Kinase Modulators and Methods of Use Thereof

Abstract

The present invention provides compounds that modulate the activity of protein kinases associated with human diseases, disorders, and conditions. Specifically, the compounds of the present invention inhibit TYK2, which is a member of the non-receptor protein kinase of the Janus kinase (JAK) family. In another aspect, the present invention provides the use of the compounds of the present invention, such as any of those described above, for making medicaments. In embodiments of this use, the medicament is useful for treating a condition in a subject.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention provides compounds that modulate the activity of kinases such as tyrosine kinase 2 (TYK2). [Background technology]

[0002] background Various medical conditions affecting millions of people are caused or exacerbated by unregulated activity of protein kinases. For example, abnormal kinase activity is associated with autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, skin disorders, eye diseases, infectious diseases, and hormone-related diseases. However, for many such disorders, there are no effective inhibitors or activators for the specific kinases that cause the disorder or its symptoms. As a result, patients continue to suffer from numerous disorders due to the lack of suitable medications for their conditions.

[0003] Abstract Members of the Janus tyrosine kinase (JAK) family are regulators of multiple signaling pathways initiated by membrane type I and type II tyrosine receptors. There are four JAK family members, including JAK1, JAK2, JAK3, and TYK2 (Schwartz et al., 2017). One such connection is with cytokine responses mediated by signal transducer and activator of transcription (STAT) signaling. The JAK-STAT signaling pathway is a chain of protein-protein interactions within cells and is involved in processes such as immunity, cell division, cell death, and tumorigenesis (Aaronson et al., Science, 2002). Binding of type I and type II cytokine receptor ligands, such as interferons and interleukins, to cell surface receptors causes these receptors to dimerize, bringing JAK-associated receptors into close proximity (Jalini et al., Genes and Cancer, 2011) and initiating a series of downstream changes. There is a large body of evidence establishing the contribution of JAK-dependent cytokines to immunopathology, and clinical benefit can be provided by blocking these cytokines with biological and small molecule inhibitors. Some examples of this are the blockade of IL-6 in rheumatoid arthritis or the blockade of IL-12 / IL-23 in inflammatory bowel disease (IBD) (Schwartz et al., 2017).

[0004] The tyrosine kinase 2 (TYK2) member of the JAK family plays a specific role in downstream signaling of interleukin (IL)-12, IL-23, and type I interferons (Baker and Isaacs, Ann Rheum Dis., 2018; Burke et al., Sci Trans Med, 2019). Like other JAK family members, TYK2 heterodimerizes with other JAK family members to provide ligand specificity and regulate downstream signaling pathways (Figure 1). Many of these pathways are altered in disease and drive chronic inflammation in IBD, psoriasis, and systemic lupus erythematosus (SLE) (Schwartz et al., Nat Rev Drug Dis, 2017). In addition to the role of the TYK2 signaling cascade in disease, strong genetic evidence exists for the role of TYK2. Genetic association studies have linked the TYK2 locus to susceptibility effects in SLE, psoriasis, and multiple sclerosis (MS). This identification has been repeated and expanded in numerous recent analyses, and TYK2 is now recognized as a susceptibility gene in various inflammatory and autoimmune diseases, including type 1 diabetes (T1D). A common feature of these diseases is altered immunological function and activation, as well as downstream target organ damage (Li et al., PLOS One, 2020).

[0005] The use of small molecule inhibitors of TYK2 has enabled confirmation of some of these hypotheses. Previous studies in human-derived PBMCs have demonstrated the ability of TYK2 inhibition to reduce IL-12 / IL-23 signaling in rodents, and human TYK2 inhibition has also been shown to be effective in preclinical disease models of psoriasis and ulcerative colitis (Burke et al., Sci Trans Med, 2020). This preclinical efficacy in rodents has since been translated to humans, with ducravacitinib showing efficacy in psoriasis patients (Armstrong et al., Ann of Rheu Dis, 2020). The genetic contribution of TYK2 has also been confirmed preclinically through the use of TYK2 knockout (KO) or transgenic (TG) animals. For example, type I interferon signaling was reduced in TYK2 KO animals compared to WT mice (Karaghiosoff, Immunity, 2000), and TG animals carrying the P1104 protective variant of TYK2 were nearly completely protected in an experimental autoimmune encephalitis (EAE) mouse model of MS (Gorman et al., Front in Immunology, 2019). Together, this large body of evidence provides data supporting a role for cytokine signaling and the development of safe TYK2 inhibitors for various inflammatory disorders. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Aaronson et al. Science 2002 [Non-patent document 2] Jalini et al, Genes and Cancer 2011 [Non-patent document 3] Baker and Isaacs, Ann Rheum Dis., 2018 [Non-patent document 4] Burke et al, Sci Trans Med, 2019 [Non-patent document 5] Schwartz et al, Nat Rev Drug Dis, 2017 [Non-patent document 6] Li et al., PLOS One, 2020 [Non-Patent Document 7] Burke et al, Sci Trans Med, 2020 [Non-patent document 8] Armstrong et al, Ann of Rheu Dis, 2020 [Non-Patent Document 9] Karaghiosoff, Immunity, 2000 [Non-Patent Document 10] Gorman et al, Frnt in Immunology, 2019 Summary of the Invention [Means for solving the problem]

[0007] The present invention provides compounds that modulate the activity of protein kinases associated with human diseases, disorders, and conditions. Specifically, the compounds of the present invention inhibit TYK2, a member of the Janus kinase (JAK) family of non-receptor protein kinases. Altered or unregulated TYK2 activity promotes inflammation and is implicated in autoimmune diseases such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease. Accordingly, embodiments of the present invention are useful as pharmaceutical compositions for the treatment of such autoimmune conditions. The present invention also provides methods of using these compounds to modulate kinase activity in cells and treat conditions, such as autoimmune conditions, in which modulation of kinase activity provides a therapeutic benefit.

[0008] In one aspect, the compound of the present invention is a compound of formula (I): [ka] and pharmaceutically acceptable salts thereof, In formula (I): X is CH or N; Y is CH, S, or NH; L is a single bond, a double bond, a triple bond, a substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, —C(O)NH—, —NHC(O)—, O, NH, or S; R 1 is alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, methyl, CD3, or H; R 2 is H, halo, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, or a 5- or 6-membered, substituted or unsubstituted, aryl, or monocyclic or bicyclic heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S, and N; wherein the substitutions on the 5- or 6-membered aryl or heteroaryl ring are: H, halo, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkyl, nitro, cyano, -CH2-cycloalkyl, -CF2-cycloalkyl (-CF2-cycloalky), -CH(CH3)-cycloalkyl, -CH2-aryl, -CF3, -CF2-aryl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and esters thereof), sulfonyl, alkylsulfonyl, arylsulfonyl, sulfonamido, amino, 3- to 6-membered cycloalkyl or heterocycloalkyl, 3- to 6-membered aryl or heteroaryl, any of which may bear one or more substituents; R 3is H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, aminoalkyl, aminocycloalkyl, aminoheterocycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-phenyl, -NH, -NH-CH-CF, substituted or unsubstituted -C(=O)cycloalkyl, substituted or unsubstituted -NH-C(=O)cycloalkyl, -NH-C(=O)alkyl, substituted or unsubstituted -NH-C(=O)cycloalkyl, substituted or unsubstituted aminoalkylaryl; and R 4 is selected from the group consisting of: H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, and alkylhydroxyl.

