RU2810338C2 - Heteroaryl compounds as irak type ii inhibitors and their use - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: group of inventions includes a compound of formula I, its pharmaceutically acceptable salt, a pharmaceutical composition containing it, a method of inhibition and a method of treatment. In formula I, A' represents either C=O, CH₂, CHOH or NH; L represents a divalent group selected from the following: C_6-10 aryl, 3–8 membered saturated or partially unsaturated carbocyclic ring; each of which is optionally substituted with one or two halogens; X represents either CR or N; Y represents NR or S; Z represents either CR or N; R¹ represents C_6-10 aryl, which is optionally substituted with one or two substituents selected from halogen, C_1-6 alkyl or -CN; R² represents -R, C_1-6 haloalkyl; each R independently represents hydrogen, C_1-6 alkyl, a saturated 3–7 membered heterocyclic ring containing 1 heteroatom representing oxygen; each of which is optionally substituted with one substituent selected from C_1-6 alkyl, -OH or -CN.

EFFECT: compound of formula (I) with inhibitory activity against IRAK.

20 cl, 31 ex

Description

Field of technology to which the invention relates

[0001] The present invention provides compounds of formula (I) as IRAK inhibitors and their use in the treatment of cancer and other diseases associated with increased expression of IRAK, including inflammatory disorders, autoimmune disorders and cancer.

BACKGROUND OF THE INVENTION

[0002] Kinases catalyze the phosphorylation of proteins, lipids, sugars, nucleosides and other cellular metabolites and play key roles in all aspects of eukaryotic cell physiology. In particular, protein kinases and lipid kinases are involved in signaling events that control cell activation, growth, differentiation and survival under the influence of extracellular mediators or stimuli such as growth factors, cytokines or chemokines. Typically, protein kinases are divided into two groups: protein kinases that preferentially phosphorylate tyrosine residues, and protein kinases that preferentially phosphorylate serine and/or threonine residues.

[0003] 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 controlling adaptive and innate immune responses. Kinase targets of particular interest are members of the IRAK family.

[0004] IRAKs (IL-1 receptor associated kinases) are Ser/Thr signaling pathway kinases downstream of TNF-R, IL-1β-R, IL-18R and toll-like receptors. IRAKs, in turn, mediate the activation of JNK/p38 and NFκB, leading to the production of proinflammatory cytokines. Of the four family members, only IRAK1 and IRAK4 have kinase activity, with IRAK4 acting upstream of IRAK1 within the same pathway. In myeloid cells, IRAK1 is required for LPS-induced IL-8 and INF-γ release, STAT3 activation, IL10 release, and integrin-β2-mediated cell spreading. In pDCs, IRAK mediates TLR7 and TLR9-induced INF-α release. In T cells, IRAK mediates IL-2 production and proliferation, as well as IL-18-induced Th1 cell proliferation and INF-γ production. IRAK expression is particularly high in endothelium, epithelium, macrophages, monocytes, mast cells, granulocytes, dendritic cells, B, T and NK cells. Mice deficient in IRAK-1 or IRAK-4 exhibit impaired INF-α production in response to TLR7/9 activation, failure to activate NF-κB in response to IL-18 or IL-1, and a dramatic reduction in INF-γTh1 and NK-γ production. cells. They are also protected in models of LPS-induced heart failure, CIA, Carageenan, pulmonary inflammation and fibrosis, and MOG-induced EAE. Phosphorylation of IRAK1 is enhanced by LPS treatment of synoviocytes in patients with RA. SNPs in IRAK1 are associated with SLE.

[0005] Interleukin-1 receptor associated kinases (IRAKs) play a key role in regulating the intracellular network of signals that control inflammation (Ringwood and Li, 2008. Cytokine 42, 1-7). IRAKs are expressed in many cell types and can mediate signals from various cellular receptors, including toll-like receptors (TLRs). IRAK4 is considered an initial protein kinase activated downstream of the interleukin-1 receptor (IL-1) and all toll-like receptors (TLRs) except TLR3, and initiates signaling to the innate immune system through rapid activation of IRAK1 and slower activation of IRAK2. IRAK1 was first identified through biochemical purification of IL-1 dependent kinase activity, which coimmunoprecipitates with IL-1 receptor type 1 (Cao et al., 1996. Science 271(5252): 1128-31). IRAK2 was identified during a human expressed sequence tag (EST) database search for sequences homologous to IRAKI (Muzio et al., 1997. Science 278(5343): 1612-5). IRAK3 (also called IRAKM) was identified using a mouse EST sequence encoding a polypeptide with significant homology to IRAK1 to screen a human phytohemagglutinin-activated peripheral blood leukocyte (PBL) cDNA library (Wesche et al., 1999. J. Biol. Chem. 274( 27): 19403-10). IRAK4 was identified by database searching for IRAK-like sequences and PCR of a universal cDNA library (Li et al., 2002. Proc. Natl. Acad. Sci. USA 99(8):5567-5572).

[0006] Mice that express a catalytically inactive mutant of IRAK4 instead of the wild-type kinase are completely resistant to septic shock induced by several TLR agonists and are attenuated in their response to IL-1. Children deficient in IRAK4 activity due to a genetic defect suffer from repeated infections caused by pyogenic bacteria. It appears that IRAK-dependent TLRs and IL-1Rs are vital for childhood immunity against some pyogenic bacteria, but play a reserve role in immune defense against most infections in adults. Therefore, IRAK4 inhibitors may be useful for treating chronic inflammatory diseases in adults without making them overly susceptible to bacterial and viral infections (Cohen, 2009. Current Opinion in Cell Biology 21, 1-8). Potent IRAK4 inhibitors have been developed (Buckley et al., 2008. Bioorg Med Chem Lett. 18(12):3656-60). IRAK1 is essential for TLR7- and TLR9-mediated IRF7 activation and interferon-alpha (IFN-α) production, suggesting that IRAK1 inhibitors may be useful for the treatment of systemic lupus erythematosus (SLE). IRAK2 is activated downstream of IRAK4 and plays an important role in the production of proinflammatory cytokines. Therefore, IRAK2 inhibitors may be useful for the treatment of inflammatory diseases.

The essence of the invention

[0007] In one aspect, the invention provides a compound of formula (I):

I

and pharmaceutically acceptable derivatives, solvates, salts, hydrates and stereoisomers thereof, wherein A', L, X, Y, Z, R ¹ and R ² are each as defined below and described in the embodiments.

[0008] In another aspect, the invention provides compounds of formula (I) that are suitable for the treatment and/or prevention of disorders associated with IRAK. In yet another aspect, the invention provides compounds capable of modulating, especially inhibiting, the activity or action of IRAK in disease states in mammals, especially humans.

[0009] In accordance with another aspect of the invention, methods are provided for the treatment and/or prevention of disorders selected from autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurodegenerative disorders, bacterial and viral infections, allergies, asthma, pancreatitis, multiple organ failure, kidney diseases, platelet aggregation, cancer, organ transplantation, sperm motility, red blood cell deficiency, transplant rejection, lung injury, respiratory disease, ischemic conditions and cancer.

[0010] In another aspect, the present invention provides compounds of formula (I) that are selective for IRAK-4 and/or IRAK-1 with a type II binding mode.

[0011] In another aspect, the present invention provides compounds of formula (I) that are selective for IRAK-4 and IRAK-1 with a type II binding mode.

Detailed Description of Some Embodiments

1. General description of the compounds of the invention

[0012] In some aspects, the present invention provides IRAK inhibitors. In some embodiments, such compounds include compounds of the formulas described herein, or a pharmaceutically acceptable salt thereof, wherein each variable has the meanings defined and described herein.

2. Connections and definitions

[0013] The compounds of this invention include those described generally above and are further illustrated by the classes, subclasses and types set forth herein. In this description, unless otherwise indicated, the following definitions are used. For the purposes of the present invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, according to the CAS version of the Handbook of Chemistry and Physics, ^75th Ed. In addition, general principles of organic chemistry are given in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", ^5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0014] The term "aliphatic" or "aliphatic group" as used herein means a straight (i.e., straight-chain) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or that contains one or more unsaturated units, either a monocyclic hydrocarbon or a bicyclic a hydrocarbon that is fully saturated or that contains one or more unsaturated units but is not aromatic (also referred to herein as "carbocycle", "cycloaliphatic" or "cycloalkyl"), having one point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic groups contain 1-4 aliphatic carbon atoms. In yet other embodiments, the aliphatic groups contain 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C ₃ -C ₆ hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, and which has a single point of attachment at the rest of the molecule. Examples of aliphatic groups are linear or branched, substituted or unsubstituted C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl) )alkenyl.

[0015] The term "lower alkyl" refers to a straight or branched chain C _1-4 alkyl group. Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0016] The term "lower haloalkyl" refers to a C _1-4 straight or branched alkyl group that is substituted with one or more halogen atoms.

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

[0018] The term “unsaturated” as used herein means that the moiety has one or more unsaturated units.

[0019] As used herein, the term “divalent C _1-8 (or C _1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” refers to divalent alkylene, alkenylene and alkynylene chains that are unbranched or branched as defined herein description.

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

[0021] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for the substituted aliphatic group.

[0022] The term "halogen" means F, Cl, Br or I.

[0023] 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 cycle in the system is aromatic, and each cycle of the system contains from three to seven members in the cycle. The term "aryl" is used interchangeably with the term "aryl ring". In some embodiments of the present invention, "aryl" refers to an aromatic ring system. Examples of aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the like, which optionally include one or more substituents. Also included within the scope of the term "aryl" as used herein is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl or tetrahydronaphthyl and the like.

[0024] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, such as "heteroaralkyl" or "heteroaralkoxy", refer to groups having from 5 to 10 ring atoms, preferably having 5, 6 or 9 ring atoms; having 6, 10 or 14 π-electrons shared in a cyclic system; and containing, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to a nitrogen, oxygen or sulfur atom and includes any oxidized form of nitrogen or sulfur and any quaternary form of basic nitrogen. Гетероарильные группы включают, без ограничения, тиенил, фуранил, пирролил, имидазолил, пиразолил, триазолил, тетразолил, оксазолил, изоксазолил, оксадиазолил, тиазолил, изотиазолил, тиадиазолил, пиридил, пиридазинил, пиримидинил, пиразинил, индолизинил, пуринил, нафтиридинил и птеридинил. The terms “heteroaryl” and “heteroar-” as used herein also include groups in which the heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein the radical or attachment point is located on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzoimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxa zinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido [2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group is optionally mono- or bicyclic. The term “heteroaryl” is used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” each of which includes rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with heteroaryl, where the alkyl and heteroaryl moieties are independently and independently substituted.

[0025] In this specification, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is either saturated , or partially unsaturated and contains, in addition to carbon atoms, one or more, preferably from one to four heteroatoms, as defined above. When used in connection with a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or ⁺ NR (as in N-substituted pyrrolidinyl).

[0026] The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom, resulting in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thia zepinil, morpholinil and quinuclidinil. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein and also include groups in which the heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3 H -indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, where the radical or attachment site is on a heterocyclyl ring. The heterocyclyl group is optionally mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with heterocyclyl, wherein the alkyl and heterocyclic moieties are independently and optionally substituted.

[0027] As used herein, the term “partially unsaturated” refers to a cyclic moiety that contains at least one double or triple bond. It should be understood that the term "partially unsaturated" includes rings containing multiple sites of unsaturation, but does not include aryl or heteroaryl moieties, as defined herein.

[0028]As used herein, some compounds of the invention contain "optionally substituted" moieties. In general, the term “substituted,” whether or not preceded by the term “optionally,” means that one or more hydrogen atoms of the moiety are substituted with a suitable substituent. "Substituted" refers to one or more hydrogen atoms that are present, either explicitly or implicitly, in the structure (specifically, applies at least to ; And applies at least to , , or . Unless otherwise specified, 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 the specified group, the substituent is either the same or different in every position. The combinations of substituents provided by the present invention are preferably those that lead to the formation of stable or chemically feasible compounds. The term “stable” as used herein refers to compounds that do not change significantly when exposed to the conditions necessary for their production, detection and, in some embodiments of the present invention, their isolation, purification and use in accordance with one or more purposes disclosed in this description.

[0029]Suitable monovalent substituents on the substitutable carbon atom of the "optionally substituted" group are independently deuterium; halogen; -(CH₂)_0-4R°; -(CH₂)_0-4OR°; -O(CH₂)_0-4R°, -O-(CH₂)_0-4C(O)OR°; -(CH₂)_0-4CH(OR°)₂; -(CH₂)_0-4SR°; -(CH₂)_0-4Ph, which are optionally substituted with R°; -(CH₂)_0-4O(CH₂)_0-1Ph, which is optionally substituted with R°; -CH=CHPh, which is optionally substituted with R°; -(CH₂)_0-4O(CH₂)_0-1-pyridyl, which is optionally substituted with R°; -NO₂; -CN; -N₃; (CH₂)_0-4N(R°)₂; -(CH₂)_0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH₂)_0-4N(R°)C(O)NR°₂; N(R°)C(S)NR°₂; -(CH₂)_0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; N(R°)N(R°)C(O)NR°₂; N(R°)N(R°)C(O)OR°; -(CH₂)_0-4C(O)R°; -C(S)R°; -(CH₂)_0-4C(O)OR°; -(CH₂)_0-4C(O)SR°; (CH₂)_0-4C(O)OSiR°₃; -(CH₂)_0-4OC(O)R°; -OC(O)(CH₂)_0-4SR°, SC(S)SR°; -(CH₂)_0-4SC(O)R°; -(CH₂)_0-4C(O)NR°₂; -C(S)NR°₂; -C(S)SR°; -SC(S)SR°, (CH₂)_0-4OC(O)NR°₂; C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH₂C(O)R°; -C(NOR°)R°; (CH₂)_0-4SSR°; -(CH₂)_0-4S(O)₂R°; -(CH₂)_0-4S(O)₂OR°; -(CH₂)_0-4OS(O)₂R°; -S(O)₂NR°₂; (CH₂)_0-4S(O)R°; N(R°)S(O)₂NR°₂; -N(R°)S(O)₂R°; -N(OR°)R°; -C(NH)NR°₂; -P(O)₂R°; P(O)R°₂; OP(O)R°₂; -OP(O)(OR°)₂; SiR°₃; -(WITH_1-4 straight or branched chain alkylene)O-N(R°)₂; or with_1-4 straight or branched chain alkylene)C(O)O-N(R°)₂, wherein each R° is optionally substituted as defined below and is independently hydrogen, C_1-6 aliphatic group, -CH₂Ph, -O(CH₂)_0-1Ph, -CH₂-(5-6 membered heteroaryl ring), or 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or regardless of the above definition, two available independent R°, together with their intermediate atom(s), form a 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur atom, which is optionally substituted as defined below.

[0030] Suitable monovalent substituents on R° (or a ring formed by two independent instances of R° together with their intermediate atoms) are independently deuterium, halogen, -(CH ₂ ) _0-2 R ^• , - (haloR ^• ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^• , -(CH ₂ ) _0-2 CH(OR ^• ) ₂ ; O(haloR ^• ), -CN, -N ₃ , -(CH ₂ ) _0-2 C(O)R ^• , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^• , -(CH ₂ ) _0-2 SR ^• , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^• , -(CH ₂ ) _0-2 NR ^• ₂ , -NO ₂ , -SiR ^• ₃ , -OSiR ^• ₃ , C(O)SR ^• _, -(C _1-4 straight or branched chain alkylene)C(O) OR ^• , or -SSR ^• , wherein each R ^• is unsubstituted or, when preceded by a "halo", is substituted with only one or more halogens, and independently selected from a C _1-4 aliphatic group, -CH ₂ Ph, -O (CH ₂ ) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom R° include =O and =S.

[0031] Suitable divalent substituents on the saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) ₂ R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3 O- or -S(C(R ^* ₂ )) _2-3 S-, where for each independent occurrence of R ^* selected from a hydrogen atom, a C _1-6 aliphatic group that is substituted as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to the vicinal substitutable carbon atoms of the "optionally substituted" group include -O(CR ^* ₂ ) _2-3O- , wherein each independent occurrence of R ^* is selected from a hydrogen atom of a _C1-6 aliphatic group , which is optionally substituted, as defined below, or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0032] Suitable substituents on the aliphatic group on R ^* include halogen, -R ^• , (haloR ^• ), OH, -OR ^• , -O(haloR ^• ), -CN, -C(O)OH, -C(O )OR ^• , -NH ₂ , -NHR ^• , -NR ^• ₂ or -NO ₂ wherein each R ^• is unsubstituted or, when preceded by a "halo", is substituted with only one or more halogens, and is independently C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0033] Suitable substituents for the substitutable nitrogen atom in the "optionally substituted" group include -R ^† , -NR ^† ₂ , -C(O)R ^† , -C(O)OR ^† , -C(O)C(O )R ^† , -C(O)CH ₂ C(O)R ^† , -S(O) ₂ R ^† , S(O) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , -C(NH) NR ^† ₂ or -N(R ^† )S(O) ₂ R ^† ; where each R ^† independently represents a hydrogen atom, a C _1-6 aliphatic group that is optionally substituted, as defined below, with an unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms, independently selected from nitrogen, oxygen or sulfur, or regardless of the above definition, the two independent R ^† present, together with their intermediate atom(s), form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl mono- or bicyclic ring , having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0034] Suitable substituents on the aliphatic group on R ^† are independently halogen, -R ^• , (haloR ^• ), -OH, -OR ^• , -O(haloR ^• ), -CN, -C(O)OH, - C(O)OR ^• , -NH ₂ , -NHR ^• , -NR ^• ₂ or NO ₂ , wherein each R ^• is unsubstituted or, when preceded by a "halo", is substituted with only one or more halogens, and independently represents is a C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring containing 0-4 heteroatoms independently selected from the nitrogen atom, oxygen or sulfur.

