Pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazinyl compounds useful as IRAK4 inhibitors

Abstract

The present invention relates to a compound of formula (I) TIFF2022541265000013.tif26153 Disclosed herein are compounds, or salts or prodrugs thereof, wherein R1, R2, R3, and R4 are defined herein. Also disclosed are methods of using the compounds as IRAK4 modulators and pharmaceutical compositions containing the compounds. These compounds are useful for treating, preventing, or delaying inflammatory and autoimmune diseases, or for treating cancer.

Description

[Technical field]

[0001] (Related Applications) This application claims priority to U.S. Provisional Application No. 62 / 875,567, filed July 18, 2019, which is incorporated by reference in its entirety. [Background technology]

[0002] The present invention generally relates to pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazinyl compounds useful as kinase inhibitors, such as modulating IRAK4. The invention provides pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazinyl compounds, compositions containing the compounds, and methods of using them. The invention further relates to pharmaceutical compositions containing at least one compound according to the invention, useful for treating conditions associated with kinase modulation, and methods of inhibiting kinase activity, such as IRAK4 in a mammal.

[0003] Toll / IL-1 receptor family members are key regulators of inflammation and host resistance. The Toll-like receptor (TLR) family recognizes molecular patterns derived from infectious organisms (e.g., bacteria, fungi, parasites, and viruses) (reviewed in Kawai, T. et al., Nature Immunol., 11:373-384 (2010)). Ligand binding to the receptor induces dimerization and recruitment of adaptor molecules to conserved cytoplasmic motifs in the receptor called Toll / IL-1 receptor (TIR) ​​domains. All TLRs except TLR3 recruit the adaptor molecule, MyD88. The IL-1 receptor family also contains a cytoplasmic TIR motif and recruits MyD88 upon ligand binding (reviewed in Sims, JE et al., Nature Rev. Immunol., 10:89-102 (2010)).

[0004] Members of the IRAK family of serine / threonine kinases are recruited to their receptors via interaction with MyD88. The family is composed of four members. Several lines of evidence have demonstrated that IRAK4 plays a critical and essential role in initiating signaling through MyD88-dependent TLR and IL-1R family members. Structural data confirm that IRAK4 directly interacts with MyD88 and then recruits either IRAK1 or IRAK2 to the receptor complex, facilitating downstream signaling (Lin, S. et al., Nature, 465:885-890 (2010)). IRAK4 directly phosphorylates IRAK1, facilitating downstream signaling to the E3 ubiquitin ligase TRAF6, which results in activation of the serine / threonine kinase TAK1 and subsequent activation of the NFκB pathway and MAPK cascade (Flannery, S. et al., Biochem. Pharmacol., 80:1981-1991 (2010)). A subset of human patients has been identified as lacking expression of IRAK4 (Picard, C. et al., Science, 299:2076-2079 (2003)). Cells from these patients are unresponsive to all TLR agonists except TLR3, as well as IL-1 family members such as IL-1β and IL-18 (Ku, C. et al., J. Exp. Med., 204:2407-2422 (2007)). Deletion of IRAK4 in mice resulted in a marked inhibition of IL-1, IL-18 and all TLR-dependent responses except TLR3 (Suzuki, N. et al., Nature, 416:750-754 (2002)).In contrast, deletion of either IRAK1 (Thomas, JA et al., J. Immunol., 163:978-984 (1999); Swantek, JL et al., J. Immunol., 164:4301-4306 (2000)) or IRAK2 (Wan, Y. et al., J. Biol. Chem., 284:10367-10375 (2009)) resulted in partial loss of signaling. Furthermore, IRAK4 is the only member of the IRAK family whose kinase activity has been shown to be required for initiation of signaling. Replacement of wild-type IRAK4 with a kinase-inactive mutant (KDKI) in the mouse genome attenuated signaling through all MyD88-dependent receptors, including IL-1, IL-18, and all TLRs except TLR3 (Koziczak-Holbro, M. et al., J. Biol. Chem., 282:13552-13560 (2007); Kawagoe, T. et al., J. Exp. Med., 204:1013-1024 (2007); and Fraczek, J. et al., J. Biol. Chem., 283:31697-31705 (2008)).

[0005] Compared to wild-type animals, mouse models of IRAK4 KDKI have demonstrated reduced risk of multiple sclerosis (Staschke, KA et al., J. Immunol., 183:568-577 (2009)), rheumatoid arthritis (Koziczak-Holbro, M. et al., Arthritis Rheum., 60:1661-1671 (2009)), atherosclerosis (Kim, TW et al., J. Immunol., 186:2871-2880 (2011) and Rekhter, M. et al., Biochem. Biophys. Res. Comm., 367:642-648 (2008)), and myocardial infarction (Maekawa, Y. et al., Circulation, 120:1401-1414 (2013)). (2009)) significantly reduced disease severity. As mentioned above, IRAK4 inhibitors block all MyD88-dependent signaling. MyD88-dependent TLRs have been shown to contribute to the pathogenesis of multiple sclerosis, rheumatoid arthritis, cardiovascular disease, metabolic syndrome, sepsis, systemic lupus erythematosus, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), autoimmune uveitis, asthma, allergy, type I diabetes, and allograft rejection (Keogh, B. et al., Trends Pharmacol. Sci., 32:435-442 (2011); Mann, DL, Circ. Res., 108:1133-1145 (2011); Horton, CG et al., Mediators Inflamm., Article ID 498980 (2010), doi:10.1155 / 2010 / 498980; Goldstein, DR et al., J. Heart Lung Transplant., 24:1721-1729 (2012)). (2005); and Cario, E., Inflamm. Bowel Dis., 16:1583-1597 (2010)). Oncogenically active MyD88 mutations in diffuse large B-cell lymphoma have been identified as sensitive to IRAK4 inhibition (Ngo, VN et al., Nature, 470:115-121 (2011)).Whole genome sequencing has also identified MyD88 mutations associated with chronic lymphocytic leukemia, suggesting that IRAK4 inhibitors may also be useful in treating leukemia (Puente, XS et al., Nature, 475:101-105 (2011)).

[0006] In addition to inhibiting TLR signaling, IRAK4 inhibitors also inhibit signaling by IL-1 family members. Neutralization of IL-1 has been shown to be effective against several diseases, such as gout; gouty arthritis; type 2 diabetes; autoinflammatory diseases (such as cryopyrin-associated periodic fever syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF), adult Still's disease, etc.); systemic juvenile idiopathic arthritis; stroke; graft-versus-host disease (GVHD); smoldering multiple myeloma; recurrent pericarditis; osteoarthropathy; and emphysema (Dinarello, CA, Eur. J. Immunol., 41:1203-1217 (2011) and Couillin, I. et al., J. Immunol., 183:8195-8202 (2009)). In a mouse model of Alzheimer's disease, inhibition of IL-1 receptor improved cognitive impairment, reduced tau pathology, and reduced amyloid-β oligomers (Kitazawa, M. et al., J. Immunol., 187:6539-6549 (2011)). IL-1 has also been shown to be closely related to adaptive immunity and to activate the differentiation of a subset of TH17 effector T cells (Chung, Y. et al., Immunity, 30:576-587 (2009)). Therefore, IRAK4 inhibitors are predicted to be effective against TH17-related diseases such as multiple sclerosis, psoriasis, inflammatory bowel disease, autoimmune uveitis, and rheumatoid arthritis (Wilke, CM et al., Trends Immunol., 32:603-661 (2011)).