[0009] In certain embodiments, Y is NH.

[0010] In certain embodiments, R1 is methyl or ethyl.

[0011] In certain embodiments, L is a single bond.

[0012] In certain embodiments, X is CH.

[0013] In certain embodiments, X is N.

[0014] In certain embodiments, R 3 teeth: [ka] and wherein R4 is H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, or cyano.

[0015] In certain embodiments, R3 teeth: [ka] is.

[0016] In certain embodiments, R 2 teeth: [ka] where L 2 is a substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or a bond connecting these groups; A or B is independently a 5- or 6-membered, substituted or unsubstituted, aryl or heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S, and N, where the substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halo, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH-cycloalkyl, -CF-cycloalkyl, -CH(CH) -cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamido, amino, 3- to 6-membered cycloalkyl or heterocycloalkyl, 3- to 6-membered aryl or heteroaryl, any of which may bear one or more substituents.

[0017] In certain embodiments, R 2 is phenyl.

[0018] In certain embodiments, R 2 teeth: [ka] wherein each X is independently N or CH; R 5 is: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0019] In certain embodiments, R 2 teeth: [ka] wherein Z is O or S, and each X is independently N or CH; R5 is: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0020] In certain embodiments, R 2 teeth: [ka] wherein each X is independently N or CH; R5 is: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0021] In certain embodiments, LR 2 teeth: [ka] wherein each X is independently N or CH; Z is independently O or NR 6 and R 5 and R 5' independently represents H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n=1, 2, or 3.

[0022] In certain embodiments, LR 2 teeth: [ka] where Z is N or O; each X is independently N or CH; R5 and R5' are independently H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0023] In certain embodiments, LR 2 teeth: [ka] wherein R5 is: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0024] In another preferred embodiment, the compound of formula (I) is:

[0025] [ka] [ka] [ka]

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[0026] In another aspect, the present invention provides pharmaceutical compositions containing one or more compounds of the invention, eg, any of the compounds described above.

[0027] In another aspect, the present invention provides a method for modulating the activity of a kinase by contacting a cell containing the kinase with one or more compounds of the present invention, such as any of those described above. The compound can inhibit the activity of the kinase. The compound can increase the activity of the kinase. The kinase can be a JAK family kinase. The kinase can be LRRK2, NUAK1, or TYK2.

[0028] In another aspect, the present invention provides a method of treating a condition in a subject by administering to the subject a compound of the present invention, such as any of those described above. The condition can be characterized by elevated activity of a kinase. The condition can be characterized by altered activity of a kinase. The kinase can be a JAK family kinase. The kinase can be LRRK2, NUAK1, or TYK2. The condition can be an autoimmune disease, an inflammatory disease, a bone disease, a metabolic disease, a neurological or neurodegenerative disease, cancer, a cardiovascular disease, an allergy, asthma, Alzheimer's disease, Parkinson's disease, a skin disorder, an eye disease, an infectious disease, or a hormone-related disease.

[0029] In another aspect, the present invention provides the use of a compound of the present invention, such as any of those described above, to make a medicament. In an embodiment of this use, the medicament is useful for treating a condition in a subject.

[0030] In an embodiment of this use, the condition is characterized by elevated or altered activity of a kinase. In an embodiment of this use, the kinase is a JAK family kinase. In an embodiment of this use, the kinase is LRRK2, NUAK1, or TYK2.

[0031] In embodiments of this use, the condition is an autoimmune disease, an inflammatory disease, a bone disease, a metabolic disease, a neurological or neurodegenerative disease, cancer, a cardiovascular disease, an allergy, asthma, Alzheimer's disease, Parkinson's disease, a skin disorder, an eye disease, an infectious disease, or a hormone-related disease. [Brief explanation of the drawings]

[0032] [Figure 1] Figure 1 provides an overview of the JAK and TYK2 signaling pathways. DETAILED DESCRIPTION OF THE INVENTION

[0033] Detailed Description chemical definition The expression alkyl refers to the radical of a linear or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1~8In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1~7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents; e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10It is alkyl. Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0034] The term heteroalkyl refers to an alkyl group, as defined above, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, where the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or where the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 alkyl).

[0035] The term alkenyl refers to the radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds). 2~20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2~3In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), and hexenyl (C6). Further examples of alkenyl include heptenyl (C7), octenyl (C8), and octatrienyl (C8). Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0036] The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined above, further containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), where the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or where the one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~10In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2~7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2~6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2~4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2~3 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroalkenyl"). 2~6 alkenyl).

[0037] The term cycloalkyl refers to a saturated or partially unsaturated (e.g., cycloalkenyl) cyclic group containing one or more rings, for example, two or three rings, and containing from 3 to 14 ring carbon atoms, for example, from 3 to 10 (e.g., 3, 4, 5, 6, or 7) ring carbon atoms. The term cycloalkyl also refers to groups in which one or more hydrogen atoms have been replaced by fluorine, chlorine, bromine, or iodine atoms, or by OH, ═O, SH, ═S, NH, ═NH, N, or NO groups, thus, for example, cyclic ketones, such as cyclohexanone, 2-cyclohexanone, or cyclopentanone. Further specific examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decalinyl, bicyclo[4.3.0]nonyl, tetralin, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl groups.

[0038] The term "cycloheteroalkyl" or "heterocycloalkyl" refers to a cycloalkyl group as defined above in which one or more (e.g., one, two, or three) ring carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms, or by an SO or SO group. A cycloheteroalkyl or heterocycloalkyl group can have one or two rings containing from three to ten (e.g., three, four, five, six, or seven) ring atoms (e.g., C, O, N, or S). A cycloheteroalkyl or heterocycloalkyl group includes a cycloheteroalkenyl or heterocycloalkenyl group. The term "cycloheteroalkyl" or "heterocycloalkyl" further refers to groups substituted by a fluorine, chlorine, bromine, or iodine atom, or by an OH, =0, SH, =S, NH, =NH, N, or NO group. Examples are piperidinyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl groups, and also lactams, lactones, cyclic imides and cyclic acid anhydrides.