[0035] In some embodiments, the terms “optionally substituted”, “optionally substituted alkyl”, “optionally substituted alkenyl”, “optionally substituted alkynyl”, “optionally substituted carbocyclic”, “optionally substituted aryl”, “optionally substituted heteroaryl”, “ "optionally substituted heterocyclic" and any other optionally substituted groups as used herein refer to groups that are substituted or unsubstituted by independently replacing one, two, or three or more hydrogen atoms therein with typical substituents, including, without limitation:

-F, -C, -Br, -I, deuterium,

-OH, protected by hydroxy, alkoxy, oxo, thioxo,

-NO ₂ , -CN, CF ₃ , N ₃ ,

-NH ₂ , protected amino, -NH alkyl, -NH alkenyl, -NH alkynyl, -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,

-CONH ₂ , -CONH-alkyl, -CONH-alkenyl, -CONH-alkynyl, -CONH-carbocyclyl, -CONH-aryl, -CONH-heteroaryl, -CONH-heterocyclyl,

-OCO ₂ -alkyl, -OCO ₂ -alkenyl, -OCO ₂ -alkynyl, -OCO _{2 -carbocyclyl, -OCO 2 -aryl} , -OCO ₂ -heteroaryl, -OCO ₂ -heterocyclyl, -OCONH ₂ , -OCONH-alkyl , -OCONH-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, -NHCO ₂ -alkyl, -NHCO ₂ -alkenyl _, -NHCO ₂ -alkynyl, -NHCO ₂ -carbocyclyl, -NHCO 2 -aryl, -NHCO ₂ -heteroaryl, -NHCO ₂ -heterocyclyl, -NHC (O)NH ₂ , -NHC(O)NH-alkyl, -NHC(O)NH-alkenyl, -NHC(O)NH-alkenyl, -NHC(O)NH-carbocyclyl, -NHC(O)NH-aryl , -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocyclyl, NHC(S)NH ₂ , -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)NH ₂ , -NHC( NH)NH- alkyl, -NHC(NH)NH- -alkenyl, -NHC(NH)NH- alkenyl, -NHC(NH)NH- carbocyclyl, -NHC(NH)NH-aryl, -NHC(NH)NH- heteroaryl, -NHC(NH)NH-heterocyclyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, -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, -C(NH)NH-aryl, -C(NH) NH-heteroaryl, -C(NH)NH-heterocyclyl,

-S(O)-alkyl, -S(O)-alkenyl, -S(O)-alkynyl, - S(O)-carbocyclyl, -S(O)-aryl, -S(O)-heteroaryl, -S (O)-heterocyclyl -SO ₂ NH ₂ , -SO ₂ NH-alkyl, -SO ₂ NH-alkenyl, -SO ₂ NH-alkynyl, -SO ₂ NH-carbocyclyl, -SO ₂ NH-aryl, -SO ₂ NH -heteroaryl, -SO ₂ NH-heterocyclyl,

-NHSO ₂ -alkyl, -NHSO ₂ -alkenyl, -NHSO ₂ -alkynyl _, -NHSO ₂ -carbocyclyl, -NHSO 2 -aryl, -NHSO ₂ -heteroaryl, -NHSO ₂ -heterocyclyl,

-CH ₂ NH ₂ , -CH ₂ SO ₂ CH ₃ ,

-mono-, di- or tri-alkylsilyl,

-alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, -cycloalkyl, -carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl , -S-alkenyl, -S-alkynyl, -S-carbocyclyl, -S-aryl, -S-heteroaryl, S-heterocyclyl or methylthiomethyl.

[0036] As used herein, the term "pharmaceutically acceptable salt" refers to those salts that are medically suitable for use in contact with tissues of humans and lower animals and do not cause undue toxicity, irritation, allergic reaction, or the like, and have a reasonable benefit/risk ratio. "Pharmaceutically acceptable salts" are well known in the art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are amino salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid , citric acid, succinic acid or malonic acid, or by other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate , pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

[0037] Salts derived from suitable bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Examples of alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts and the like. Other pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkylsulfonate and arylsulfonate.

[0038] Unless otherwise stated, structures described herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R- and S-configurations for each asymmetric center, Z- and E-isomers with a double bond, and conformational Z- and E-isomers. Therefore, individual stereochemical isomers, as well as enantiomeric, diastereomeric and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of this invention are included within the scope of the present invention.

[0039] In addition, unless otherwise indicated, the structures described herein also include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures described herein, including the replacement of hydrogen with deuterium or tritium, or the replacement of carbon with ¹³ C- or ¹⁴ C-rich carbon, are within the scope of the present invention. In some embodiments, the group contains one or more deuterium atoms.

[0040] In addition, the compound of formula I is intended to include isotopically labeled forms thereof. The isotopically labeled form of a compound of formula I is identical to the title compound except that one or more atoms of the compound are replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of the atom that is normally found in nature. Examples of isotopes that are readily available on the market and that can be incorporated into a compound of formula I by well known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ CI, respectively. A compound of formula I, a prodrug form thereof or a pharmaceutically acceptable salt which contains one or more of the above isotopes and/or other isotopes of other atoms is also part of the present invention. The isotopically labeled compound of formula I can be used in a number of useful ways. For example, an isotope-labeled compound of formula I, in which, for example, a radioisotope such as ³ H or ¹⁴ C is included, is suitable for analyzing the tissue distribution of a drug and/or substrate. These radioactive isotopes, such as tritium ( ^3H ) and carbon-14 ( ^14C ), are particularly preferred due to their ease of preparation and excellent detectability. The inclusion of heavier isotopes, for example, deuterium ( ^2H ), in a compound of Formula I provides therapeutic benefits due to the greater metabolic stability of the isotopically labeled compound. Greater metabolic stability results directly in increased in vivo half-life or reduced dosage, which in most cases represents a preferred embodiment of the present invention. An isotopically labeled compound of formula I can generally be prepared by the procedures set forth in the synthesis schemes and in the accompanying description in the Examples and Preparation Methods section of this application by replacing the non-isotopically labeled reagent with a readily available isotope-labeled reagent.

[0041] Deuterium ( ^2H ) may also be included in a compound of formula I to alter the oxidative metabolism of the compound through a primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction that results from the exchange of isotopic nuclei, which in turn is caused by a change in the ground state energy required to form a covalent bond after this isotope exchange. Exchange of a heavier isotope typically results in a decrease in the ground state energy of a chemical bond and thus causes a decrease in the rate of bond cleavage under rate limitation. When bond cleavage occurs directly at or near a saddle point along the reaction coordinate for the formation of multiple products, the product distribution ratio can change significantly. To explain: in the case where deuterium binds to a carbon atom in a position in which no exchange occurs, differences in the rate k _M /k _D = 2-7 are typical. If such a rate difference is successfully applied to an oxidation-sensitive compound of Formula I, the in vivo profile of that compound may be radically altered and may result in improved pharmacokinetic properties.

[0042] When identifying and developing therapeutic agents, one skilled in the art can optimize pharmacokinetic parameters while maintaining desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information on the course of this type of oxidative metabolism, which in turn allows the rational design of deuterated compounds of formula I with improved stability due to resistance to such oxidative metabolism. Thus, significant improvements are achieved in the pharmacokinetic profiles of the compounds of formula I, which can be quantified as increases in in vivo half-life (t/2), concentration at maximum therapeutic effect ( _Cmax ), area under the dose-response curve (AUC) and F; as well as in the form of a decrease in clearance, dose and material costs.

[0043] The following is intended to illustrate the above: a compound of formula I, which has numerous potential sites for oxidative metabolism, for example, benzyl hydrogen atoms and hydrogen atoms connected to a nitrogen atom, is prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms such that some, most or all of these hydrogen atoms are replaced by deuterium atoms. Determination of half-life allows a favorable and accurate determination of the degree of improvement in resistance to oxidative metabolism. It was found that the half-life of the original compound can be increased up to 100% as a result of deuterium-hydrogen exchange of this type.

[0044] Deuterium-hydrogen exchange in a compound of formula I can also be used to achieve beneficial modification of the metabolite spectrum of the parent compound to reduce or eliminate unwanted toxic metabolites. For example, if a toxic metabolite arises from oxidative cleavage of a carbon-hydrogen (C-H) bond, then it is reasonably expected that the deuterated analogue will greatly reduce or eliminate the formation of the unwanted metabolite, even in the case where the particular oxidation is not the rate-limiting step. Additional prior art information regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55 , 3992-3997, 1990, Reider et al., J. Org. Chem. 52 , 3326-3334, 1987, Foster, Adv. Drug Res. 14 , 1-40, 1985, Gillette et al, Biochemistry 33 (10) 2927-2937, 1994, and Jarman et al. Carcinogenesis 16 (4), 683-688, 1993.

[0045] As used herein, the term “modulator” is defined as a compound that binds to and/or inhibits a target with measurable affinity. In some embodiments, the modulator has an IC ₅₀ value and/or binding constant of less than about 50 μM, less than about 1 μM, less than about 500 nM, less than about 100 nM, or less than about 10 nM.

[0046] The terms “measurable affinity” and “markedly inhibit” as used herein mean a measurable change in IRAK activity between a sample containing a compound of the present invention or a composition thereof and IRAK and an equivalent sample containing IRAK in the absence of said compound or composition thereof. compositions.

[0047] The combinations of substituents and variables provided by this invention are only those that lead to the formation of stable compounds. The term “stable” as used herein refers to compounds that are stable enough to be manufactured and that maintain 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 subject).

[0048] The listing of chemical groups in any definition of a variable in this description includes definitions of the specified variable as any single group or combination of listed groups. The reference to an embodiment for a variable in this specification includes this embodiment as any single embodiment or in combination with any other embodiments or parts thereof.

3. Description of typical connections

[0049] In accordance with one aspect, the present invention provides a compound of formula I ,

I

or a pharmaceutically acceptable salt thereof, where:

A' is C=O, C(R) ₂ or NR;

L represents a divalent group selected from C _3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted;

X represents CR or N;

Y represents NR or S;

Z represents CR or N;

R ¹ is a C _3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6 -membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted;

R ² represents -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , SO ₂ R, SOR, C(O)R, CO ₂ R, C(O)N(R) ₂ , -NRC(O)R, NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

each R independently represents hydrogen, a C _1-6 aliphatic group, a C _3-10 aryl group, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from atom nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; or

two R groups on the same atom, taken together with the atom to which they are attached, form a C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocyclic ring containing 1- 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; where each is optionally replaced.

[0050] In some embodiments, A' is C=O. In some embodiments, A' is C(R) ₂ . In some embodiments, A' is NR.

[0051] In some embodiments, A' is C=O, CH ₂ , CHOH, or NH.

[0052] In some embodiments, A' is C=O. In some embodiments, A' is CH ₂ . In some embodiments, A' is CHOH. In some embodiments, A' is NH.

[0053] In some embodiments, L is a divalent, optionally substituted C _3-10 aryl. In some embodiments, L is an optionally substituted 3-8 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, L is an optionally substituted 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, L is a divalent, optionally substituted, 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0054] In some embodiments, L is a divalent group selected from the following: phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctanyl, [4.3.0]bicyclononanyl, [4.4.0]bicyclodecanyl, [2.2.2]bicyclooctanyl, fluorenyl, indanyl, tetrahydronaphthyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl , benzimidazolinyl, carbazolyl, NH carbazolyl , carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanil, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl , indolizinyl, indolyl, 3H-indolyl, isoindolinyl, isoindolenyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4 -oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyra zinil, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofu ranil, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H- 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, azetidinyl and xanthenyl; each of which is optionally substituted.

[0055] In some embodiments, L is a divalent group selected from the following: phenyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, isoxazolyl, oxadiazolyl, 1,2, 3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, thiazolyl, thienyl, thiophenyl, oxetanyl and azetidinyl, each of which is optionally substituted.

[0056] In some embodiments, L is a divalent group selected from the following: phenyl, cyclohexyl, and cyclohexenyl; each of which is optionally substituted.

[0057] In some embodiments, L is a divalent group selected from the following:

, , , , , , , And .

[0058] In some embodiments, in the above definitions of L, each group may face in the direction shown or in the opposite direction (for example, imagines how , so ).

[0059] In some embodiments, X is CR. In some embodiments, X is CH. In some embodiments, X is N.

[0060] In some embodiments, Y is NR. In some embodiments, Y is NMe. In some embodiments, Y is S.

[0061] In some embodiments, Z is CR. In some embodiments, Z is CH. In some embodiments, Z is N.

[0062] In some embodiments, Z is N, Y is NR, and X is CR.

[0063] In some embodiments, Z is N, Y is NR, and X is N.

[0064] In some embodiments, Z is N, Y is S, and X is CR.

[0065] In some embodiments, Z is CR, Y is NR, and X is N.

[0066] In some embodiments, R ¹ is C _3-10 aryl.

[0067] In some embodiments, R ¹ is

, , or .

[0068] In some embodiments, R ² is a C _1-6 aliphatic group, a C _3-10 aryl group, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms, independently selected from a nitrogen, oxygen or sulfur atom, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from a nitrogen, oxygen or sulfur atom; where each is optionally replaced.

[0069] In some embodiments, R ² is a C _1-6 aliphatic group.

[0070] In some embodiments, R ² is C _3-10 aryl.

[0071] In some embodiments, R ² is a 3-8 membered saturated or partially unsaturated carbocyclic ring.

[0072] In some embodiments, R ² is a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0073] In some embodiments, R ² is a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0074] In some embodiments, R ² is a C _1-6 aliphatic group or a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0075] In some embodiments, R ² is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, straight or branched chain pentyl, or straight or branched chain hexyl, or R ² is 4 -membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0076] In some embodiments, R ² is -CF ₃

, , , or .

[0077] In some embodiments, each of A', L, X, Y, Z, R, R ¹ and R ² has the meanings defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combinations.

[0078] In some embodiments, the present invention provides a compound of formula I-a ,

I-a;

[0079] or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y, R ¹ and R ² is as defined above and described in the embodiments, in the foregoing classes and subclasses herein, alone or in combination.

[0080] In some embodiments, the present invention provides a compound of formula Ib ,

I-b;

or a pharmaceutically acceptable salt thereof, wherein each of L, X, R ¹ and R ² has the meanings defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combination.

[0081] In some embodiments, the present invention provides a compound of formula I-c ,

I-c;

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y, R ¹ and R ² is as defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combination.

[0082] In some embodiments, the present invention provides a compound of formula Id ,

I-d;

or a pharmaceutically acceptable salt thereof, wherein each of L, X, R ¹ and R ² has the meanings defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combination.

[0083] In some embodiments, the present invention provides a compound of formula Ie ,

I-e;

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y, Z, R ¹ and R ² is as defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combination.

[0084] In some embodiments, the present invention provides a compound of formula If ,

I-f;

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y, R ¹ and R ² is as defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combination.

[0085] In some embodiments, the present invention provides a compound of formula Ig ,

I-g;

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Y, R ¹ and R ² is as defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combination.

[0086] In some embodiments, the present invention provides a compound of formula Ih ,

I-h;

or a pharmaceutically acceptable salt thereof, wherein each of L, X, R ¹ and R ² has the meanings defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combination.

[0087] In some embodiments, the present invention provides a compound of formula Ij ,

I-j;

or a pharmaceutically acceptable salt thereof, wherein each of L, X, Z, R ¹ and R ² is as defined above and described in the embodiments, in the above classes and subclasses herein, alone or in combination.

[0088] In some embodiments, the present invention provides a compound selected from Table 1:

Table 1

1 2 3 4 5 6 7 8 9 10 eleven 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29

[0089] In some embodiments, the present invention provides a compound selected from those depicted above, or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compounds of the present invention exhibit increased microsomal stability and permeability.

[0091] Various structural images may show a heteroatom without an attached group, radical, charge or counterion. Those skilled in the art will be aware that such images are intended to indicate that the heteroatom is attached to a hydrogen atom (for example, under should be understood ).

[0092] In some embodiments, the compounds of the present invention are synthesized in accordance with the schemes shown in the examples below.

4. Applications, preparation and administration

Pharmaceutically acceptable compositions

[0093] In accordance with another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, excipient or excipient. The amount of compound in the compositions of this invention is such that it is effective to measurably inhibit IRAK, or a mutant thereof, in a biological sample or in a patient. In some embodiments, the amount of compound in the compositions of this invention is such that it is effective to measurably inhibit IRAK, or a mutant thereof, in a biological sample or in a patient. In some embodiments, the composition of the present invention is prepared for administration to a patient in need of such a composition.

[0094] The term “patient” or “subject” as used herein means an animal, preferably a mammal, and most preferably a human.

[0095] The term "pharmaceutically acceptable carrier, excipient or excipient" refers to a non-toxic carrier, excipient or excipient that does not interfere with the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, excipients or excipients used in the compositions of this invention include, but are not limited to, ion exchange resins, alumina, aluminum stearate, lecithin, whey proteins such as human serum albumin, buffers such as phosphates, glycine, sorbic acid acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silicon dioxide, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium derivative of carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block copolymers, polyethylene glycol and lanolin.