[0007] Because symptoms can be ameliorated by treatments such as modulation of protein kinases, it is apparent that novel compounds capable of modulating protein kinases (e.g., IRAK4) and methods using these compounds may provide substantial therapeutic benefit to a wide range of patients. Summary of the Invention

[0008] The present invention relates to a class of novel pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazinyl compounds that have been found to be effective inhibitors of protein kinases such as IRAK4. These compounds provide useful pharmaceutical agents with desirable stability, bioavailability, therapeutic index, and toxicity values ​​important to their druggability.

[0009] The present invention provides compounds of formula (I) or stereoisomers, tautomers, pharma- ceutically acceptable salts, solvates or prodrugs thereof, which are useful as inhibitors of IRAK4 and are useful in the treatment of proliferative, allergic, autoimmune and inflammatory diseases.

[0010] The present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier and at least one compound of the present invention or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0011] The present invention also provides a method for inhibiting IRAK4, comprising administering to a host in need of treatment a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0012] The present invention also provides methods for treating proliferative, metabolic, allergic, autoimmune and inflammatory diseases, comprising administering to a host in need of treatment a therapeutically effective amount of at least one compound of the present invention, or a stereoisomer, tautomer, pharma-ceutically acceptable salt, solvate, or prodrug thereof.

[0013] Certain embodiments provide methods for treating inflammatory and autoimmune diseases, more preferably treating inflammatory diseases. Specific inflammatory and autoimmune diseases include, but are not limited to, Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease, Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, diffuse lupus, psoriasis, cryopyrin-associated periodic fever syndrome (CAPS), TNF receptor-associated periodic syndrome (TRAPS), familial Mediterranean fever (FMF), adult Still's disease, systemic juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.

[0014] Certain embodiments provide methods for treating gout and gouty arthritis.

[0015] Another preferred embodiment is a method for treating metabolic diseases such as type 2 diabetes and atherosclerosis.

[0016] One embodiment provides a method for treating cancer, comprising administering to a host in need of treatment a therapeutically effective amount of at least one compound of the invention, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof.

[0017] The present invention also provides a compound of the present invention or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof, for use in therapy.

[0018] The present invention also provides the use of a compound of the present invention, or a stereoisomer, tautomer, pharma- ceutically acceptable salt, solvate, or prodrug thereof, for the manufacture of a medicament for the treatment of cancer.

[0019] The invention also provides a compound of formula (I) or a pharmaceutical composition in a kit containing instructions for use of the compound or composition.

[0020] The present invention also provides processes and intermediates for making the compounds of the present invention or stereoisomers, tautomers, pharma- ceutically acceptable salts, solvates, or prodrugs thereof.

[0021] These and other features of the present invention are set forth in the broader disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The first aspect of the present invention is a compound of formula (I): [ka] [In the formula, R1 is -NHR 1a or -NHCH2R 1a and; R 1a is C 4-6 Cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl, which are F, Cl, -OH, -CN, C 1-3 Alkyl, C 1-2 Fluoroalkyl, -C(O)(C 1-3 alkyl), -C(O)O(C 1-3 alkyl), and -NR x C(O)O(C 1-3 substituted with 0 to 2 substituents independently selected from alkyl, R2 is (i) C substituted with 0 to 4 substituents independently selected from F, Cl, -OH, and -CN 1-6 Alkyl; or (ii) C 3-6 A cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, where the cyclic group is selected from F, —OH, —CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, and C 1-2 substituted with 0-3 substituents independently selected from hydroxyalkyl; R3 is phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridinonyl, or pyrimidinyl, each of which is selected from F, Cl, -OH, -CN, C 1-2 substituted with 0-3 substituents selected from alkyl, -CF3, and -CH2OH; Each R4 is independently F, Cl, -CH3, or -CN; Each R x is hydrogen or -CH3; and n is 0, 1, or 2. or a salt or prodrug thereof.

[0023] In one embodiment, the compound is a compound represented by the formula: R 1a But, C 5-6 cycloalkyl, pyrrolidinyl, or piperidinyl, which are F, -OH, -CN, C 1-2 Alkyl, C1 fluoroalkyl, -C(O)(C 1-2 alkyl), -C(O)O(C 1-2 alkyl), and -NR x C(O)O(C 1-2 substituted with 0 to 2 substituents independently selected from alkyl, R2 is C substituted with 0 to 3 substituents independently selected from F, Cl, -OH, and -CN; 1-3 is alkyl; R3 is phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, or pyrimidinyl, each of which is substituted with 0-2 substituents selected from F, Cl, -OH, -CN, -CH3, -CF3, and -CH2OH; and n is 0 or 1 The present invention provides a compound of formula (I) wherein:

[0024] In one embodiment, R 1a But, C 5-6 cycloalkyl, pyrrolidinyl, or piperidinyl, which are F, -OH, -CN, C 1-2Alkyl, C1 fluoroalkyl, -C(O)(C 1-2 alkyl), -C(O)O(C 1-2 alkyl), and -NR x C(O)O(C 1-2 The present invention provides a compound of formula (I) or a salt or prodrug thereof, wherein R is substituted with 0 to 2 substituents independently selected from the group consisting of alkyl, aryl ... 1a is cyclohexyl or piperidinyl, each substituted with 0-1 substituents selected from -CH3, -C(O)CH3, -C(O)OCH3, and -NHC(O)OCH3.

[0025] In one embodiment, the compound is a compound represented by the formula: R1 is -NHR 1a or -NHCH2R 1a and; R 1a is cyclohexyl or piperidinyl, each substituted with 0-1 substituents selected from -CH3, -C(O)CH3, -C(O)OCH3, and -NHC(O)OCH3; R2 is -CH(CH3)2; R3 is pyridinyl; and The present invention provides a compound of formula (I) or a salt or prodrug thereof, wherein n is 0.

[0026] In one embodiment, R1 is -NHR 1a or a salt or prodrug thereof. This embodiment includes a compound of formula (I) 1a But, C 5-6 cycloalkyl, pyrrolidinyl, or piperidinyl, which are F, -OH, -CN, C 1-2 Alkyl, C1 fluoroalkyl, -C(O)(C 1-2 alkyl), -C(O)O(C 1-2 alkyl), and -NR x C(O)O(C 1-2 Also included in this embodiment are compounds substituted with 0 to 2 substituents independently selected from R 1ais cyclohexyl or piperidinyl, each substituted with 0-1 substituents selected from -CH3, -C(O)CH3, -C(O)OCH3, and -NHC(O)OCH3.

[0027] In one embodiment, R1 is -NHCH2R 1a or a salt or prodrug thereof. This embodiment includes a compound of formula (I) 1a But, C 5-6 cycloalkyl, pyrrolidinyl, or piperidinyl, which are F, -OH, -CN, C 1-2 Alkyl, C1 fluoroalkyl, -C(O)(C 1-2 alkyl), -C(O)O(C 1-2 alkyl), and -NR x C(O)O(C 1-2 Also included in this embodiment are compounds substituted with 0 to 2 substituents independently selected from R 1a is cyclohexyl or piperidinyl, each substituted with 0-1 substituents selected from -CH3, -C(O)CH3, -C(O)OCH3, and -NHC(O)OCH3.