[0039] The expression alkylcycloalkyl refers to groups that contain both a cycloalkyl group and further alkyl, alkenyl or alkyl groups, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl groups. Alkylcycloalkyl groups preferably include cycloalkyl groups that contain one or two rings with 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms and one or two alkyl or alkynyl groups with 1 or 2 to 6 carbon atoms.

[0040] The term "heteroalkylcycloalkyl" refers to an alkylcycloalkyl group as defined above, in which one or more (e.g., one, two, or three) carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus, or sulfur atoms, or by an SO or SO group. Heteroalkylcycloalkyl groups preferably contain one or two rings with 3 to 10 (e.g., three, four, five, six, or seven) ring atoms and one or two alkyl, alkenyl, alkynyl, or heteroalkyl groups with 1 or 2 to 6 carbon atoms. Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl, and heteroalkylheterocycloalkenyl, in which the ring groups are saturated or mono-, di-, or tri-unsaturated.

[0041] The term aryl refers to an aromatic group containing one or more rings, for example two or three rings, and containing from 6 to 14 ring carbon atoms, for example from 6 to 10 ring carbon atoms. The term aryl also refers to groups substituted by fluorine, chlorine, bromine or iodine atoms, or by CH3, OH, SH, NH2, N3 or NO2 groups. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl groups.

[0042] The term heteroaryl refers to an aromatic group containing one or more rings, e.g., two or three rings, containing from five to fourteen ring atoms, e.g., from five to ten ring atoms, and containing one or more (e.g., one, two, three, or four) oxygen, nitrogen, phosphorus, or sulfur ring atoms. The term heteroaryl further refers to groups substituted by fluorine, chlorine, bromine, or iodine atoms, or by CH3, OH, SH, N3, NH2, or NO2 groups. Examples are pyridyl (e.g., 4-pyridyl), imidazolyl (e.g., 2-imidazolyl), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidyl, 2,3′-bifuryl, pyrazolyl (e.g., 3-pyrazolyl) and isoquinolinyl groups.

[0043] The term "aralkyl" refers to a group containing an aryl, as defined above, and also an alkyl, alkenyl, alkynyl, and / or cycloalkyl group, such as an aryl-alkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl, and alkylarylcycloalkenyl group. Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene, and indane. The aralkyl group preferably contains one or two aromatic ring systems containing 6 to 10 carbon atoms and one or two alkyl, alkenyl, and / or alkynyl groups containing 1, 2, or 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms.

[0044] The term "heteroaralkyl" refers to an aralkyl group as defined above, in which one or more (for example, one, two, three, or four) carbon atoms are replaced by oxygen, nitrogen, silicon, selenium, phosphorus, boron, or sulfur atoms, i.e., a group comprising both an aryl or heteroaryl, respectively, and also an alkyl, alkenyl, alkynyl, and / or heteroalkyl, and / or cycloalkyl, and / or heterocycloalkyl group according to the above definitions. Heteroaralkyl groups preferably comprise one or two aromatic ring systems containing 5 or 6 to 10 ring carbon atoms, and one or two alkyl, alkenyl, and / or alkynyl groups containing 1 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms, in which one, two, three, or four of these carbon atoms are replaced by oxygen, sulfur, or nitrogen atoms.

[0045] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl, and heteroarylheteroalkylheterocycloalkyl groups, in which the cyclic groups are saturated or mono-, di-, or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridino, 2-, 3-, or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3-, or 4-carboxyphenylalkyl groups.

[0046] As mentioned above, the expressions cycloalkyl, cycloheteroalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to groups substituted by fluorine, chlorine, bromine or iodine atoms or by CH, OH, ═O, SH, ═S, NH, ═NH, N or NO groups.

[0047] The term carbocyclyl or carbocyclic refers to a ring having from 3 to 10 ring carbon atoms ("C 3~10 "Carbocyclyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3~7In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), and cyclohexadienyl (C). Exemplary C 3~8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3~6 Examples include carbocyclyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (G), cyclooctenyl (G), bicyclo[2.2.1]heptanyl (C7), and bicyclo[2.2.2]octanyl (G). Exemplary C 3~10 Carbocyclyl groups include, but are not limited to, the Gs carbocyclyl groups described above, as well as cyclononyl (C), cyclononenyl (C), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), and spiro[4.5]decanyl (C 10) and the like. As the above examples illustrate, in certain embodiments, carbocyclyl groups are either monocyclic ("monocyclic carbocyclyl") or include fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic carbocyclyl"), and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, the point of attachment being on the carbocyclyl ring; in such instances, the number of carbons continues to indicate the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0048] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having from 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0049] The terms heterocyclyl or heterocyclic refer to a radical of a 3- to 14-membered non-aromatic ring system ("3- to 14-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or at a nitrogen atom, as valence allows. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or fused ring systems, such as bicyclic, bridged, or spiro ring systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0050] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system ("5- to 10-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system ("5- to 8-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system ("5- to 6-membered heterocyclyl") having ring carbon atoms and 1 to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0051] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxolanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0052] The term "optionally substituted" means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced with a possible substituent, e.g., a substituent that, upon substitution, results in a stable compound. A stable compound is one that does not spontaneously undergo transformation, e.g., by rearrangement, cyclization, elimination, or other reaction. A heteroatom, such as nitrogen, can have a substituent, such as any suitable substituent described herein, that satisfies the valence of the heteroatom and results in the formation of a stable moiety.

[0053] For example, but without limitation, optional substituents include fluorine, chlorine, bromine, and sulfur atoms, as well as CF, CN, OH, ═O, SH, ═S, NH, ═NH, N, and NO groups. Optional substituents also include C1-C 10 Alkyl, C2-C 10 Alkenyl, C1-C 10 Heteroalkyl, C3-C 16 Cycloalkyl, C2-C 17 Heterocycloalkyl, C4-C 20 Alkylcycloalkyl, C2-C 19 Heteroalkylcycloalkyl, C6-C 18 Aryl, C 1~17 Heteroaryl, C7-C 20 Aralkyl or C2-C 19 Heteroaralkyl, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 heteroalkyl, C3-C 10 Cycloalkyl, C2-C9 heterocycloalkyl, C7-C 12 Alkylcycloalkyl, C2-C 11 Heteroalkylcycloalkyl, C6-C 10 Aryl, C1-C9 heteroaryl, C7-C 12 Aralkyl, C2-C 11 Heteroaralkyl and C1-C 10 Haloalkyl groups are included.

[0054] Exemplary substituents are F, Cl, Br, OH, SH, ═O, NH, amino, C 1~4 Alkyl, C 1~4 Heteroalkyl cyclopropyl, SF5, NO, NO2.

[0055] Other exemplary substituents are F, Cl, Br, OH, SH, ═O, NH, C 1~4 alkyl (e.g., methyl, ethyl, t-butyl), NMe2, CONH2, CH2NMe2, NHSO2Me, C(CH3)2CN, COMe, OMe, SMe, COOMe, COOEt, CH2COOH, OCH2COOH, COOH, SOMe, SO2Me, cyclopropyl, SO2NH2, SO2NHMe, SO2CH2CH2OH, NHCH2CH2OH, CH2CH2OCH3, SF5, SO2NMe2, NO, NO2, OCF3, SO2CF3, CN or CF3.