[0096] The term "pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of a compound of the present invention which, when administered to a recipient, is capable of forming, directly or indirectly, the compound of the present invention or an inhibitory metabolite thereof or its remainder.

[0097] The compositions of the present invention are administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or through an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial administration or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of the present invention include an aqueous or oily suspension. These suspensions are prepared in accordance with methods 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 a solution in 1,3-butanediol. Acceptable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution. In addition to this, sterile fixed oils are commonly used as a solvent or suspending medium.

[0098] For this purpose, any soft fixed oil used includes synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectable preparations, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxyethylene variants. These oily solutions or suspensions also contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersing agents, which are commonly used for the preparation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms may also be used for the purpose of preparing the composition.

[0099] The pharmaceutically acceptable compositions of this invention are administered orally in any orally acceptable dosage form. Examples of oral dosage forms are capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also commonly added. For oral administration in capsule form, suitable diluents include lactose and dried corn starch. If aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. Optionally, certain sweeteners, flavorings or colors are also added, if desired.

[00100] Alternatively, the pharmaceutically acceptable compositions of this invention are administered in the form of suppositories for rectal administration. They 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 will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[00101] Pharmaceutically acceptable compositions of this invention are also applied topically, particularly when the target of treatment is areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestine. Suitable topical compositions are readily prepared for each of the designated sites or organs.

[00102] Topical administration to the lower intestinal tract can be provided in the form of compositions for rectal use (see above) or in the form of suitable compositions for enema. Topical transdermal patches are also used.

[00103] For topical use, the pharmaceutically acceptable compositions of the invention are formulated as a suitable ointment containing the active ingredient which is suspended or dissolved in one or more carriers. Examples of carriers for topical administration of the compounds of the present invention are mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions of the invention may be formulated as a suitable lotion or cream containing the active ingredients which are suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[00104] The pharmaceutically acceptable compositions of this invention are optionally administered as a nasal aerosol or by inhalation. Such compositions are prepared in accordance with techniques well known in the art of pharmaceutical formulation and are formulated as solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons and/or other conventional solubilizing or dispersing agents.

[00105] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. These medications may be given with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered separately from food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[00106] The amount of compounds of the present invention, which are optionally combined with carrier materials to formulate a unit dosage form, will vary depending on the patient and the particular route of administration. Preferably, the present compositions should be formulated so that a dose of the compound in the range of 0.01-100 mg/kg body weight/day can be administered to a patient receiving the compositions.

[00107] It should also be kept in mind that the specific dose and treatment regimen for any particular patient will depend on numerous factors, including the potency of the particular compound used, age, body weight, general health, gender, diet, time of administration, the rate of elimination, the combination of drugs, and the decisions of the attending physician, as well as the severity of the specific disease being treated. The amount of a compound of the present invention in the composition will also depend on the particular compound in the composition.

Uses of compounds and pharmaceutically acceptable compositions

[00108] The present invention also provides a method of treating a subject suffering from IRAK-related disorders, comprising administering to said subject an effective amount of a compound of Formula I and related formulas.

[00109] The present invention preferably provides a method wherein the IRAK-related disorder is an autoimmune disease or a condition associated with an overactive immune response or cancer. The present invention also provides a method of treating a subject suffering from an immunoregulatory disorder, comprising administering to said subject a compound of formula (I) and related formulas in an amount effective to treat said immunoregulatory disorder.

[00110] The present invention preferably relates to a method in which the immunoregulatory disorder is an autoimmune or chronic inflammatory disease selected from the group consisting of: allergic diseases, amyotrophic lateral sclerosis (ALS), systemic lupus erythematosus, chronic rheumatoid arthritis, diabetes mellitus I type, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy and asthma.

[00111] The present invention also provides a method wherein the immunoregulatory disorder is a bone marrow pathology or organ transplant rejection or graft-versus-host disease.

[00112] The present invention further provides a method wherein the immunoregulatory disorder is selected from the group consisting of: organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases, including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigoid, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis , uveitis associated illumination of Bekhceta, keratitis, herpetic keratitis, conical cornea, dystrophy of the epithelium of the cornea, leukoma of the cornea, pemphigoid conjunctiva, ulcer of Muren, scleritis, ophthalmopathy of the Graves, fogt-coyanagi-harade, sarcoidosis, pollen allergies, inpective illumination of respiratory trains, bronchi acute asthma, allergic asthma, endogenous asthma, exogenous asthma, dust asthma, chronic or inveterate asthma, late-onset asthma and airway hypersensitivity, bronchitis, gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, damage intestines associated with thermal burns, celiac disease, 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 syndrome , Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, true erythrocyte aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, pneumofibrosis, 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 granulomatosis, Sjögren's syndrome, obesity , eosinophilic fasciitis , gum lesions, periodontium, alveolar bone, dental osseous substance, glomerulonephritis, male alopecia or senile alopecia, by preventing hair loss or promoting hair growth and/or stimulating hair restoration and growth, muscular dystrophy, pyoderma and Sézary's syndrome, Addison's disease, ischemic -reperfusion injury to organs occurring during preservation, transplantation or ischemic disease, endotoxic shock, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, toxinosis caused by oxygen poisoning or drugs, lung cancer, emphysema, cataract, siderosis, retinitis pigmentosa, senile macular degeneration, vitreal scarring, alkali burn of the cornea, dermatitis, erythema multiforme, linear IgA-dependent bullous dermatitis and cementitious dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution , aging, carcinogenesis, carcinoma metastasis and hypobaropathy, histamine or leukotriene-C4 release disease, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, toxin-induced necrosis, viral hepatitis, shock or anoxia, viral hepatitis B, hepatitis C, cirrhosis, alcoholic cirrhosis, liver failure, fulminant liver failure, late-onset liver failure, acute-to-chronic liver failure, increasing chemotherapy effect, cytomegalovirus infection, CMV infection, AIDS, cancer, dementia, Parkinson's disease, trauma and chronic bacterial infection.

[00113] In some embodiments, the disorders associated with IRAK are selected from the following: rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, type I diabetes, diabetes type II, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult Still's disease, gout, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease and cancer.

[00114] In some embodiments, the cancer is selected from carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningiomas, adenocarcinomas, melanomas and leukemia or lymphoid malignancies. More specific examples of such cancers include squamous cell cancer (eg, squamous cell carcinoma), lung cancer, including small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma and squamous cell carcinoma of the lung, peritoneal cancer, hepatocellular carcinoma , stomach cancer, including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer (including metastatic breast cancer), colon cancer, rectal cancer colon, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocarcinoma, anal carcinoma, penile carcinoma, testicular cancer, esophageal cancer, biliary tract tumors, and cancer head and neck.

[00115] In some embodiments, the cancer is brain, lung, colon, epidermoid, squamous cell, bladder, stomach, pancreatic, breast, head, neck, kidney, liver, ovarian, prostate, colorectal cancer, cancer of the uterus, rectum, esophagus, testicle, female genital organs, thyroid cancer, melanoma, hematological malignancies such as acute myeloid leukemia, multiple myeloma, chronic myeloid leukemia, myeloid cell leukemia, glioma, Kaposi's sarcoma or any other type of dense tumors or tumors of liquid tissues. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is colon cancer.

[00116] In various embodiments, compounds of formula (I) and related formulas exhibit an IC ₅₀ for binding to IRAK of less than about 5 μM, preferably less than about 1 μM, and even more preferably less than about 0.100 μM.

[00117] The method of the present invention can be carried out both in vitro and in vivo . The susceptibility of a particular cell to treatment with the compounds of the present invention may, in particular, be determined by in vitro testing, both in research and in clinical use. Typically, the cell culture is combined with a compound of the invention at varying concentrations for a period of time sufficient to allow the active agents to inhibit IRAK activity, typically from about 1 hour to 1 week. In vitro processing can be accomplished using cultured cells from a biopsy sample or cell line.

[00118] The host or patient may belong to any mammalian species, for example, primate species, in particular humans; rodents, including mice, rats and hamsters; rabbits, horses, cows, dogs, cats, etc. Animal models are of interest for experimental research because they serve as models for the treatment of human diseases.

[00119] To identify the signal transduction pathway and to detect interactions between different signal transduction pathways, various scientists have developed suitable models or model systems, for example, cell culture models and transgenic animal models. To establish certain stages in the signal transduction cascade, interfacing connections can be used to modulate the signal. The compounds of the present invention can also be used as reagents for testing IRAK-dependent signal transduction pathways in animals and/or cell culture models or for the treatment of clinical diseases described in this application.

[00120] In addition, the following statement in this description regarding the use of compounds of formula (I) and derivatives thereof for the preparation of a medicament for prophylaxis or therapeutic effects and/or monitoring is considered to be valid and applies without limitation to the use of the compound for inhibiting IRAK activity, if appropriate.

[00121] The present invention also relates to the use of compounds of formula (I) and/or physiologically acceptable salts thereof for the prophylaxis or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by IRAK activity. Furthermore, the present invention relates to the use of compounds of formula (I) and/or physiologically acceptable salts thereof for the preparation of a medicament for the prophylaxis or therapeutic treatment and/or monitoring of diseases that are caused, mediated and/or propagated by IRAK activity. In some embodiments, the invention provides the use of a compound of Formula I or physiologically acceptable salts thereof for the preparation of a medicament for the prevention or treatment of an IRAK-mediated disorder.

[00122] The compounds of formula (I) and/or their physiologically acceptable salts may further be used as an intermediate for the preparation of other active drug ingredients. Said medicinal product is preferably prepared in a reagent-free manner, for example by combining the active ingredient with at least one solid, liquid and/or semi-liquid carrier or inert excipient, optionally in combination with one or more other active substances in an appropriate dosage form.

[00123] The compounds of formula (I) of the present invention can be administered before or after the onset of the disease once or several times, providing a therapeutic effect. The above compounds and drugs of the present invention are particularly used for therapeutic purposes. A therapeutically significant effect eliminates to some extent one or more symptoms of a disorder, or returns to normal, either partially or completely, one or more physiological or biochemical parameters associated with the cause of the disease or pathological condition. Monitoring is considered a form of treatment provided that the compounds are administered at certain intervals, for example, to enhance the response and completely eliminate pathogenic factors and/or symptoms of the disease. Either identical connections or different connections can be used. The methods of the invention can also be used to reduce the likelihood of developing a disease or even to prevent the onset of disorders associated with IRAK activity in advance or to treat emerging and ongoing symptoms.

[00124] In the context of the present invention, prophylactic treatment is appropriate if the subject has any predisposition to the above physiological or pathological conditions, for example, a family predisposition, a genetic defect or a previous disease.

[00125] The invention also relates to a medicinal product containing at least one compound of the present invention and/or pharmaceutically acceptable derivatives, salts, solvates and stereoisomers thereof, including mixtures thereof in all proportions. In some embodiments, the invention relates to a medicinal product containing at least one compound of the present invention and/or physiologically acceptable salts thereof.

[00126] "Drug" in the context of the present invention is any substance used in the field of medicine that contains one or more compounds of formula (I) or preparations thereof (for example, a pharmaceutical composition or pharmaceutical composition) and which can be used for prophylaxis, treatment, medical follow-up or rehabilitation of patients who suffer from diseases associated with IRAK activity, in such a way that a pathogenetic modification of their general condition or the condition of specific areas of the body can be established, at least temporarily.

[00127] In various embodiments, the active ingredient may be administered alone or in combination with other treatments. A synergistic effect can be achieved by using more than one compound in a pharmaceutical composition, i.e. a compound of formula (I) is combined with at least another agent as an active ingredient, which is either another compound of formula (I) or a compound with another structural framework. The active ingredients can be used either simultaneously or sequentially.

[00128] Included herein are methods of treatment in which at least one chemical drug provided herein is administered in combination with an anti-inflammatory agent. Anti-inflammatory agents include, but are not limited to, NSAIDs, non-specific and COX-2-specific cyclooxygenase enzyme inhibitors, gold compounds, corticosteroids, methotrexate, tumor necrosis factor (TNF) antagonists, immunosuppressants and methotrexate.

[00129] Examples of NSAIDs include, but are not limited to, ibuprofen, flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations of diclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen, nabumetone sodium, sulfasalazine, tolmetin sodium and hydroxychloroquine. Examples of NSAIDs also include COX-2 specific inhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

[00130] In some embodiments, the anti-inflammatory agent is a salicylate. Salicylates include, but are not limited to, acetylsalicylic acid or aspirin, sodium salicylate, and choline and magnesium salicylates.

[00131] The anti-inflammatory agent may also be a corticosteroid. For example, the corticosteroid may be cortisone, dexamethasone, methylprednisolone, prednisolone, prednisolone sodium phosphate, or prednisone.

[00132] In further embodiments, the anti-inflammatory agent is a gold compound such as sodium gold thiomalate or auranofin.

[00133] The invention also includes 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.

[00134] Other embodiments of the invention relate to combinations in which at least one anti-inflammatory compound is an anti-monoclonal antibody (such as eculizumab or pexelizumab), a TNF antagonist such as entanercept, or infliximab, which is an anti-TNF-alpha monoclonal antibody .

[00135] Still other embodiments of the invention relate to combinations in which at least one active agent is an immunosuppressive compound, such as an immunosuppressive compound selected from methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine and mycophenolate mofetil.

[00136] The described compounds of formula I can be administered in combination with other known therapeutic agents, including anticancer agents. In the present invention, the term “anti-cancer agent” refers to any agent that is administered to a patient with cancer for the treatment of cancer.

[00137] The anticancer treatment defined above may be used as monotherapy or may include, in addition to the compounds of Formula I disclosed herein, conventional surgery, radiation therapy, or drug therapy. Such drug therapy, such as chemotherapy or targeted therapy, may include one or more, but preferably one of the following antineoplastic agents:

Alkylating agents: such Kakkantretamin, Bendamustin, Busufan, Karmustin, Chlorambucil, Chlormetin, Cyclophosphamide, Dakarbazin, Iphospamide, Improsepan, Tosylat, Lomustin, Melpalalan, Mitobronitol, Mitolactol, Nimustin, Ranimustine, Temozolomid, Tyotep, Thyotep, Treepan, Mehsan, Mehsan loretamine, karkkvonon; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobromane, trofosfamide, uramustine, TH-302 ⁴ , VAL-083 ⁴ ;

Platinum compounds : such as carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin; lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA altering agents : such as camrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; amsacrine, brostallicin, pixantrone, laromustine ^1.3 ;

Topoisomerase inhibitors : such as etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan, amonafide, belotecan, elliptinium acetate, voreloxin;

Microtubule modifiers : such as cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabulin, tesetaxel;

Антиметаболиты : такие какаспарагиназа ³ , азацитидин, левофолинат кальция, капецитабин, кладрибин, цитарабин, эноцитабин, флоксуридин, флударабин, фторурацил, гемцитабин, меркаптопурин, метотрексат, неларабин, пеметрексед, пралатрексат, азатиоприн, тиогуанин, кармофур; doxyfluridine, elacitarabine, raltitrexed, sapacitabine, tegafur ^2,3 , trimetrexate;

Anticancer antibiotics : such as bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, cynostatin, zorubicin, daunurobicin, plicamycin, aclarubicin, peplomycin, pyrarubicin;

Hormones/Antagonists : such as cabarelix, abiraterone, bicalutamide, buserelin, calusterone, chlortrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide , octreotide, prednisolone , raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; akolbifen, danazol, deslorelin, epithiostanol, orteronel, enzalutamide ^1,3 ;

Aromatase inhibitors : such as aminogluethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formstan;

Small molecule kinase inhibitors : such as crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosin, ponatinib, radotinib, rigosertib, tipifarnib, tianti nib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib ⁴ , cabozantinib S-malate ^1,3 , ibrutinib ^1,3 , icotinib ⁴ , buparlisib ² , cipatinib ⁴ , cobimetinib ^1,3 , idelalisib ^1,3 , fedratinib ¹ , XL-647 ⁴ ;

Photosensitizers : such as methoxsalen ³ ; sodium porfimer, talaporfin, temoporfin;

Antibodies : such as calemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab ^2,3 ; catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab ^1,2,3 , onartuz umab ^1,3 , racotumomab ¹ , tabalumab ^1.3 , EMD-525797 ⁴ , nivolumab ^1.3 ;

Cytokines : such as aldesleukin, interferon alpha ² , interferon alpha2a ³ , interferon alpha2b ^2,3 ; celmoleukin, tazonermin, teceleukin, oprelvekin ^1,3 , recombinant interferon beta-1a ⁴ ;

Drug conjugates : such as denileukin diftitox, ibritumomab tiuxetan, iobenguane 1123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; cintredequin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technetium (99mTc) arcitumomab ^1.3 , vintafolide ^1.3 ;

Vaccines : such as sipuleucel ³ ; witespen ³ , emepepimut-S ³ , oncoVAX ⁴ , rindopepimut ³ , trovax ⁴ , MGN-1601 ⁴ , MGN-1703 ⁴ ; and Other : alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel ³ , sisofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vis modegib, zoledronic acid, vorinostat ; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxyl, iniparib, ixazomib, ionidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazole, ridaforolimus, tasquinimod, telotristat, thymalfasin, tirapazamine, tosedostat, trabedersen, ubenimex, valspodar, gendicin ⁴ , picibanil ⁴ , rheolysin ⁴ , retaspimycin hydrochloride ^1,3 , trebananib ^2,3 , virulysin ⁴ , carfilzomib ^1,3 , endostatin ^{4, immucotel 4 ,} belinostat ³ , MGN-1703 ⁴ .