[0028] In one embodiment, R 1a But, C 5-6 Cycloalkyl, F, -OH, -CN, C 1-2 Alkyl, C1 fluoroalkyl, -C(O)(C 1-2 alkyl), -C(O)O(C 1-2 alkyl), and -NR x C(O)O(C 1-2 The present invention provides a compound of formula (I) or a salt or prodrug thereof, wherein the compound is substituted with 0 to 2 substituents independently selected from:

[0029] In one embodiment, R 1a is pyrrolidinyl or piperidinyl, respectively F, -OH, -CN, C 1-2 Alkyl, C1 fluoroalkyl, -C(O)(C 1-2alkyl), -C(O)O(C 1-2 alkyl), and -NR x C(O)O(C 1-2 The present invention provides a compound of formula (I) or a salt or prodrug thereof, wherein the compound is substituted with 0 to 2 substituents independently selected from:

[0030] In some embodiments, R2 is selected from the group consisting of: (i) C substituted with 0-4 substituents independently selected from F, Cl, -OH, and -CN. 1-5 alkyl; or (ii) C 3-6 A cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, where the cyclic group is selected from F, —OH, —CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, and C 1-2 The present invention provides a compound of formula (I) or a salt or prodrug thereof, wherein R2 is substituted with 0-3 substituents independently selected from hydroxyalkyl. This embodiment includes compounds of formula (I) or a salt or prodrug thereof, wherein R2 is substituted with 0-3 substituents independently selected from hydroxyalkyl, ... 1-4 alkyl; or (ii) C 3-6 A cyclic group selected from cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, where the cyclic group is selected from F, —OH, —CN, C 1-2 Alkyl, -CF3, and C 1-2 Included are compounds that are substituted with 0-3 substituents independently selected from hydroxyalkyl.

[0031] In one embodiment, R2 is a C substituted with 0-4 substituents independently selected from F, Cl, -OH, and -CN. 1-6 The present invention provides a compound of formula (I) or a salt or prodrug thereof, wherein R2 is C substituted with 0-3 substituents independently selected from F, Cl, -OH, and -CN. 1-3 Also included within this embodiment are compounds where R2 is -CH(CH3)2.

[0032] In one embodiment, R2 is C 3-6 A cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, where the cyclic group is selected from F, —OH, —CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, and C 1-2 The present invention provides a compound of formula (I) or a salt or prodrug thereof, wherein R2 is substituted with 0 to 3 substituents independently selected from hydroxyalkyl. 3-6 cycloalkyl, tetrahydrofuranyl, tetrahydropyranyl, and pyrazolyl, where the cyclic group is F, -OH, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, and C 1-2 Included in this embodiment are compounds substituted with 0-3 substituents independently selected from hydroxyalkyl. Further included in this embodiment are compounds where R2 is selected from F, -OH, -CN, C 1-2 Alkyl, -CF3, and C 1-2 C substituted with 0 to 3 substituents independently selected from hydroxyalkyl 3-6 Included are compounds which are cycloalkyl.

[0033] An embodiment provides a compound of formula (I) or a salt or prodrug thereof, wherein R3 is phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, or pyrimidinyl, each of which is substituted with 0-2 substituents independently selected from F, Cl, -OH, -CN, -CH3, -CF3, and -CH2OH. Included in this embodiment are compounds where R3 is phenyl, pyridinyl, or pyrimidinyl, each of which is substituted with 0-2 substituents independently selected from F, Cl, -OH, -CN, -CH3, -CF3, and -CH2OH. Also included in this embodiment are compounds where R3 is pyridinyl.

[0034] An embodiment provides a compound of formula (I) or a salt or prodrug thereof, wherein each R4 is independently F, Cl, -CH3, or -CN; and n is 0 or 1. Included in this embodiment are compounds where n is 0.

[0035] In one embodiment, the compound is 1-Isopropyl-N-(piperidin-4-ylmethyl)-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (1); Methyl 4-(((1-isopropyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)methyl)piperidine-1-carboxylate (2); 1-Isopropyl-N-(piperidin-4-ylmethyl)-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (3); Methyl 4-(((1-isopropyl-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)methyl)piperidine-1-carboxylate (4); 1-Isopropyl-N-((1-methylpiperidin-4-yl)methyl)-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (5); Methyl (4-((1-isopropyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)cyclohexyl)carbamate (6); Methyl (4-((1-isopropyl-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)cyclohexyl)carbamate (7); 1-(4-((1-isopropyl-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)piperidin-1-yl)ethan-1-one (8); and 1-Isopropyl-N-(piperidin-4-yl)-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (9) The present invention provides a compound of formula (I) or a salt thereof, selected from:

[0036] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.6 μM.

[0037] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.1 μM.

[0038] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.05 μM.

[0039] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.025 μM.

[0040] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.015 μM.

[0041] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.01 μM.

[0042] (definition) The features and advantages of the present invention may be more readily understood by those skilled in the art upon reading the following detailed description. It is understood that, for clarity, certain features of the invention that are described in the context of another embodiment may be combined to form a single embodiment. Conversely, various features of the invention that are described in the context of a single embodiment for brevity may also be combined to form subcombinations thereof. The embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0043] Unless otherwise stated herein, references in the singular may also include the plural, for example, "a" and "an" may refer to either "one" or "one or more."

[0044] As used herein, the phrase "a compound" refers to at least one compound. For example, a compound of formula (I) includes one compound of formula (I) and two or more compounds of formula (I).

[0045] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to include enough hydrogen atoms to satisfy the valences.

[0046] The definitions set forth herein take precedence over definitions set forth in any patents, patent applications, and / or published patent applications incorporated herein by reference.

[0047] Listed below are definitions of various terms used to describe this invention. These definitions apply to those terms as they are used throughout the specification, either individually or as part of a larger group (unless otherwise limited in specific instances).

[0048] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0049] According to the practice used in the art, [ka] is used in structural formulas herein to represent the bond that is the point of attachment of a moiety or substituent to a core or backbone structure.

[0050] The terms "halo" and "halogen" as used herein refer to F, Cl, Br, and I.

[0051] The term "cyano" refers to the group --CN.

[0052] The term "amino" refers to the group -NH2.

[0053] The term "oxo" refers to the group =O.

[0054] The term "alkyl" as used herein refers to both branched and straight chain saturated aliphatic hydrocarbon groups, for example, having 1 to 12 carbon atoms, 1 to 6 carbon atoms, and 1 to 4 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and i-propyl), butyl (e.g., n-butyl, i-butyl, sec-butyl, and t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylpentyl, 2-ethylbutyl, 3-methylpentyl, and 4-methylpentyl. When a number appears in subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular group may contain. For example, "C 1-6 "Alkyl" means straight and branched chain alkyl groups having from 1 to 6 carbon atoms.

[0055] As used herein, the term "fluoroalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups substituted with one or more fluorine atoms. For example, 1-4 "Fluoroalkyl" is meant to include C1, C2, C3, and C4 alkyl groups substituted with one or more fluorine atoms. Representative examples of fluoroalkyl groups include, but are not limited to, -CF3 and -CH2CF3.

[0056] The term "hydroxyalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CHOH, -CHCHOH, and -CHCHOH. 1-4 Hydroxyalkyl is an example.