[0056] Other exemplary substituents are F, Cl, Br, Me, OMe, CN, or CF3.

[0057] The term halogen preferably refers to F, Cl, Br or I.

[0058] According to certain embodiments, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl, and heteroaralkyl groups described herein may be optionally substituted.

[0059] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl, or heteroaralkyl group contains more than one ring, the rings may be joined to each other through single or double bonds, or the rings may be annulated.

[0060] Other optional substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR CC , -C(O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(O)R aa , -OCO2R aa , -C(O)N(R bb )2, -C(O)N(R aa )(R bb ), -OC(O)N(R bb )2, -NR bb C(O)R aa , -NR bb CO2R aa , -NR bb C(O)N(R bb )2, -C(NR bb )R aa , -C(NR bb ) OR aa , -OC(NR bb )R aa , -OC(NR bb ) OR aa , -C(NR bb )N(R bb )2, -OC(NR bb )N(R bb )2, -NR bb C(NR bb )N(R bb )2, -C(O)NR bb SO2R aa , -NR bb SO2R aa , -SO2N(R bb )2, -SO2R aa , -SO2OR aa , -OSO2R aa , -S(O)R aa , e.g., -S(O)R aa, -OS(O)R aa , -Si(R aa )3, -OSi(R aa )3-C(S)N(R bb )2, -C(O)SR aa , -C(S)SR aa , -SC(S)SR aa , -SC(O)SR aa , -OC(O)SR aa , -SC(O)OR aa , -SC(O)R aa , -P(O)2R aa , -OP(O)2R aa , -P(O)(R aa )2, -OP(O)(R aa )2, -OP(O)(OR cc )2, -P(O)2N(R bb )2, -OP(O)2N(R bb )2, -P(O)(NR bb )2, -OP(O)(NR bb )2, -NR bb P(O)(OR cc )2, -NR bb P(O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd or two geminal hydrogens on the carbon atom are substituted with groups =O, =S, =NN(R bb )2, =NNRbb C(O)R aa , =NNR bb C(O)OR aa , =NNR bb S(O)2R aa , =NR bb , or =NOR cc has been replaced by; where:

[0061] R aa Each example of C 1~10 Alkyl, C 1~10 Heteroalkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloheteroalkyl, C 3~10 Cycloalkenyl, C 3~10 Cycloheteroalkenyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa and the groups taken together form a 3- to 14-membered cycloalkyl, 3- to 14-membered cycloheteroalkyl, 3- to 14-membered heterocyclyl, or 5- to 14-membered heteroaryl ring, where each alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0062] R bb Each example is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(O)R aa , -C(O)N(R cc )2, -CO2R aa , -SO2R aa , -C(NR cc ) OR aa , -C(NR cc )N(R cc )2, -SO2N(Rcc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(S)N(R cc )2, -C(O)SR cc , -C(S)SR cc , -P(O)2R aa , -P(O)(R aa )2, -P(O)2N(R cc )2, -P(O)(NR cc )2, C 1~10 Alkyl, C 1~10 Heteroalkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 3~10 Cycloalkyl, C 3~10 Cycloheteroalkyl, C 3~10 Cycloalkenyl, C 3~10 Cycloheteroalkenyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aa and the groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently have 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0063] R cc Each instance of is independently hydrogen, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R aaThe groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd substituted with a group;

[0064] R dd Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(Rn);CX - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(O)R ee , -CO2H, -CO2R ee , -OC(O)R ee , -OCO2R ee , -C(O)N(R ff )2, -OC(O)N(R ff )2, -NR ff C(O)R ee , -NR ff CO2R ee , -NR ff C(O)N(R ff )2, -C(NR ff ) OR ee , -OC(NR ff )R ee , -OC(NR ff ) OR ee , -C(NR ff )N(R ff )2, -OC(NR ff )N(R ff )2, -NR ff C(NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(O)Ree , e.g., -S(O)R cc , -Si(R ee )3, -OSi(R ee )3, -C(S)N(R ff )2, -C(O)SR ee , -C(S)SR ee , -SC(S)SR ee , -P(O)2R ee , -P(O)(R ee )2, -OP(O)(R ee )2, -OP(O)(OR ee )2, C 1~6 Alkyl, C 1~6 Heteroalkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd The substituents may be taken together to form =O or =S;

[0065] R ee Each example of C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 3~10 Carbocyclyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg substituted with a group;

[0066] R ff Each instance of is independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 3~10Carbocyclyl, 3- to 10-membered heterocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or two R ff The groups taken together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R gg is substituted with a group; and

[0067] R gg Each example is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 Alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - -MR + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(O)NH2, -C(O)N(C 1~6 alkyl)2, -OC(O)NH(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(O)N(C1~6 alkyl)2, -NHC(O)NH(C 1~6 alkyl), -NHC(O)NH2, -C(NH)O(C 1~6 alkyl), -OC(NH)(C 1~6 alkyl), -OC(NH)OC 1~6 Alkyl, -C(NH)N(C 1~6 alkyl)2, -C(NH)NH(C 1~6 alkyl), -C(NH)NH2, -OC(NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(S)N(C 1~6 alkyl)2, C(S)NH(C 1~6 alkyl), C(S)NH2, -C(O)S(C 1~6 alkyl), -C(S)SC 1~6 Alkyl, -SC(S)SC 1~6 Alkyl, -P(O)2(C 1~6 alkyl), -P(O)(C 1~6 alkyl)2, -OP(O)(C 1~6 alkyl)2, -OP(O)(OC 1~6 Alkyl)2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 3~10 Carbocyclyl, C 3~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may together form =O or =S; where X- is the counterion.

[0068] compound In certain aspects, the present invention provides a compound of formula (I): [ka] and pharmaceutically acceptable salts thereof, In formula (I): X is CH or N; Y is CH, S, or NH; L is a single bond, a double bond, a triple bond, a substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, —C(O)NH—, —NHC(O)—, O, NH, or S; R 1 is alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, methyl, CD3, or H; R 2 is H, halo, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, or a 5- or 6-membered, substituted or unsubstituted, aryl, or monocyclic or bicyclic heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S, and N; wherein the substitutions on the 5- or 6-membered aryl or heteroaryl ring are: H, halo, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, thioalkyl, nitro, cyano, -CH2-cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF3, -CF2-aryl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and esters thereof), sulfonyl, alkylsulfonyl, arylsulfonyl, sulfonamido, amino, 3- to 6-membered cycloalkyl or heterocycloalkyl, 3- to 6-membered aryl or heteroaryl, any of which may bear one or more substituents; R 3 is H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, aminoalkyl, aminocycloalkyl, aminoheterocycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-phenyl, -NH, -NH-CH-CF, substituted or unsubstituted -C(=O)cycloalkyl, substituted or unsubstituted -NH-C(=O)cycloalkyl, -NH-C(=O)alkyl, substituted or unsubstituted -NH-C(=O)cycloalkyl, substituted or unsubstituted aminoalkylaryl; and R 4 is selected from the group consisting of: H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, and alkylhydroxyl.