( ¹ INN (proposed international nonproprietary name); ² Rec. INN (suggested international nonproprietary name); ³ US name (US Directory of National Nonproprietary Names name); ⁴ no INN).

[00138] In accordance with another aspect, the present invention provides a reagent kit consisting of individual packages of an effective amount of a compound of the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all ratios and, optionally, an effective amount of the additional active ingredient. This set of reagents includes suitable containers such as boxes, individual vials, bags or ampoules. The reagent kit may, for example, include individual ampoules, each containing an effective amount of a compound of the invention and/or pharmaceutically acceptable salts, derivatives, solvates and stereoisomers thereof, including mixtures thereof in all proportions, and an effective amount of an additional active ingredient in dissolved or lyophilized form.

[00139] Thus, it is particularly preferred: (1) The compound of formula I ,

I

or a pharmaceutically acceptable salt thereof, where:

A' is C=O, C(R) ₂ or NR;

L represents a divalent group selected from C _3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted;

X represents CR or N;

Y represents NR or S;

Z represents CR or N;

R ¹ is a C _3-10 aryl, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or 5-6 -membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted;

R ² represents -R, halogen, -haloalkyl, -OR, -SR, -CN, -NO ₂ , SO ₂ R, SOR, C(O)R, CO ₂ R, C(O)N(R) ₂ , -NRC(O)R, NRC(O)N(R) ₂ , -NRSO ₂ R or -N(R) ₂ ;

each R independently represents hydrogen, a C _1-6 aliphatic group, a C _3-10 aryl group, a 3-8 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from atom nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; each of which is optionally substituted; or

two R groups on the same atom, taken together with the atom to which they are attached, form a C _3-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring, 3-7 membered heterocyclic ring containing 1- 4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 5-6 membered monocyclic heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; where each is optionally replaced.

(2) The compound as described herein, preferably as described above and/or below, and more preferably as described in section (1), where A' represents C=O, CH ₂ , CHOH or NH.

(3) The compound as described herein, preferably as described above and/or below, and more preferably as described in section (1) and/or section (2), wherein L represents a divalent group selected from the following: phenyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl; 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, piperazinyl, piperidinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, thiazolyl, thienyl, thiophenyl, oxetanyl and azetidinyl, each of which is optionally substituted.

(4) The compound as described herein, preferably as described above and/or below, and more preferably as described in one or more sections (1) to (3), wherein L represents a divalent group selected from the following:

, , , , , , , And .

(5) The compound as described herein, preferably as described above and/or below, and more preferably as described in one or more sections (1) to (4), wherein R ¹ is C _3-10 aryl.

(6) The compound as described herein, preferably as described above and/or below, and more preferably as described in one or more sections (1) to (5), wherein R ¹ is

, , or .

(7) A compound as described herein, preferably as described above and/or below, and more preferably as described in one or more sections (1) to (6), wherein R ² represents a C _1-6 aliphatic group or a 3-7 membered heterocyclic ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

(8) The compound as described herein, preferably as described above and/or below, and more preferably as described in one or more sections (1) to (7), wherein R ² represents methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, straight or branched pentyl or straight or branched hexyl, or R ² is a 4-membered heterocyclic ring containing 1-4 heteroatoms independently selected from a nitrogen atom, oxygen or sulfur.

(9) The compound as described herein, preferably as described above and/or below, and more preferably as described in one or more sections (1) to (8), wherein R ² is -CF ₃ .

, , , or .

(10) A compound as described herein, preferably as described above and/or below, more preferably as described in one or more sections (1) to (9), and especially as described in section (1), having the formula Ia ,

I-a;

or a pharmaceutically acceptable salt thereof.

(11) A compound as described herein, preferably as described above and/or below, more preferably as described in one or more sections (1) to (10), and especially as described in section (1), having the formula I-s ,

I-c;

or a pharmaceutically acceptable salt thereof.

(12) A compound as described herein, preferably as described above and/or below, more preferably as described in one or more sections (1) to (10), and especially as described in section (1), having the formula Ie ,

I-e;

or a pharmaceutically acceptable salt thereof.

(13) A compound as described herein, preferably as described above and/or below, more preferably as described in one or more sections (1) to (10), and especially as described in section (1), having the formula Ih ,

I-h;

or a pharmaceutically acceptable salt thereof.

(14) A compound as described herein, preferably as described above and/or below, more preferably as described in one or more sections (1) to (10), and especially as described in section (1), selected from table 1.

(15) A pharmaceutical composition containing a compound as described herein, preferably as described above and/or below, more preferably as described in one or more sections (1) to (14), and especially as described in section (1 ), and a pharmaceutically acceptable excipient, carrier, or excipient.

(16) A method of inhibiting the activity of IRAK or a mutant thereof in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with a compound described herein, preferably as described above and/or below, more preferably as described in one or more of sections (1) to (14), and especially as described in section (1), or with a physiologically acceptable salt thereof.

(17) A method of treating an IRAK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient a compound as described herein, preferably as described above and/or below, more preferably as described in one or more sections (1) - (14), and especially as described in section (1).

(18) The method described herein, preferably as described above and/or below, more preferably as described in section (16) and/or section (17), and especially as described in section (17) where the violation is selected of the following: 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 (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, Still's disease in adults, gout, pseudogout, SAPHO syndrome, Castleman disease, endometriosis; sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease and cancer.

(19) A method of treating a subject as described herein, preferably as described above and/or below, and more preferably a method of treating cancer in a subject, said method comprising the step of administering to said subject a compound as described herein, preferably as described above and/or below, more preferably as described in one or more sections (1) to (14), and especially as described in section (1), or a physiologically acceptable salt thereof.

(20) The method described herein, preferably as described above and/or below, more preferably as described in section (16), section (17), section (18) and/or section (19), and especially as described in section (18), where the disorder is selected from rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis and multiple sclerosis.

[00140] As used herein, the terms “therapy,” “treat,” and “treatment” refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as defined herein. In some embodiments, treatment is administered after the development of one or more symptoms. 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 (eg, based on symptom history and/or genetic or other predisposition factors). Treatment is continued after the symptoms have disappeared, for example to prevent the development of symptoms or delay their recurrence.

[00141] The compounds and compositions in accordance with the method of the present invention are administered using any amount and any route of administration effective to treat or reduce the severity of the above disorder. The exact amount required will vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the infection, the particular agent, its route of administration, and the like. The compounds of the invention are preferably formulated in unit dosage form for ease of administration and dose uniformity. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent suitable for use in the patient being treated. It should be understood, however, that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within the bounds of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of that disorder; the activity of the particular compound used; the specific composition used; the age, body weight, general health, gender and diet of the patient; timing of administration, route of administration, and rate of elimination of the particular compound used; duration of treatment; drugs used in combination or concurrently with the particular compound used, and similar factors well known in the medical field.

[00142] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (in the form of powders, ointments or drops), buccally, as an oral or nasal spray, or the like. depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention are administered orally or parenterally in doses of from about 0.01 mg/kg to about 100 mg/kg, and preferably from about 1 mg/kg to about 50 mg/kg of the subject's body weight per day, one or several times a day in order to obtain the desired therapeutic effect.

[00143] In some embodiments, the therapeutically effective amount of a compound of formula (I) and related formulas, as well as other active ingredient, depends on a number of factors, including, for example, the age and weight of the animal, the precise condition of the disease that requires treatment, and its severity, the nature of the drug and the method of administration, and is ultimately determined by the attending physician or veterinarian. However, an effective amount of the compound will typically range from 0.1 to 100 mg/kg body weight of the recipient (mammal) per day, and preferably will typically range from 1 to 10 mg/kg body weight per day. Thus, the actual amount per day for a 70 kg adult mammal is usually from 70 to 700 mg, which amount may be administered as a single dose per day or usually as a series of partial 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 a physiologically functional derivative thereof may be defined as a proportion of the effective amount of the compound itself.

[00144] In some embodiments, pharmaceutical compositions can be administered in dosage units that contain a predetermined amount of active ingredient per dosage unit. Such a dosage unit may contain, for example, from 0.5 mg to 1 g, preferably from 1 mg to 700 mg, preferably from 5 mg to 100 mg of the compound according to the invention, depending on the condition of the disease to be treated, the method administration and the age, weight and condition of the patient, or the pharmaceutical formulations can be administered in dosage units that contain a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations are those containing a daily dose or a portion of a daily dose as defined above, or a corresponding portion of the active ingredient. Moreover, pharmaceutical compositions of this type can also be prepared by a method that is well known in the pharmaceutical field.

[00145] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, liquid dosage forms 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, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed, peanut, corn, sprout, olive, castor and sesame oils), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitol fatty acid esters and mixtures thereof . In addition to inert diluents, oral compositions may also contain excipients such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents and flavoring agents.

[00146] Injectable preparations, for example, sterile aqueous or oleaginous injectable suspensions, can be prepared in a known manner using suitable dispersing, wetting and/or suspending agents. A sterile injectable preparation is also a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. Acceptable carriers and solvents that may be used include water, USP Ringer's solution, and isotonic sodium chloride solution. In addition to this, sterile fixed oils are commonly used as a solvent or suspending medium. For this purpose, any soft, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable drugs.

[00147] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilants in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media prior to use.

[00148] In order to prolong the effect of the compound of the present invention, it is often necessary to slow down the absorption of the compound when administered subcutaneously or intramuscularly. This is achieved by using a liquid suspension of a crystalline or amorphous substance that has poor solubility in water. The rate of absorption of the compound then depends on the rate of its dissolution, which in turn may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by preparing microencapsulated matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the type of specific polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injection forms are also prepared by incorporating the compound into liposomes or microemulsions that are compatible with body tissues.

[00149] 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 suppository wax, which are solid at ambient temperature, but become liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[00150] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and/or a) excipients or diluents, such as starches, lactose, sucrose, glucose, mannitol and silica acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic, c) humectants such as glycerin, d) disintegrants such as agar-agar, calcium carbonate, potato starch or tapioca starch , alginic acid, some silicates and sodium carbonate, e) dissolution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form also optionally includes buffering agents.

[00151] Solid compositions of this type are also used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be formulated with coatings or coatings, such as enteric coatings, coatings and other coatings known in the art of pharmaceutical formulation. They optionally contain opalescent components and may also be a composition that releases the active ingredient(s) only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of potting compositions that can be used include polymeric materials and waxes. Solid compositions of this type are also used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[00152] The active compounds may also be in the form of microcapsules with one or more excipients, as described above. Solid dosage forms in the form of tablets, dragees, capsules, pills and granules can be formulated with coatings or shells, such as enteric coatings, controlled release coatings and other coatings known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms also contain, as is common in practice, additional substances other than inert diluents, for example tableting lubricants and other tabletting auxiliaries such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form also optionally includes buffering agents. They optionally contain opalescent components and may also be a composition that releases the active ingredient(s) only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of potting compositions that can be used include polymeric materials and waxes.

[00153] Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers, if necessary. It is intended that ophthalmic compositions, ear drops and eye drops also fall within the scope of this invention. It is further contemplated that the present invention utilizes transdermal patches which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of a compound through the skin. The rate can be controlled either by a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[00154] In one embodiment, the invention relates to a method of inhibiting IRAK activity in a biological sample, which includes the step of contacting said biological sample with a compound of the present invention or a composition containing said compound.

[00155] According to another embodiment, the invention relates to a method of inhibiting the activity of IRAK or a mutant thereof in a biological sample in a positive manner, which includes the step of contacting said biological sample with a compound of the present invention or a composition containing said compound.

[00156] The compounds of the present invention are useful in vitro as unique tools for understanding the biological role of IRAK, including the assessment of many factors believed to influence and be influenced by IRAK production and IRAK interaction. The compounds of the present invention are also useful in the development of other compounds that interact with IRAK, since the compounds of the present invention provide important structure-response (SAR) information that facilitates this development. The compounds of the present invention that bind to IRAK can be used as reagents for detecting IRAK in living cells, fixed cells, biological fluids, tissue homogenates, purified natural biological substances, etc. For example, by labeling such compounds, cells expressing IRAK can be identified. In addition, based on their ability to bind IRAK, the compounds of the present invention can be used in in situ staining, FACS (fluorescent activated cell sorting), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), ELISA (enzyme-linked immunosorbent assay ) etc., in the purification of an enzyme or in the purification of cells expressing IRAK within permeabilized cells. The compounds of the present invention can also be used as commercial research reagents for various medical research and diagnostic purposes. Such uses may include, but are not limited to: use as a calibration standard to quantify the activity of potential IRAK inhibitors in various functional assays; use as blocking reagents in random screening of compounds, e.g. in the search for new families of IRAK ligands, wherein the compounds can be used to block the reduction of the IRAK compounds claimed in the present invention; use in co-crystallization with the IRAK enzyme, i.e. the compounds of the present invention will allow the formation of crystals of the compound associated with IRAK, which makes it possible to determine the structure of the enzyme/compound using X-ray crystallography; other research and diagnostic applications in which it is preferable to activate IRAK or such activation is conveniently calibrated against a known amount of IRAK inhibitor, etc.; use in assays as probes to determine IRAK expression in cells; and developing assays to identify compounds that bind to the same site as IRAK-binding ligands.

[00157] The compounds of the invention can be used either alone or in combination with physical measurements to diagnose the effectiveness of treatment. Pharmaceutical compositions containing these compounds, and the use of these compounds for the treatment of IRAK-mediated conditions, is a promising new approach for a wide range of treatments that cause direct and immediate improvements in health in both humans and animals. The orally bioavailable and active new chemical compounds of the invention improve patient convenience and compliance with physician-prescribed therapy.

[00158] The compounds of formula (I), their salts, isomers, tautomers, enantiomeric forms, diastereomers, racemates, derivatives, prodrugs and/or metabolites are characterized by high specificity and stability, low production cost and ease of handling. These features provide the basis for reproducible, cross-reactive action and reliable and safe interaction with the target structure.

[00159] The term “biological sample” as used herein includes, without limitation, cell cultures or extracts thereof; biopsy material obtained from a mammal, or extracts thereof; as well as blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[00160] Modulation of the activity of IRAK or a mutant thereof in a biological sample is useful for a variety of purposes that are known to one of ordinary skill in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, storage of biological specimens, and performing biological assays.

[00161] The term "about" as used herein to refer to numbers, values, ranges and/or quantities preferably means "about" and/or "approximately". The meaning of these terms is well known in the art and preferably includes the variance, deviation and/or variability of the corresponding number, magnitude, range and/or amount of ±15% and especially ±10%.

[00162] In any case, the term "about" as used herein to refer to numbers, values, ranges and/or amounts preferably means "about" and/or "approximately". The meaning of these terms is well known in the art and preferably includes a variance, deviation and/or variability of the corresponding number, magnitude, range and/or amount of at least ±5% or ±5%.

[00163] The terms “disorder(s)” and “disease(s)” as used herein are well known and understood in the art. In the context of the present invention, they are preferably used as synonyms and, thus, are preferably interchangeable unless the context in which they are used implies otherwise.

[00164] In a medical context, including, without limitation, treatment regimens, dosing schedules and clinical trial designs, for convenience and/or ease of use by patients, medical personnel and/or physicians, as well as for reliability and/or reproducibility of results, etc. etc., the terms "week"/"one week", "month"/"one month" and/or "year"/"one year" may be used with slight deviations from the definitions of the Gregorian calendar. For example, in said medical context, a month often refers to 28 days, and a year often refers to 48 weeks.

[00165] Thus, in the context of the present invention, the term “week” or “one week” preferably refers to a period of time of about 5, about 6, or about 7 days, more preferably about 7 days.

[00166] In a medical context, the term “month” or “one month” preferably refers to a period of time of about 28, about 29, about 30, or about 31 days, more preferably about 28, about 30, or about 31 days.

[00167] In a medical context, the term "year" or "one year" preferably refers to a period of time of about 12 months, or a period of time of about 48, about 50, or about 52 weeks, more preferably 12 months or about 48 weeks, or about 52 weeks .

[00168] Particularly preferred embodiments of the invention are those as described herein, wherein the characteristics of two or more preferred, more preferred and/or particularly preferred embodiments, aspects and/or objects are combined in one embodiment, aspect and/or object. Preferably, according to this invention, preferred objects or embodiments may be combined with other preferred objects or embodiments; more preferred objects or embodiments may be combined with other less preferred or even more preferred objects or embodiments; particularly preferred objects or embodiments may be combined with other merely preferred or even more preferred objects or embodiments, and the like.

Examples

[00169] As indicated in the examples below, in some embodiments the compounds are prepared in accordance with the following general procedures. It should be understood that while general procedures demonstrate 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, as well as subclasses and species of each of the specified compounds given in this description.

[00170] The symbols and conventions used in the following process descriptions, flowcharts, and examples correspond to those used in contemporary scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.

[00171] All NMR experiments were recorded on a Bruker Avance III 400 NMR spectrometer equipped with a Bruker PABBO BB-1H/DZ GRD probe at 400 MHz for proton NMR or a Bruker DPX-300 MHz. Most deuterated solvents typically contained between 0.03% and 0.05% v/v. tetramethylsilane, which was used as a reference signal (set at δ 0.00 for both ¹ H and ¹³ C). In cases where deuterated solvents did not contain tetramethylsilane, the residual peaks of non-deuterated solvents were used as a reference signal, according to published guidelines (J. Org. Chem., Vol. 62, No. 21, 1997). Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are expressed in hertz (Hz). The splitting patterns are described by visible multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintuplet), m (multiplet), br. (widened).

