Tricyclic Heteroaryl Compounds Useful as IRAK4 Inhibitors

Abstract

Formula (I) or (II): [0003] Disclosed are compounds of the formula TIFF2023513488000090.tif26153, or salts or prodrugs thereof, where X, R1, R2, R3, and n are as 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 / 969,406, filed February 3, 2020, which is incorporated by reference in its entirety. [Background technology]

[0002] The present invention generally relates to tricyclic heteroaryl compounds useful as kinase inhibitors, such as modulating IRAK4. The present invention provides tricyclic heteroaryl compounds, compositions comprising the compounds, and methods of using them. The present invention further relates to pharmaceutical compositions comprising at least one of the compounds according to the present 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 recruits the adaptor molecule MyD88 to a conserved cytoplasmic motif in the receptor called the Toll / IL-1 receptor (TIR) ​​domain. 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 associate with their receptors through interaction with MyD88. The family is composed of four members. Several lines of evidence have demonstrated that IRAK4 plays an important and essential role in initiating signaling through MyD88-dependent TLR and IL-1R family members. Structural data confirm that IRAK4 interacts directly with MyD88, which in turn associates with either IRAK1 or IRAK2 in 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)), the severity of disease was significantly reduced. 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 novel tricyclic heteroaryl 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) and formula (II) or stereoisomers, tautomers, pharma- ceutically acceptable salts, solvates or prodrugs thereof, which are useful as inhibitors of IRAK4 and 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, including, but 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 syndromes (CAPS), TNF receptor-associated periodic syndromes (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 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 formula (II) 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 which follows. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] A first aspect of the present invention is a compound represented by formula (I) or formula (II): [ka] [In the formula, X is CR 3a or N; R 1 teeth, (i) -C(O)NR x R 1a ;or (ii) pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, each of which is 0 to 2 R 1b Replaced with; R 1a teeth, (i) 0 to 6 R w C replaced with 1-6 Alkyl; or (ii)-(CR x R x ) 0-3 R 1c and; Each R w are independently F, Cl, -CN, -OH, -OCH 3 , -NR x R x , -NR x C(O)(C 1-3 alkyl), -NR x C(O)(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl; Each R 1b independently -CR x R x (C3-6 cycloalkyl), tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or 0 to 6 R w C replaced with 1-6 is alkyl; R 1c is C 3-6 cycloalkyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxidetetrahydrothiophenyl, dioxidethiomorpholinyl, isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, each of which is F, Cl, -CN, -OH, -NR x R x , C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, -NR x C(O)(C 1-3 alkyl), -NR x C(O)O(C 1-3 alkyl), and -S(O) 2 (C 1-2 substituted with 0 to 3 substituents independently selected from alkyl, R 2 teeth, (i) hydrogen; (ii) C 1-6 Alkyl, F, Cl, -OH, -CN, C 3-6 substituted with 0 to 4 substituents independently selected from cycloalkyl, cycloalkyl, and dimethoxyphenyl; or (ii) C 3-6 A cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrazolyl, and thiazolyl, said cyclic group being selected from F, Cl, -OH, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Hydroxyalkyl, and -S(O) 2 (C 1-2 substituted with 0 to 3 substituents independently selected from alkyl, R3 -CN, -C(O)NR x R x or a cyclic group selected from phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridinonyl, and pyrimidinyl, each of which is selected from F, Cl, —OH, —CN, C 1-2 Alkyl, -CF 3 , and -CH 2 OH; R 3a is hydrogen or R 3 and; Each R x is hydrogen or -CH 3 and n is 0, 1, or 2. or a salt thereof.

[0023] In certain embodiments, there is provided a compound of formula (I) or a salt thereof:

[0024] In certain embodiments, there is provided a compound of formula (II) or a salt thereof:

[0025] In certain embodiments, X is CR 3a The compound of this embodiment has the formula (Ia): [ka] In this embodiment, R 3a Also included in this embodiment are compounds in which R 3a But R 3 Compounds in which:

[0026] In one embodiment, there is provided a compound of formula (I) or a salt thereof, wherein X is N. The compound of this embodiment has the formula (Ib): [ka] It has the structure:

[0027] In certain embodiments, X is CR 3a The compound of this embodiment has the formula (IIa): [ka] It has the structure: In this embodiment, 3a Also included in this embodiment are compounds in which R 3a But R 3 Compounds in which:

[0028] In one embodiment, there is provided a compound of formula (II) or a salt thereof, wherein X is N. The compound of this embodiment has the formula (IIb): [ka] It has the structure:

[0029] In one embodiment, a compound of formula (Ic): [ka] The present invention provides a compound of formula (I) having the structure:

[0030] In certain embodiments, X is CR 3a The compound of this embodiment has the formula (Id): [ka] It has the structure:

[0031] In certain embodiments, X is CR 3a and R 3a is hydrogen. The compound of this embodiment has the formula (Ie): [ka] It has the structure:

[0032] In certain embodiments, there is provided a compound of formula (Ic) or a salt thereof, wherein X is N. The compound of this embodiment has the formula (If): [ka] It has the structure:

[0033] In one embodiment, a compound of formula (IIc): [ka] The present invention provides a compound of formula (II) having the structure:

[0034] In certain embodiments, X is CR 3a The compound of this embodiment has the formula (IId): [ka] It has the structure:

[0035] In certain embodiments, X is CR 3a and R 3a is hydrogen. The compound of this embodiment has the formula (IIe): [ka] It has the structure:

[0036] In certain embodiments, there is provided a compound of formula (IIc) or a salt thereof, wherein X is N. The compound of this embodiment has the formula (IIf): [ka] It has the structure:

[0037] In certain embodiments, compounds of Formula (I) or Formula (II), or salts thereof, are provided, wherein X is CH.

[0038] In certain embodiments, in formula R 1 -C(O)NR x R 1a In this embodiment, there is provided a compound of formula (I) or (II), or a salt thereof, wherein R 1 -C(O)NHR 1a Compounds in which:

[0039] In certain embodiments, in formula R 1 -C(O)NR x R 1a and R 1a However, 0 to 6 R w C replaced with 1-6 In one embodiment, a compound of formula (I) or (II), or a salt thereof, is provided, wherein R 1a But -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 C(CH 3 ) 2 F, -CH 2 CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2CHFCH(CH 3 )OH, -CH 2 CHFC(CH 3 ) 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 C(CH 3 ) 2 NH 2 , -CH 2 CF 2 CH 2 NH 2 , or -CH 2 CH 2 C(CH 3 ) 2 NHC(O)CH 3 Compounds in which:

[0040] In certain embodiments, in formula R 1 -C(O)NR x R 1a and R 1a But -(CR x R x ) 0-3 R 1c In accordance with this embodiment, there is provided a compound of formula (I) or (II), or a salt thereof, wherein R 1a But -(CH 2 ) 0-3 R 1c Also included in this embodiment are compounds in which R 1a -CH(cyclopropyl)CH 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 NHC(O)(cyclopropyl), R 1c , -CH 2 R 1c , or -CH 2 CH 2 R 1c Further included in this embodiment are compounds in which R 1cis cyclopropyl, cyclobutyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, dioxidetetrahydrothiophenyl, dioxidethiomorpholinyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or tetrazolyl, each of which is F, -OH, -NH 2 , -CH 3 , -CH 2 OH, -C(CH 3 ) 2 OH, -NHC(O)CH 3 , -NHC(O)OCH 3 , and -S(O) 2 CH 3 The present invention also includes compounds substituted with 0 to 3 substituents independently selected from:

[0041] In certain embodiments, in formula R 1 is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, each of which is 0 to 2 R 1b In accordance with this embodiment, there is provided a compound of formula (I) or (II), or a salt thereof, wherein R 1 isoxazolyl, oxazolyl, oxadiazolyl, or triazolyl, each of which is 0 to 1 R 1b Also included in this embodiment are compounds substituted with 1 isoxazolyl, oxadiazolyl, or triazolyl, each R 1b The compounds include those substituted with

[0042] In certain embodiments, in formula R 2 is (i) hydrogen, or (ii) C 1-6 Alkyl, F, Cl, -OH, -CN, C 3-6 Provided herein is a compound of formula (I) or (II), or a salt thereof, substituted with 0 to 4 substituents independently selected from cycloalkyl, and dimethoxyphenyl. 2 is hydrogen, -CH 2 CH 3, -CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH(CH 3 )CH 2 OH, -CH 2 (cyclopropyl), -CH(CH 3 ) (cyclopropyl), or -CH 2 (dimethoxyphenyl).

[0043] In certain embodiments, in formula R 2 But, C 3-6 A cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrazolyl, and thiazolyl, said cyclic group being selected from F, Cl, -OH, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Hydroxyalkyl, and -S(O) 2 (C 1-2

[0023] In accordance with this embodiment, there is provided a compound of formula (I) or (II), or a salt thereof, wherein R is substituted with 0 to 3 substituents independently selected from the group consisting of alkyl, aryl ... 2 is cyclopropyl, cyclobutyl, difluorocyclobutyl, oxetanyl, tetrahydrofuranyl, (methylsulfonyl)piperidinyl, thiazolyl, or (difluoroethyl)pyrazolyl.

[0044] In certain embodiments, in formula R 3 -CN, -C(O)NR x R x or a cyclic group selected from phenyl, pyrazolyl, imidazolyl, pyridinyl, pyridinonyl, and pyrimidinyl, each cyclic group being selected from F, Cl, -OH, -CN, C 1-2 Alkyl, -CF 3 , and -CH 2The present invention provides a compound of formula (I) or (II), or a salt thereof, wherein R is substituted with 0 to 3 substituents selected from OH. 3 -CN, -C(O)NH 2 , pyrazolyl, or pyridinonyl.

[0045] In certain embodiments, in formula R 3 is -CN or -C(O)NR x R x In accordance with this embodiment, there is provided a compound of formula (I) or (II), or a salt thereof, wherein R 3 is -CN or -C(O)NHR x Also included in this embodiment are compounds in which R 3 is -CN or -C(O)NH 2 Further included in this embodiment are compounds in which R 3 is -CN.

[0046] In certain embodiments, in formula R 3 is a cyclic group selected from phenyl, pyrazolyl, imidazolyl, pyridinyl, pyridinonyl, and pyrimidinyl, each cyclic group being selected from F, Cl, -OH, -CN, C 1-2 Alkyl, -CF 3 , and -CH 2 In one embodiment, the compound of formula (I) or (II) or a salt thereof is substituted with 0 to 3 substituents selected from pyrazolyl, imidazolyl, pyridinyl, pyridinonyl, and pyrimidinyl, each of which is selected from F, Cl, -OH, -CN, -C, -OH, -C ... 1-2 Alkyl, -CF 3 , and -CH 2 Also included in this embodiment are compounds in which R 3 is pyrazolyl or pyridinonyl.

[0047] In certain embodiments, X is CH or N; R 1 (i) -C(O)NR x R 1a or (ii) isoxazolyl, oxadiazolyl, or triazolyl, each of which is R 1b Replaced by; R 1a But -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 C(CH 3 ) 2 F, -CH 2 CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CHFCH(CH 3 )OH, -CH 2 CHFC(CH 3 ) 2 OH, -CH 2 CH 2 OCH 3 , -CH 2 CH 2 C(CH 3 ) 2 NH 2 , -CH 2 CF 2 CH 2 NH 2 , -CH 2 CH 2 C(CH 3 )2 NHC(O)CH 3 、 -CH(Cyclopropyl)CH 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 NHC(O)(Cyclopropyl), R 1c 、 -CH 2 R 1c 、 or -CH 2 CH 2 R 1c ; R 1b is -CH 2 CH 2 CH 3 、 -CH 2 CH(CH 3 ) 2 、 -CH 2 CH 2 CH(CH 3 ) 2 、 -CH 2 (Cyclopropyl), Tetrahydropyranyl, Piperidinyl, or Morpholinyl; R 1c is Cyclopropyl, Cyclobutyl, Oxetanyl, Pyrrolidinyl, Piperidinyl, Morpholinyl, Tetrahydropyranyl, Dioxidotetrahydrothiophenyl, Dioxidothiomorpholinyl, Isooxazolyl, Oxazolyl, Thiazolyl, Triazolyl, or Tetrazolyl, each independently selected from 0 to 3 substituents selected from F, -OH, -NH 2 、 -CH 3 、 -CH 2 OH, -C(CH 3 ) 2 OH, -NHC(O)CH 3 、 -NHC(O)OCH 3 、 and -S(O) 2 CH 3 ; R 2 is Hydrogen, -CH 2 CH 3 、 -CH(CH 3 ) 2 、 -CH(CH 3 )CH 2 CH 3 、 -CH 2 CHF2 , -CH 2 CF 3 , -CH(CH 3 )CH 2 OH, -CH 2 (cyclopropyl), -CH(CH 3 ) (cyclopropyl), -CH 2 (dimethoxyphenyl), cyclopropyl, cyclobutyl, difluorocyclobutyl, oxetanyl, tetrahydrofuranyl, (methylsulfonyl)piperidinyl, thiazolyl, or (difluoroethyl)pyrazolyl; and R 3 -CN, -C(O)NH 2 , pyrazolyl, or pyridinonyl, or a salt thereof.