[0069] In certain embodiments, Y is NH.

[0070] In certain embodiments, R1 is methyl or ethyl.

[0071] In certain embodiments, L is a single bond.

[0072] In certain embodiments, X is CH.

[0073] In certain embodiments, X is N.

[0074] In certain embodiments, R 3 teeth: [ka] wherein R4 is H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, or cyano.

[0075] In certain embodiments, R 3 teeth: [ka] is.

[0076] In certain embodiments, R 2 teeth: [ka] where L 2 is a substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or a bond connecting these groups; A or B is independently a 5- or 6-membered, substituted or unsubstituted, aryl or heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S, and N, where the substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halo, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH-cycloalkyl, -CF-cycloalkyl, -CH(CH) -cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxy, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamido, amino, 3- to 6-membered cycloalkyl or heterocycloalkyl, 3- to 6-membered aryl or heteroaryl, any of which may bear one or more substituents.

[0077] In certain embodiments, R 2 is phenyl.

[0078] In certain embodiments, R 2 teeth: [ka] wherein each X is independently N or CH; R 5 is: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0079] In certain embodiments, R 2 teeth: [ka] wherein Z is O or S, and each X is independently N or CH; R5 is: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0080] In certain embodiments, R 2 teeth: [ka] wherein each X is independently N or CH; R5 is: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’where R 6 and R 6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0081] In certain embodiments, LR 2 teeth: [ka] wherein each X is independently N or CH; Z is independently O or NR 6 and R 5 and R 5 ' independently represents H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R6’ is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n=1, 2, or 3.

[0082] In certain embodiments, LR 2 teeth: [ka] where Z is N or O; each X is independently N or CH; R5 and R5' are independently H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spiro bicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0083] In certain embodiments, LR 2 teeth: [ka] wherein R5 is: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR 6 , -SR 6 , -NHR 6 , -NH(CO)R 6 , -C(O)R 6 , -C(O)NHR 6 , -S(O)R 6 , -S(O)NHR 6 , -S(O)(NH)R 6 , -S(O)(NMe)R 6 , -(CH2) n S(O)R 6 , -(CH2) n OR 6 , -P(O)R 6 R 6’ where R 6 and R 6’is independently alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted fused bicycloheteroalkyl, substituted or unsubstituted bridged bicycloheteroalkyl, substituted or unsubstituted spirobicycloheteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3.

[0084] In another preferred embodiment, the compound of formula (I) is:

[0085] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

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[0086] Pharmaceutical Compositions The present invention provides pharmaceutical compositions containing one or more of the compounds described above, or pharmaceutically acceptable esters, prodrugs, hydrates, solvates, or salts of such compounds, optionally in combination with a pharmaceutically acceptable carrier. The present invention further provides such compounds for the preparation of medicaments for the treatment of one or more of the diseases mentioned herein.

[0087] Pharmaceutical compositions can contain one or more compounds of the present invention in a therapeutically effective amount.A therapeutically effective amount of a compound according to the present invention means an amount of compound that is effective to prevent, alleviate or ameliorate the symptoms of disease or prolong the survival of the subject being treated.Determining a therapeutically effective amount is within the knowledge of the art.

[0088] The therapeutically effective amount or dosage of a compound according to the invention can vary within wide limits and can be determined by methods known in the art. Such dosage can be adjusted to the individual requirements in each particular case, including the particular compound administered, the route of administration, the condition being treated, and the patient being treated.

[0089] The compositions of the present invention may contain one or more vehicles for delivery of the compounds of the present invention. For example, the compositions may include particles such as nanoparticles, microparticles, liposomes, micelles, and viral particles.

[0090] Examples of pharmaceutically acceptable salts of sufficiently basic compounds of the present invention are salts of physiologically acceptable mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.In addition, sufficiently acidic compounds of the present invention can form alkali metal salts or alkaline earth metal salts, such as sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or salts of organic bases, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of these are also further examples of the salts of the present invention.Compounds of the present invention can be solvated, particularly hydrated. Hydration may occur during the process of preparation or as a result of the hygroscopic nature of the compounds of the invention that are initially free of water. Solvates and / or hydrates may exist, for example, in solid or liquid form.

[0091] It should be recognized that certain compounds of the present invention may have tautomeric forms (only one of which may be specifically mentioned or illustrated in the following description), different geometric isomers (which are usually described as cis / trans isomers or more commonly as (E) and (Z) isomers), or different optical isomers (which are usually named under the Cahn-Ingold-Prelog or R / S system) resulting from one or more chiral carbon atoms. All these tautomeric forms, geometric or optical isomers (as well as racemates and diastereomers) and polymorphic forms are included in the present invention. Because the compounds of the present invention may contain asymmetric C atoms, they can exist either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers, or optically pure compounds. The present invention encompasses both all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any ratio.

[0092] According to a further embodiment of the present invention, one or more hydrogen atoms of the compounds of the present invention can be replaced by deuterium. Deuterium modification improves the metabolic properties of the drug with little or no change to the drug's inherent pharmacology. Deuterium substitution at specific molecular positions improves metabolic stability, reduces the formation of toxic metabolites, and / or increases the formation of desired active metabolites. Thus, the present invention also encompasses partially or fully deuterated compounds of the present invention. The term hydrogen also encompasses deuterium.

[0093] The therapeutic use of the compounds according to the invention, their pharmaceutically acceptable salts, solvates and hydrates, respectively, as well as formulations and pharmaceutical compositions, also falls within the scope of the present invention. Pharmaceutical compositions according to the present invention may contain at least one compound of the present invention as an active ingredient, and, if necessary, carrier substances and / or adjuvants.

[0094] The present invention also relates to prodrugs consisting of a compound of the present invention and at least one pharmaceutically acceptable protecting group, which is cleaved under physiological conditions, such as an alkoxy, arylalkyloxy, acyl, acyloxymethyl group (e.g., pivaloyloxymethyl), a 2-alkyl, 2-aryl, or 2-arylalkyloxycarbonyl-2-alkylideneethyl group, or an acyloxy group (as defined herein), such as ethoxy, benzyloxy, acetyl, or acetyloxy, or, particularly for compounds of the present invention having a hydroxy group (-OH): sulfate, phosphate (-OPO or -OCHOPO) or an ester of an amino acid. For example, the composition may contain a prodrug of the hydroxy group of a compound of the present invention.