[00172] The following abbreviations refer to the abbreviations used below:

Ac (acetyl); ACN (acetonitrile); atm (atmosphere); DIEA (diisopropylethylamine); °C (degrees Celsius); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); dppf (1,1' ^- bis-diphenylphosphine ferrocene); eq. (equivalent); EtOAc (ethyl acetate); g (gram); HATU (N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylmethanaminium hexafluorophosphate); HPLC (high performance liquid chromatography); h (hour); LC (liquid chromatography); LDA (lithium diisopropylamine); MeOH (methanol); min (minute); ml (milliliter); mmol (millimole); MS (mass spectroscopy); NMR (nuclear magnetic resonance); O/N (overnight); PE (petroleum ether); CT (room temperature); TBDMS (tert-butyldimethylsilyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TMS (trimethylsilyl).

[00173] UHPLC/MS analyzes were performed on a Waters AquityH instrument with an SQ detector (ESI), and LC/MS on an Agilent 1200 Series instrument with a quadrupole detector or on a SHIMADZU LCMS instrument consisting of a UFLC 20-AD system and LCMS 2020 MS -detector.

[00174] Purity was measured using a Waters AquityH equipped with an XBridge C8, 3.5 µm, 4.6 x 50 mm column using water/ACN with 0.1% TFA as eluent, gradient from 0 to 100% per 8 min (indicated as “UHPLC”) unless otherwise noted.

[00175] Microwave reactions were performed using the Biotage Initiator Microwave Synthesizer using standard protocols known in the art.

[00176] The compounds of this invention were prepared from readily available starting materials using several synthetic approaches, using both liquid-phase and solid-phase chemical protocols, or mixed solution and solid-phase chemical protocols. Examples of synthesis methods are described in the examples below. Unless otherwise indicated, the compounds of this invention, obtained as a racemic mixture, can be separated to obtain an enantiomerically enriched mixture or a pure enantiomer.

[00177] Commercially available starting materials used in the following experimental description were purchased from Sigma-Aldrich or Fisher unless otherwise noted.

Intermediate 1: 3-(4-aminophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[00178] Mixture of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (300 mg, 1.37 mmol, 1.0 eq.), 3-bromo-1-methyl-1H-pyrazolo[ 3,4-d]pyrimidin-4-amine (310 mg, 1.36 mmol, 1.0 eq.), Pd(dppf)Cl ₂ (100 mg, 0.14 mmol, 0.10 eq.) in dioxane (12 ml) and a solution of sodium bicarbonate (110 mg, 1.31 mmol, 1.0 eq.) in water (4 ml) were purged with nitrogen in a sealed tube and then heated at 100°C for 2 hours. The resulting solution then concentrated under reduced pressure, diluted with water (50 ml) and extracted with ethyl acetate (3 x 20 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (300 mg, 82%) as a yellow solid. LC/MS: 241.0 [M+H].

Intermediate 2: 3-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

[00179] A mixture of 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (231 mg; 1.01 mol, 1.2 eq.), 3-fluoro-4-( 4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (200 mg; 0.84 mmol, 1 eq.), Pd(dppf)Cl ₂ DCM (138 mg ; 0.17 mmol; 0.2 eq.) and cesium carbonate (605 mg; 1.8 mmol; 2.2 eq.) in 1,4-dioxane (4 ml) and water (1 ml) were stirred overnight at 100°C in a nitrogen atmosphere. The reaction mixture was then filtered through a pad of celite. The filtrate was diluted with EtOAc (50 ml) and washed with 1M NaOH (2 x 30 ml) and brine (2 x 30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. Purification by flash silica gel chromatography (DCM:MeOH, gradient 99:1 to 80:20) gave the title compound (95 mg, 44%) as a brown solid. LC/MS: 259.1 [M+H].

Intermediate 3: 3-(4-amino-3-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

[00180] The title compound was prepared in a manner similar to that described for Intermediate 2, but starting from 2-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl )-phenylamine (200 mg; 0.84 mmol), as a white solid (90 mg, 41%).

Intermediate 4: 3-(4-amino-3-chlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

[00181] The title compound was prepared in a manner similar to that described for Intermediate 2, but starting from 4-amino-3-chlorophenylboronic acid pinacol ester (200 mg; 0.79 mmol), as a white solid (111 mg , 51%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.88 (s, 1H), 8.33 (t, J=8.4 Hz, 1H), 8.26 (s , 1H), 7.48-7.34 (m, 6H), 6.42 (s, 1H), 5.76 (s, 1H), 3.95 (s, 3H), 2.40 (s, 3H), 1.29 (s, 9H). UHPLC: (254 nm) 100% purity; Rt 1.66 min. UHPLC/MS: 275.2 [M+H].

Intermediate 5: 5-(4-amino-2-fluorophenyl)-thieno[2,3-d]pyrimidin-4-ylamine

[00182] The title compound was prepared using a procedure similar to that described for Intermediate 2, but starting from 5-bromo-thieno[2,3-d]pyrimidin-4-ylamine (233 mg; 1.0 mmol) and pinacol complex 4-amino-2-fluorophenylboronic acid ester (200 mg, 0.84 mmol), as a yellow oil (126 mg, 57%).

Intermediate 6: 5-(4-amino-3-fluorophenyl)-thieno[2,3-d]pyrimidin-4-ylamine

[00183] The title compound was prepared in a manner similar to that described for Intermediate 2, but starting from 4-amino-3-fluorophenylboronic acid pinacol ester (200 mg; 0.84 mmol) and 5-bromo-thieno[2, 3-d]pyrimidin-4-ylamine (233 mg, 1.0 mmol), as a white solid (132 mg, 60%).

Intermediate 7: 3-(4-amino-2-chlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

[00184] The title compound was prepared in a manner similar to that described for Intermediate 2, but starting from 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (216 mg; 1. 0 mmol) and 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg; 0.79 mmol), as a white solid ( 169 mg, 78%).

Intermediate 8: 3-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-1-[2-fluoro-4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]urea

[00185] A solution of 4-nitrophenyl chloroformate (440 mg, 2.07 mmol, 1.0 eq.), dichloromethane (5 ml), pyridine (235 mg, 2.91 mmol, 1.4 eq.) and 3-tert- butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (prepared as described in Molecules, 2014, Volume 19, Issue 2, 2004-2028, 520 mg, 1.92 mmol, 0.93 eq.) in DCM (5 ml), kept under nitrogen, stirred at 5°C for 2 hours, after which 2-fluoro-4-(tetramethyl-1,3,2-dioxaborolane-2- yl)aniline (470 mg, 1.88 mmol, 0.9 eq.) and DIEA (520 mg, 3.94 mmol, 1.9 eq.). The resulting reaction mixture was stirred for another 3 hours at RT. The solvent was removed under reduced pressure and the crude material was purified by flash chromatography on silica gel (EtOAc:PE; 1:1) to obtain the title compound as a yellow solid (300 mg, 19%).

Intermediate 9: 5-(4-amino-2-chlorophenyl)-thieno[2,3-d]pyrimidin-4-ylamine

[00186] The title compound was prepared in a manner similar to that described for Intermediate 2, but starting from 5-bromo-thieno[2,3-d]pyrimidin-4-ylamine (218 mg; 0.95 mmol; 1.2 eq.) and 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg; 0.79 mmol; 1.0 eq.), as a white amorphous solid (71 mg, 32%).

Intermediate 10: 5-(4-amino-2-chlorophenyl)thieno[2,3-d]pyrimidin-4-ylamine

[00187] The title compound was prepared in a manner similar to that described for Intermediate 2, but starting from 5-bromo-thieno[2,3-d]pyrimidin-4-ylamine (218 mg; 0.95 mmol; 1.20 eq.) and 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (200 mg; 0.79 mmol; 1.0 eq.), as a yellow oil (71 mg, 32%).

Intermediate 11: 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(4,4,5,5-tetramethyl-[1,3,2 ]dioxaborolan-2-yl)phenyl]urea

[00188] A solution of (4-isocyanatophenyl)boronic acid pinacol ester (200 mg; 0.82 mmol; 1.0 eq.) in DCM (1 ml) was slowly added to the solution of 5-tert-butyl-2-p-tolyl -2H-pyrazol-3-ylamine (187 mg; 0.82 mmol; 1.0 eq.) in DCM (17 ml) maintained under nitrogen atmosphere at 0°C. The reaction mixture was then allowed to warm at RT and stirred for 16 hours. The solvent was removed under reduced pressure and the crude material was purified by preparative HPLC (C18 X-Bridge column 30x250 mm, 10 μm, gradient 30-95% ACN with 0.1 % ammonium hydroxide) to obtain the title compound as a white solid (172 mg, 45%).

Intermediate 12: 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine

[00189] Step 1: N-[(2,4-dimethoxyphenyl)methyl]-3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine

A solution of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (1.10 g, 3.74 mmol, 1.00 eq.) and (2,4-dimethoxyphenyl)methanamine (1.97 g, 11.2 mmol, 3.0 eq.) in DMSO (20 ml) was stirred O/N at 120°C under nitrogen atmosphere. The reaction mixture was then diluted with water (30 ml) and extracted with DCM (2 x 30 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash silica gel chromatography (DCM:MeOH, gradient 100:1-10:1) gave the title compound as a brown solid (1.3 g, 67%). LC/MS: 410.9 [M+H].

[00190] Step 2: 3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine

N-[(2,4-dimethoxyphenyl)methyl]-3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine solution (1.3 g, 2.54 mmol, 1.0 eq.) in TFA (10 ml) was heated for 3 hours at 50°C. The TFA was then removed under reduced pressure and the resulting oil was diluted with EtOAc (50 ml). The resultant was washed with sodium bicarbonate (30 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a brown solid (450 mg, 58%). LC/MS: 260.8 [M+H].

[00191] Step 3: 3-iodo-1-methyl-1H-pyrazolo[4,3-c]pyridin-4-amine

A mixture of 3-iodo-1H-pyrazolo[4,3-c]pyridin-4-amine (100 mg, 0.33 mmol, 1.0 eq.), sodium hydride (19 mg, 0.79 mmol, 1.20 eq.) and MeI (56 mg, 0.39 mmol, 1.2 eq.) were stirred for 2 h at RT in DMF (3 ml). The reaction was then quenched by adding 5 ml sat. NH ₄ Cl and extracted with DCM (2×10 ml). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash silica gel chromatography (EtOAc:PE, gradient 1:10 to 1:1) gave the title compound as a brown solid (60 mg, 62%). LC/MS (Kinetex EVO C18 100A column, 3.0x50 mm, 2.6 µm; water/5mM NH ₄ HCO ₃ /acetonitrile 10 to 95%, 254 nm): 93% purity; 274.7 [M+H].

Intermediate 13: 3-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-1-[4-(tetramethyl-1,3,2 -dioxaborolan-2-yl)phenyl]urea

[00192] The title compound was prepared in a manner similar to that described for Intermediate 8, but starting from 3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine ( 520 mg, 1.92 mmol, 1.00 eq.) and 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (440 mg, 1.91 mmol, 0.99 eq.), in as a yellow solid (600 mg, 59%). LC/MS (Shim-pack XR-ODS column, 3.0 x 50 mm, 2.2 µm; water/ACN with 0.05% TFA, gradient from 5 to 100% over 2.2 min, hold 1, 0 min; 254 nm): 86.0% purity; 503.2 [M+H].

Intermediate 14: N-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-2-[4-(tetramethyl-1,3,2 -dioxaborolan-2-yl)phenyl]acetamide

[00193] A solution of HATU (228 mg, 0.57 mmol, 1.05 eq.) in DMF (2 ml) was added dropwise to a solution of 2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl )phenyl]acetic acid (150 mg, 0.54 mmol, 1.0 eq.), 3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine ( 180 mg, 0.63 mmol, 1.16 eq.) and DIEA (222 mg, 1.63 mmol, 3.0 eq.) in DMF (3 ml). The reaction mixture was then stirred at 15°C for 16 hours and concentrated under reduced pressure. Purification by preparative TLC on silica gel (PE:EtOAc, 5:1) gave the title compound as a yellow oil (65 mg, 16%). LC/MS: 502.4 [M+H].

Intermediate 15: N-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-2-[2-fluoro-4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]acetamide

[00194] Step 1: 2-(4-bromo-2-fluorophenyl)-N-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}acetamide

The title compound was prepared using a procedure similar to that described for Intermediate 14, but starting from 4-bromo-2-fluorobenzoic acid (500 mg, 2.17 mmol, 1.0 eq.) and 3-tert-butyl-1- [4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (611 mg, 2.26 mmol, 1.0 eq.), as yellow solid (1.38 g, 100%) . LC/MS (Kinetex EVO C18 100A column, 3.0x50 mm, 2.6 µm; water/5mM NH ₄ HCO ₃ /acetonitrile 10 to 95%, 254 nm): 76.0% purity; 472.2 [M+H].

[00195] Step 2: N-{3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}-2-[2-fluoro-4-(tetramethyl-1, 3,2-dioxaborolan-2-yl)phenyl]acetamide

Mixture of 2-(4-bromo-2-fluorophenyl)-N-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl]acetamide (200 mg, 0.32 mmol, 1.0 eq.), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (133 mg , 0.50 mmol, 1.55 eq.), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (33 mg, 0.04 mmol, 0.12 eq.) and AcOK (66 mg, 0.64 mmol, 2.0 eq.) in dioxane (5 ml) in a sealed tube was purged with nitrogen, then heated at 100°C for 3.5 hours. The solvent was then removed under reduced pressure and the residue was diluted with DCM, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a black oil (300 mg, 100%). LC/MS): 520.3 [M+H].

Intermediate 16: 2-[5-({[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl}amino)-1-(4-methylphenyl)-1H- pyrazol-3-yl]-2-methylpropyl acetate

[00196] The title compound was prepared in a manner similar to that described for Intermediate 8, but starting from 2-[5-amino-1-(4-methylphenyl)-1H-pyrazol-3-yl]-2-methylpropyl acetate (prepared as described in Journal of Medicinal Chemistry, 46(22), 4676-4686; 2003; 290 mg, 0.96 mmol, 0.93 eq.) and 2-chloro-4-(tetramethyl-1,3,2-dioxaborolane -2-yl)aniline (250 mg, 0.94 mmol, 0.90 eq.), as a yellow solid (300 mg, 51%). LC/MS: 567.2 [M+H].

Intermediate 17: 3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-amine

[00197] Step 1: 3-(3-methyloxetan-3-yl)-3-oxopropanenitrile

A solution of t-BuOK (9 g, 78.60 mmol, 2.00 eq.) in THF (30 mL) was added dropwise to a solution of benzyl 3-methyloxetane-3-carboxylate (9 g, 39.28 mmol, 1.00 eq. 0 equiv.) and MeCN (2.1 ml, 39.95 mmol, 1.02 equiv.) in THF (100 ml) maintained under nitrogen atmosphere. The reaction mixture was stirred for 16 hours at 25°C. It was then concentrated under reduced pressure and purified by flash chromatography on silica gel (EtOAc:PE, gradient 1:4 to 1:2) to give the title compound as a yellow oil (4.0 g, 66%).

[00198] Step 2: 3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-amine

A solution of 3-(3-methyloxetan-3-yl)-3-oxopropanenitrile (7.8 g, 50.4 mmol, 1.0 eq), (4-methylphenyl)hydrazine hydrochloride (8.17 g, 50.5 mmol , 1.0 eq.) and AcOH (310 mg, 5.06 mmol, 0.1 eq.) in EtOH (150 ml) were stirred for 16 h at 50°C. The solvent was removed under reduced pressure and purified by flash chromatography on silica gel (EtOAc:PE, gradient 1:4 to 1:2), then on a C18 silica gel column (MeOH:water, gradient 1:4 to 1:3), with obtaining the title compound as a yellow solid (1 g, 9%). 1H NMR (300 MHz, DMSO-d6) δ 7.45 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.1 Hz, 2H), 5.46 (s, 1H ), 5.27 (s,2H), 4.78 (d, J=5.2 Hz,2H), 4.40 (d, J=5.2 Hz,2H), 2.34 (s,3H ), 1.5 9 (c,3H). LC/MS (Kinetex EVO C18 100A column, 3.0x50 mm, 2.6 µm; water/5mM NH ₄ HCO ₃ /acetonitrile 10 to 95%, 254 nm): 97% purity; 244.2 [M+H]; melting point: 136-140 °C.

Intermediate 18: 1-[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[3-(3-methyloxetan-3-yl)-1-(4 -methylphenyl)-1H-pyrazol-5-yl]urea

[00199] The title compound was prepared in a manner similar to that described for Intermediate 8, but starting from 3-(3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-amine (101 mg, 0.40 mmol, 1.0 eq.) and 2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (114 mg, 0.40 mmol, 1.01 eq. ), as a yellow solid (140 mg, 54%). LC/MS (Phenomenex Kinetext Column 3.0 x 50 mm, 2.7 µm; water/ACN with 0.05% TFA, gradient 5 to 100% over 1.1 min, hold 0.5 min; 254 nm ): 80% purity; 523.3 [M+H].