[0048] In certain embodiments, in formula R 2 But -CH(CH 3 ) 2 and R 3 is -CN.

[0049] In certain embodiments, X is CH; R 2 But -CH(CH 3 ) 2 and R 3 is -CN.

[0050] In certain embodiments, X is CH; R 2 But -CH(CH 3 ) 2 and R 3 is -CN, or a salt thereof.

[0051] In certain embodiments, X is CH; R 2 But -CH(CH 3 ) 2 and R 3is -CN, or a salt thereof.

[0052] In certain embodiments, X is CH; R 2 But -CH(CH 3 ) 2 and R 3 is -CN, or a salt thereof.

[0053] In certain embodiments, X is CH; R 2 But -CH(CH 3 ) 2 and R 3 is -CN, or a salt thereof.

[0054] In certain embodiments, in formula R 2 But -CH(CH 3 ) 2 and R 3 is -CN, or a salt thereof.

[0055] In certain embodiments, in formula R 2 But -CH(CH 3 ) 2 and R 3 is -CN, or a salt thereof.

[0056] In certain embodiments, in formula R 1 -C(O)NHR 1a and R 1a is -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CHF 2 , -CH2 CH 2 CF 3 , -CH 2 CH 2 C(CH 3 ) 2 F, -CH 2 CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CHFCH(CH 3 )OH, -CH 2 CHFC(CH 3 ) 2 OH, or -CH 2 CH 2 OCH 3 In accordance with this embodiment, there is provided a compound of formula (I) or (II), or a salt thereof, wherein R 1a But -CH 2 CH 2 C(CH 3 ) 2 F, -CH 2 CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CHFCH(CH 3 )OH, or -CH 2 CHFC(CH 3 ) 2 OH is included.

[0057] In certain embodiments, in formula R 1 -C(O)NHR 1a R 1a But -CH 2 CH 2 CH3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 C(CH 3 ) 2 F, -CH 2 CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CHFCH(CH 3 )OH, -CH 2 CHFC(CH 3 ) 2 OH, or -CH 2 CH 2 OCH 3 R 2 But -CH(CH 3 ) 2 and R 3 is -CN. Within this embodiment, compounds are provided according to formula (I) or formula (II), or a salt thereof, wherein X is -CN. Within this embodiment, compounds are provided wherein X is CH.

[0058] In certain embodiments, in formula R 1 -C(O)NHR 1a R 1a But -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH3 ) 2 , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , -CH 2 CH 2 C(CH 3 ) 2 F, -CH 2 CH 2 CH(CH 3 )OH, -CH 2 C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 C(CH 3 ) 2 OH, -CH 2 CHFCH(CH 3 )OH, -CH 2 CHFC(CH 3 ) 2 OH, or -CH 2 CH 2 OCH 3 R 2 But -CH(CH 3 ) 2 and R 3 is -CN. Within this embodiment, compounds are provided according to formula (Ic) or (IIc), or a salt thereof, wherein X is -CN. Within this embodiment, compounds are provided wherein X is CH.

[0059] In one embodiment, the compound is (R)-7-cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (1); (R)-7-cyano-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (2 );(R)-7-cyano-4-((3,3-difluorocyclobutyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (3);(R)-7-cyano-4-(cyclobutylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (4); 7-cyano-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (5); 7-cyano-4-(isopropylamino)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (6); 7-cyano-N-((3-(hydroxymethyl)oxetan-3-yl)methyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (7); 7-cyano-N-((1-(hydroxymethyl)cyclopropyl)methyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (8); 7-cyano-N-(3-hydroxy-2,2-dimethylpropyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (9); 7-cyano-N-((1R,4R)-4-hydroxycyclohexyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (10); 7-cyano-4-(isopropylamino)-N-(tetrahydro-2H-pyran-4-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (11); N-((1R,4R)-4-aminocyclohexyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (12);N-((1R,4R)-4-acetamidocyclohexyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (13); 7-cyano-4-(isopropylamino)-N-(oxazol-4-ylmethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (14); 7-cyano-4-(isopropylamino)-N-((3-methylisoxazol-5-yl)methyl)-5H-pyrido[3,2-b]indole-3-carboxamide (15); 7-cyano-N-(1-cyclopropyl-3-hydroxypropyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (16); 7-cyano-4-(isopropylamino)-N-(2-methoxyethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (17); 7-cyano-4-(isopropylamino)-N-(thiazol-2-ylmethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (18); 7-cyano-4-(isopropylamino)-N-(piperidin-4-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (19); N-((1H-1,2,4-triazol-5-yl)methyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (20); 7-Cyano-N-isopentyl-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (21); (R)-7-Cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (22); (R)-7-Cyano-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (23); 7-Cyano-N-((1s,3s)-3-hydroxycyclobutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (24);7-Cyano-N-(3-hydroxybutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (25);(R)-7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-((tetrahydrofuran-3-yl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (26); 7-Cyano-4-(isopropylamino)-N-(3,3,3-trifluoropropyl)-5H-pyrido[3,2-b]indole-3-carboxamide (27);(S)-7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-((tetrahydrofuran-3-yl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (28);(S)-7-Cyano Ano-4-((1-cyclopropylethyl)amino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (29); (S)-7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-((1-hydroxypropan-2-yl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (30); 7-Cyano-N-(3,3-difluoropropyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (31);(R)-4-(sec-butylamino)-7-cyano-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (32); 7-Cyano-4-((cyclopropylmethyl)amino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (33); 7-Cyano-N-(2-cyclopropylethyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (34); 7-Cyano-4-(isopropylamino)-N-(2-morpholinoethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (35); 7-Cyano-4-((2,2-difluoroethyl)amino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (36);7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-((2,2,2-trifluoroethyl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (37); 7-Cyano-N-(3-fluoro-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (38); 7-Cyano-N-((1R,3R)-3-(2-hydroxypropan-2-yl)cyclobutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (39); 4-(tert-Butylamino)-7-cyano-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (40); 7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (41); 7-Cyano-4-(oxetan-3-ylamino)-N-(3,3,3-trifluoropropyl)-5H-pyrido[3,2-b]indole-3-carboxamide (42); 7-Cyano-N-(2-(3,3-difluoro-1-hydroxycyclobutyl)ethyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (43); 7-Cyano-4-(cyclopropylamino)-N-((1R,3R)-3-(2-hydroxypropan-2-yl)cyclobutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (44); 7-Cyano-4-(cyclopropylamino)-N-((1R,3R)-3-hydroxycyclobutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (45); 7-Cyano-4-(cyclopropylamino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (46); N-((1R,3R)-3-aminocyclobutyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (47); N3-(3-Hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3,7-dicarboxamide (48);N-((1R,3R)-3-acetamidocyclobutyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (49); methyl((1R,3R)-3-(7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide)cyclobutyl)carbamate (50); N-(3-amino-2,2-difluoropropyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (51); N-(3-amino-3-methylbutyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (52); 7-Cyano-4-(isopropylamino)-N-(2-(pyrrolidin-3-yl)ethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (53); 4-Amino-7-cyano-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (54); 7-Cyano-4-(ethylamino)-N-(2-(piperidin-3-yl)ethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (55); 7-Cyano-4-((3,4-dimethoxybenzyl)amino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (56); 7-cyano-4-(ethylamino)-N-(2-(pyrrolidin-2-yl)ethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (57); 7-cyano-4-(ethylamino)-N-(2-(piperidin-2-yl)ethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (58); 7-cyano-N-(3-(cyclopropanecarboxamido)-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (59); N-(3-acetamido-3-methylbutyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (60);7-Cyano-N-((1,1-dioxidotetrahydrothiophen-3-yl)methyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (61); 7-Cyano-N-(2-(1,1-dioxidothiomorpholino)ethyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (62); 7-Cyano-4-(isopropylamino)-N-(1-(methylsulfonyl)piperidin-4-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (63); (R)-7-Cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(methylsulfonyl)piperidin-4-yl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (64); N-(2-(1H-tetrazol-5-yl)ethyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (65); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-(thiazol-5-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (66); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-(1H-pyrazole-4-yl) (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-(6-oxo-1,6-dihydropyridin-3-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (67); (R)-7-cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxamide (69); 3-(5-isobutyl-1H-1,2,4-triazol-3-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile·TFA (70); 4-(isopropylamino)-3-(5-propyl-1H-1,2,4-triazol-3-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (71);4-(isopropylamino)-3-(3-propyl-1,2,4-oxadiazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (72); 3-(1-isopentyl-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (73); 3-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (74); 4-(isopropylamino)-3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (75); 4-(isopropylamino)-3-(3-(piperidin-4-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (76); 4-(isopropylamino)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (77); 4-(isopropylamino)-3-(3-(morpholin-2-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (78); 4-(isopropylamino)-3-(3-(piperidin-3-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (79); The compound of formula (I) or a salt thereof is provided, which is 4-(isopropylamino)-3-(3-(piperidin-2-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (80); (R)-6-cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxamide (81); or 6-cyano-N-(2-cyclopropylethyl)-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxamide (82).

[0060] In one embodiment, the IRAK4 IC 50The compound of formula (I) is provided, wherein the value of is ≦0.6 μM.

[0061] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.1 μM.

[0062] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.05 μM.

[0063] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.025 μM.

[0064] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.015 μM.

[0065] In one embodiment, the IRAK4 IC 50 The compound of formula (I) is provided, wherein the value of is ≦0.01 μM.

[0066] In one embodiment, the IRAK4 IC 50 The compound of formula (II) is provided, wherein the value of is ≦0.6 μM.

[0067] In one embodiment, the IRAK4 IC 50 The compound of formula (II) is provided, wherein the value of is ≦0.1 μM.

[0068] In one embodiment, the IRAK4 IC 50 The compound of formula (II) is provided, wherein the value of is ≦0.05 μM.

[0069] In one embodiment, the IRAK4 IC 50 The compound of formula (II) is provided, wherein the value of is ≦0.025 μM.

[0070] In one embodiment, the IRAK4 IC 50 The compound of formula (II) is provided, wherein the value of is ≦0.015 μM.

[0071] In one embodiment, the IRAK4 IC 50 The compound of formula (II) is provided, wherein the value of is ≦0.01 μM.

[0072] (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.

[0073] 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."

[0074] 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).

[0075] Unless otherwise specified, any heteroatom with unsatisfied valences is assumed to include enough hydrogen atoms to satisfy the valences.

[0076] 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.

[0077] 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).

[0078] Throughout the specification, groups and substituents may be chosen by one skilled in the art to provide stable moieties and compounds.

[0079] 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.

[0080] The terms "halo" and "halogen" as used herein refer to F, Cl, Br, and I.

[0081] The term "cyano" refers to the group --CN.

[0082] The term "amino" refers to the group -NH 2 This refers to.

[0083] The term "oxo" refers to the group =O.

[0084] 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.

[0085] 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" means a C alkyl group substituted with one or more fluorine atoms. 1 , C 2 , C 3 , and C 4 Representative examples of fluoroalkyl groups include, but are not limited to, -CF 3 and -CH 2 CF 3 Examples include:

[0086] The term "hydroxyalkyl" includes both branched and straight chain saturated alkyl groups substituted with one or more hydroxyl groups. For example, "hydroxyalkyl" includes -CH 2 OH, -CH 2 CH 2 OH, and C 1-4 Hydroxyalkyl is an example.