[0095] As used herein, the term "pharmaceutically acceptable ester" refers specifically to esters that are hydrolyzed in vivo, and includes esters that are easily decomposed in the human body to release the parent compound or its salt.Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acid, alkenoic acid, cycloalkanoic acid and alkanedioic acid, each alkyl or alkenyl moiety preferably having 6 or less carbon atoms.Specific examples of esters include, but are not limited to, formate, acetate, propionate, butyrate, acrylate and ethylsuccinate.

[0096] The present invention also relates to prodrugs, biohydrolyzable esters, biohydrolyzable amides, polymorphs, tautomers, stereoisomers, metabolites, N-oxides, biohydrolyzable carbamates, biohydrolyzable ethers, physiologically functional derivatives, atropisomers, or in vivo hydrolyzable precursors, diastereomers or mixtures of diastereomers, chemically protected forms, affinity reagents, complexes, chelates and stereoisomers of the compounds of the invention.

[0097] As mentioned above, therapeutically useful agents, including solvates, salts, or formulations thereof, are also included within the scope of the present invention. Generally, the compounds of the present invention are administered either alone or in combination with any other therapeutic agent by using methods known and accepted in the art.

[0098] For oral administration, such therapeutically useful agents can be administered by one of the following routes: orally, for example, in the form of tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, such as soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions, or syrups; parenterally, including intravenous, intramuscular, and subcutaneous injection, for example, injectable solutions or suspensions, rectally as suppositories, by inhalation or insufflation, for example, as powder formulations, as microcrystals, or as sprays (e.g., liquid aerosols), transdermally, via a transdermal delivery system (TDS), for example, a plaster containing the active ingredient, or intranasally. For the preparation of such tablets, pills, semisolids, coated tablets, dragees, and hard, e.g., gelatin capsules, the therapeutically useful products can be mixed with pharmaceutically inert, inorganic or organic additives, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salts, and dried skim milk. For the preparation of soft capsules, additives such as vegetable, petroleum, animal, or synthetic oils, waxes, fats, polyols, etc. may be used. For the preparation of liquid solutions, emulsions, suspensions, or syrups, additives such as water, alcohol, aqueous saline, aqueous dextrose, polyols, glycerin, lipids, phospholipids, cyclodextrins, vegetable, petroleum, animal, or synthetic oils may be used. Particularly useful are lipids, such as phospholipids (e.g., of natural origin and / or with a particle size between 300 and 350 nm) in phosphate-buffered saline (pH = 7-8, e.g., 7.4). For suppositories, additives such as vegetable, petroleum, animal, or synthetic oils, waxes, fats, and polyols may be used. For aerosol formulations, compressed gases suitable for this purpose, such as oxygen, nitrogen, and carbon dioxide, may be used. Pharmaceutically useful agents may also contain additives for preservation and stabilization, such as stabilizers, emulsifiers, sweeteners, flavoring agents, salts for changing osmotic pressure, buffers, coating additives, and antioxidants.

[0099] Generally, for oral or parenteral administration to an adult weighing approximately 80 kg, a daily dosage of about 10 mg to about 10,000 mg, or about 20 mg to about 1,000 mg, should be appropriate, although this upper limit can be exceeded if necessary. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it can be given as a continuous infusion or subcutaneous injection.

[0100] Methods for making compounds The present invention also provides methods of making compounds of the invention, such as those described above. Synthetic schemes for making certain compounds of Formula (I) are provided in the Examples below.

[0101] How to Treat the Condition The compounds and compositions of the present invention modulate the activity of one or more protein kinases. These compounds and compositions may inhibit, activate, or otherwise alter kinase activity. As a result, these compounds and compositions can be used to diagnose, treat, or prevent conditions, such as diseases, disorders, or other conditions in which modulation of kinase activity provides a therapeutic benefit.

[0102] Diseases, disorders, and conditions that can be diagnosed and / or treated using the compositions and methods of the present invention include those associated with abnormal activity, e.g., increased or decreased activity, of one or more kinases. The kinase may be a serine-threonine kinase or a tyrosine kinase, such as a receptor tyrosine kinase or a non-receptor tyrosine kinase. The kinase may be a member of the JAK family. For example, but not limited to, the kinase may be death-associated protein kinase 1 (DAPK1), leucine-rich repeat kinase 2 (LRRK2), NUAK family SNF1-like kinase 1 (NUAK1, also known as AMPK-related protein kinase 5 or ARK5), spleen tyrosine kinase (SYK), or non-receptor tyrosine protein kinase TYK2 (TYK2), and may include mutants of any of the above-mentioned kinases.

[0103] The disease, disorder, or condition can be associated with abnormal DAPK1 activity, for example, Alzheimer's disease, atherosclerosis, brain injury, breast cancer, e.g., triple-negative breast cancer, cancer, ceramide and glutamate toxicity, drug resistance, e.g., resistance to cancer drugs, epilepsy, heart failure, ischemia, myofibrillar degeneration, neurodegenerative disease, seizures, tumor metastasis, tumor suppression, ulcerative colitis, or viral infection.

[0104] The disease, disorder, or condition may be associated with aberrant LRRK2 activity, for example, Alzheimer's disease, Crohn's disease, inflammatory bowel disease, inflammatory disease, leprosy, neurodegenerative disease, non-skin cancer, or Parkinson's disease, including familial Parkinson's disease, sporadic Parkinson's disease, late-onset Parkinson's disease (PD), and type 8 Parkinson's disease.

[0105] The disease, disorder, or condition may be associated with aberrant NUAK1 activity, for example, cancer, such as colorectal cancer, stomach cancer, endometrial cancer, or multiple myeloma, diabetes, fibrosis, neurodegenerative disease, or umbilical hernia.

[0106] The disease, disorder, or condition may be associated with abnormal SYK activity, and may include, for example, allergic diseases, anaphylactic shock, aneurysms, arteriosclerosis, asthma, autoimmune diseases, B-cell lymphoma, breast cancer, ductal carcinoma in situ (BCIS), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), eosinophilic inflammation, episcleritis, follicular lymphoma, functional gastrointestinal disorders, fungal keratitis, gastric cancer, head and neck cancer, heart attack, hemolytic anemia, heparin-induced thrombocytopenia, immune thrombocytopenia purpura, and the like. purpura), an infection, such as a fungal, viral, or bacterial infection, keratoconjunctivitis sicca, mantle cell lymphoma (MCL), multiple sclerosis, myelodysplastic syndrome, myocardial infarction, nasopharyngeal carcinoma, non-Hodgkin's lymphoma, rheumatoid arthritis, scleritis, stroke, or systemic lupus.

[0107] The disease, disorder, or condition may be associated with aberrant TYK2 activity, for example, an autoimmune disorder, Crohn's disease, hyper-IgE syndrome, inflammatory bowel disease, multiple sclerosis (MS), multiple sclerosis (MS), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes (T1D), or ulcerative colitis.

