8, and the solution is made up to l l and sterilized by irradiation. This solution could be used in the form of eye drops.

(D) Ointment: 500 mg of an active ient according to the invention is mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A e of 1 kg of an active ingredient according to the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is pressed to give tablets in a conventional manner in such a way that each tablet ns 10 mg of active ingredient.

(F) Coated tablets: Tablets are d analogously to Example E and subsequently are coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth and (G) Capsules: 2 kg of an active ingredient according to the invention are uced into hard gelatin capsules in a conventional manner in such a way that each capsule contains 20 mg of the active ient.

(H) Ampoules: A solution of 1 kg of an active ingredient according to the invention in 60 l of bidistilled water is sterile filtered, transferred into ampoules, is lyophilized under sterile ions and is sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

(I) Inhalation spray: 14 g of an active ingredient ing to the invention are dissolved in 10 l of isotonic NaCl solution, and the solution is transferred into commercially available spray containers with a pump mechanism. The solution could be sprayed into the mouth or nose. One spray shot (about 0.1 ml) corresponds to a dose of about 0.14 mg.

While a number of embodiments of this invention are described , it is apparent that the basic examples may be altered to provide other embodiments that utilize the nds and methods of this invention. Therefore, it will be appreciated that the scope of this ion is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

Claims (14)

1. A compound of formula I, or a pharmaceutically able salt thereof, wherein: Ring A is pyrazolyl; which is optionally substituted; X is absent, or ; Y is an optionally tuted C1–6 aliphatic; N N N N N N N N or ; W is CH or N; each R is independently hydrogen, C1–6 aliphatic, C3–10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 ed heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; or two R groups on the same atom are taken together with the atom to which they are ed to form a C3–10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 ed heterocyclic ring having 1-4 heteroatoms independently ed from nitrogen, oxygen, or sulfur, or a 5-6 ed monocyclic heteroaryl ring having 1-4 atoms ndently selected from nitrogen, oxygen, or sulfur; each of which is optionally substituted; each R1 is independently -R, halogen, -OR, –SR, –CN, – NO2, -SO2R, -SOR, -C(O)R, -CO2R, (R)2, -NRC(O)R, -NRC(O)N(R)2, -NRSO2R, or –N(R)2; R2 is hydrogen; R4 is hydrogen; and n is 0, 1, 2, 3, 4, or 5; and wherein “optionally substituted” means groups that are unsubstituted or substituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with one or more substituents selected from the group consisting of: -F, -Cl, -Br, -I, deuterium, -OH, alkoxy, oxo, -NO2, -CN, CF3, -NH2, -NH alkyl, -NH-alkenyl, kynyl, -NH-cycloalkyl, - NH-aryl, -NH-heteroaryl, -NH-heterocyclic, -dialkylamino, -diarylamino, -diheteroarylamino, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, -O-aryl, -O-heteroaryl, -O-heterocyclic, - C(O)-alkyl, -C(O)-alkenyl, -C(O)-alkynyl, -C(O)-carbocyclyl, -C(O)-aryl, -C(O)-heteroaryl, - C(O)-heterocyclyl, -CONH2, -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH- carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl, -NHC(O)-alkyl, - NHC(O)-alkenyl, -NHC(O)-alkynyl, -NHC(O)-carbocyclyl, -NHC(O)-aryl, )- heteroaryl, -NHC(O)-heterocyclyl, -CH2NH2, -CH2SO2CH3, -alkyl, -alkenyl, -alkynyl, -aryl, - arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, alkyl, -carbocyclic, - heterocyclic, koxyalkyl, polyalkoxy, -methoxymethoxy, and -methoxyethoxy.

2. The compound of claim 1, wherein Ring A is or .

3. The nd of claim 1, wherein Y is methylene, ethylene, propylene, i-propylene, n-butylene, or s-butylene; each of which is optionally substituted.

4. The compound of claim 1, wherein Z is –O-, NN N or .

5. The compound of claim 1, of formula I-a, W N O NH Z A X or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1, of formula I-b, or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1, of formula I-c, or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1, ed from the group consisting of: HN O N N N 1 2 3 4 5 6 N N HN O N N NH 7 8 9 10 11 12 HN O NH NN N N 13 14 and 15, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a ceutically acceptable adjuvant, r, or vehicle.

10. Use of a compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an IRAK-mediated disorder in a patient in need thereof.

11. The use of claim 10, wherein the disorder is selected from Rheumatoid Arthritis, tic arthritis, Osteoarthritis, Systemic Lupus Erythematosus, Lupus nephritis, Ankylosing Spondylitis, Osteoporosis, Systemic sclerosis, Multiple Sclerosis, Psoriasis, Type I es, Type II diabetes, Inflammatory Bowel Disease (Cronh’s Disease and Ulcerative s), Hyperimmunoglobulinemia D and periodic fever syndrome, Cryopyrin-associated ic syndromes, zler's syndrome, Systemic juvenile idiopathic arthritis, Adult's onset Still's disease, Gout, Pseudogout, SAPHO syndrome, Castleman's disease, Sepsis, Stroke, Atherosclerosis, Celiac disease, DIRA (Deficiency of IL-1 Receptor Antagonist), Alzheimer’s disease, Parkinson’s disease, and Cancer.

12. A compound ing to claim 1 substantially as herein described or exemplified.

13. A pharmaceutical composition according to claim 9 substantially as herein bed or exemplified.

14. A use according to claim 10 substantially as herein described or exemplified.