[0087] 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 the symbol "C" is followed by a number in subscript, the subscript more specifically qualifies the number of carbon atoms that a particular cycloalkyl group may contain. For example, "C 3 -C 6 "Cycloalkyl" means a cycloalkyl group having 3 to 6 carbon atoms.

[0088] 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.

[0089] The compounds of formula (I) and formula (II) may be provided as amorphous solids or crystalline solids. The compounds of formula (I) and formula (II) may be provided as amorphous solids by lyophilization.

[0090] In addition, solvates (e.g., hydrates) of the compounds of formula (I) and formula (II) should be considered within the scope of the present invention. The term "solvate" refers to a physical association of a compound of formula (I) or a compound of formula (II) 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.

[0091] Various forms of prodrugs are well known in the art and are described in Rautio, J. et al., Nature Review Drug Discovery, 17, 559-587 (2018).

[0092] In addition, the compounds of formula (I) and formula (II) may be isolated and purified after their preparation to obtain compositions containing 99% or more of the compounds of formula (I) and formula (II) ("substantially pure"), which are then used or formulated as described herein. Such "substantially pure" compounds of formula (I) and "substantially pure" compounds of formula (II) are also considered to be part of the present invention herein.

[0093] 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.

[0094] "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.

[0095] 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.

[0096] 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 Isotopically labeled compounds of the invention can be prepared by conventional techniques generally 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 otherwise used. For example, methyl (-CH 3 ) contains a deuterated methyl group (e.g. -CD 3 ) is also included.

[0097] (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.

[0098] Thus, the compounds of formula (I) and formula (II) 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) and formula (II) have useful selectivity for RAK4 activity, and preferably have higher selectivity for at least 20 fold structures to 1,000 or more fold structures.

[0099] 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 a 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.

[0100] In view of the activity of the compounds of the present invention as selective inhibitors of IRAK4, the compounds of formula (I) and formula (II) 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).

[0101] 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.

[0102] In certain embodiments, the compounds of Formula (I) and Formula (II) 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).

[0103] 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).

[0104] 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.

[0105] The present invention therefore provides a method of treating the above conditions, which comprises administering to a subject in need of such treatment a therapeutically effective amount of at least one compound of formula (I) or formula (II) 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 the disease.

[0106] A method for treating an IRAK4 kinase-related condition may be characterized by administering a compound of formula (I) alone, a compound of formula (II) alone or in combination with each other and / or in combination 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 the claimed compounds that is effective for inhibiting IRAK4 and / or treating a disease associated with IRAK4.

[0107] 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.

[0108] 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).

[0109] 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.

[0110] Accordingly, the present invention further includes compositions comprising one or more compounds of Formula (I) and / or Formula (II) and a pharma- ceutically acceptable carrier.

[0111] "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.

[0112] 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 site of treatment required or the amount of compound of formula (I) to be delivered.

[0113] The compounds according to formula (II) may be administered by any method appropriate to the condition to be treated, which may vary depending on the site of treatment required or the amount of compound of formula (II) to be delivered.

[0114] The present invention also includes a class of pharmaceutical compositions comprising a compound of formula (I) and / or a compound of formula (II) 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 compounds of formula (I) and formula (II) 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, the pharmaceutical carrier may include a mixture of mannitol or lactose and microcrystalline cellulose. The mixture may include additional ingredients, such as, for example, 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, as an oral dosage form or by infusion.

[0115] 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.

[0116] 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.

[0117] Tablets can be prepared, for example, by mixing at least one compound of formula (I) and / or formula (II) 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.

[0118] Hard gelatin capsules can be prepared, for example, by mixing at least one compound of Formula (I) and / or Formula (II) with at least one inert solid diluent (e.g., calcium carbonate, calcium phosphate, and kaolin).

[0119] Soft gelatin capsules can be prepared, for example, by mixing at least one compound of formula (I) and / or formula (II) 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).

[0120] Aqueous suspensions may be prepared, for example, by mixing at least one compound of formula (I) and / or formula (II) 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).

[0121] Oily suspensions can be prepared, for example, by suspending at least one compound of formula (I) and / or formula (II) 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).

[0122] Dispersible powders and granules can be prepared, for example, by mixing at least one compound of formula (I) and / or formula (II) 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).

[0123] At least one emulsion of at least one compound of formula (I) and / or formula (II) may be prepared, for example, as an oil-in-water emulsion. The oil phase of the emulsion containing the compound of formula (I) and / or formula (II) 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 acting as a stabilizer. It is also preferred to include both oil and fat. Together, the emulsifier, with or without stabilizer, makes up the so-called emulsifying wax, and the wax, together with the oil and fat, 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.

[0124] In addition, the compounds of formula (I) and / or formula (II) 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.

[0125] 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).

[0126] 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.

[0127] Sterile injectable oil-in-water microemulsions can be prepared, for example, by: 1) dissolving at least one compound of formula (I) and / or formula (II) 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.

[0128] 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).

[0129] 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-cyclodextrins, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropylcyclodextrins, or other solubilizing derivatives.

[0130] 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).

[0131] 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.

[0132] 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.

[0133] 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.

[0134] The pharmaceutical compositions of the present invention include at least one compound of formula (II) and optionally an additive selected from any pharma- ceutically acceptable carrier, adjuvant, and vehicle. Another composition of the present invention includes a compound of formula (II) as described herein, or a prodrug thereof, and a pharma- ceutically acceptable carrier, adjuvant, or vehicle.

[0135] 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.

[0136] 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 include a bottle, jar, vial, flask, syringe, tube (e.g., for cream formulations), or any other container used in manufacturing, holding, storing, or distributing a pharmaceutical formulation.

[0137] 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.

[0138] A package insert is a label, tag, marker, or other written matter 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) that governs the region in which the product is sold. Preferably, the package insert specifically describes the indication that 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, paper or plastic with adhesive, etc.) on which the desired information is placed (e.g., printed or affixed).

[0139] (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 appreciated by those skilled in the art. Preferred methods include, but are not limited to, the following:

[0140] 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).

[0141] Scheme 1 outlines alternative methods by which compounds of general formula I may be prepared starting from appropriately substituted dichloropyridines 2a-1. Pyridines 2a-1 may be reacted with a variety of amines to give intermediates 2a-2. 2a-1 may be further reacted using standard cross-coupling methods to give 2-aryl substituted intermediates 2a-3. The nitro group of 2a-3 may be reduced to an amine using a suitable reagent (e.g., palladium catalyst in the presence of hydrogen) to give amine 2a-4. 2a-4 may be heated in a suitable solvent (e.g., NMP or DMA) at a temperature at which cyclization can occur (typically >120° C.) to produce the final compound. [ka]

[0142] Compounds of another general formula can be prepared according to the method outlined in Scheme 2. Boc amino bromide 2b-1 can be alkylated using a suitable base and alkylating reagent to give 2b-2. Cyclization of 2b-2 to 2b-3 can be initiated by reaction with a strong base (e.g. potassium tert-butoxide) in a suitable solvent (e.g. THF). Decarboxylation to 2b-4 can be carried out in the presence of a strong acid (e.g. TFA). Furthermore, reaction with diethyl 2-(ethoxymethylene)malonate gives 2b-5, which can be cyclized by treatment at elevated temperature to give tricyclic compound 2b-6. Reaction of this tricyclic bromide with a cyanating reagent gives 2b-7, which can then be further chlorinated with a chlorinating reagent (e.g. POCl). 3 ) can provide 2b-8. Treatment with various nucleophilic amines can provide intermediates (e.g., 2b-9) whose ester group can be hydrolyzed using common saponification conditions to provide 2b-10. This acid intermediate can be treated with various amines in the presence of an amide bond coupling agent (e.g., HATU) to provide compounds of general formula I. [ka] Alternatively, intermediate 2b-6 can be reacted with a chlorinating reagent (e.g., POCl) as outlined in Scheme 3. 3 ), which can then be further reacted with amines to give intermediates such as 3-2. 3-2 can be reacted with a variety of aryl cross-coupling agents (e.g., pyrazole-3-boronic acid) in the presence of a cross-coupling catalyst to give intermediates such as 3-3. Hydrolysis to 3-4 as described above and coupling with amines to form the amide bond can give other compounds of general formula I. [ka]

[0143] Yet another method for preparing compounds of general formula I is outlined in Scheme 4. Nitroazaindole 4-1 is reacted with a reducing agent (e.g., Zn and NH 4Cl) can give the amine 4-2. Treatment of this amine with diethyl 2-(ethoxymethylene)malonate gives 4-3, which can be further cyclized to 4-4 by heating in the presence of a strong acid (e.g., PPA). Subsequent chlorination and amine displacement gives intermediates such as 4-5, which can be further reacted with a cyanating reagent to give intermediate 4-6. Hydrolysis gives 4-7, which can be reacted with various amines to form an amide bond to give other compounds of general formula (I). [ka]

[0144] Scheme 5 focuses on the synthesis of 1,2,4 triazole analogs from the acid intermediate 5-1 described in the previous scheme. Briefly, 5-1 can be reacted with a variety of substituted alkylimidic acids followed by hydrazine to afford triazoles of general formula (I). [ka]

[0145] Esters of general intermediate structure 6-1 can be converted to aldehydes 6-2 with a suitable reducing agent (e.g., DIBAL-H) ​​and then further converted to alkynes 6-3 using general methods described in the available literature. Treatment of 6-3 with an appropriately substituted azide (e.g., cyclopropylmethyl azide) in the presence of a copper catalyst can provide compounds of general formula (I). [ka]

[0146] Alternatively, intermediate 6-3 in Scheme 7 may be reacted with an alkyl chlorooxime in the presence of an amine (eg TEA) to give other compounds of general formula I. [ka]

[0147] Compounds of a different lineage can be produced according to the method outlined in Scheme 8. Aryl bromide 8-1 can be reacted with an appropriately substituted pyridine borate ester to obtain intermediate 8-2. By heating 8-2 in a solvent (such as dichlorobenzene) in the presence of DPPE, cyclic intermediate 8-3 can be obtained. Treating 8-3 with an oxidizing agent (such as hydrogen peroxide) gives the N-oxide (8-4), which can be treated with an amine at a high temperature to obtain 8-5. Hydrolysis is carried out to give 8-6, and a general amine is used to form an amide bond, and another compound of general formula (I) can be obtained.

Chemical formula

[0148] (Example) The compounds of the present invention and the intermediates used in the production of the compounds of the present invention can be produced using the methods shown in the following examples and related methods. The methods and conditions used in these examples, as well as the actual compounds produced in these examples, are not meant to be limiting and are meant to illustrate how the compounds of the present invention can be produced. The starting materials and reagents used in these examples are generally commercially available, reported in the chemical literature, or may be prepared by using the procedures described in the chemical literature if the production method is not described herein. The present invention is further defined in the following examples. It should be understood that the examples are provided by way of illustration only. From the above considerations and examples, those skilled in the art can elucidate the essential features of the present invention and 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.

[0149] 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).