[0057] The term "cycloalkyl" as used herein refers to a group derived from a non-aromatic monocyclic or polycyclic hydrocarbon molecule by removing one hydrogen atom from a saturated ring carbon atom. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. When a number appears as a subscript after the symbol "C," the subscript more specifically qualifies the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C3-C6 cycloalkyl" refers to a cycloalkyl group having from 3 to 6 carbon atoms.

[0058] As used herein, the phrase "pharmacologically acceptable" refers to compounds, substances, compositions, and / or dosage forms that are suitable, within the scope of ordinary medical judgment, for contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication and that afford a reasonable benefit / risk ratio.

[0059] The compound of formula (I) may be provided as an amorphous solid or a crystalline solid. The compound of formula (I) may be provided as an amorphous solid by lyophilization.

[0060] In addition, solvates (e.g., hydrates) of the compounds of formula (I) should be considered within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) with one or more organic or inorganic solvent molecules. This physical association includes hydrogen bonding. In some cases, it is possible to isolate the solvate, for example when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" includes both solution-phase and isolable solvates. Examples of solvates include hydrates, ethanolates, methanolates, isopropanolates, acetonitrile solvates, and ethyl acetate solvates. Methods of solvation are known in the art.

[0061] Various forms of prodrugs are well known in the art: a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31, (Academic Press, 1996); b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113 - 191 (Harwood Academic Publishers, 1991); and d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer, (Wiley-VCH, 2003) e) Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018) It is described in.

[0062] In addition, the compounds of formula (I) may be isolated and purified following their preparation to obtain compositions containing 99% or greater of the compounds of formula (I) ("substantially pure"), which are then used or formulated as described herein. Such "substantially pure" compounds of formula (I) are also considered herein to be part of the invention.

[0063] By "stable compound" and "stable structure" is intended a compound that is sufficiently robust that it will not decompose upon isolation to a useful degree of purity from a reaction mixture, or upon formulation into an efficacious therapeutic agent. The present invention embodies stable compounds.

[0064] "Therapeutically effective amount" is intended to include an amount of a compound of the invention alone, or in combination with the claimed compounds, or in combination with other active ingredients, that is effective to act as an inhibitor of IRAK4, or to treat or prevent autoimmune and / or inflammatory diseases (e.g., multiple sclerosis and rheumatoid arthritis), or to treat cancer.

[0065] As used herein, the terms "treating" or "treatment", in the treatment of a condition in a mammal, particularly a human, includes: (a) preventing the mammal from acquiring the condition, particularly when the mammal is susceptible to, but has not yet been diagnosed as having, the condition; (b) inhibiting the condition, i.e., arresting the progression of the condition; and / or (C) alleviating the condition, i.e., causing regression of the condition.

[0066] The compounds of the present invention are intended to contain all isotopes of atoms contained in the compounds. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include 13 C and 14 C. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those of skill in the art, or by methods analogous to those described herein, substituting the appropriate isotopically labeled reagent for the non-labeled reagent used elsewhere. For example, methyl (-CH3) also includes deuterated methyl groups (e.g., -CD3).

[0067] (Usefulness) The compounds of the present invention modulate kinase activity, including modulation of IRAK4. Other types of kinase activity that may be modulated by the compounds of the present invention include, but are not limited to, the Pelle / IRAK family and mutants thereof.

[0068] Thus, the compounds of formula (I) are useful for treating conditions related to the modulation of kinase activity, particularly the selective inhibition of IRAK4 activity or the inhibition of IRAK and other Pelle family kinases, including TLR / IL-1 family receptor-associated diseases in which cytokine levels are modulated as a result of intracellular signaling.Furthermore, the compounds of formula (I) have useful selectivity for RAK4 activity, and preferably have higher selectivity for at least 20 fold structures to 1,000 fold structures or more.

[0069] The term "treating" or "treatment" as used herein encompasses the treatment of a condition in a mammal, particularly a human, and includes (a) preventing or delaying the mammal from acquiring the condition, particularly where the mammal is susceptible to, but has not yet been diagnosed as having, the condition; (b) inhibiting the condition, i.e., arresting the progression of the condition; and / or (c) achieving complete or partial alleviation of the symptoms or condition, and / or palliating, ameliorating, relieving, or curing the disease or disorder and / or its symptoms.

[0070] In view of the activity of the compounds of the present invention as selective inhibitors of IRAK4, the compounds of formula (I) are useful in the treatment of TLR / IL-1 family receptor-associated diseases, including but not limited to inflammatory diseases (e.g., Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease); autoimmune diseases (e.g., Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis); autoinflammatory diseases (e.g., CAPS, TRAPS, FMF, adult Still's disease, systemic juvenile idiopathic arthritis, gout, gouty arthritis); metabolic diseases (e.g., type 2 diabetes, atherosclerosis, myocardial infarction); bone destructive diseases (e.g., bone resorption diseases, osteoarthropathy, osteoporosis, multiple myelopathy, osteoporosis ... myeloma-associated bone disease); proliferative disorders (e.g., acute myelogenous leukemia, chronic myelogenous leukemia); angiogenic diseases (e.g., angiogenic diseases including solid tumors, intraocular angiogenesis, and childhood hemangiomas); infectious diseases (e.g., sepsis, septic shock, and bacterial dysentery); neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, cerebral ischemia or traumatic neurodegenerative diseases), neoplastic diseases (e.g., metastatic melanoma, Kaposi's sarcoma, multiple myeloma), and viral diseases (e.g., HIV infection and CMV retinitis, AIDS).

[0071] In particular, specific conditions or diseases that may be treated with the compounds of the present invention include, but are not limited to, pancreatitis (acute or chronic), asthma, allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft versus host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis, pancreatic beta cell disease; Diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, allograft rejection, fever and myalgia due to infection, cachexia following infection, keloid formation, scar tissue formation, ulcerative colitis, fever, influenza, osteoporosis, osteoarthritis, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, sepsis, septic shock, and bacillary dysentery; Alzheimer's disease, Parkinson's disease, cerebral ischemia or traumatic neurodegenerative diseases; angiogenic diseases (e.g., solid tumors, intraocular neovascular diseases, and infantile hemangiomas); viral diseases (e.g., acute hepatitis (e.g., hepatitis A, B, and C) infection, HIV infection and CMV retinitis, AIDS, ARC or malignant tumors, and herpes); stroke, myocardial ischemia, ischemia in stroke heart attack, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, thrombosis, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome , prostaglandin endoperoxidase synthase 2-associated conditions, and pemphigus vulgaris. A preferred method of treatment is one in which the condition is selected from Crohn's disease, ulcerative colitis, allograft rejection, rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, and pemphigus vulgaris. Alternatively, a preferred method of treatment is one in which the condition is selected from ischemia-reperfusion injury (e.g., cerebral ischemia-reperfusion injury due to stroke and cardiac ischemia-reperfusion injury due to myocardial infarction).Other preferred methods of treatment are those where the condition is multiple myeloma.

[0072] In certain embodiments, the compounds of Formula (I) are effective in treating cancer (e.g., Waldenstrom's macroglobulinemia (WM), diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), cutaneous diffuse large B-cell lymphoma, and primary CNS lymphoma).