Intermediate 19: N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-hydroxy-2-[4-(tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl]acetamide

[00200] Step 1: N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl ]-2-[(trimethylsilyl)oxy]acetamide

Chlorotrimethylsilane (188 mg, 1.64 mmol, 2.0 eq.) was added to a solution of 2-(4-bromophenyl)-2-hydroxyacetic acid (200 mg, 0.82 mmol, 1.00 eq.), 4-dimethylaminopyridine (10.6 mg, 0.08 mmol, 0.10 eq.) and pyridine (137 mg, 1.65 mmol, 2.00 eq.) in DCM (2 ml) maintained under nitrogen. The reaction mixture was stirred at RT for 4 hours. It was then cooled to 0°C. DMF (0.2 mL) then oxalyl chloride (115 mg, 0.86 mmol, 1.05 eq.) was added dropwise and the reaction mixture was stirred for 1 h at 0°C. The mixture was allowed to warm to RT, after which a solution of 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (218 mg, 0.86 mmol, 1.04 eq) in pyridine (0 .2 ml) and stirred for an additional 2 hours at 15°C. After dilution with water, the mixture was extracted with DCM (3 x 5 ml). The combined organic layers were washed with sat. NaHCO ₃ and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by preparative TLC (PE:EtOAc, 5:1) gave the title compound as a yellow solid (95 mg, 24%).

[00201] Step 2: N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-hydroxy-2-[4-(tetramethyl-1,3,2-dioxaborolane-2 -yl)phenyl]acetamide

The title compound was prepared in a manner similar to that described for Intermediate 15, Step 2, but starting from 2-(4-bromophenyl)-N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol- 5-yl]-2-hydroxyacetamide (85 mg, 0.17 mmol, 1.0 eq.), as a yellow solid (80 mg, 58%). LC/MS: 490.4 [M+H].

Intermediate 20: 2-(5-amino-1-p-tolyl-1H-pyrazol-3-yl)-2-methylpropionitrile

[00202] The title compound was prepared in a manner similar to that described for Intermediate 17, Step 2, but starting from 2,2-dimethyl-3-oxopentanedinitrile. LC/MS: 241.1 [M+H].

Intermediate 21: 2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine

[00203] The title compound was prepared in a manner similar to that described for Intermediate 15, Step 2, but starting from 4-bromo-2-chloro-3-fluorophenylamine (100 mg; 0.45 mmol), as a brown solid (100 mg, 83%). UHPLC/MS: 272.3 [M+H].

Intermediate 22: 5-(4-amino-3-chloro-2-fluorophenyl)thieno[2,3-d]pyrimidin-4-ylamine

[00204] The title compound was prepared in a manner similar to that described for Intermediate 2, but starting from 5-bromo-thieno[2,3-d]pyrimidin-4-ylamine (102 mg; 0.44 mmol; 1.2 eq.) and 2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (100 mg; 0.37 mmol; 1 eq. .), as a yellow solid (31 mg, 29%).

Intermediate 23: 1-(4-methylphenyl)-3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-amine

[00205] A solution of 5,5,5-trifluoro-4,4-dimethyl-3-oxopentanenitrile (4 g, 19 mmol, 1.0 eq.) and (4-methylphenyl)hydrazine hydrochloride (3.3 g, 19.8 mmol, 1.04 eq.) in EtOH (50 ml) was heated at 80°C for 16 hours. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on C18 silica gel (water:MeOH; 1:1) with obtaining the title compound as a yellow solid (2 g, 35%). 1H NMR (400 MHz, DMSO-d6) d 7.43 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.1 Hz, 2H), 5.50 (s, 1H ), 5.29 (s, 2H), 2.34 (s, 3H), 1.4 (s, 6H). LC/MS: 284.1 [M+H]. melting point: 90°C.

Intermediate 24: 5-(4-aminocyclohex-1-en-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

[00206] Step 1: tert-butyl-N-(4-{4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl}cyclohex-3-en-1-yl)carbamate

The title compound was prepared by a procedure similar to that described for Intermediate 2, but starting from tert-butyl-N-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1- yl]carbamate (501 mg, 1.47 mmol, 1.20 eq.) and 5-iodo-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (372 mg, 1.22 mmol , 1.00 eq.), as a brown solid (200 mg, 43%). LC/MS (Ascentis Express C18 column, 3.0 x 50 mm, 0.7 µm; water/ACN with 0.05% TFA, gradient 5 to 100% over 1.2 min, hold 0.5 min; 254 nm): 90% purity; 344.0 [M+H].

[00207] Step 2: 5-(4-aminocyclohex-1-en-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine

Tert-Butyl-N-(4-[4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl]cyclohex-3-en-1-yl)carbamate solution (200 mg, 0.52 mmol, 1.0 eq., 90%) and trifluoroacetic acid (1 ml) in DCM (5 ml) were stirred for 3 hours at 25°C. The pH was then adjusted to 8 by adding NH ₄ OH and the mixture was diluted with DCM (20 ml). The organic phase was washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound as a brown solid (130 mg, 92%). LC/MS (Ascentis Express C18 column, 3.0 x 50 mm, 2.7 µm; water/ACN with 0.05% TFA, gradient 5% to 100% over 1.2 min, hold 0.5 min ; 254 nm): 90% purity; 244.0 [M+H].

Intermediate 25: 3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolane- 2-yl)phenyl]urea

[00208] A solution of 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (300 mg, 1.18 mmol, 1.0 eq.) and DIEA (641 mg, 4.7 mmol , 4.0 equiv.) in DCM (1 ml) was added dropwise to a solution of triphosgene (69 mg, 0.22 mmol, 0.6 equiv.) in DCM (5 ml) maintained at 0°C under nitrogen atmosphere. The reaction mixture was stirred for 20 min at 0°C and added to a solution of 2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (323 mg, 1.3 mmol, 1.1 equiv .) in DCM (3 ml). The resulting reaction mixture was stirred for 3 hours at RT, washed with saturated NH ₄ Cl (2 x 10 mL) and brine (1 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash silica gel chromatography (DCM:MeOH; 3:1) gave the title compound as a brown solid (180 mg, 20%). LC/MS: 493.0 [M+H].

Example 1: 1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-3-{3-tert-butyl-1-[4- (propan-2-yl)phenyl]-1H-pyrazol-5-yl}urea (15)

[00209] A solution of 3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (prepared as described in Molecules, 2014, Volume 19, Issue 2, 2004-2028, 257 mg, 1.00 mmol, 1.0 eq.) in DCM (2 ml) was added dropwise to a solution of 4-nitrophenyl chloroformate (220 mg, 1.09 mmol, 1.1 eq.) and pyridine (120 mg, 1.0 eq.) 52 mmol, 1.6 equiv) in DCM (20 ml) maintained at 5°C. 3-(4-Aminophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate 1, 240 mg, 1.00 mmol, 1.0 eq.) and DIEA were then added (260 mg, 2.01 mmol, 2.0 eq.) and the resulting reaction mixture was stirred at 25°C for 16 hours. It was then concentrated in vacuo and purified by pre-HPLC (column, Gemini-NX C18 AXAI , 21.2 x 150 mm, 5 µm; water with 10 mM NH ₄ HCO ₃ and ACN, gradient from 40% to 63% over 10 min) to give the title compound as a yellow solid (6 mg, 19 %). 1H NMR (400 MHz, DMSO-d6): 9.24 (s, 1), 8.48 (s, 1), 8.25 (s, 1), 7.59 (m, 4), 7.43 (m, 4), 6.40 (s, 1), 3.94 (s, 3), 2.98 (t, 1, J=6.8 Hz), 1.28 (s, 9), 1 .25 (d, 6, J=7.2 Hz); LC/MS (Shim-pack XR-ODS column, 3.0 x 50 mm, 2.2 µm; water/ACN with 0.05% TFA, gradient 5 to 100% over 3.6 min, dwell 1, 0 min; 254 nm): (purity) 97.9%; 524.3 [M+H].

Example 2: 1-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorophenyl]-3-(5-tert-butyl-2- p-tolyl-2H-pyrazol-3-yl)urea (2)

[00210] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (67 mg; 0.29 mmol; 1. 5 eq.) and 3-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (intermediate 2, 50 mg; 0.19 mmol; 1 .0 eq.), as a white solid (15 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.88 (s, 1H), 8.33 (t, J=8.4 Hz, 1H), 8.26 (s , 1H), 7.48-7.34 (m, 6H), 6.42 (s, 1H), 5.76 (s, 1H), 3.95 (s, 3H), 2.40 (s, 3H), 1.29 (s, 9H). UHPLC: (254 nm) 100% purity; RT 3.5 min. UHPLC/MS: 514.5 [M+H].

Example 3: 1-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorophenyl]-3-[5-tert-butyl-2- (4-isopropylphenyl)-2H-pyrazol-3-yl]urea (11)

[00211] The title compound was prepared by a procedure similar to that described for Example 1, but starting from 3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-amine (86 mg, 0.32 mmol, 1.0 eq.), as a white solid (20 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.54 (s, 1H), 8.24 (s, 1H), 7.66-7.60 (m, 1H) , 7.46-7.39 (m,5H), 7.25-7.21 (m, 1H), 6.39 (s, 1H), 3.94 (s,3H), 3.00-2 .95 (m, 1H), 1.28 (s.9H), 1.26-1.24 (d, J=6.9 Hz, 6H); LC/MS (Kinetex EVO C18 100A column, 3.0×50 mm, 2.6 µm, water with 5 mM NH ₄ HCO ₃ /ACN, gradient from 10% to 95% over 2.0 min, hold 0, 5 min; 254 nm): 99.6% purity; 542.3 [M+H]. mp.: from 160.0°C to 162.0°C.

Example 4: 1-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl]-3-(5-tert-butyl-2- p-tolyl-2H-pyrazol-3-yl)urea (6)

[00212] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (44 mg; 0.19 mmol; 1. 0 eq.) and 3-(4-amino-3-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (intermediate 3, 50 mg; 0.19 mmol; 1 .0 eq.), as a white solid (15 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 8.88 (s, 1H), 8.33 (t, J=8.6 Hz, 1H), 8.26 (s , 1H), 7.50-7.31 (m, 6H), 6.42 (s, 1H), 3.95 (s, 3H), 2.40 (s, 3H), 1.29 (s, 8H). UHPLC: (254 nm) 100% purity; RT 3.5 min. UHPLC/MS: 514.5 [M+H].

Example 5: 1-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chlorophenyl]-3-(5-tert-butyl-2- p-tolyl-2H-pyrazol-3-yl)urea (4)

[00213] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (658 mg; 2.87 mmol; 1. 0 eq.) and 3-(4-amino-3-chlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (intermediate 4, 789 mg; 2.87 mmol; 1 .0 eq.), as a white solid (41 mg, 3%). 1H NMR (400 MHz, DMSO-d6) d 9.21 (s, 1H), 8.77 (s, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.26 (s , 1H), 7.68 (d, J=2.1 Hz, 1H), 7.58 (dd, J=8.6, 2.1 Hz, 1H), 7.45-7.33 (m, 4H), 6.41 (s, 1H), 3.95 (s, 3H), 2.39 (s, 3H), 1.29 (s, 9H). UHPLC: (254 nm) 100% purity; Rt 3.65 min. UHPLC/MS: 530.5 [M+H].

Example 6: 1-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-fluorophenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol- 3-yl)urea (12)

[00214] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (73 mg; 0.32 mmol) and 3 -(4-amino-2-fluorophenyl)isothiazolo[5,4-d]pyrimidin-4-ylamine (intermediate 5, 83 mg; 0.32 mmol), as a white solid (34 mg, 20%). 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.61 (dd, J=12.4, 2.1 Hz, 1H), 7.52 (s, 1H), 7.45-7.33 (m, 5H), 7.23 (dd, J=8.4, 2.1 Hz, 1H), 6.39 (s, 1H), 2.39 (s, 3H), 1.29 (s, 8H). UHPLC: (254 nm) 100% purity; Rt 3.81 min. UHPLC/MS: 516 [M+H].

Example 7: 1-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-fluorophenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol- 3-yl)urea (9)

[00215] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (116 mg; 0.51 mmol) and 5 -(4-amino-3-fluorophenyl)thieno[2,3-d]pyrimidin-4-ylamine (intermediate 6, 132 mg, 0.51 mmol), as a yellow solid (27 mg, 10%). 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.88 (s, 1H), 8.35 (s, 1H), 8.29 (t, J=8.5 Hz , 1H), 7.49 (s, 1H), 7.44-7.34 (m, 5H), 7.29-7.19 (m, 1H), 6.41 (s, 1H), 2. 40 (s, 3H), 1.29 (s, 10H). UHPLC: (254 nm) 100% purity; Rt 3.7 min. UHPLC/MS: 516 [M+H].

Example 8: 1-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-chlorophenyl]-3-(5-tert-butyl-2- p-tolyl-2H-pyrazol-3-yl)urea (8)

[00216] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (42 mg; 0.18 mmol) and 3 -(4-amino-2-chlorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (intermediate 7, 50 mg, 0.18 mmol), as a white solid ( 8 mg, 8%). 1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 7.86 (d, J=1.9 Hz , 1H), 7.49-7.24 (m, 5H), 6.39 (s, 1H), 3.94 (s, 3H), 2.39 (s, 3H), 1.30 (s, 9H). UHPLC: (254 nm) 96% purity; Rt 3.63 min. UHPLC/MS: 530.3 [M+H].

Example 9: 1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-3-{3-tert-butyl-1- [4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl}urea (10)

[00217] A mixture of 3-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl]-1-[2-fluoro-4-(tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]urea (intermediate 8, 160 mg, 0.29 mmol, 1.0 eq), 3-iodo-1-methyl-1H-pyrazolo[3,4- d]pyrimidin-4-amine (101 mg, 0.35 mmol, 1.2 eq.), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (25 mg, 0.03 mmol, 0.10 eq.) and KOAc (90.4 mg, 0.90 mmol, 3.1 eq.) in dioxane (15 ml) and water (1.5 ml) was purged with nitrogen and heated in MW for 1 h at 80°C in a sealed tube . The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (DCM:MeOH, 20:1) to give the title compound as a white solid (30 mg, 19%). mp.: 166-168 °C. 1H NMR (400 MHz, DMSO-d6) δ 9.13-9.12 (m, 1H), 8.94 (s, 1H), 8.34-8.30 (m, 1H), 8.24 ( s, 1H), 7.45-7.41 (m, 6H), 6.40 (s, 1H), 3.92 (s, 3H), 2.99-2.95 (m, 1H), 1 .26-1.23 (m, 15H). LC/MS (XBridge C18 column, 4.6 × 50 mm; 3.5 µm; water with 5 mM NH ₄ HCO ₃ /ACN; gradient from 10% to 95% over 1.2 min, hold 1.0 min ; 254 nm): 99% (purity); 542.2 [M+H].

Example 10: 1-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-chlorophenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol- 3-yl)urea (14)

[00218] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (58 mg; 0.26 mmol; 1. 0 eq.) and 5-(4-amino-2-chlorophenyl)-thieno[2,3-d]pyrimidin-4-ylamine (intermediate 9, 71 mg; 0.26 mmol; 1.0 eq.), as a yellow foam (12 mg, 12%). 1H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.50 (s, 1H), 8.34 (s, 1H), 7.87 (d, J=2.0 Hz , 1H), 7.48 (s, 1H), 7.44-7.32 (m, 6H), 6.39 (s, 1H), 2.39 (s, 3H), 1.29 (s, 9H). UHPLC: (254 nm) 100% purity; Rt 3.97 min. LC/MS: 533.2 [M+H].

Example 11: 1-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol- 3-yl)urea (20)

[00219] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (76 mg; 0.33 mmol; 1. 0 eq.) and 5-(4-amino-3-chlorophenyl)thieno[2,3-d]pyrimidin-4-ylamine (intermediate 10, 91 mg; 0.33 mmol; 1.0 eq.) as yellow foam (10 mg, 5%). 1H NMR (400 MHz, DMSO-d6) d 9.20 (s, 1H), 8.78 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=8.5 Hz , 1H), 7.58 (d, J=2.1 Hz, 1H), 7.52 (s, 1H), 7.44-7.34 (m, 5H), 6.40 (s, 1H) , 2.39 (s, 3H), 1.29 (s, 8H). UHPLC: (254 nm) 99% purity; Rt 3.93 min. LC/MS: 533.2 [M+H].

Example 12: 1-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)phenyl]-3-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl )urea (13)

[00220] A mixture of 5-bromo-thieno[2,3-d]pyrimidin-4-ylamine (100 mg; 0.43 mmol; 1.2 eq.), 1-(5-tert-butyl-2-p- tolyl-2H-pyrazol-3-yl)-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]urea (172 mg; 0. 36 mmol; 1.0 eq.), Pd(dppf)Cl ₂ DCM (59 mg; 0.73 mmol; 0.2 eq.) and cesium carbonate (260 mg; 0.8 mmol; 2.2 eq. ) in 1,4-dioxane (3.5 ml) and water (1 ml) was stirred overnight at 100°C under nitrogen atmosphere. The reaction mixture was then filtered through a pad of celite. The filtrate was diluted with EtOAc (50 ml) and washed with 1M NaOH (2 x 30 ml) and brine (2 x 30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. Preparative HPLC purification (C18 X-Bridge 30x250mm, 10 µm column, 30-95 ACN gradient with 0.1% ammonium hydroxide) gave the title compound as a white powder (41 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 7.57 (d, J=8.6 Hz , 2H), 7.48-7.28 (m, 7H), 6.38 (s, 1H), 2.39 (s, 3H), 1.29 (s, 9H). UHPLC: (254 nm) 100% purity; Rt 3.63 min. LC/MS: 598.3 [M+H].