[0108] The disease, disorder, or condition is an airway / obstructive airway disease or disorder, e.g., rhinorrhea, tracheal constriction, airway constriction, acute, allergic, atrophic or chronic rhinitis (e.g., caseous rhinitis, hypertrophic rhinitis, suppurative rhinitis, sicca), rhinitis medicamentosa, membranous rhinitis (including croupus, fibrous, and pseudomembranous rhinitis), scrofulous rhinitis, perennial allergic rhinitis, seasonal rhinitis (including neurogenic rhinitis (hay fever) and vasomotor rhinitis), hay fever, asthma (e.g., bronchial, atopic, allergic, endogenous, extrinsic, exercise-induced, cold-induced, occupational, bacterial infection), Infection-induced and dust-induced asthma, in particular chronic or especially chronic or refractory asthma (e.g., late-onset asthma and airway hyperresponsiveness), bronchitis (including chronic, acute, arachidic, catarrhal, croupus, tuberculous and eosinophilic bronchitis), cardiobronchitis, pneumoconiosis, chronic inflammatory diseases of the lungs resulting in interstitial fibrosis, such as interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis or ILD associated with rheumatoid arthritis, or other autoimmune conditions), acute lung injury (ALI), adult respiratory distress syndrome (ARES), RDS), chronic obstructive pulmonary, airway or lung disease (CORD, COAD, COLD or COPD, e.g., irreversible COPD), chronic sinusitis, conjunctivitis (e.g., allergic conjunctivitis), cystic fibrosis, extrinsic allergic alveolitis (such as farmer's lung and related diseases), pulmonary fibrosis, hypersensitivity lung disease, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, nasal congestion, nasal polyposis, otitis media, and cough (inflammatory-related or iatrogenically induced chronic cough), pleurisy, pulmonary congestion, emphysema, bronchiectasis, sarcoidosis, idiopathic fibrosing alveolitis pulmonary fibrosis, including fibrosis exacerbated by anti-tumor treatments and chronic infections, including tuberculosis and aspergillosis and other fungal infections; vascular and thrombotic disorders of the pulmonary vasculature and pulmonary hypertension; colds and acute viral infections, including those caused by respiratory syncytial virus, influenza, coronaviruses (including SARS) and adenoviruses; allergic bronchopulmonary mycosis, emphysema, diffuse panbronchiolitis, systemic anaphylaxis or hypersensitivity reactions; drug-induced allergies (e.g., to penicillin, cephalosporins); insect sting allergies;and may include food-related allergies (e.g., migraines, rhinitis, and eczema), anaphylactic shock, or vasospasm, which may have effects remote from the gut.

[0109] The disease, disorder, or condition may be a disease or disorder related to bones and joints, such as osteoporosis, arthritis (including rheumatic, infectious, autoimmune, chronic, and malignant), seronegative spondyloarthritis (e.g., ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesopathy, Bechet's disease, Marie-Strümpel arthritis, inflammatory bowel disease arthritis, and Reiter's disease), systemic sclerosis, osteoarthritis,osteoarthrosis, both primary and secondary to congenital hip dysplasia, cervical spondylosis and lumbar spondylitis, and pain in the lower back and neck, Still's disease, reactive arthritis and undifferentiated spondarthropathy, septic arthritis and other infection-related arthropathies and bone disorders, such as tuberculosis, including Pott's disease and Poncet's syndrome, acute and chronic crystal-induced synovitis, including urate gout, calcium pyrophosphate deposition disease, and calcium apatite-associated tendon, bursa, and synovial inflammation, primary and secondary Sjogren's syndrome, systemic sclerosis and limited scleroderma, mixed connective tissue disease, and undifferentiated connective tissue disease, polymyalgia rheumatica inflammatory myopathies, including juvenile arthritis, including idiopathic inflammatory arthritis of any joint distribution and related syndromes; other joint diseases (e.g., intervertebral disc degeneration or degeneration of the temporomandibular joint); rheumatic fever and its systemic complications; vasculitis syndromes, including giant cell arteritis, Takayasu's arteritis, polyarteritis nodosa, microscopic polyarteritis, and vasculitis syndromes associated with viral infections; hypersensitivity reactions; cryoglobulins; paraproteins; low back pain; familial Mediterranean fever; Muckle-Wells syndrome; and familial Irish fever. Fever, Kikuchi's disease, drug-induced arthralgia, tendonitis, polychondritis, and myopathy, osteoporosis, osteomalacia such as osteoporosis, osteopenia, osteogenesis imperfecta, osteopetrosis, osteofibrosis, osteonecrosis, Paget's disease of bone, hypophosphatemia, Felty's syndrome, Still's disease, loosening of prosthetic joint implants, muscle or joint sprains or strains, tendinitis, fasciitis, glenohumeral periarthritis, cervicobrachial syndrome, or tenosynovitis.

[0110] The disease, disorder, or condition is a disease or disorder related to the skin or eyes, for example, glaucoma, ocular hypertension, cataracts, retinal detachment, psoriasis (including plaque psoriasis, pustular psoriasis, arthritic psoriasis, and erythrodermic psoriasis), palmoplantar pustulosis, xerodoma, eczematous diseases (such as atopic dermatitis, ultraviolet radiation dermatitis, contact dermatitis, and seborrheic dermatitis), phytodermatitis, photodermatitis, cutaneous eosinophilia, etc. skin ulcers, cutaneous lupus erythematosus, contact hypersensitivity / allergic contact dermatitis (including sensitivity to poison ivy, sumac, or poison oak), and eosinophilic pustular folliculitis (ofuji disease), pruritus, drug rash, urticaria (acute or chronic, allergic or non-allergic), acne, erythema, dermatitis herpetiformis, scleroderma, vitiligo, lichen planus, lichen sclerosus and atrophicus, pyoderma gangrenosum gangrenosum), cutaneous sarcoidosis, pemphigus, ocular pemphigoid, pemphigoid, epidermolysis bullosa, angioedema, vasculitis syndromes, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness, Sweet's syndrome, Stevens-Johnson syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis (both infectious and non-infectious), subcutaneous panniculitis, cutaneous lymphoma, non-melanoma skin cancer and other dysplastic lesions, blepharitis, iritis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, sarcoidosis, xerosis infections including viral, fungal, and bacterial infection), allergic conjunctivitis, increased fibrosis, keloids, scar reduction, post-surgical scarring, epidermolysis bullosa, dry eyes, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis, ocular neovascularization, corneal damage and scarring, all forms of macular degeneration, macular edema, macular dystrophy, abnormal wound healing, scleritis, episcleritis, pachydermia, peripheral ulcerative keratitis, fungal keratitis, herpetic keratitis, invasive aspergillosis; keratoconus, dystorphia epithelialis comeae, or severe intraocular inflammation.