[0073] In addition, the kinase inhibitors of the present invention inhibit the expression of inducible inflammatory proteins (e.g., prostaglandin endoperoxide synthase-2 (PGHS-2, cyclooxygenase-2 (COX-2), IL-1, IL-6, IL-18, also referred to as chemokines). Accordingly, further IRAK4-associated conditions include edema, analgesia, fever and pain (e.g., neuromuscular pain, headache, cancer pain, dental pain and arthritis pain). The compounds of the present invention may also be used to treat animal viral infections, such as lentivirus infections (e.g., but not limited to, equine infectious anemia virus); or retrovirus infections (feline immunodeficiency virus, bovine immunodeficiency virus, and canine immunodeficiency virus).

[0074] The terms "IRAK4-associated condition" or "IRAK4-associated disease or disorder" as used herein are meant to encompass all of the above-mentioned conditions, as well as any other condition affected by IRAK4 kinase activity, which may recur over time.

[0075] The present invention therefore provides a method of treating the above conditions, comprising administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or a salt thereof. A "therapeutically effective amount" is intended to include an amount of a compound of the present invention that is effective, when administered alone or in combination, to inhibit IRAK4 and / or treat a disease.

[0076] Methods for treating IRAK4 kinase-related conditions may be characterized by administering compounds of formula (I) alone or in combination with each other and / or with other suitable therapeutic agents effective in treating such conditions. Thus, "therapeutically effective amount" is also intended to include an amount of the combination of claimed compounds effective for inhibiting IRAK4 and / or treating a disease associated with IRAK4.

[0077] Examples of other therapeutic agents include corticosteroids, rolipram, calphostin, cytokine suppressive anti-inflammatory drugs (CSAIDs), interleukin-10, glucocorticoids, salicylates, nitric oxide, and other immunosuppressants; nuclear transport inhibitors (e.g., deoxyspergualin (DSG)), nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, celecoxib, and rofecoxib), steroids (e.g., prednisone or dexamethasone), antivirals (e.g., abacavir), antiproliferatives (e.g., methotrexate, leflunomide, FK506, (tacrolimus, PROGRAF®), antimalarials (e.g., hydroxychloroquine), cytotoxic drugs (e.g., azathioprine and cyclophosphamide), TNF-α inhibitors (e.g., tenidap, anti-TNF antibodies or soluble TNF receptors, and rapamycin (sirolimus or RAPAMUNE®)), or derivatives thereof.

[0078] The other therapeutic agents described above may be used in combination with the compounds of the present invention, for example, in amounts as described in the PDR or as determined by one skilled in the art. In the methods of the present invention, the other therapeutic agents may be administered before, simultaneously, or after the administration of the compounds of the present invention. The present invention also provides pharmaceutical compositions capable of treating IRAK4 kinase-related conditions (e.g., TLR and IL-1 family receptor-mediated diseases described above).

[0079] The compositions of the present invention may contain and be formulated with other therapeutic agents as described above according to techniques well known to those skilled in the art of pharmaceutical formulation, for example, using conventional solid or liquid vehicles or diluents, as well as pharmaceutical excipients (e.g., additives, binders, preservatives, stabilizers, flavoring agents, and the like) of a type appropriate to the desired method of administration.

[0080] Accordingly, the present invention further includes compositions comprising one or more compounds of formula (I) and a pharma- ceutically acceptable carrier.

[0081] "Pharmaceutically acceptable carrier" refers to a medium generally accepted in the field of delivering biologically active agents to animals, particularly mammals. Pharmaceutically acceptable carriers are formulated according to many factors well within the expertise of those skilled in the art. These factors include, but are not limited to, the type and nature of the active agent being formulated, the patient to whom the composition containing the active agent will be administered, the intended route of administration of the composition, and the targeted therapeutic index. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include many different components and additives in addition to the active agent, and such additional components are included in the formulation for a variety of reasons, such as for stabilization of the active agent, binders, and the like, known to those skilled in the art. Descriptions of suitable pharmacopoeia acceptable carriers and factors in selecting them can be found in a variety of readily available texts, such as Remington's Pharmaceutical Sciences, 17th Edition (1985), the entire contents of which are incorporated herein by reference.

[0082] The compounds according to formula (I) may be administered by any method appropriate to the condition to be treated, which may vary depending on the need for site-specific treatment or the amount of compound of formula (I) to be delivered.

[0083] The present invention also includes a class of pharmaceutical compositions comprising a compound of formula (I) and one or more non-toxic, pharma- ceutically acceptable carriers and / or diluents and / or adjuvants (substances collectively referred to herein as "carriers") and, optionally, other active ingredients. The compound of formula (I) may be administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such route, and in a dosage effective for the intended treatment. The compounds and compositions of the present invention may be administered, for example, orally, transmucosally, or parenterally, including intravascularly, intravenously, intraperitoneally, subcutaneously, intramuscularly, and intrasternally, in dosage unit formulations containing conventional pharma-ceutically acceptable carriers, adjuvants, and vehicles. For example, pharmaceutical carriers may include mixtures of mannitol or lactose and microcrystalline cellulose. The mixtures may include additional ingredients, such as lubricants (e.g., magnesium stearate) and disintegrants (e.g., crospovidone). The carrier mixture may be filled into gelatin capsules or compressed into tablets. The pharmaceutical composition may be administered, for example, in oral dosage form or as an infusion.

[0084] For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, liquid capsule, suspension, or liquid. The pharmaceutical composition is preferably formulated in a dosage unit form with a specific amount of active ingredient. For example, the pharmaceutical composition may be provided as a tablet or capsule containing an amount of active ingredient ranging from about 0.1 to 1000 mg, preferably from about 0.25 to 250 mg, more preferably from about 0.5 to 100 mg. The appropriate daily dose to be administered to a human or other mammal may vary widely depending on the patient's condition and other factors, but can be determined using routine methods.

[0085] Any pharmaceutical composition discussed herein can be delivered orally, for example, via any acceptable and suitable oral formulation. Examples of oral formulations include, but are not limited to, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders or granules, emulsions, hard and soft capsules, liquid capsules, syrups, and elixirs. Pharmaceutical compositions for oral administration can be prepared according to any method known in the art for preparing pharmaceutical compositions for oral administration. In order to provide a medicament that is easy to swallow, the pharmaceutical compositions described in the present invention can include at least one substance selected from sweeteners, flavoring agents, coloring agents, demulcents, antioxidants, and preservatives.

[0086] Tablets can be prepared, for example, by mixing at least one compound of formula (I) with at least one non-toxic pharma- ceutically acceptable additive suitable for tablet preparation. Examples of additives include, but are not limited to, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate, and sodium phosphate), granulating and disintegrating agents (e.g., microcrystalline cellulose, croscarmellose sodium, corn starch, and alginic acid), binding agents (e.g., starch, gelatin, polyvinylpyrrolidone, and gum arabic), and lubricants (e.g., magnesium stearate, stearic acid, and talc). In addition, tablets can be uncoated or coated by known techniques to mask the unpleasant taste of unpleasant drugs or to delay disintegration and absorption of the active ingredient in the digestive tract, thus prolonging the effect of the active ingredient for a longer period of time. Examples of water-soluble taste-masking materials include, but are not limited to, hydroxypropyl methylcellulose and hydroxypropyl cellulose. Examples of time delay materials include, but are not limited to, ethyl cellulose and cellulose acetate butyrate.