Example 13: 1-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-3-fluorophenyl]-3-(2-p-tolyl-5- trifluoromethyl-2H-pyrazol-3-yl)urea (26)

[00221] The title compound was prepared in a manner similar to that described for Example 1, but starting from 2-p-tolyl-5-trifluoromethyl-2H-pyrazol-3-ylamine (56 mg; 0.23 mmol; 1.0 eq. .) and 3-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (intermediate 2, 60 mg; 0.23 mmol; 1.0 eq.), in the form of a white powder (7 mg, 6%). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 9.20 (s, 1H), 8.31 (t, J=8.6 Hz, 1H), 8.26 (s , 1H), 7.57-7.39 (m, 6H), 6.91 (s, 1H), 3.95 (s, 3H), 2.44 (s, 3H). UHPLC: (254 nm) 100% purity; Rt 3.72 min. LC/MS: 525.2 [M+H].

Example 14: 1-[4-(4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl]-3-[5-tert-butyl-2-(4- isopropylphenyl)-2H-pyrazol-3-yl]urea (16)

[00222]The title compound was prepared according to a procedure similar to that described for Example 9, but starting from 3-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5-yl]- 1-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (intermediate 13, 200 mg, 0.38 mmol, 1.0 eq.) and 3-iodo-1-methyl -1H-pyrazolo[4,3-c]pyridin-4-amine (intermediate 12, 130 mg, 0.45 mmol, 1.2 eq.), as a white solid (20 mg, 10%). 1H NMR (400 MHz, DMSO-d6): δ 9.22 (s, 1H), 8.48 (s, 1H), 7.74-7.73 (d, J=6 Hz, 1H), 7. 59-7.51 (m, 4H), 7.44-7.38 (m, 4H), 6.83-6.82 (d, J=6 Hz,1H), 6.38 (s,1H) .5.74 (s,2H), 3.94 (s,3H), 2.98-2.95 (m, 1H), 1.27 (s,9H), 1.25-1.23 (d , J=6.8 Hz,6H); LC/MS (Kinetex 2.6u XB-C18 100A column, 3.0 x 50 mm, 2.6 µm; water/ACN with 0.05% TFA, gradient from 5% to 95% over 1.2 min, hold 0.55 min; 254 nm): 99% purity; 523 [M+H]. mp.: 152-154 °C.

Example 15: 2-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-N-[5-tert-butyl-2-(4- isopropylphenyl)-2H-pyrazol-3-yl]acetamide (21)

[00223] The title compound was prepared by a procedure similar to that described for Example 9, but starting from N-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5- yl]-2-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (intermediate 14, 65 mg, 0.09 mmol, 1.0 eq.) and 3-iodo- 1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol, 1.1 eq.), as a white solid (15 mg, 32%). 1H NMR (300 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.68 (d, J=8.0 Hz, 2H), 7.44-7.34 (m, 3H), 7. 24-7.17 (m, 2H), 7.09 (m, 2H), 6.64 (s,1H), 5.40 (s,2H), 4.12 (s,3H), 3.78 (c,2H), 2.80 (m, 1H), 1.33 (c,9H), 1.11 (d, J=6.9 Hz, 6H). LC/MS (Kinetex EVO C18 100A column, 3.0×50 mm, 2.6 µm; water with 5 mM NH ₄ HCO ₃ /ACN, gradient from 10% to 95% over 2.0 min, hold 0, 5 min; 254 nm): 100% purity; 523.3 [M+H]. melting point: 218-219 °C.

Example 16: 2-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl]-N-[5-tert-butyl-2- (4-isopropylphenyl)-2H-pyrazol-3-yl]acetamide (19)

[00224] The title compound was prepared by a procedure similar to that described for Example 9, but starting from N-[3-tert-butyl-1-[4-(propan-2-yl)phenyl]-1H-pyrazol-5- yl]-2-[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (300 mg, 0.32 mmol, 1.0 eq.) and 3-iodo- 1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (150 mg, 0.38 mmol, 1.2 eq.), as a white solid (30 mg, 17%). 1H NMR (400 MHz, CDCl ₃ ) δ 8.41 (s, 1H), 7.54-7.43 (m, 4H), 7.29 (m, 2H), 7.24 (m, 2H), 6.63 (s, 1H), 5.81 (s, 2H), 4.12 (s, 3H), 3.77 (s, 2H), 2.89 (m, 1H), 1.33 (s ,9H), 1.19 (d, J=6.9 Hz, 6H). LC/MS (Kinetex EVO C18 100A column, 3.0x50 mm, 2.6 µm; water/5 mM NH ₄ HCO ₃ /acetonitrile 10 to 95%, 254 nm): 100% purity; 541.3 [M+H].

Example 17: 1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)-3-[3-(1-hydroxy-2 -methylpropan-2-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (22)

[00225] Step 1: 2-(5-{3-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chlorophenyl]ureido}-1-p -tolyl-1H-pyrazol-3-yl)-2-methylpropyl acetate

The title compound was prepared using a procedure similar to that described for Example 9, but starting from 2-[5-([[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamoyl] amino)-1-(4-methylphenyl)-1H-pyrazol-3-yl]-2-methylpropyl acetate (intermediate 16, 200 mg, 0.35 mmol, 1.00 eq.) and 3-iodo-1-methyl -1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.36 mmol, 1.03 eq.), as an off-white solid (15 mg, 7%). 1H NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.79 (s, 1H), 8.29-8.27 (d, 1H), 8.24 (s, 1H) , 7.66-7.65 (d,1H), 7.57-7.54 (dd,1H), 7.41-7.39 (d,2H), 7.36-7.34 (d, 2H), 6.43 (c,1H), 4.09 (c,2H), 3.92 (c,3H), 2.37 (c,3H), 2.01 (c,3H), 1, 27 (c.6H). LC/MS (Kinetex EVO C18 100A column, 3.0×50 mm, 2.6 µm; water with 5 mM NH₄HCO₃/ACN; gradient from 10% to 95% over 2.0 min, hold for 0.5 min; 254 nm): 96% purity; 588.2 [M+H]. mp.: 126-128 °C.

[00226] Step 2: 1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)-3-[3-(1-hydroxy-2 -methylpropan-2-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea

A solution of 2-(5-[[(4-[4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-chlorophenyl)carbamoyl]amino]-1-(4 -methylphenyl)-1H-pyrazol-3-yl)-2-methylpropyl acetate (100 mg, 0.15 mmol, 1.00 eq.) and potassium carbonate (33 mg, 0.23 mmol, 1.5 eq.) in MeOH (5 ml) was stirred for 2 hours at RT. The solvent was removed under reduced pressure. Preparative HPLC purification (Gemini-NX C18 AXAI Packed column, 21.2 x 150 mm, 5 µm, water with 0.05% NH₄OH/ACN 33% to 46% over 8 min) gave the title compound as a white solid (10 mg, 12%). 1H NMR (300 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.78 (s, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.26 (s , 1H), 7.67 (d, J = 2.0 Hz, 1H), 7.57 (dd, J = 8.6, 2.1 Hz, 1H), 7.45-7.33 (m, 4H), 6.91 (s, 1H), 6.39 (s, 1H), 4.62 (t, J=5.5 Hz, 1H), 3.94 (s, 3H), 3.44 ( d, J=5.1 Hz, 2H), 2.38 (s.3H), 1.22 (s.6H). LC/MS (Kinetex EVO C18 100A column, 3.0×50 mm, 2.6 µm; water with 5 mM NH₄HCO₃/ACN, gradient from 10% to 95% over 2.0 min, hold for 0.5 min; 254 nm): 98% (purity); 546.3 [M+H], mp.: 192-194 °C.

Example 18: 1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)-3-[3-(3-methyloxetane-3 -yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (24)

[00227]The title compound was prepared by a procedure similar to that described for Example 9, but starting from 1-[2-chloro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-3-[3-( 3-methyloxetan-3-yl)-1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (intermediate 18, 120 mg, 0.18 mmol, 1.0 eq.) and 3-iodo- 1-Methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate 17, 68 mg, 0.22 mmol, 1.2 eq.), as a white solid (10 mg, 10% ). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.83 (s, 1H), 8.30 (d, J=8.6 Hz, 1H), 8.26 (s , 1H), 7.68 (d, J=2.0 Hz, 1H), 7.58 (dd, J=8.5, 2.0 Hz, 1H), 7.41 (d, 4H), 6 .93 (s, 1H), 6.54 (s, 1H), 4.85 (d, J=5.3 Hz, 2H), 4.47 (d, J=5.4 Hz, 2H), 3 .94 (c.3H), 2.40 (c.3H), 1.67 (c.3H). LC/MS (Shim-pack XR-ODS column, 3.0 x 50 mm, 2.2 µm; water/ACN with 0.05% TFA, gradient 5 to 100% over 2.2 min, dwell 1, 0 min; 254 nm): 95% purity; 544.2 [M+H]. m.p.: 170-172 °C.

Example 19: 2-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-N-(5-tert-butyl-2-p-tolyl -2H-pyrazol-3-yl)-2-hydroxyacetamide (17)

[00228]The title compound was prepared by a procedure similar to that described for Example 9, but starting from N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-2-hydroxy-2-[ 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetamide (intermediate 19, 40 mg, 0.07 mmol, 1.0 eq.) and 3-iodo-1-methyl-1H- pyrazolo[3,4-d]pyrimidin-4-amine (22 mg, 0.07 mmol, 1.10 eq.), as a white solid (21 mg, 62%). 1H NMR (300 MHz, DMSO-d6) δ 9.87 (s, 1H), 8.28 (s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.55 (d , J=8.1 Hz, 2H), 7.34-7.24 (m, 2H), 7.19 (d, J=8.3 Hz, 2H), 6.66-6.57 (m, 1H), 6.30 (s, 1H), 5.18-5.12 (m, 1H), 3.97 (s, 3H), 2.30 (s, 3H), 1.26 (s, 9H ). LC/MS (Shim-pack XR-ODS column, 3.0 x 50 mm, 2.2 µm; water/ACN with 0.05% TFA, gradient 5% to 100% over 2.2 min, hold 1 .0 min; 254 nm): 99% purity; 511.3 [M+H]. m.p.: 260-262 °C.

Example 20: 2-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-N-(5-tert-butyl-2-p-tolyl -2H-pyrazol-3-yl)-2-oxoacetamide (7)

[00229] A solution of 2-(4-[4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-N-[3-tert-butyl-1-(4 -methylphenyl)-1H-pyrazol-5-yl]-2-hydroxyacetamide (50 mg, 0.09 mmol, 1.0 eq.) and IBX (52 mg, 0.18 mmol, 2.0 eq.) in DMSO (1 ml) was stirred for 4 hours at 20°C. Pre-HPLC purification (Gemini-NX C18 AXAI Packed column, 21.2 x 150 mm, 5 µm, water with 0.05% NH ₄ OH/ACN, gradient from 50% to 62% over 8 min) gave the results indicated in title compound as a yellow solid (20 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.30 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.84 (d , J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.3 Hz, 2H), 7.05 (s, 2H ), 6.53 (s, 1H), 3.99 (c,3H), 2.37 (c,3H), 1.32 (c,9H). LC/MS (Phenomenex Gemini-NX C18 column, 3.0 × 50 mm, 3.0 µm; water with 6.5 mM NH ₄ HCO ₃ /ACN, gradient from 5% to 95% over 2.2 min, hold 1.0 min; 254 nm): 99% purity; 509.1 [M+H].

Example 21: 1-(4-{4-aminothieno[2,3-d]pyrimidin-5-yl}-2-chlorophenyl)-3-[3-(1-hydroxy-2-methylpropan-2-yl)- 1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (27)

[00230] Step 1: 2-(5-{3-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]ureido}-1-p-tolyl-1H-pyrazol-3 -yl)-2-methylpropyl acetate

The title compound was prepared by a procedure similar to that described for Example 1, but starting from 2-(5-amino-1-p-tolyl-1H-pyrazol-3-yl)-2-methylpropyl ester (prepared as described in Journal of Medicinal Chemistry, 46(22), 4676-4686; 2003; 208 mg; 0.72 mmol; 1.0 eq.) and 5-(4-amino-3-chlorophenyl)thieno[2,3-d]pyrimidine -4-ylamine (intermediate 10; 200 mg; 0.72 mmol; 1.0 eq.), as a white solid (40 mg, 9%). 1H NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.78 (s, 1H), 8.35 (s, 1H), 8.25 (d, J=8.6 Hz , 1H), 7.63-7.27 (m, 7H), 6.45 (s, 1H), 4.12 (s, 2H), 2.39 (s, 3H), 2.04 (s, 3H), 1.29 (s, 6H). UHPLC/MS: 590.3 [M+H].

[00231] Stage 2: 1-(4-{4-aminothieno[2,3-d]pyrimidin-5-yl}-2-chlorophenyl)-3-[3-(1-hydroxy-2-methylpropan-2-yl)-1-( 4-methylphenyl)-1H-pyrazol-5-yl]urea

Solution of 2-(5-{3-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]ureido}-1-p-tolyl-1H-pyrazol-3-yl )-2-methylpropyl ester (40 mg; 0.07 mmol; 1.0 eq.) and K ₂ CO ₃ (28 mg, 0.20 mmol; 3 eq.) in MeOH (2 ml) were stirred for 1 h at CT. The reaction mixture was then diluted with saturated sodium bicarbonate solution (2 ml) and extracted with EtOAc (3 x 3 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification by flash silica gel chromatography (EP:EtOAc, gradient 100:0 to 0:100) gave the title compound as a white solid (27 mg, 73%). 1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.77 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=8.5 Hz , 1H), 7.57 (d, J=2.1 Hz, 1H), 7.52 (s, 1H), 7.47-7.33 (m, 4H), 6.39 (s, 1H) , 4.59 (t, J=5.6 Hz, 1H), 3.45 (d, J=5.5 Hz, 2H), 2.39 (s, 3H), 1.23 (s, 6H) . UHPLC: (254 nm) 100% purity; Rt 3.13 min. LC/MS: 551.0 [M+H].

Example 22: 1-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-3-[5-(cyanodimethylmethyl)-2-p-tolyl-2H-pyrazol- 3-yl]urea (25)

[00232] The title compound was prepared following a procedure similar to that described for Example 1, but starting from 2-(5-amino-1-p-tolyl-1H-pyrazol-3-yl)-2-methylpropionitrile (intermediate 21; 43 mg; 0.18 mmol; 1.0 eq.) and 5-(4-amino-3-chlorophenyl)thieno[2,3-d]pyrimidin-4-ylamine (intermediate 10; 50 mg; 0.18 mmol; 1.0 eq.), as a white solid (18 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 9.36 (s, 1H), 8.86 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=8.5 Hz , 1H), 7.58 (d, J=2.1 Hz, 1H), 7.53 (s, 1H), 7.48-7.38 (m, 5H), 6.62 (s, 1H) , 5.76 (s, 1H), 2.42 (s, 3H), 1.71 (s, 6H). UHPLC: (254 nm) 99% purity; Rt 3.69 min. UHPLC/MS: 543.0 [M+H].

Example 23: 1-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chloro-3-fluorophenyl]-3-(5-tert-butyl-2-p-tolyl- 2H-pyrazol-3-yl)urea (23)

[00233] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (24 mg; 0.11 mmol; 1. 0 eq.) and 5-(4-amino-3-chloro-2-fluorophenyl)thieno[2,3-d]pyrimidin-4-ylamine (intermediate 23; 31 mg; 0.11 mmol; 1.0 eq. .), as a white solid (3 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.90 (s, 1H), 8.35 (s, 1H), 8.13 (d, J=8.2 Hz , 1H), 7.59 (s, 1H), 7.48-7.28 (m, 4H), 6.41 (s, 1H), 2.40 (s, 3H), 1.29 (s, 9H). UHPLC: (254 nm) 100% purity; Rt 4.02 min. UHPLC/MS: 550.0 [M+H].

Example 24: 1-[4-(4-aminothieno[2,3-d]pyrimidin-5-yl)-2-chlorophenyl]-3-[2-p-tolyl-5-(2,2,2-trifluoro -1,1-dimethylethyl)-2H-pyrazol-3-yl]urea (18)

[00234] The title compound was prepared by a procedure similar to that described for Example 1, but starting from 2-p-tolyl-5-(2,2,2-trifluoro-1,1-dimethylethyl)-2H-pyrazol-3- ylamine (51 mg; 0.18 mmol; 1.0 eq.) and 5-(4-amino-3-chlorophenyl)-thieno[2,3-d]pyrimidin-4-ylamine (intermediate 10; 50 mg; 0.18 mmol; 1.0 eq.), as a white solid (14 mg, 13%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.83 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=8.6 Hz , 1H), 7.58 (d, J=2.1 Hz, 1H), 7.53 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.42-7 .37 (m, 3H), 6.59 (s, 1H), 2.41 (s, 3H), 1.53 (s, 6H). UHPLC: (254 nm) 100% purity; Rt 4.28 min. LC/MS: 586.0 [M+H].