[0150] 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 18 Separation 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]

[0151] Example 1 (R)-7-Cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide [ka]

[0152] Method 1: Intermediate 1A: 6-chloro-4-(isopropylamino)-5-nitronicotinic acid ethyl ester [ka] A solution of ethyl 4,6-dichloro-5-nitronicotinate (0.28 g, 1.06 mmol), propan-2-amine (0.066 g, 1.11 mmol), and triethylamine (0.294 mL, 2.11 mmol) in acetonitrile (5 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, washed with water, and dried (MgSO 4 ) and concentrated. The resulting crude material was purified by ISCO flash chromatography (silica gel; hexane / ethyl acetate 100:0 to 0:100 gradient) to give ethyl 6-chloro-4-(isopropylamino)-5-nitronicotinate (0.297 g, 98% yield) as a yellow oil. 1 H NMR (400MHz, chloroform-d) δ 8.92 (d, J=7.7Hz, 1H), 8.73 (s, 1H), 4.39 (q, J=7.1Hz, 2H), 3.65-3.50 (m, 1H), 1.45-1.38 (m, 3H), 1.25 (d, J=6.2Hz, 6H); LCMS m / z 288.2(M+1)

[0153] Intermediate 1B: ethyl 6-(4-cyano-2-fluorophenyl)-4-(isopropylamino)-5-nitronicotinate [ka] A mixture of ethyl 6-chloro-4-(isopropylamino)-5-nitronicotinate (67 mg, 0.23 mmol), (4-cyano-2-fluorophenyl)boronic acid (42.2 mg, 0.26 mmol), sodium carbonate (49.4 mg, 0.47 mmol), and bis(triphenylphosphine)palladium(II) dichloride (16.4 mg, 0.023 mmol) in EtOH (1.5 mL) and toluene (2 mL) was degassed with nitrogen and stirred at 80 °C overnight. The reaction mixture was concentrated, diluted with EtOAc, washed with water, and the organic layer was dried (MgSO 4The crude product was purified by ISCO flash chromatography (silica gel; hexane / ethyl acetate 100:0 to 50:50 gradient) to give ethyl 6-(4-cyano-2-fluorophenyl)-4-(isopropylamino)-5-nitronicotinate (50.7 mg, 59% yield) as a yellowish brown solid. 1 H NMR (400MHz, chloroform-d) δ 9.03-8.95 (m, 2H), 7.57-7.43 (m, 3H), 4.43 (q, J=7.1Hz, 2H), 3.54 (dt, J=8.8, 6.3Hz, 1H), 1.47-1.41 (m, 3H), 1.28-1.22 (m, 6H); LCMS m / z 373.1(M+1).

[0154] Intermediate 1C: ethyl 5-amino-6-(4-cyano-2-fluorophenyl)-4-(isopropylamino)nicotinate [ka] A mixture of ethyl 6-(4-cyano-2-fluorophenyl)-4-(isopropylamino)-5-nitronicotinate (50 mg, 0.134 mmol) and iron (30 mg, 0.537 mmol) in acetic acid (4 mL) was stirred at 80° C. for 1 h, and the mixture was cooled to room temperature, filtered through Celite, and concentrated. The concentrated filtrate was diluted with EtOAc and saturated NaHCO 3 , washed with water, and the organic layer was dried (MgSO 4 ), and concentrated to give crude ethyl 5-amino-6-(4-cyano-2-fluorophenyl)-4-(isopropylamino)nicotinate (40.6 mg, 88% yield) as a brown sticky material. 1H NMR (400MHz, chloroform-d) δ 8.65 (s, 1H), 7.75-7.67 (m, 1H), 7.60 (dd, J=7.9, 1.5Hz, 1H), 7.51 (dd, J=9.2, 1.3Hz, 1H), 7.05-6.93 (m, 1H), 4.40 (q, J=7.2Hz, 2H), 4.06-3.88 (m, 1H), 1.42 (t, J=7.1Hz, 3H), 1.21 (d, J=6.4Hz, 6H); LCMS m / z 343.2(M+1).

[0155] Intermediate 1D: 7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate ethyl [ka] A mixture of ethyl 5-amino-6-(4-cyano-2-fluorophenyl)-4-(isopropylamino)nicotinate (40 mg, 0.117 mmol) and potassium carbonate (64.6 mg, 0.467 mmol) in DMA (0.5 mL) was stirred at 140° C. overnight, cooled to room temperature, and diluted with EtOAc. The organic layer was washed with saturated NaHCO 3 and water, and then the organic layer was dried (MgSO 4 The crude product was purified by preparative HPLC (Phen Luna Axia C18 5 μm; 30x100 mm column; detection: 220 nm; flow rate = 40 mL / min; gradient: 20% B to 100% B over 10 min, followed by 100% B for 5 min; A = 10:90:0.1 MeOH-H 2 O-TFA and B = 90:10:0.1 MeOH-H 2 The reaction was purified using 0-TFA to give ethyl 7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate (9.6 mg, 19% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 11.99 (br s, 1H), 8.97 (s, 1H), 8.43 (d, J=8.6Hz, 1H), 8.19 (s, 1H), 7.70 (d, J=8.3Hz, 1H), 4.62 (br s, 1H), 4.41 (q, J=7.0Hz, 2H), 1.49-1.32 (m, 9H); LCMS m / z 323.2(M+1)

[0156] Method 2: Intermediate 1E: tert-Butyl (5-bromo-2-cyanophenyl)carbamate [ka] A mixture of 2-amino-4-bromobenzonitrile (5 g, 25.4 mmol), di-tert-butyl dicarbonate (6.65 g, 30.5 mmol), DMAP (3.10 g, 25.4 mmol), and triethylamine (3.54 mL, 25.4 mmol) in DCM (100 mL) was stirred at room temperature overnight, and the mono- and bis-Boc products, as well as starting material, were observed by LCMS. An additional 0.5 equiv. of BOC 2 2H2O (3 g) was added and stirring was continued for 18 h. The reaction mixture was then washed with water and dried (MgSO 4 ) and concentrated. The crude material was purified by ISCO flash chromatography (silica gel; hexanes / DCM 100:0 to 0:100 gradient) to give tert-butyl (5-bromo-2-cyanophenyl)carbamate (4.5 g, 54% yield) as a white solid.

[0157] Intermediate 1F: tert-Butyl N-(5-bromo-2-cyanophenyl)-N-(tert-butoxycarbonyl)glycinate [ka] To a suspension of 60% NaH (0.727 g, 18.2 mmol) in DMF (80 mL) was added a solution of tert-butyl (5-bromo-2-cyanophenyl)carbamate (4.5 g, 15.1 mmol) in DMF (20 mL), followed by tert-butyl 2-bromoacetate (2.407 mL, 16.7 mmol), stirred at room temperature for 20 min, and the reaction was quenched with water. The mixture was extracted with EtOAc, and the organic layer was further washed with saturated NaHCO 3 and water, and the organic layer was dried (MgSO 4 ), concentrated, and the crude material was purified by ISCO flash chromatography (silica gel; hexanes / ethyl acetate 100:0 to 50:50 gradient) to give tert-butyl N-(5-bromo-2-cyanophenyl)-N-(tert-butoxycarbonyl)glycinate (6.05 g, 78% yield) as a yellow oil which solidified upon standing.

[0158] Intermediate 1G: Di-tert-butyl 3-amino-6-bromo-1H-indole-1,2-dicarboxylate [ka] To a solution of tert-butyl 2-((5-bromo-2-cyanophenyl)(tert-butoxycarbonyl)amino)acetate (6 g, 14.6 mmol) in THF (100 mL) was added potassium tert-butoxide (1.80 g, 16.1 mmol) in two portions and stirred at room temperature for 30 min. LCMS showed the reaction was complete. The mixture was added to water, extracted with EtOAc, and dried (MgSO 4 The crude was dissolved in DCM and sonicated after the formation of a white precipitate. The solid was collected to give di-tert-butyl 3-amino-6-bromo-1H-indole-1,2-dicarboxylate (2.06 g, 34% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6) δ 7.98 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.4, 1.7 Hz, 1H), 6.28 - 6.23 (m, 2H), 1.54 (d, J = 5.6 Hz, 18H)

[0159] Intermediate 1H: 6 - Bromo - 1H - indole - 3 - amine

Chem.

[0160] Intermediate 1I: Diethyl 2 - (((6 - bromo - 1H - indol - 3 - yl)amino)methylene)malonate

Chem.

[0161] Intermediate 1J: 7-bromo-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate ethyl [ka] Diethyl 2-(((6-bromo-1H-indol-3-yl)amino)methylene)malonate (1.18 g, 3.1 mmol) in diphenyl ether (10 mL) was stirred at 250-255 °C for 15 min, then cooled to room temperature, diluted with ether / hexanes (1:1) and stirred for 10 min. The solid was collected by filtration and washed with hexanes to give ethyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate (1.17 g, 113% yield) as a dark brown solid. LCMS m / z 335 (M+2)

[0162] Intermediate 1K: 7-cyano-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate ethyl [ka] Ethyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate (1.1 g, 3.28 mmol), zinc (0.150 g, 2.3 mmol), zinc cyanide (0.347 g, 2.95 mmol), and Pd 2 (dba) 3A mixture of (0.150 g, 0.164 mmol) in DMF (12 mL) was degassed with nitrogen, then tri-tert-butylphosphine (0.088 mL, 0.328 mmol) was added and stirred at 120° C. for 2 h, then cooled to room temperature. The resulting mixture was filtered through Celite, washed with DMF, the filtrate was diluted with water (80 mL) and the solid was collected by filtration and washed with water followed by ether to give crude ethyl 7-cyano-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate (1.11 g, 84% yield) as a dark brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 8.54 (s, 1H), 8.28 (d, J=8.3Hz, 1H), 7.96-7.90 (m, 1H), 7.56 (dd, J=8.4, 1.4Hz, 1H), 4.26 (q, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H); LCMS m / z 282(M+1) Alternative: A suspension of ethyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate (2.35 g, 7.01 mmol) and copper(I) cyanide (0.942 g, 10.52 mmol) in NMP (15 mL) was purged with nitrogen and stirred at 170° C. overnight. The mixture was cooled to room temperature, poured into ice-cold water and stirred for 15 min. The solid was collected by filtration and washed with water and ether to give crude ethyl 7-cyano-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate (1.8 g, 5.12 mmol, 73% yield) as a brown solid. LCMS m / z 282 (M+1)

[0163] Intermediate 1L: 4-chloro-7-cyano-5H-pyrido[3,2-b]indole-3-carboxylate ethyl [ka] Ethyl 7-cyano-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate (1.11 g, 3.95 mmol), N,N-dimethylaniline (0.335 g, 2.76 mmol), and POCl 3 (0.368 mL, 3.95 mmol) was heated at 70 °C overnight and the reaction was complete. It was concentrated and POCl 3 (0.368 mL, 3.95 mmol) was added and heated at 90° C. for 5 h. After cooling, the mixture was concentrated, diluted with EtOAc and saturated NaHCO 3 The organic layer was dried (MgSO 4 ), concentrated, and the resulting crude material was purified using ISCO flash chromatography (silica gel; hexane / ethyl acetate 100:0 to 0:100 gradient) to give ethyl 4-chloro-7-cyano-5H-pyrido[3,2-b]indole-3-carboxylate (0.386 g, 33% yield) as a light brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.68 (s, 1H), 8.95 (s, 1H), 8.43 (d, J=8.2Hz, 1H), 8.12-8.08 (m, 1H), 7.71 (dd, J=8.2, 1.3Hz, 1H), 4.43 (q, J=7.1Hz, 2H), 1.39 (t, J=7.1Hz, 3H); LCMS m / z 300(M+1)

[0164] Intermediate 1M: ethyl 7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate [ka] A solution of ethyl 4-chloro-7-cyano-5H-pyrido[3,2-b]indole-3-carboxylate (0.230 g, 0.77 mmol), propan-2-amine (0.136 g, 2.3 mmol), and triethylamine (0.535 mL, 3.84 mmol) in DMA (3 mL) was stirred at 100 °C for 6 h, the mixture was then cooled to room temperature, diluted with EtOAc, and then with water and saturated NaHCO3 The organic layer was dried (MgSO 4 ), and concentrated to give crude ethyl 7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate (0.244 g, 99% yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.47 (s, 1H), 8.84 (s, 1H), 8.61 (br d, J=8.9Hz, 1H), 8.27 (d, J=8.6Hz, 1H), 8.06 (dd, J=1.3, 0.7Hz, 1H), 7.57 (dd, J=8.2, 1.3Hz, 1H), 4.60-4.44 (m, 1H), 4.35 (q, J=7.2Hz, 2H), 1.41-1.28 (m, 9H); LCMS m / z 323.2(M+1)

[0165] Intermediate 1N: 7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylic acid [ka] A solution of ethyl 7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate (92 mg, 0.29 mmol) and NaOH (1N, 0.86 mL, 0.86 mmol) in dioxane (2 mL) was stirred at 80° C. overnight, cooled to room temperature, and acidified to pH ∼6. The resulting mixture was filtered and concentrated to give the crude product as a brown solid, containing sodium chloride (1 equiv). LCMS m / z 295.1 (M+1).