[0087] Hard gelatin capsules may be prepared, for example, by mixing at least one compound of formula (I) with at least one inert solid diluent, such as calcium carbonate, calcium phosphate, and kaolin.

[0088] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) with at least one water-soluble carrier (e.g., polyethylene glycol) and at least one oil medium (e.g., peanut oil, liquid paraffin, and olive oil).

[0089] Aqueous suspensions may be prepared, for example, by mixing at least one compound of formula (I) with at least one additive suitable for the preparation of aqueous suspensions. Examples of additives suitable for the preparation of aqueous suspensions include, but are not limited to, suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, alginic acid, polyvinylpyrrolidone, gum tragacanth, and gum arabic), dispersing or wetting agents (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and Examples of suitable condensation products include condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitol monooleate), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). The aqueous suspension may also contain at least one preservative (e.g., ethyl p-hydroxybenzoate and n-propyl p-hydroxybenzoate), at least one coloring agent, at least one flavoring agent, and / or at least one sweetening agent (e.g., but not limited to, sucrose, saccharin, and aspartame).

[0090] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) in either vegetable oil (e.g., peanut oil, olive oil, sesame oil, and coconut oil) or mineral oil (e.g., liquid paraffin). Oily suspensions can also include at least one thickening agent (e.g., beeswax, hard paraffin, and cetyl alcohol). To provide a palatable oily suspension, at least one sweetener already described above and / or at least one flavoring agent can be added to the oily suspension. Oily suspensions can further include at least one preservative, including but not limited to, for example, an antioxidant (e.g., butylated hydroxyanisole, and alpha-tocopherol).

[0091] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) with at least one dispersing agent and / or wetting agent, at least one suspending agent, and / or at least one preservative. Suitable dispersing agents, wetting agents, and suspending agents have already been described above. Examples of preservatives include, but are not limited to, antioxidants (e.g., ascorbic acid). In addition, dispersible powders and granules can also include at least one excipient (e.g., but are not limited to, sweeteners, flavoring agents, and coloring agents).

[0092] At least one emulsion of the compound of formula (I) may be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion containing the compound of formula (I) may be composed of known ingredients in a known manner. The oil phase may be provided, for example, but not limited to, vegetable oils (e.g., olive oil and peanut oil), mineral oils (e.g., liquid paraffin), and mixtures thereof. The oil phase may include only an emulsifier, but may also include a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. Suitable emulsifiers include, but are not limited to, naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of partial esters and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier, with or without a stabilizer, makes up the so-called emulsifying wax, and the wax, with oils and fats, makes up the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation.The emulsion may also include sweeteners, flavorings, preservatives, and / or antioxidants.Emulsifiers and emulsion stabilizers suitable for use in the formulation of the present invention include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate, sodium lauryl sulfate, glyceryl distearate, alone or with wax; or other materials known in the art.

[0093] In addition, the compound of formula (I) can be delivered, for example, intravenously, subcutaneously, and / or intramuscularly via any pharma- ceutically acceptable and suitable injection form. Examples of injection forms include, but are not limited to, sterile aqueous solutions containing acceptable vehicles and solvents (e.g., water, Ringer's solution, and isotonic sodium chloride solution), sterile oil-in-water microemulsions, and aqueous or oily suspensions.

[0094] Preparations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules by using one or more carriers or diluents described for use in preparations for oral administration, or by using other suitable dispersing or wetting agents and suspending agents. The compound may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, tragacanth gum, and / or various buffer solutions. Other adjuvants and methods of administration are known and widely known in the pharmaceutical field. The active ingredient may also be administered by injection in a composition with a suitable carrier (e.g., saline, dextrose, or water), or cyclodextrin (i.e., Captisol), solubilizing cosolvent (i.e., propylene glycol), or solubilizing micelle (i.e., Tween 80).

[0095] A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol). Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any sterile fixed oil may be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used as injectable preparations.

[0096] Sterile injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving at least one compound of formula (I) in an oil phase (e.g., a mixture of soybean oil and lecithin), 2) combining the oil phase containing formula (I) with a mixture of water and glycerol, and 3) treating the combination to form a microemulsion.

[0097] Sterile aqueous suspension or sterile oily suspension can be prepared according to a method known to those skilled in the art. For example, sterile aqueous solution or sterile aqueous suspension can be prepared using a non-toxic, parenterally acceptable diluent or solvent (e.g., 1,3-butanediol), and sterile oily suspension can be prepared using a non-toxic, acceptable solvent or suspension medium (e.g., sterile fixed oil (e.g., synthetic monoglyceride or diglyceride), and fatty acid (e.g., oleic acid).

[0098] Pharmaceutically acceptable carriers, adjuvants, and vehicles that may be used in the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) (e.g., d-α-tocopherol polyethylene glycol 1000 succinate), surfactants used in pharmaceutical dosage forms (e.g., Tween, polyethoxylated castor oil (e.g., CREMOPHOR surfactants (BASF), or other similar polymeric delivery matrices), serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (e.g., protamine sulfate, glyceryl stearate, sorbitol ... Examples of suitable cyclodextrins include cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropylcyclodextrin, or other solubilizing derivatives.

[0099] The pharma- ceutical active compounds of the present invention can be processed according to conventional pharmaceutical methods to prepare medicaments for administration to patients (e.g., humans and other mammals). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations (e.g., sterilization) and / or can contain conventional adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc.). Tablets and pills can additionally be prepared with enteric coatings. Such compositions can also contain adjuvants (e.g., wetting agents, sweeteners, flavoring agents, and aromatic agents).

[0100] The amount of compound administered to treat a condition using the compounds and / or compositions of the present invention, and the dosing schedule will depend on a variety of factors, such as age, weight, sex, the condition of the patient, the type of disease, the severity of the disease, the route and frequency of administration, and the specific compound utilized. Thus, the dosing schedule may vary widely, but can be routinely determined using standard methods. A daily dose of about 0.001 to 100 mg / kg body weight, preferably between about 0.0025 to about 50 mg / kg body weight, and most preferably between about 0.005 to 10 mg / kg body weight, may be appropriate. The daily dose may be administered 1 to 4 times a day. Other dosing schedules include weekly and biday cycles.

[0101] For treatment, the active compound of the present invention is usually combined with one or more adjuvants suitable for intended administration route.When administered orally, the compound can be mixed with lactose, sucrose, starch powder, cellulose ester of alkanoic acid, cellulose alkyl ester, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration.Such capsules or tablets can include controlled release formulations, and can be provided with active compound dispersed in hydroxypropylmethylcellulose.

[0102] The pharmaceutical compositions of the present invention include at least one compound of formula (I) and optionally an excipient selected from any pharma- ceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present invention includes a compound of formula (I) as described herein, or a prodrug thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0103] The present invention also includes an article of manufacture. As used herein, article of manufacture is intended to include, but is not limited to, kits and packages. The article of manufacture of the present invention includes (a) a first container, (b) a pharmaceutical composition contained within the first container, wherein the composition includes a first therapeutic agent, which includes a compound of the present invention or a pharma- ceutically acceptable salt form thereof, and (c) a package insert that describes that the pharmaceutical composition can be used to treat cardiovascular disease, diuresis, and / or natriuresis, as defined above. In other embodiments, the package insert describes that the pharmaceutical composition can be used in combination with a second therapeutic agent (as defined above) to treat cardiovascular disease, diuresis, and / or natriuresis. The article of manufacture may further include (d) a second container, wherein components (a) and (b) are contained within the second container, and component (c) is located within or outside the second container. Located within the first and second containers means that each container holds the item within an area.