Example 25: 1-[4-(4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)cyclohex-3-enyl]-3-(5-tert-butyl-2 -p-tolyl-2H-pyrazol-3-yl)urea (1)

[00235]A solution of 3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-amine (94 mg, 0.37 mmol, 1.0 eq.) and DIEA (201 mg, 1.48 mmol, 4. 0 equiv.) in DCM (2 ml) was added dropwise to a solution of triphosgene (69 mg, 0.22 mmol, 0.60 equiv.) in DCM (2 ml) maintained at 0°C under nitrogen atmosphere. The reaction mixture was stirred for 2 hours at 0°C, after which a solution of 5-(4-aminocyclohex-1-en-1-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4- amine (intermediate 24; 100 mg, 0.37 mmol, 1.0 eq.) in DMF (2 ml). The resulting reaction mixture was stirred for 4 hours at RT and diluted with DCM (10 ml). It was washed with a saturated NH solution₄Cl (2 x 10 ml) and brine (1 x 10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. Pre-HPLC purification (XBridge BEH130 Prep C18 OBD column, 19x150 mm, 5 µm, water with 0.05% NH₄OH/ACN, 36% ACN for 17 min) gave the title compound as a white solid (16 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ 8.09-8.04 (m, 2H), 7.36-7.29 (m, 4H), 7.18 (s, 1H), 6.68- 6.65 (m, 1H), 6.29-6.25 (m, 3H), 5.62 (s, 1H), 3.85-3.81 (m, 1H), 3.66 (s, 3H), 2.49-2.43 (m, 3H), 2.36 (s, 3H), 2.08-2.01 (m, 1H), 1.91-1.88 (m, 1H) , 1.68-1.62 (m, 1H), 1.25 (s, 9H). LC/MS (Ascentis Express C18 column, 3.0 x 50 mm, 2.7 µm; water/ACN with 0.05% TFA, gradient 5% to 100% over 1.2 min, hold 0.5 min ; 254 nm): 96% purity; 499.3 [M+H]. mp.: 145-147 °C.

Example 26: 1-[4-(4-amino-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-2-fluorophenyl]-3-(5-tert-butyl-2- p-tolyl-2H-pyrazol-3-yl)urea (3)

[00236] The title compound was prepared by a procedure similar to that described for Example 9, but starting from 3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[2 -fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]urea (intermediate 25, 150 mg, 0.27 mmol, 1.0 eq.) and 3-iodo-1-methyl -1H-pyrazolo[4,3-c]pyridin-4-amine (intermediate 12, 894 mg, 3.1 mmol, 11.3 eq.), as a white solid (10 mg, 7%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 8.86 (s,1H), 8.27 (t, J=8.4 Hz, 1H), 7.73 (d , J=6.1 Hz,1H), 7.49-7.27 (m,6H), 6.82 (d, J=6.0 Hz,1H), 6.38 (s, 1H), 5 .79 (c,2H), 3.93 (c,3H), 2.36 (c,3H), 2.04 (s, 1H), 1.25 (c,10H). LC/MS (Poroshell HPH-C18 column, 3.0x50 mm, 2.7 µm; water with 5 mM NH ₄ HCO ₃ /ACN, gradient from 10% to 95% over 2.2 min, hold 1, 0 min; 254 nm): 100% pure; 513.0 [M+H].

Example 27: 3-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-1-[(1s,4s)-4-{4-amino-7-methyl-7H -pyrrolo[2,3-d]pyrimidin-5-yl}cyclohexyl]urea (5)

[00237]Solution of 1-(4-[4-amino-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl]cyclohex-3-en-1-yl)-3-[3-tert-butyl -1-(4-methylphenyl)-1H-pyrazol-5-yl]urea (60 mg, 0.11 mmol, 1.0 eq.) in MeOH (5 ml) was hydrogenated (1 atm, 0.1 MPa) in for 48 hours in the presence of palladium on carbon (20 mg). The reaction mixture was then filtered through a pad of celite and concentrated under reduced pressure. Pre-HPLC purification (X-Bridge Prep C18 OBD column, 19x150 mm, 5 µm, water with 10 mM NH₄HCO₃+0.1%NH₄OH/ACN, gradient 38.0% to 40% over 20 min) gave the title compound as a white solid (9.9 mg, 17%). 1H NMR (300 MHz, DMSO-d6): δ 8.05-8.03 (m, 2H), 7.36-7.30 (m, 4H), 6.83 (s, 1H), 6.74 -6.71 (m, 1H), 6.43 (s, 2H), 6.29 (s, 1H), 3.86 (m, 1H), 3.58 (s, 3H), 2.97 ( s, 1H), 2.32 (s, 3H), 2.01-1.56 (m, 6H), 1.40 (m, 2H), 1.21 (s, 9H). LC/MS (Shim-pack XR-ODS column, 3.0 x 50 mm, 2.2 µm; water/ACN with 0.05% TFA, gradient 5% to 100% over 2.0 min, hold 0 .7 min; 254 nm): 95% purity; 501.3 [M+H]. m.p.: 228-230 °C.

Example 28: 1-(4-{4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-chlorophenyl)-3-[3-tert-butyl-1- (4-cyanophenyl)-1H-pyrazol-5-yl]urea (28)

[00238] The title compound was prepared by a procedure similar to that described for Example 1, but starting from 4-[5-amino-3-(1,1-dimethylethyl)-1H - pyrazol-1-yl]benzonitrile, as beige solid. 1 H NMR (400 MH, DMSO-d6) δ 1.30 (s, 9H), 3.99 (s, 3H), 5.76 (s, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.69 (d, J=1.6 Hz, 1H), 7.77 (d, J=7.2 Hz, 2H), 7.98 (d, J=7.2 Hz, 2H), 8.20 (d, J=8.5 Hz, 1H), 8.39 (s, 1H), 8.80 (s, 1H), 9.43 (s, 1H). HPLC (Atlantis dC18, 254x4.6 mm, 5 µm, TFA 0.1% gradient in water/ACN from 10% to 100% over 15 min, 254 nm) 98.0% purity; RT 12.7 min. LC/MS (ESI-): 539.0 [MH].

Example 29: 1-[4-(4-amino-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-chlorophenyl]-3-[5-tert-butyl-2- (3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-yl]urea (29)

[00239] The title compound was prepared in a manner similar to that described for Example 1, but starting from 5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazol-3-ylamine, as beige solid. 1 H NMR (400 MH, DMSO-d6) δ 1.28 (s, 9H), 2.29 (s, 3H), 3.98 (s, 3H), 4.5 (br s, 2H), 6.41 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.37 (d, J=11.8 Hz, 1H), 7.45 (t, J=8 .3 Hz, 1H), 7.57 (d, J=8.6 Hz, 1H), 7.69 (d, J=1.4 Hz, 1H), 8.29 (d, J=8.6 Hz, 1H), 8.80 (s, 1H), 9.28 (s, 1H). HPLC: (Atlantis dC18, 254x4.6 mm, 5 µm, TFA 0.1% gradient in water/ACN from 10% to 100% over 15 min, 254 nm) 97.3% purity; RT 13.3 min. LC/MS (ESI-): 546.0 [MH].

Example 30: Enzymatic and Cellular Assays

[00240] IRAK4 Enzymatic Assay:

IRAK4 is a purified recombinant human enzyme (His-TEV-IRAK4 (1-460)). In this assay, IRAK4 hydrolyzes ATP, autophosphorylates, and phosphorylates the generic peptide substrate serine/threonine (STK: 61ST1BLC from CisBio International). IRAK-4 inhibition measurements were performed in a 384-well luminescent assay-based format (ADP-Glo ^™ Kinase Assay from Promega). Purified human recombinant IRAK4 (0.3 μg/ml) and serial diluted compounds in DMSO (concentration range 10 μM to 0.5 nM) or controls (1% DMSO) were incubated for 15 min at RT in assay buffer. containing 50 mM HEPES pH 7.0, fatty acid free BSA 0.1%, dithiothreitol (DTT) 2 mM, MgCl ₂ 10 mM, EGTA 0.5 mM, Triton-X-100 0.01%, MnCl ₂ 5 mm. The kinase reaction was then initiated by the addition of ATP (2 μM) and the peptide substrate STK1-biotin peptide (300 nM). After 2 h of incubation at RT, the reaction was stopped and unconsumed ATP was depleted by adding ADP-Glo ^™ reagent according to the supplier's instructions. After 40 min of incubation at RT, kinase detection reagent was added to the assay plate according to the supplier's instructions. After 20 min of incubation at RT, the luminescence signal was measured using a plate luminometer (PerkinElmer Envision or equivalent reader).

[00241] IRAK1 Enzymatic Assay:

IRAK1 is a purified recombinant human enzyme (His-TEV-IRAK1 (194-712)). In this assay, IRAK1 hydrolyzes ATP and autophosphorylates. IRAK-1 inhibition measurements were performed in a 384-well luminescent assay-based format (ADP-Glo ^™ Kinase Assay from Promega). Purified human recombinant IRAK1 (0.3 μg/ml) and serial diluted compounds in DMSO (concentration range 10 μM to 0.5 nM) or controls (1% DMSO) were incubated for 15 min at RT in assay buffer. containing 50 mM HEPES pH 7.0, fatty acid free BSA 0.1%, dithiothreitol (DTT) 2 mM, MgCl ₂ 10 mM, EGTA 0.5 mM, Triton-X-100 0.01%. The kinase reaction was then initiated by adding ATP at a concentration of 1 μM. After 2 h of incubation at RT, the reaction was stopped and unconsumed ATP was depleted by adding ADP-Glo ^™ reagent according to the supplier's instructions. After 40 min of incubation at RT, kinase detection reagent was added to the assay plate according to the supplier's instructions. After 20 min of incubation at RT, the luminescence signal was measured using a luminometer (PerkinElmer Envision or equivalent reader).

[00242] TLR7-induced IL-6 in human PBMCs

The human PBMC assay was used as one of the functional assays to monitor the activity of small molecule inhibitors of IRAK 1 and IRAK4 on TLR7-induced IL-6 secretion in human mononuclear cells (PBMCs). Human PBMCs were obtained from buffy coats (whole blood enriched with leukocytes and platelets) obtained from healthy volunteers, used fresh or frozen, plated in assay medium (RPMI+2%P/S/L-glu+10% HI-FBS ) and were pretreated with compounds in DMSO/medium (concentration range 25 μM to 0.4 nM) or control (0.25% DMSO) for 30 min at 37°C in assay medium. Subsequently, after pretreatment with IRAK1 and IRAK4 inhibitors, PBMC were stimulated with TLR7 specific ligand (2 μM) overnight (16–18 h) at 37°C. After completion of incubation, the supernatant was transferred to a 384-well PE AlphaPlate-384 plate and IL-6 was quantified using the Perkin Elmer IL-6 Alpha LISA kit (AL223C). The plates are read on an Envision ^® plate reader with Alpha Technology ^® .

The results are presented in the following table.

*IC ₅₀ > 5 µM

** IC ₅₀ varies from 1 µM to 5 µM

*** IC ₅₀ varies from 100 nM to 1.0 µM

****IC ₅₀ <100 nM

NT=not tested

Example Compound IRAK1 IRAK4 PBMC 1 15 **** *** **** 2 2 **** **** **** 3 eleven **** *** **** 4 6 **** **** **** 5 4 **** **** **** 6 12 **** *** **** 7 9 **** **** **** 8 8 **** **** **** 9 10 **** **** **** 10 14 **** *** **** eleven 20 **** ** **** 12 13 **** *** **** 13 26 *** * *** 14 16 **** *** **** 15 21 **** ** ** 16 19 **** *** ** 17 22 **** ** **** 18 24 **** ** *** 19 17 **** *** *** 20 7 **** **** ** 21 27 *** * * 22 25 *** ** * 23 23 **** ** **** 24 18 **** *** **** 25 1 **** **** NT 26 3 **** *** **** 27 5 *** ** NT 28 28 **** *** NT 29 29 **** *** NT

Example 31: Pharmaceuticals

[00243] (A) Injection vials: A solution of 100 g of the active ingredient according to the invention and 5 g of disodium hydrogen phosphate in 3 L of double-distilled water was adjusted to pH 6.5 using 2 N. hydrochloric acid, subjected to sterilizing filtration, transferred to injection vials, lyophilized under sterile conditions and hermetically sealed under sterile conditions. Each injection vial contained 5 mg of active ingredient.

[00244] (B) Suppositories: A mixture of 20 g of the active ingredient of the invention was melted with 100 g of soy lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contained 20 mg of active ingredient.

[00245] (C) Solution: A solution was prepared from 1 g of the active ingredient of the invention, 9.38 g of NaH ₂ PO ₄ 2H ₂ O, 28.48 g of Na ₂ HPO ₄ 12H ₂ O and 0.1 g of benzalkonium chloride in 940 ml double-distilled water. The pH value was adjusted to 6.8, and the solution was made to 1 L and sterilized by irradiation. This solution can be used as eye drops.

[00246] (E) Ointment: 500 mg of the active ingredient of the invention was mixed with 99.5 g of petroleum jelly under aseptic conditions.

[00247] (E) Tablets: A mixture of 1 kg of the active ingredient of the invention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate was compressed in a conventional manner to obtain tablets such that each tablet contained 10 mg of active ingredient.

[00248] (F) Coated Tablets: The tablets were compressed as in Example E and then coated in the usual manner with a coating of sucrose, potato starch, talc, tragacanth and color.

[00249] (G) Capsules: 2 kg of the active ingredient of the invention were filled into hard gelatin capsules in the usual manner such that each capsule contained 20 mg of the active ingredient.

[00250] (H) Ampoules: A solution of 1 kg of the active ingredient of the invention in 60 L of bidistilled water was subjected to sterilization filtration, transferred into ampoules, lyophilized under sterile conditions and hermetically sealed under sterile conditions. Each ampoule contained 10 mg of active ingredient.

[00251] (I) Inhalation spray: 14 g of the active ingredient of the invention was dissolved in 10 L of isotonic NaCl solution, and the solution was transferred into commercially available spray containers using a pump mechanism. The solution can be sprayed into the mouth or nose. One spray (approximately 0.1 ml) corresponds to a dose of approximately 0.14 mg.

[00252] Although several embodiments of the present invention are described herein, it will be appreciated that the basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present invention. Thus, it should be understood that the scope of the present invention is defined by the appended claims and not by the specific embodiments presented in the examples.

Claims (48)

1. Compound of formula I I, or a pharmaceutically acceptable salt thereof, where A' represents C=O, CH ₂ , CHOH or NH; L represents a divalent group selected from the following: C _6-10 aryl, 3-8 membered saturated or partially unsaturated carbocyclic ring; each of which is optionally substituted with one or two halogens; X represents CR or N; Y represents NR or S; Z represents CR or N; R ¹ represents C _6-10 aryl, which is optionally substituted with one or two substituents selected from halogen, C _1-6 alkyl or -CN; R ² represents -R, C _1-6 haloalkyl; each R independently represents hydrogen, C _1-6 alkyl, a saturated 3-7 membered heterocyclic ring containing 1 heteroatom representing oxygen; each of which is optionally substituted with one substituent selected from C _1-6 alkyl, -OH or -CN. 2. A compound according to claim 1, wherein A' represents CH ₂ , CHOH or NH. 3. A compound according to any of the preceding claims, wherein L represents a divalent group selected from the following: phenyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, each of which is optionally substituted with one or two halogens. 4. A compound according to any of the preceding claims, wherein L represents a divalent group selected from the following: , , , , , , , And . 5. A compound according to any of the preceding claims, wherein R ¹ represents C _6-10 aryl. 6. A compound according to any of the preceding claims, wherein R ¹ is , , or . 7. A compound according to any of the preceding claims, wherein R ² represents a C _1-6 haloalkyl. 8. A compound according to any of the preceding claims, wherein R ² is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, straight or branched chain pentyl or straight or branched chain hexyl, or R ² is a 4-membered heterocyclic ring containing 1 heteroatom, representing oxygen. 9. A compound as claimed in any one of the preceding claims, wherein R ² is -CF ₃ , , , or . 10. Compound according to claim 1 of formula I-a I-a or a pharmaceutically acceptable salt thereof. 11. Compound according to claim 1 of formula I-c I-c or a pharmaceutically acceptable salt thereof. 12. Compound according to claim 1 of formula I-e I-e or a pharmaceutically acceptable salt thereof. 13. Compound according to claim 1 of formula I-h I-h or a pharmaceutically acceptable salt thereof. 14. The connection according to claim 1, selected from 1 2 3 4 5 6 7 8 9 10 eleven 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 or a pharmaceutically acceptable salt thereof. 15. A pharmaceutical composition having inhibitory activity against IRAK, containing a compound according to claim 1 in an effective amount and a pharmaceutically acceptable excipient, carrier or excipient. 16. A method of inhibiting the activity of IRAK or a mutant thereof in a patient or in a biological sample, comprising the step of administering to said patient or contacting said biological sample with an effective amount of a compound according to claim 1 or a physiologically acceptable salt thereof. 17. A method of treating an IRAK-mediated disorder in a patient in need thereof, comprising the step of administering to said patient an effective amount of a compound according to claim 1. 18. The method of claim 17, wherein the disorder is selected from the following: 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, Crohn's disease, ulcerative colitis, hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult Still's disease, gout, pseudogout, SAPHO syndrome, Castleman's disease, endometriosis; sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Parkinson's disease and cancer. 19. The method of claim 18, wherein the disorder is selected from rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis and multiple sclerosis. 20. A method of treating IRAK-mediated cancer in a subject, comprising the step of administering to said subject an effective amount of a compound of claim 1 or a physiologically acceptable salt thereof.