[0166] Example 1: 7-Cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylic acid (6 mg, 0.020 mmol) prepared by Method 1, BOP (9.0 mg, 0.02 mmol), (R)-4-amino-3-fluoro-2-methylbutan-2-ol (2.47 mg, 0.02 mmol), and a solution of triethylamine (0.014 mL, 0.102 mmol) / DMF (0.5 mL) were stirred at room temperature for 1 hour, and the resulting crude product was directly purified by preparative HPLC (Phen Luna Axia C18 5 μm; 21.2 x 100 mm column; detection: 220 nm; flow rate = 40 mL / min; gradient: elution from 20% B to 100% B over 10 minutes, then elution at 100% B for 5 minutes; A = 10:90:0.1 MeOH-H 2 O-TFA and B = 90:10:0.1 MeOH-H 2 O-TFA) to give (R)-7-cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide·TFA (1.9 mg, 18% yield) as an off-white solid. 1 H NMR (400 MHz, chloroform-d) δ 11.36 (br. s., 1H), 10.21 (br. s., 1H), 8.45 (s, 1H), 8.14 (d, J = 8.3 Hz, 2H), 7.87 (s, 1H), 7.39 - 7.34 (m, 1H), 4.70 - 4.52 (m, 1H), 4.43 - 4.31 (m, 1H), 4.12 - 3.95 (m, 1H), 3.78 - 3.62 (m, 1H), 1.48 (dd, J = 10.9, 6.2 Hz, 6H), 1.44 - 1.37 (m, 6H); LCMS m / z 398.2 (M+1)

Table 2

Table 3

Table 4

[0167] Example 66 (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-(thiazol-5-yl)-5H-pyrido[3,2-b]indole-3-carboxamide [ka]

[0168] Intermediate 66A: 7-Bromo-4-chloro-5H-pyrido[3,2-b]indole-3-carboxylate ethyl [ka] Ethyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrido[3,2-b]indole-3-carboxylate (1.7 g, 5.07 mmol) and POCl 3 A suspension of (5 mL, 53.6 mmol) in toluene (15 mL) was stirred at 110 °C for 10 h, cooled to room temperature and concentrated. The resulting mixture was diluted with EtOAc, washed with potassium phosphate solution (1.5 M) and dried (MgSO 4) and concentrated. The resulting crude product was purified using ISCO flash chromatography (silica gel; gradient of hexane / ethyl acetate (containing 10% ammonium hydroxide) 100:0 to 0:100) to give ethyl 7-bromo-4-chloro-5H-pyrido[3,2-b]indole-3-carboxylate (1.11 g, 62% yield) as a dark brown solid. LCMS m / z 355.0 (M+2)

[0169] Intermediate 66B: 7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate ethyl [ka] A solution of ethyl 7-bromo-4-chloro-5H-pyrido[3,2-b]indole-3-carboxylate (0.4 g, 1.13 mmol), propan-2-amine (0.134 g, 2.26 mmol), and triethylamine (0.47 mL, 3.4 mmol) in DMA (4 mL) was stirred at 110 °C overnight, and the resulting mixture was cooled to room temperature, diluted with EtOAc, and diluted with saturated NH 4 The organic layer was dried (MgSO 4 ) and concentrated to give crude ethyl 7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate (0.412 g, 97% yield) as a brown solid. LCMS m / z 378.0 (M+2)

[0170] Intermediate 66C: 4-(isopropylamino)-7-(thiazol-5-yl)-5H-pyrido[3,2-b]indole-3-carboxylate ethyl ester·TFA [ka] A mixture of ethyl 7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate (50 mg, 0.133 mmol), sodium carbonate (42.3 mg, 0.4 mmol), bis(triphenylphosphine)palladium(II) dichloride (9.33 mg, 0.013 mmol), and thiazole-5-boronic acid pinacol ester (33.7 mg, 0.16 mmol) in THF (1.5 mL) and water (0.2 mL) was purged with nitrogen and stirred at 70 °C for 3 days. The mixture was diluted with EtOAc, washed with water, and dried (MgSO 4 The crude product was purified by preparative HPLC (Phen Luna Axia C18 5μ; 30x100mm column; detection: 220nm; flow rate = 40mL / min; gradient: 40%B to 100%B over 10min, followed by 100%B for 5min; A = 10:90:0.1 MeOH-H 2 O-TFA and B = 90:10:0.1 MeOH-H 2 The reaction was purified using 0-TFA to give ethyl 4-(isopropylamino)-7-(thiazol-5-yl)-5H-pyrido[3,2-b]indole-3-carboxylate·TFA as a light brown solid (11.8 mg, 17.96% yield). 1 H NMR (400MHz, chloroform-d) δ 11.48 (br s, 1H), 9.66 (d, J=8.2Hz, 1H), 8.89-8.82 (m, 1H), 8.43 (s, 1H), 8.10 (s, 1H), 7.90 (d, J=8.4Hz, 1H), 7.52 (s, 1H), 7.22 (dd, J=8.5, 1.4Hz, 1H), 4.63-4.50 (m, 1H), 4.18 (q, J=7.1Hz, 2H), 1.50 (d, J=6.2Hz, 6H), 1.41-1.33 (m, 3H); LCMS m / z 381.1(M+1).

[0171] Intermediate 66D: ethyl 4-(isopropylamino)-7-(thiazol-5-yl)-5H-pyrido[3,2-b]indole-3-carboxylate·TFA [ka] A solution of ethyl 4-(isopropylamino)-7-(thiazol-5-yl)-5H-pyrido[3,2-b]indole-3-carboxylate·TFA (11.8 mg, 0.024 mmol) and NaOH (1N, 0.119 mL, 0.119 mmol) in dioxane (1 mL) was stirred at 75 °C overnight, then additional NaOH (1N, 0.1 mL) was added and heating was continued for 1 h. The mixture was cooled to room temperature, acidified with HCl (1N) and concentrated (containing 1 equiv. NaCl). The crude product was dissolved in DMF and (R)-4-amino-3-fluoro-2-methylbutan-2-ol (2.89 mg, 0.024 mmol), BOP (10.55 mg, 0.024 mmol), and triethylamine (9.98 μL, 0.072 mmol) were added, stirred for 45 min, filtered, and concentrated. The concentrated filtrate was diluted with EtOAc, washed with water and dried (MgSO 4 ) and concentrated. The resulting crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 19x200mm, particle size: 5μm; mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); gradient: 10-60% B over 20min, followed by 100% B for 5min; flow rate: 20mL / min). The product-containing fractions were combined and dried on a centrifugal evaporator to give (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-(thiazol-5-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (2.0mg, 18% yield). 1 H NMR (500 MHz, DMSO-d 6) δ 11.12 (br s, 1H), 9.28-9.08 (m, 1H), 8.73 (br s, 1H), 8.46 (br d, J=8.7Hz, 2H), 8.19 (br d, J=6.6Hz, 1H), 7.86 (s, 1H), 7.60 (br s, 1H), 4.49-4.30 (m, 2H), 3.83-3.65 (m, 1H), 1.27 (dd, J=5.9, 2.1Hz, 6H), 1.19 (br d, J=6.5Hz, 6H)(one proton obscured by water peak); LCMS m / z 456.1(M+1) [Table 11]

[0172] Example 69 (R)-7-Cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxamide [ka]

[0173] Intermediate 69A: 6-Bromo-3-nitro-1H-pyrrolo[3,2-b]pyridine [ka] Fuming nitric acid (0.25 mL, 5.58 mmol) was added to a suspension of 6-bromo-1H-pyrrolo[3,2-b]pyridine (1 g, 5.08 mmol) in sulfuric acid (15 mL) at 0 °C and stirred at 0 °C for 1.5 h. Ice-cold water (20 mL) was added and the pH was adjusted to about pH 7-8 using NaOH (5N). The solid was collected by filtration, washed with water, and the product was azeotroped with MeOH to give crude 6-bromo-3-nitro-1H-pyrrolo[3,2-b]pyridine (1.21 g, 99% yield) as an orange-yellow solid. 1 H NMR (400 MHz, methanol-d 4) δ 8.48 (s, 1H), 8.34 (d, J=2.0Hz, 1H), 7.96 (d, J=2.0Hz, 1H); LCMS m / z 242.0(M+2)

[0174] Intermediate 69B: 6-Bromo-1H-pyrrolo[3,2-b]pyridin-3-amine [ka] A mixture of 6-bromo-3-nitro-1H-pyrrolo[3,2-b]pyridine (1.2 g, 4.96 mmol), zinc (1.62 g, 24.8 mmol), and ammonium chloride (1.33 g, 24.8 mmol) in MeOH (9 mL) and water (1 mL) was heated to reflux for 1 min and then stirred at room temperature for 30 min. The mixture was filtered, concentrated, diluted with EtOAc, and filtered again to remove insoluble black solids. The filtrate was then diluted with saturated NaHCO 3 The aqueous layer was washed with EtOAc (3x) and the combined organic layers were dried (MgSO 4 ) and concentrated to give crude 6-bromo-1H-pyrrolo[3,2-b]pyridin-3-amine (1.12 g, 100% yield) as a dark brown solid. LCMS m / z 211.9 (M+1)

[0175] Intermediate 69C: diethyl 2-(((6-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)amino)methylene)malonate [ka] A suspension of 6-bromo-1H-pyrrolo[3,2-b]pyridin-3-amine (1.1 g, 5.2 mmol) and diethyl 2-(ethoxymethylene)malonate (1.12 g, 5.2 mmol) was heated at 120° C. for 1 h, cooled to room temperature, diluted with 10% ether / hexanes, and stirred overnight. The resulting solid was collected by filtration to give crude diethyl 2-(((6-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)amino)methylene)malonate.

[0176] Intermediate 69D: 7-Bromo-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate ethyl ester·TFA [ka] A mixture of diethyl 2-(((6-bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)amino)methylene)malonate and PPA (0.485 mL) was stirred at 110 °C overnight, cooled to room temperature, neutralized with NaOH (2M), and extracted with EtOAc (3x). The extracted organic layer was dried (MgSO 4 ) and concentrated, and the resulting crude material was purified by ISCO flash chromatography (silica gel; gradient of hexane / ethyl acetate / MeOH 100:0 to 0:90:10). The product was purified by preparative HPLC (Phen Luna Axia C18 5 μm; 30x100 mm column; detection: 220 nm); flow rate=40 mL / min; gradient: 20% B to 100% B over 10 min, then 100% B for 5 min; A=10:90:0.1 MeOH-H 2 O-TFA and B = 90:10:0.1 MeOH-H 2 The mixture was re-purified using TFA to give ethyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate (20.5 mg) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.32 (s, 1H), 8.65 (d, J=2.0Hz, 1H), 8.38 (s, 1H), 8.12 (d, J=2.0Hz, 1H), 4.25 (d, J=7.1Hz, 2H), 1.31 (t, J=7.1Hz, 3H); LCMS m / z 338.0(M+2)

[0177] Intermediate 69E: 7-bromo-4-chloro-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate ethyl [ka] Ethyl 7-bromo-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate (0.103 g, 0.306 mmol) and POCl 3 A solution of (1.5 mL, 16.1 mmol) was stirred at 90 °C overnight, and the mixture was concentrated, diluted with EtOAc and saturated NaHCO 3 and water. The organic layer was dried (MgSO 4 ), and concentrated to give crude ethyl 7-bromo-4-chloro-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate (0.106 g, 98% yield) as a brown solid.

[0178] Intermediate 69F: 7-bromo-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate ethyl [ka] A solution of ethyl 7-bromo-4-chloro-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate (0.1 g, 0.28 mmol), propan-2-amine (0.050 g, 0.85 mmol), and triethylamine (0.2 mL, 1.41 mmol) in DMA (1 mL) was stirred at 120 °C for 4 h, cooled to room temperature, diluted with EtOAc, and washed with water and 10% LiCl. The organic layer was dried (MgSO 4 ) and concentrated to give crude ethyl 7-bromo-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate as a brown solid.