[0104] The first container is a container used to hold a pharmaceutical composition. This container can be for manufacturing, storage, distribution, and / or individual / bulk sales. The first container is intended to cover bottles, jars, vials, flasks, syringes, tubes (e.g., for cream formulations), or any other containers used in manufacturing, holding, storing, or distributing pharmaceutical formulations.

[0105] The second container is for holding the first container and, optionally, the package insert. Examples of the second container include, but are not limited to, boxes (e.g., cardboard or plastic), wooden boxes, corrugated boxes, bags (e.g., paper or plastic bags), pouches, and cloth bags. The package insert can be physically attached to the first container by tape, glue, staples, or other attachment methods, or can be present in the second container without being attached to the first container by physical means. Alternatively, the package insert is located on the outside of the second container. When located on the outside of the second container, the package insert is preferably physically attached by tape, glue, staples, or other attachment methods. Alternatively, the package insert can be in close proximity to or in contact with the outside of the second container without being physically attached.

[0106] A package insert is a label, tag, marker, or other written object that describes information related to the pharmaceutical composition placed in the first container. The described information is usually determined by a regulatory agency (e.g., the U.S. Food and Drug Administration) governing the geographic area in which the product is sold. Preferably, the package insert specifically describes the indications for which the pharmaceutical composition is approved. The package insert may be made of any material that allows a person to read the information contained therein or thereon. Preferably, the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information is placed (e.g., printed or affixed).

[0107] (Manufacturing method) The compounds of the present invention can be prepared by various methods well known to those skilled in the art of organic synthesis. The compounds of the present invention can be prepared using the methods described below and synthetic methods known in the art of organic chemical synthesis, or variations thereof that will be understood by those skilled in the art. Preferred methods include, but are not limited to, the following:

[0108] The reactions and techniques described in this section are carried out in solvents suitable for the reagents and materials used and are appropriate for the transformations effected. It is also understood that in the description of the synthetic methods described below, all reaction conditions presented (including the choice of solvent, reaction atmosphere, reaction temperature, experimental time and work-up method) are selected to be conditions that are standard for the reaction, which should be readily recognized by those skilled in the art. It is understood by those skilled in the art of organic synthesis that the functional groups present on various parts of the molecule must be compatible with the reagents and reactions presented. Such restrictions on the substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods must be used. The reactions may require the decision to change the order of synthetic steps or to select a particular reaction sequence differently in order to obtain the desired compound of the invention. It is also recognized that another important consideration in planning any synthetic route in this field is the judicious selection of protecting groups used to protect reactive functional groups present in the desired compound described in the invention. For the experienced experimenter, an authoritative reference describing many protecting group alternatives is Protective Groups In Organic Synthesis by Greene et al. (Third Edition, Wiley & Sons, 1999).

[0109] Compounds of formula (I) may be prepared according to the methods outlined in the following schemes. For example, in scheme 1, chloro-bromo intermediate 1A may be reacted with hydrazine in the presence of a base (e.g., triethylamine) and a solvent to give intermediate 1B. Intermediate 1B may be reacted with a variety of cross-coupling agents to form compounds (e.g., 1C). Finally, 1C may be reacted with a variety of alkylating agents or other carbon-nitrogen bond forming conditions to give the final compounds of general formula I. [ka]

[0110] (Example) The compounds of the present invention and intermediates used in the preparation of the compounds of the present invention may be prepared using the methods shown in the following examples and related methods. The methods and conditions used in these examples, and the actual compounds prepared in these examples, are not meant to be limiting, but are meant to illustrate how the compounds of the present invention may be prepared. The starting materials and reagents used in these examples are generally commercially available or reported in the chemical literature, or may be prepared by using steps described in the chemical literature, unless the preparation method is described herein. The present invention is further defined in the following examples, which should be understood to be given by way of illustration only. From the above discussion and examples, one skilled in the art will be able to ascertain the essential features of the present invention, and may make changes and modifications to adapt the present invention to a wide range of conditions and applications without departing from the spirit and scope of the invention. As a result, the present invention is not limited by the examples described below, but rather is defined by the claims appended hereto.

[0111] In the described examples, the phrase "dried and concentrated" generally refers to drying a solution in an organic solvent with either sodium sulfate or magnesium sulfate, followed by filtration and removal of the solvent from the filtrate (generally under reduced pressure and at a temperature appropriate to the stability of the material being prepared).

[0112] Column chromatography was performed on prepacked silica gel cartridges using an Isco medium pressure chromatography apparatus (Teledyne Corporation) eluted with the solvents or solvent mixtures indicated. Preparative high performance liquid chromatography (HPLC) was performed using a reversed-phase column (Waters Sunfire C) of appropriate size for the amount of material to be separated. 18 , Waters XBridge C 18 , PHENOMENEX(R) Axia C 18Separation was performed using a column chromatography column (e.g., YMC S5 ODS) and typically eluted with a gradient of increasing concentrations of methanol or acetonitrile in water also containing 0.05% or 0.1% trifluoroacetic acid or 10 mM ammonium acetate, with elution rates appropriate to the column size. Chemical names were determined using ChemDraw Ultra (version 9.0.5 (CambridgeSoft)). The following abbreviations are used: [Table 1]

[0113] HPLC conditions: Method A: Waters Acquity UPLC BEH C18, 2.1 x 50 mm, particle size: 1.7 μm; Mobile phase A: 5:95 acetonitrile:water (containing 10 mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10 mM ammonium acetate); Temperature: 50 °C; Gradient: 0-100% B over 3 min, followed by 100% B for 0.75 min; Flow rate: 1.0 mL / min; Detection: UV (220 nm).

[0114] Example 1 1-Isopropyl-N-(piperidin-4-ylmethyl)-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine [ka]

[0115] Intermediate 1A: 8-Bromo-1-isopropyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine [ka] To a suspension of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carbonitrile (200 mg, 0.78 mmol) in DMF (3 mL) was added isopropylhydrazine hydrochloride (95 mg, 0.86 mmol) and Na2CO3 (174 mg, 1.64 mmol). The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and extracted with EA. The extracted organic layer was washed with NaHCO3 and brine, then dried over Na2SO4 and filtered. After concentration, the product was purified by column chromatography to give 8-bromo-1-isopropyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (128 mg, 56% yield). 1 H NMR(500MHz, CDCl3) δ 8.16 (s, 1H), 7.72 (d, J=1.5Hz, 1H), 6.68 (d, J=2.7Hz, 1H), 4.76 (m, 1H), 4.14(br s, 2H), 1.59 (s, 3H), 1.57 (s, 3H)

[0116] Intermediate 1B: 1-isopropyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine [ka] A mixture of 8-bromo-1-isopropyl-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (26 mg, 0.088 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (19.94 mg, 0.097 mmol), K3PO4 (0.133 mL, 0.265 mmol) and PdCl2(dppf)-CH2Cl2 (1.53 mg, 4.42 μmol) in 1,4-dioxane (2 mL) was purged with N2. The reaction vessel was sealed and heated in a microwave reactor at 120 °C for 0.5 h. The reaction mixture was cooled to room temperature and the product was directly purified by preparative HPLC.

[0117] Example 1: To a suspension of 1-isopropyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (25 mg, 0.086 mmol) in MeOH (3 mL) was added acetic acid (15.4 mg, 0.26 mmol), tert-butyl 4-formylpiperidine-1-carboxylate (23.7 mg, 0.111 mmol), and NaBH3CN (8.6 mg, 0.14 mmol). The reaction vessel was sealed and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated and passed through a short silica gel column and the product fraction was concentrated and briefly dried. DCM was added to dissolve the product, followed by the addition of TFA. The mixture was monitored by LCMS for conversion of the free amine. After completion of the reaction, the mixture was directly purified by preparative HPLC to give 1-isopropyl-N-(piperidin-4-ylmethyl)-8-(pyridin-3-yl)-1H-dipyrrolo[1,2-b:2',3'-d]pyridazin-3-amine (2 mg, 6% yield). 1 H NMR(500MHz, DMSO-d6)δ 9.05(br s, 1H), 8.47 (s, 1H), 8.42(br s, 1H), 8.35 (s, 1H), 8.19(br d, J=7.5Hz, 1H), 7.45-7.37 (m, 2H), 6.40(br s, 1H), 4.99(br s, 1H), 3.19-3.05 (m, 3H), 2.63(br s, 2H), 1.89-1.69 (m, 4H), 1.46(br d, J=6.1Hz, 6H), 1.24 (m, 2H); LCMS m / z 389.9(M + ); HPLC retention time: 1.25 min, condition A

[0118] The examples in Table 1 were prepared following the general procedures described in Example 1 using the appropriate starting materials. [Table 2] [Table 3]

[0119] Biological Assays The pharmacological properties of the compounds of the invention may be determined by a number of biological assays. The following exemplary biological assays have been carried out with the compounds of the invention.

[0120] IRAK4 inhibition assay The assay was performed in U-bottom 384-well plates. The final assay volume consisted of enzyme and substrate (fluorescently labeled peptide and ATP) and test compound / assay buffer (20 mM HEPES, pH 7.2, 10 mM MgCl 2、 The volume was adjusted to 30 μL by adding 15 μL of 0.015% Brij 35 and 4 mM DTT. Reactions were initiated by combining substrate and test compound with IRAK4. The reaction mixtures were incubated at room temperature for 60 minutes and 35 mM EDTA (45 μL) was added to each sample to stop the reaction. The reaction mixtures were analyzed by electrophoretic separation of fluorescent substrate and phosphorylated product using a Caliper LABCHIP® 3000 (Caliper, Hopkinton, MA). Inhibition data were calculated relative to a no enzyme control reaction with 100% inhibition and a vehicle only reaction with 0% inhibition. Final concentrations of reagents in the assay were ATP 500 μM, FL-IPTSPITTTYFFFKKK peptide 1.5 μM, IRAK4 0.6 nM, and DMSO 1.6%.

[0121] IRAK4 whole blood assay Human whole blood containing anticoagulant ACD-A was dispensed into 384-well plates (25 μL / well) and incubated with compounds for 60 min at 37°C in a 5% CO2 incubator. Blood was stimulated with TLR2 agonist lipoteichoic acid (Invivogen, San Diego, CA) / RPMI (25 μL, Gibco) at a final concentration of 10 μg / mL for 5 h in a 5% CO2 incubator. After incubation, plates were centrifuged at 2300 rpm for 5 min. Supernatants were collected and analyzed for IL-6 content by flow cytometry bead assay (BD Biosciences, San Jose, CA).

[0122] PBMC TLR2-induced IL-6 assay Peripheral blood mononuclear cells (PBMCs) were isolated from human blood containing the anticoagulant EDTA (2.5 mM) by centrifugation using density gradient centrifugation. PBMCs (250,000 cells / well) were incubated with compounds in assay medium (RPMI with 10% heat-inactivated FCS) for 30 min at 37°C in a 5% CO2 incubator. After pretreatment with compounds, cells were stimulated with the TLR2 agonist lipoteichoic acid (10 μg / mL, Invivogen, San Diego, CA) for 5 h. After incubation, plates were centrifuged at 1800 rpm for 10 min to pellet cells. Supernatants were collected and IL-6 levels were analyzed by ELISA (BD Biosciences, San Jose, CA).

[0123] The table below shows the IRAK4 IC as measured by the IRAK4 inhibition assay, the IRAK4 whole blood assay, for the following examples of the present invention: 50 value, and whole blood EC 50 As shown in the examples below, compounds of the present invention have an IRAK IC value of less than 0.6 μM. 50 Inhibition values ​​are shown. [Table 4]

Claims

1. Formula (I) 【Chemistry 1】 [In the formula, R 1 -NHR 1a or -NHCH 2 R 1a and; R 1a is cyclohexyl or piperidinyl, each substituted with 0 to 1 substituents selected from -CH3, -C(O)CH3, -C(O)OCH3, and -NHC(O)OCH3; R 2 is -CH(CH3)2; R 3 is pyridinyl; and n is 0. or a salt thereof.

2. In the formula, R 1 But -NHR 1a 2. The compound according to claim 1, wherein:

3. In the formula, R 1a The compound according to claim 1, or a salt thereof, wherein is cyclohexyl substituted with 0 to 1 substituents selected from -CH3, -C(O)CH3, -C(O)OCH3, and -NHC(O)OCH3.

4. In the formula, R 1a The compound according to claim 1, or a salt thereof, wherein is piperidinyl substituted with 0 to 1 substituents selected from -CH3, -C(O)CH3, -C(O)OCH3, and -NHC(O)OCH3.

5. The compound is: 1-Isopropyl-N-(piperidin-4-ylmethyl)-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (1); Methyl 4-(((1-isopropyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)methyl)piperidine-1-carboxylate (2); 1-Isopropyl-N-(piperidin-4-ylmethyl)-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (3); Methyl 4-(((1-isopropyl-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)methyl)piperidine-1-carboxylate (4); 1-Isopropyl-N-((1-methylpiperidin-4-yl)methyl)-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (5); Methyl (4-((1-isopropyl-8-(pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)cyclohexyl)carbamate (6); Methyl (4-((1-isopropyl-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)cyclohexyl)carbamate (7); 1-(4-((1-isopropyl-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-yl)amino)piperidin-1-yl)ethan-1-one (8); and 1-Isopropyl-N-(piperidin-4-yl)-8-(pyridin-4-yl)-1H-pyrazolo[3,4-d]pyrrolo[1,2-b]pyridazin-3-amine (9) 2. The compound according to claim 1, or a salt thereof, selected from:

6. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 5 and a pharma- ceutically acceptable carrier or diluent.

7. A pharmaceutical composition comprising a compound or a salt thereof according to any one of claims 1 to 5 for use in therapy.

8. 10. A pharmaceutical composition comprising a compound or a salt thereof according to any one of claims 1 to 5 for use in treating an inflammatory disease, an autoimmune disease, or cancer.

9. 9. The pharmaceutical composition of claim 8, wherein the disease is selected from Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, allograft rejection, chronic obstructive pulmonary disease, Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, cryopyrin-associated periodic fever syndrome, TNF receptor-associated periodic syndrome, familial Mediterranean fever, adult Still's disease, systemic juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.

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