[0179] Intermediate 69G: 7-cyano-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate ethyl ester·TFA [ka] Ethyl 7-bromo-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate (80 mg, 0.212 mmol), zinc cyanide (50 mg, 0.42 mmol), and Pd(Ph 3 P) 4 A mixture of (24.5 mg, 0.021 mmol) in DMA (1.5 mL) was purged with nitrogen and stirred at 120° C. overnight. The reaction mixture was cooled to room temperature, diluted with EtOAc, and diluted with saturated NH 4 Cl and water, and the organic layer was dried (MgSO 4 ) and concentrated. The resulting crude product was purified by preparative HPLC (Phen Luna Axia C18 5 μm; 30x100 mm column; detection: 220 nm; flow rate = 40 mL / min; gradient: 20% B to 100% B over 10 min, followed by 100% B for 2 min; A = 10:90:0.1 MeOH-H 2 O-TFA and B = 90:10:0.1 MeOH-H 2 Purification with 0-TFA gave ethyl 7-cyano-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate·TFA (16.4 mg, 18% yield) as a brown solid. LCMS m / z 324.1 (M+1).

[0180] Intermediate 69H: 7-cyano-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylic acid [ka] A mixture of ethyl 7-cyano-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylate·TFA (16.4 mg, 0.037 mmol) and LiOH (0.19 mL, 0.19 mmol) in 1,4-dioxane (1.2 mL) was stirred at 90 °C for 5 h, cooled to room temperature, acidified with HCl (1N), and concentrated. The resulting crude was purified by preparative HPLC (Phen Luna Axia C18 5 μm; 30x100 mm column; detection: 220 nm; flow rate = 40 mL / min; gradient: 10% B to 100% B over 10 min, then 100% B for 2 min; A = 10:90:0.1 MeOH-H 2 O-TFA and B = 90:10:0.1 MeOH-H 2 O-TFA) to give the acid as a yellow solid. LCMS m / z 296.1 (M+1)

[0181] Example 69: A solution of 7-cyano-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxylic acid·TFA (8 mg, 0.020 mmol), (R)-4-amino-3-fluoro-2-methylbutan-2-ol (2.4 mg, 0.020 mmol), and BOP (8.64 mg, 0.020 mmol) and triethylamine (0.014 mL, 0.1 mmol) in DMF (0.5 mL) was stirred at room temperature for 30 min and the crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 19x200 mm, particle size: 5 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); gradient: The mixture was purified by elution with 10-50% B over 20 min, followed by elution with 100% B for 4 min; flow rate: 20 mL / min). The fractions containing the product were combined and dried in a centrifugal evaporator. 1 H NMR (500 MHz, DMSO-d 6) δ 8.84-8.74 (m, 2H), 8.57 (s, 1H), 8.46 (d, J=1.2Hz, 1H), 8.41 (br d, J=9.2Hz, 1H), 4.49 (br d, J=4.0Hz, 1H), 4.46-4.30 (m, 1H), 3.79-3.38 (m, 2H), 1.29-1.22 (m, 6H), 1.17 (br d, J=5.5Hz, 6H); LCMS m / z 399.2(M+1)

[0182] Example 70 3-(5-isobutyl-1H-1,2,4-triazol-3-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile·TFA [ka] A solution of 7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylic acid·HCl (20 mg, 0.06 mmol), ethyl 3-methylbutanimidate hydrochloride (15 mg, 0.091 mmol), BOP (29.4 mg, 0.067 mmol), and N-methylmorpholine (0.033 mL, 0.30 mmol) in DMF (1 mL) was stirred at room temperature overnight. Hydrazine (5.7 μL, 0.18 mmol) was then added, causing the reaction to become cloudy. The mixture was stirred at room temperature for 1 h and then at 50 °C for 2 h. The mixture was cooled to room temperature and purified by preparative HPLC (Phen Luna Axia C18 5 μm; 30x100 mm column; detection: 220 nm); flow rate = 40 mL / min; gradient: 10% B to 100% B over 10 min, then 100% B for 5 min; A = 10:90:0.1 MeOH-H 2 O-TFA and B = 90:10:0.1 MeOH-H 2 The mixture was purified using O-TFA to give 3-(5-isobutyl-1H-1,2,4-triazol-3-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile·TFA (1.2 mg, 4% yield) as a colorless sticky substance. 1H NMR (400 MHz, methanol-d 4 ) δ 9.09 (s, 1H), 8.35 (dd, J=8.4, 0.7Hz, 1H), 8.18 (t, J=1.0Hz, 1H), 7.68 (dd, J=8.3, 1.3Hz, 1H), 4.79-4.70 (m, 1H), 2.83-2.76 (m, LCMS m / z 374.1(M+1) [Table 12]

[0183] Example 72 4-(Isopropylamino)-3-(3-propyl-1,2,4-oxadiazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile [ka] A solution of 7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylic acid·TFA (16 mg, 0.04 mmol), N-hydroxybutylimidamide (4.80 mg, 0.047 mmol), BOP (18.20 mg, 0.041 mmol), and N-methylmorpholine (0.013 mL, 0.118 mmol) in DMF (0.8 mL) was stirred at room temperature for 2.5 h. The resulting mixture was diluted with EtOAc, washed with water (2x), and then dried (MgSO 4 ) and concentrated. The resulting crude residue was dissolved in toluene (0.8 mL) and heated at 100° C. for 1 h. The reaction mixture was concentrated and the resulting crude product was purified by preparative HPLC (Phen Luna Axia C18 5 μm; 30×100 mm column; detection: 220 nm; flow rate=40 mL / min; gradient: 10% B to 100% B over 10 min, followed by 100% B for 5 min; A=10:90:0.1 MeOH-H 2 O-TFA and B = 90:10:0.1 MeOH-H2 The mixture was purified using TFA (isopropylamino)-3-(3-propyl-1,2,4-oxadiazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (1.3 mg, 6% yield) as a pale yellow solid. 1 H NMR (400 MHz, methanol-d 4 ) δ 9.09 (s, 1H), 8.39 (dd, J=8.4, 0.7Hz, 1H), 8.22-8.15 (m, 1H), 7.68 (dd, J=8.4, 1.3Hz, 1H), 4.75 (dt, J=12.6, 6.3Hz, 1H), 2.95-2.83 (m, 2H), 1.90 (sxt, J=7.4Hz, 2H), 1.58 (d, J=6.2Hz, 6H), 1.09 (t, J=7.4Hz, 3H); LCMS m / z 361.1(M+1)

[0184] Example 73 3-(1-Isopentyl-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile [ka]

[0185] Intermediate 73A: 7-Bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carbaldehyde [ka] A solution of ethyl 7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxylate (0.264 g, 0.70 mmol) in DCM (8 mL) was cooled to -78 °C and DIBAL-H (1 M in toluene, 1.368 mL, 1.368 mmol) was added dropwise and stirred at -78 °C for 2 h. Further DIBAL-H (0.702 mL, 0.702 mmol) was added and the reaction mixture was stirred at -78 °C for 30 min and warmed to 0 °C over 30 min. The reaction was quenched with MeOH and diluted with DCM and saturated NH 4 The mixture was diluted with Cl and stirred for 15 min. The quenched mixture was extracted with DCM (2x) and dried (MgSO 4 ) and concentrated. The resulting residue was dissolved in DCE (10 mL), manganese dioxide (0.305 g, 3.51 mmol) was added and stirred at 40 °C overnight. The mixture was cooled, filtered through Celite and concentrated. The resulting crude material was purified using ISCO flash chromatography (silica gel; hexane / ethyl acetate 100:0 to 0:100 gradient) to give 7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carbaldehyde (125 mg, 54% yield) as a pale yellow solid. LCMS m / z 333.7 (M+2)

[0186] Intermediate 73B: 7-Bromo-3-ethynyl-N-isopropyl-5H-pyrido[3,2-b]indol-4-amine [ka] Freshly prepared LDA / THF (0.5 mL) was cooled to -78 °C and (trimethylsilyl)diazomethane (2 M in ether, 0.09 mL, 0.181 mmol) was added dropwise over 5 min. The mixture was stirred for 30 min and a solution of 7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carbaldehyde (50 mg, 0.151 mmol) in THF (1.5 mL) was added slowly. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight. When the reaction was approximately 40% complete as monitored by LCMS, the reaction was quenched with water, extracted with EtOAc and dried (MgSO4 The crude material was purified using ISCO flash chromatography (silica gel; hexane / ethyl acetate 100:0 to 0:100 gradient) to give 7-bromo-3-ethynyl-N-isopropyl-5H-pyrido[3,2-b]indol-4-amine (9 mg, 18% yield) as a light brown solid. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.21 (s, 1H), 8.05 (dd, J=8.4, 0.5Hz, 1H), 7.72 (dd, J=1.6, 0.5Hz, 1H), 7.34 (dd, J=8.4, 1.7Hz, 1H), 4.71 (dt, J=12.7, 6.3Hz, 1H), 3.95-3.92 (m, 1H), 1.38-1.33 (m, 6H); LCMS m / z 328.0, 330.0(M+1)

[0187] Intermediate 73C: 7-Bromo-3-(1-isopentyl-1H-1,2,3-triazol-4-yl)-N-isopropyl-5H-pyrido[3,2-b]indol-4-amine [ka] A solution of 7-bromo-3-ethynyl-N-isopropyl-5H-pyrido[3,2-b]indol-4-amine (15 mg, 0.046 mmol), 1-azido-3-methylbutane (6.72 mg, 0.06 mmol), sodium ascorbate (3.62 mg, 0.018 mmol), and copper(II) sulfate (1.46 mg, 9.14 μmol) in t-BuOH (0.5 mL) and water (0.5 mL) was heated at 60 °C for 1.5 h, cooled, diluted with EtOAc, and washed with water. The organic layer was dried (MgSO 4 ) and concentrated to give crude 7-bromo-3-(1-isopentyl-1H-1,2,3-triazol-4-yl)-N-isopropyl-5H-pyrido[3,2-b]indol-4-amine (23 mg, 100% yield) as a brown sticky material. LCMS m / z 443.0 (M+2)

[0188] Example 73: 7-Bromo-3-(1-isopentyl-1H-1,2,3-triazol-4-yl)-N-isopropyl-5H-pyrido[3,2-b]indol-4-amine (21 mg, 0.048 mmol), zinc cyanide (11.17 mg, 0.095 mmol), and Pd(Ph 3 P) 4 A mixture of (5.5 mg, 4.76 μmol) in DMA (0.8 mL) was stirred at 100° C. overnight. LCMS showed the reaction was complete. The mixture was cooled, filtered, and the filtrate was diluted with EtOAc and saturated NH 4 Cl, washed with water and dried (MgSO 4 ) and concentrated. The crude material was purified by preparative LC / MS (conditions: column: XBridge C18, 19x200mm, particle size: 5μm; mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); gradient: 40-80% B over 19min, followed by 100% B for 5min; flow rate: 20mL / min). The product-containing fractions were combined and dried on a centrifugal evaporator to give 3-(1-isopentyl-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (8.6mg, 44.3% yield). 1 H NMR (500 MHz, methanol-d 4 ) δ 8.57-8.52 (m, 2H), 8.34 (d, J=8.1Hz, 1H), 7.98 (d, J=0.9Hz, 1H), 7.52 (dd, J=8.1, 1.4Hz, 1H), 4.59-4.51 (m, 2H), 4.42 (quin, LCMS m / z 388.2(M+1) [Table 13]

[0189] Example 76 4-(Isopropylamino)-3-(3-(piperidin-4-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile [ka]

[0190] Intermediate 76A: tert-Butyl 4-(5-(7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl)isoxazol-3-yl)piperidine-1-carboxylate·TFA [ka] A solution of 7-bromo-3-ethynyl-N-isopropyl-5H-pyrido[3,2-b]indol-4-amine (16.5 mg, 0.05 mmol), tert-butyl 4-(chloro(hydroxyimino)methyl)piperidine-1-carboxylate (39.6 mg, 0.151 mmol), and triethylamine (0.028 mL, 0.20 mmol) in DCE (1.2 mL) was heated at 60 °C for 18 h. A small amount of regioisomer was observed by LCMS. The mixture was cooled to room temperature, diluted with DCM, washed with water, and dried (MgSO 4 The crude product was purified by preparative HPLC (Phen Luna Axia C18 5 μm; 21.2×100 mm column; detection: 220 nm; flow rate: 40 mL / min; gradient: 20% B to 100% B over 12 min, followed by 100% B for 2 min; A=10:90:0.05 MeOH-H 2 O-TFA and B = 90:10:0.05 MeOH-H 2 Purification using O-TFA) afforded tert-butyl 4-(5-(7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl)isoxazol-3-yl)piperidine-1-carboxylate·TFA (8.7 mg, 26% yield) as a brown sticky material.

[0191] Intermediate 76B: tert-butyl 4-(5-(7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl)isoxazol-3-yl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-(5-(7-bromo-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl)isoxazol-3-yl)piperidine-1-carboxylate·TFA (8.7 mg, 0.013 mmol), zinc cyanide (3.06 mg, 0.026 mmol) in DMA (0.5 mL) was purged with nitrogen and stirred at 90 °C for 18 h. Further zinc cyanide (3.06 mg, 0.026 mmol) and Pd(Ph 3 P) 4 (1.504 mg, 1.301 μmol) was added and heated at 120° C. for 24 h, after which the product was observed by LCMS. The reaction mixture was cooled to room temperature, filtered, diluted with EtOAc, and washed with saturated NH 4 Cl, washed with water and dried (MgSO 4 ) and concentrated to give crude tert-butyl 4-(5-(7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl)isoxazol-3-yl)piperidine-1-carboxylate.

[0192] Example 71: A solution of tert-butyl 4-(5-(7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indol-3-yl)isoxazol-3-yl)piperidine-1-carboxylate in TFA (0.5 mL, 6.49 mmol) and DCM (0.5 mL) was stirred for 15 min and concentrated. The resulting crude was purified by preparative HPLC (Phen Luna Axia C18 5 μm; 21.2x100 mm column; detection: 220 nm; flow rate = 40 mL / min; gradient: 10% B to 100% B over 10 min, then 100% B for 2 min; A = 10:90:0.1 MeOH-H 2O-TFA and B = 90:10:0.1 MeOH-H 2 The mixture was purified using 0-TFA) to give 4-(isopropylamino)-3-(3-(piperidin-4-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile·2TFA (3 mg, 36% yield). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.53 (s, 1H), 8.37 (dd, J=8.4, 0.6Hz, 1H), 8.19 (s, 1H), 7.69 (dd, J=8.4, 1.3Hz, 1H), 6.92 (s, 1H), 4.15 (d, J=6.1Hz, 1H), 3.53 LCMS m / z 401.1(M+1) [Table 14]

[0193] Example 81 (R)-6-Cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxamide [ka]

[0194] Intermediate 81A: methyl 5-(5-cyano-2-nitrophenyl)nicotinate [ka] A mixture of 3-bromo-4-nitrobenzonitrile (0.59 g, 2.6 mmol), methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (0.684 g, 2.6 mmol), potassium phosphate tripotassium (1.66 g, 7.8 mmol), and bis(triphenylphosphine)palladium(II) chloride (0.091 g, 0.13 mmol) in THF (15 mL) and water (3 mL) was stirred at 90 °C for 5 h, diluted with EtOAc, washed with saturated sodium bicarbonate, and dried (MgSO 4 ) and concentrated. The resulting crude product was purified by ISCO flash chromatography (silica gel / hexane-EtOAc 100:0 to 0:100 gradient) to give methyl 5-(5-cyano-2-nitrophenyl)nicotinate (370 mg, 50% yield). LCMS m / z 284.0 (M+1)

[0195] Intermediates 81B and 81C: methyl 8-cyano-5H-pyrido[4,3-b]indole-4-carboxylate and methyl 6-cyano-9H-pyrido[2,3-b]indole-3-carboxylate [ka] A mixture of methyl 5-(5-cyano-2-nitrophenyl)nicotinate (370 mg, 1.31 mmol), DPPF (651 mg, 1.63 mmol) / 1,2-dichlorobenzene (1.5 mL, 13.1 mmol) was purged with nitrogen and stirred at 150° C. for 1 h. The reaction mixture was cooled and concentrated, and the resulting residue was recrystallized from DMF to give methyl 6-cyano-9H-pyrido[2,3-b]indole-3-carboxylate (130 mg, 40% yield) as the major product. 1 H NMR (400 MHz, DMSO-d 6) δ 12.80 (br s, 1H), 9.22 (d, J=2.0Hz, 1H), 9.07 (d, J=2.1Hz, 1H), 8.93 (s, 1H), 7.89 (br d, J=8.4Hz, 1H), 7.69 (d, J=8.4Hz, 1H), 3.93 (s, 3H); LCMS m / z 250.0(M+1)

[0196] Intermediate 81D: 6-cyano-3-(methoxycarbonyl)-9H-pyrido[2,3-b]indole 1-oxide [ka] To a stirred suspension of methyl 6-cyano-9H-pyrido[2,3-b]indole-3-carboxylate (130 mg, 0.517 mmol) in acetic acid (3 mL) in a septum-sealed vial was added hydrogen peroxide (30%, 453 μL, 5.17 mmol) in three portions over 2 h at 90 °C. The mixture was concentrated and the resulting residue was dissolved in half-saturated NaHCO 3 The solution was sonicated and the white solid was isolated by filtration, which was washed with water and dried to give crude 6-cyano-3-(methoxycarbonyl)-9H-pyrido[2,3-b]indole 1-oxide (130 mg, 94% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.01 (d, J=1.0Hz, 1H), 8.90 (d, J=1.2Hz, 1H), 8.80 (d, J=1.2Hz, 1H), 7.96 (dd, J=8.4, 1.6Hz, 1H), 7.74 (d, J=8.4Hz, 1H), 3.95 (s, 3H); LCMS m / z 267.8(M+1)

[0197] Intermediates 81E and 81F: methyl 4-chloro-6-cyano-9H-pyrido[2,3-b]indole-3-carboxylate and methyl 2-chloro-6-cyano-9H-pyrido[2,3-b]indole-3-carboxylate [ka] A stirred suspension of 6-cyano-3-(methoxycarbonyl)-9H-pyrido[2,3-b]indole 1-oxide (130 mg, 0.49 mmol) in DMF (4 mL) was added to POCl 3 (91 μL, 0.97 mmol) was added at 4° C., warmed to room temperature, and stirred for 4 h. The mixture was concentrated and the resulting residue was diluted with half-saturated NaHCO 3 The solid was then suspended in ethyl acetate, sonicated, and filtered, and the resulting solid was washed with water and dried to give a mixture of methyl 4-chloro-6-cyano-9H-pyrido[2,3-b]indole-3-carboxylate and methyl 2-chloro-6-cyano-9H-pyrido[2,3-b]indole-3-carboxylate (1.6:1, 130 mg). A mixture of the obtained chloride and propan-2-amine (26.9 mg, 0.455 mmol) in acetonitrile (2 mL) was stirred at 90° C. for 5 h and concentrated. The obtained crude product was purified by preparative HPLC (ODS column / water-CH 3 The product was purified with 50 mL of 100% ethyl acetate / TFA (gradient: 90:10:0.05 to 10:90:0.05) to give, in order of elution: methyl 6-cyano-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxylate·TFA (22 mg, 11% yield); 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.66 (s, 1H), 8.85 (s, 1H), 8.12 (s, 1H), 8.04 (d, J=10.4Hz, 1H), 7.80 (dd, J=8.4, 1.2Hz, 1H), 7.64 (d, J=8.3Hz, 1H), 4.29-4.12 (m, 1H), 3.88 (s, 3H); LCMS m / z 308.9(M+1) and methyl 2-chloro-6-cyano-9H-pyrido[2,3-b]indole-3-carboxylate·TFA (52 mg, 27% yield); 1 H NMR (100℃, 400MHz, DMSO-d 6) δ 11.69 (br. s., 1H), 8.87 (s, 1H), 8.34 (d, J=1.2Hz, 1H), 7.59 (dd, J=8.3, 1.6Hz, 1H), 7.47 (d, J=8.3Hz, 1H), 4.40 (spt, J=6.5Hz, 1H), 3.90 (s, 3H), 1.31 (d, J=6.5Hz, 6H); LCMS m / z 308.9(M+1)

[0198] Intermediate 81G: 6-cyano-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxylic acid [ka] A mixture of methyl 6-cyano-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxylate (16 mg, 0.052 mmol) and lithium hydroxide (0.5N, 156 μL, 0.078 mmol) in dioxane (0.75 mL) was heated at 90 °C for 5 h in a sealed vial. The mixture was diluted with water (1 mL), washed with ether, and the aqueous layer was concentrated. The resulting residue was dissolved in HCl (1N, 0.45 mL), sonicated, and concentrated. The crude product was triturated with water to give 6-cyano-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxylic acid·HCl (14 mg, 82% yield). LCMS m / z 295.1 (M+1)

[0199] Example 81: A mixture of (R)-4-amino-3-fluoro-2-methylbutan-2-ol, 6-cyano-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxylic acid·HCl (7 mg, 0.021 mmol), BOP (11.23 mg, 0.025 mmol) and TEA (8.85 μL, 0.063 mmol) in DMF (0.3 mL) was stirred at room temperature for 5 h. The reaction mixture was diluted with methanol and concentrated, and the resulting crude product was purified by preparative HPLC (ODS column / water-MeOH-TFA 90:10:0.1 to 10:90:0.1 gradient) to give (R)-6-cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxamide·TFA (7.4 mg, 65% yield). 1 H NMR (400 MHz, methanol-d 4 ) δ 8.47 (s, 1H), 8.37 (s, 1H), 7.83 (dd, J=8.4, 1.5Hz, 1H), 7.75 (dd, J=8.4, 0.5Hz, 1H), 4.55-4.32 (m, 2H), 3.91 (ddd, J=36.4, 14.3, 2.0Hz, 1H), 3.55 (ddd, J=15.6, 14.6, 9.5Hz, 1H), 1.44 (d, J=2.7Hz, 3H), 1.42 (d, J=2.7Hz, 3H), 1.30 (s, 3H), 1.30 (s, 3H); LCMS m / z 398.2(M+1)

[0200] [Table 15]

[0201] HPLC conditions: Method A: Waters Acquity UPLC BEH C18, 2.1x50mm, particle size: 1.7μm; Mobile phase A: 5:95 acetonitrile:water (containing 10mM ammonium acetate); Mobile phase B: 95:5 acetonitrile:water (containing 10mM ammonium acetate); Temperature: 50°C; Gradient: 0-100% B over 3 min, followed by 100% B for 0.75 min; Flow rate: 1.0mL / min; Detection: UV (220nm). Method B: Waters Acquity UPLC BEH C18, 2.1x50mm, particle size: 1.7μm; Mobile phase A: 5:95 acetonitrile:water (containing 0.1% trifluoroacetic acid); Mobile phase B: 95:5 acetonitrile:water (containing 0.1% trifluoroacetic acid); Temperature: 50°C; Gradient: 0-100% B over 3 min, followed by 100% B for 0.75 min; Flow rate: 1.0mL / min; Detection: UV (220nm). Method C: Waters Acquity UPLC BEH C18 2.1x50mm, 1.7μm; Mobile phase A: 2:98 acetonitrile:water (containing 0.05% trifluoroacetic acid); Mobile phase B: 98:2 acetonitrile:water (containing 0.05% trifluoroacetic acid); Temperature: 50°C; Gradient: 0-100% B over 1 min, then 100% B for 0.50 min; Flow rate: 1.0mL / min; Detection: UV (220nm).

[0202] Biological Assays The pharmacological properties of the compounds of the present invention may be determined by a number of biological assays. The following exemplary biological assays have been carried out with the compounds of the present invention.

[0203] IRAK4 inhibition assay The assay was performed in U-bottom 384-well plates. The final assay volume contained enzyme and substrates (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%.

[0204] IRAK4 whole blood assay Dispense human whole blood containing the anticoagulant ACD-A into a 384-well plate (25 μL / well) and incubate in 5% CO 2 Incubate with compound for 60 minutes at 37°C in an incubator with 5% CO 2 Blood was stimulated with the TLR2 agonist lipoteichoic acid (Invivogen, San Diego, CA) at a final concentration of 10 μg / mL in RPMI (25 μL, Gibco) for 5 h in an 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). [Table 16] [Table 17] [Table 18] [Table 19]

Claims

1. Formula (I) or Formula (II): 【Chemistry 1】 [In the formula, X is CR 3a or N; R 1 teeth, (i) -C(O)NR x R 1a ;or (ii) pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, each of which is 0 to 2 R 1b Replaced with; R 1a teeth, (i) 0 to 6 R w C replaced with 1-6 Alkyl; or (ii)-(CR x R x ) 0-3 R 1c and; Each R w are independently F, Cl, -CN, -OH, -OCH 3 , -NR x R x , -NR x C(O)(C 1-3 alkyl), -NR x C(O)(C 3-6 cycloalkyl), or C 3-6 is cycloalkyl; Each R 1b independently -CR x R x (C 3-6 cycloalkyl), tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, or 0 to 6 R w C replaced with 1-6 is alkyl; R 1c is C 3-6 cycloalkyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxidetetrahydrothiophenyl, dioxidethiomorpholinyl, isoxazolyl, oxazolyl, thiazolyl, oxadiazolyl, triazolyl, or tetrazolyl, each of which is F, Cl, -CN, -OH, -NR x R x , C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Hydroxyalkyl, -NR x C(O)(C 1-3 alkyl), -NR x C(O)O(C 1-3 alkyl), and -S(O) 2 (C 1-2 substituted with 0 to 3 substituents independently selected from alkyl, R 2 teeth, (i) hydrogen; (ii) C 1-6 Alkyl, F, Cl, -OH, -CN, C 3-6 substituted with 0 to 4 substituents independently selected from cycloalkyl, cycloalkyl, and dimethoxyphenyl; or (iii) C 3-6 A cyclic group selected from cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, pyrazolyl, and thiazolyl, said cyclic group being selected from F, Cl, -OH, -CN, C 1-2 Alkyl, C 1-2 Fluoroalkyl, C 1-2 Hydroxyalkyl, and -S(O) 2 (C 1-2 substituted with 0 to 3 substituents independently selected from alkyl, R 3 -CN, -C(O)NR x R x or a cyclic group selected from phenyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyridinonyl, and pyrimidinyl, each of which is selected from F, Cl, —OH, —CN, C 1-2 Alkyl, -CF 3 , and -CH 2 OH; R 3a is hydrogen or R 3 and; Each R x is hydrogen or -CH 3 and n is 0, 1, or 2. or a salt thereof.

2. 2. The compound of claim 1 having the structure of formula (I) or a salt thereof.

3. 2. The compound of claim 1 having the structure of formula (II) or a salt thereof.

4. Formula (Ia) or Formula (IIa): 【Chemistry 2】 [In the formula, X is CH or N; R 1 teeth, (i)-C(O)NHR 1a ;or (ii) isoxazolyl, oxadiazolyl, or triazolyl, each of which is R 1b Replaced with; R 1a は、-CH 2 CH 2 CH 3 、-CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CH(CH 3 ) 2 、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-CH 2 CH 2 C(CH 3 ) 2 F、-CH 2 CH 2 CH(CH 3 )OH、-CH 2 C(CH 3 ) 2 CH 2 OH、-CH 2 CH 2 C(CH 3 ) 2 OH、-CH 2 CHFCH(CH 3 )OH、-CH 2 CHFC(CH 3 ) 2 OH、-CH 2 CH 2 OH 3 、-CH 2 CH 2 C(CH 3 ) 2 NH 2 、-CH 2 CF 2 CH 2 NH 2 、-CH 2 CH 2 C(CH 3 ) 2 NHC(O)CH 3 、-CH(シクロプロピル)CH 2 CH 2 OH、-CH 2 CH 2 C(CH 3 ) 2 NHC(O)(cyclopropyl), R 1c , -CH 2 R 1c , or -CH 2 CH 2 R 1c and; R 1b is -CH 2 CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 (cyclopropyl), tetrahydropyranyl, piperidinyl, or morpholinyl; R 1c is cyclopropyl, cyclobutyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, tetrahydropyranyl, dioxidetetrahydrothiophenyl, dioxidethiomorpholinyl, isoxazolyl, oxazolyl, thiazolyl, triazolyl, or tetrazolyl, respectively, F, -OH, -NH 2 , -CH 3 , -CH 2 OH, -C(CH 3 ) 2 OH, -NHC(O)CH 3 , -NHC(O)OCH 3 , and -S(O) 2 CH 3 substituted with 0 to 3 substituents independently selected from R 2 is hydrogen, -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CHF 2 , -CH 2 CF 3 , -CH(CH 3 )CH 2 OH, -CH 2 (cyclopropyl), -CH(CH 3 ) (cyclopropyl), -CH 2 (dimethoxyphenyl), cyclopropyl, cyclobutyl, difluorocyclobutyl, oxetanyl, tetrahydrofuranyl, (methylsulfonyl)piperidinyl, thiazolyl, or (difluoroethyl)pyrazolyl; and R 3 -CN, -C(O)NH 2 , pyrazolyl, or pyridinonyl.

2. The compound of claim 1, having the structure:

5. 2. The compound according to claim 1, or a salt thereof, wherein X is CH.

6. In the formula, R 1 -C(O)NR x R 1a 2. The compound according to claim 1, wherein:

7. In the formula, R 1 is pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, or thiadiazolyl, each of which is R 1b 2. The compound of claim 1, or a salt thereof, substituted with:

8. Hereinafter, (R)-7-Cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (1); (R)-7-Cyano-4-(ethylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (2); (R)-7-cyano-4-((3,3-difluorocyclobutyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (3); (R)-7-Cyano-4-(cyclobutylamino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (4); 7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (5); 7-Cyano-4-(isopropylamino)-N-(tetrahydro-2H-pyran-3-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (6); 7-Cyano-N-((3-(hydroxymethyl)oxetan-3-yl)methyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (7); 7-Cyano-N-((1-(hydroxymethyl)cyclopropyl)methyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (8); 7-Cyano-N-(3-hydroxy-2,2-dimethylpropyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (9); 7-Cyano-N-((1R,4R)-4-hydroxycyclohexyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (10); 7-Cyano-4-(isopropylamino)-N-(tetrahydro-2H-pyran-4-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (11); N-((1R,4R)-4-aminocyclohexyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (12); N-((1R,4R)-4-acetamidocyclohexyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (13); 7-Cyano-4-(isopropylamino)-N-(oxazol-4-ylmethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (14); 7-Cyano-4-(isopropylamino)-N-((3-methylisoxazol-5-yl)methyl)-5H-pyrido[3,2-b]indole-3-carboxamide (15); 7-Cyano-N-(1-cyclopropyl-3-hydroxypropyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (16); 7-Cyano-4-(isopropylamino)-N-(2-methoxyethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (17); 7-Cyano-4-(isopropylamino)-N-(thiazol-2-ylmethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (18); 7-Cyano-4-(isopropylamino)-N-(piperidin-4-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (19); N-((1H-1,2,4-triazol-5-yl)methyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (20); 7-Cyano-N-isopentyl-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (21); (R)-7-Cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (22); (R)-7-cyano-4-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (23); 7-Cyano-N-((1s,3s)-3-hydroxycyclobutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (24); 7-Cyano-N-(3-hydroxybutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (25); (R)-7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-((tetrahydrofuran-3-yl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (26); 7-Cyano-4-(isopropylamino)-N-(3,3,3-trifluoropropyl)-5H-pyrido[3,2-b]indole-3-carboxamide (27); (S)-7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-((tetrahydrofuran-3-yl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (28); (S)-7-Cyano-4-((1-cyclopropylethyl)amino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (29); (S)-7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-((1-hydroxypropan-2-yl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (30); 7-Cyano-N-(3,3-difluoropropyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (31); (R)-4-(sec-butylamino)-7-cyano-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (32); 7-Cyano-4-((cyclopropylmethyl)amino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (33); 7-Cyano-N-(2-cyclopropylethyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (34); 7-Cyano-4-(isopropylamino)-N-(2-morpholinoethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (35); 7-Cyano-4-((2,2-difluoroethyl)amino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (36); 7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-((2,2,2-trifluoroethyl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (37); 7-Cyano-N-(3-fluoro-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (38); 7-Cyano-N-((1R,3R)-3-(2-hydroxypropan-2-yl)cyclobutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (39); 4-(tert-butylamino)-7-cyano-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (40); 7-Cyano-N-(3-hydroxy-3-methylbutyl)-4-(oxetan-3-ylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (41); 7-Cyano-4-(oxetan-3-ylamino)-N-(3,3,3-trifluoropropyl)-5H-pyrido[3,2-b]indole-3-carboxamide (42); 7-Cyano-N-(2-(3,3-difluoro-1-hydroxycyclobutyl)ethyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (43); 7-Cyano-4-(cyclopropylamino)-N-((1R,3R)-3-(2-hydroxypropan-2-yl)cyclobutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (44); 7-Cyano-4-(cyclopropylamino)-N-((1R,3R)-3-hydroxycyclobutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (45); 7-Cyano-4-(cyclopropylamino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (46); N-((1R,3R)-3-aminocyclobutyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (47); N3-(3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3,7-dicarboxamide (48); N-((1R,3R)-3-acetamidocyclobutyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (49); Methyl ((1R,3R)-3-(7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamido)cyclobutyl)carbamate (50); N-(3-amino-2,2-difluoropropyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (51); N-(3-amino-3-methylbutyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (52); 7-Cyano-4-(isopropylamino)-N-(2-(pyrrolidin-3-yl)ethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (53); 4-Amino-7-cyano-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (54); 7-Cyano-4-(ethylamino)-N-(2-(piperidin-3-yl)ethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (55); 7-Cyano-4-((3,4-dimethoxybenzyl)amino)-N-(3-hydroxy-3-methylbutyl)-5H-pyrido[3,2-b]indole-3-carboxamide (56); 7-Cyano-4-(ethylamino)-N-(2-(pyrrolidin-2-yl)ethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (57); 7-Cyano-4-(ethylamino)-N-(2-(piperidin-2-yl)ethyl)-5H-pyrido[3,2-b]indole-3-carboxamide (58); 7-Cyano-N-(3-(cyclopropanecarboxamido)-3-methylbutyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (59); N-(3-acetamido-3-methylbutyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (60); 7-Cyano-N-((1,1-dioxidotetrahydrothiophen-3-yl)methyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (61); 7-Cyano-N-(2-(1,1-dioxidothiomorpholino)ethyl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (62); 7-Cyano-4-(isopropylamino)-N-(1-(methylsulfonyl)piperidin-4-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (63); (R)-7-cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-((1-(methylsulfonyl)piperidin-4-yl)amino)-5H-pyrido[3,2-b]indole-3-carboxamide (64); N-(2-(1H-tetrazol-5-yl)ethyl)-7-cyano-4-(isopropylamino)-5H-pyrido[3,2-b]indole-3-carboxamide (65); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-(thiazol-5-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (66); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-(1H-pyrazol-4-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (67); (R)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-7-(6-oxo-1,6-dihydropyridin-3-yl)-5H-pyrido[3,2-b]indole-3-carboxamide (68); (R)-7-Cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-5H-pyrrolo[3,2-b:4,5-b']dipyridine-3-carboxamide (69); 3-(5-isobutyl-1H-1,2,4-triazol-3-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile·TFA (70); 4-(isopropylamino)-3-(5-propyl-1H-1,2,4-triazol-3-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (71); 4-(isopropylamino)-3-(3-propyl-1,2,4-oxadiazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (72); 3-(1-Isopentyl-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (73); 3-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-4-(isopropylamino)-5H-pyrido[3,2-b]indole-7-carbonitrile (74); 4-(isopropylamino)-3-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (75); 4-(isopropylamino)-3-(3-(piperidin-4-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (76); 4-(Isopropylamino)-3-(3-(tetrahydro-2H-pyran-4-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (77); 4-(isopropylamino)-3-(3-(morpholin-2-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (78); 4-(isopropylamino)-3-(3-(piperidin-3-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (79); 4-(isopropylamino)-3-(3-(piperidin-2-yl)isoxazol-5-yl)-5H-pyrido[3,2-b]indole-7-carbonitrile (80); (R)-6-cyano-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxamide (81); or 6-Cyano-N-(2-cyclopropylethyl)-4-(isopropylamino)-9H-pyrido[2,3-b]indole-3-carboxamide (82) or a salt thereof.

9. A pharmaceutical composition comprising one or more compounds according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier or diluent.

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

11. The pharmaceutical composition according to claim 10, 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 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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