[0111] The disease, disorder, or condition may be a disease or disorder associated with the gastrointestinal tract and abdomen, for example, celiac / coeliac disease (e.g., celiac sprue), cholecystitis, enteritis (including infectious, ischemic, radiation, drug-induced, and eosinophilic gastroenteritis), eosinophilic esophagitis, eosinophilic gastrointestinal inflammation, allergen-induced diarrhea, enteropathy associated with seronegative arthropathy, gastritis, autoimmune atrophic gastritis, ischemic bowel disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), colitis, Mooren's ulcer, irritable bowel syndrome, necrotizing enterocolitis, gastrointestinal ischemia, glossitis, gingivitis, periodontitis, food allergies, including reflexes. The condition may be or may include: urinary tract inflammation, proctitis, liver fibrosis and cirrhosis, pancreatitis (both acute and chronic), pancreatic fibrosis, pancreatic cirrhosis, pancreatic lithiasis, liver cirrhosis, hepatitis (congestive, autoimmune, acute, fulminant, chronic, drug-induced, alcoholic, lupoid, steatohepatitis and chronic viral), fatty liver, primary biliary cirrhosis, hepatic porphyria, and gastrointestinal-related allergic disorders, spastic colon, diverticulitis, gastrointestinal bleeding, Behcet's disease; partial hepatectomy, acute liver necrosis (e.g., necrosis caused by toxins, viral hepatitis, shock or anoxia), or hemolytic uremic syndrome.

[0112] The disease, disorder, or condition can be or include a hematological disease or disorder, such as anemia, coagulation, a myeloproliferative disorder, a bleeding disorder, leukopenia, an eosinophilic disorder, leukemia (e.g., myeloid, lymphoma, plasma cell dysplasia, a disorder of the spleen), Band's disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott-Aldrich syndrome.

[0113] The disease, disorder, or condition may be a metabolic disease or disorder, e.g., obesity, amyloidosis, branched chain disease, disorders of amino and acid metabolism such as hyperamino acidemia, hyperaminoaciduria, disorders of urea metabolism, hyperammonemia, mucopolysaccharidoses, storage diseases such as Maroteaux-Lamy syndrome, glycogen storage diseases and lipid storage diseases, glycogen storage disease I diseases such as Cori disease, malabsorption such as intestinal carbohydrate malabsorption, oligosaccharidase deficiency such as maltase, lactase, or sucrase deficiency, disorders of fructose metabolism, disorders of galactose metabolism, galactosaemia, diabetes, etc. The neurological and nervous system metabolic diseases may be or include disorders of carbohydrate utilization, hypoglycemia, disorders of pyruvate metabolism, hypolipidemia, hypolipidemia, hyperlipidemia, hyperlipoproteinemia, carnitine or carnitine acyltransferase deficiency, disorders of porphyrin metabolism, disorders of porphyrin and purine metabolism, lysosomal diseases, gangliosidoses, sphingolipidoses, sulfatidoses, leucodystrophies, or Lesch-Nyhan syndrome.

[0114] The disease, disorder, or condition may be any of the following: disorders of cerebral function or metabolism, for example, dementia, Alzheimer's disease, Huntington's chorea, Parkinson's disease, Pick's disease, toxic encephalopathy, demyelinating neuropathies such as inflammatory neuropathies, Guillain-Barré syndrome; Meniere's disease and radiculopathy, primary and secondary metabolic disorders associated with hormone deficiency such as any disorder resulting from either hyperfunction or hypofunction of any hormone-secreting endocrine gland or any combination thereof, Sipple's syndrome, pituitary dysfunction and its effects on other endocrine glands such as the thyroid, adrenal glands, ovaries, and testes, acromegaly, hyper- and hypothyroidism, euthyroid goiter, euthyroidism syndrome, thyroiditis, and disorders of the female endocrine system such as thyroid cancer, excessive or underproduction of corticosteroid hormones, adrenogenital syndrome, Cushing's syndrome, Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary aldosteronism, diabetes insipidus, diabetes mellitus, carcinoid syndrome, disorders caused by dysfunction of the parathyroid glands, pancreatic islet cell dysfunction, diabetes mellitus, estrogen deficiency, sclerosing ovarian syndrome; muscle weakness, myotonia, Duchenne and other muscular dystrophies, Steinert's myotonic dystrophy, mitochondrial myopathies such as disorders of muscle catabolism, carbohydrate and lipid storage myopathies, glycogen storage diseases, myoglobinuria, malignant hyperthermia, rheumatic polymyalgia, dermatomyositis, polymyositis (multiple myositis), primary myocardial disease, cardiomyopathies; ectodermal disorders, neurofibromatosis, scleroderma and polyarteritis nodosa, Louis-Barr syndrome, von Hippel-Lindau disease, Sturge-Weber syndrome, tuberous sclerosis, amyloidosis, porphyria; male and female sexual dysfunction; confusion and seizures due to inappropriate secretion of antidiuretic hormone from the pituitary gland, Liddle syndrome, Bartter syndrome, Fanconi I syndrome, or renal electrolyte wasting.

[0115] The disease, disorder, or condition may be or may include a condition associated with transplant rejection, such as acute and chronic allograft rejection after solid organ transplants, e.g., kidney, heart, liver, lung, and corneal transplants, chronic graft-versus-host disease, skin graft rejection, and bone marrow transplant rejection, or immunosuppression.

[0116] The disease, disorder, or condition may be or include a condition related to the genitourinary tract, such as nephritis (interstitial, acute interstitial (allergic), and glomerulonephritis), nephrotic syndrome, cystitis including acute and chronic (interstitial) cystitis and Hunners ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, vulvovaginal candidiasis, Peyronie's disease, and erectile dysfunction, kidney disease, renal fibrosis, pyelonephritis, secondary atrophic kidney, steroid-dependent and steroid-resistant nephrosis, or Goodpasture's syndrome.

[0117] The disease, disorder, or condition may be a disease or disorder related to the CNS, for example, neurodegenerative diseases, Alzheimer's disease and other cementing disorders including CJD and nvCJD, amyloidosis and other demyelinating syndromes, cerebral atherosclerosis and vasculitis, temporal arteritis, myasthenia gravis, post-operative, visceral pain, headache, migraine, neuralgia (including trigeminal), atypical facial pain, acute and chronic severe pain including joint pain and bone pain. pain (acute, intermittent or persistent, whether of central or peripheral origin), pain resulting from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic and HIV-associated neuropathies, neurosarcoidosis, injury to the brain, cerebrovascular disease and its outcomes, Parkinson's disease, corticobasal degeneration, motor neuron disease, dementia including ALS (amyotrophic lateral sclerosis), multiple sclerosis, traumatic brain injury, stroke, post-stroke, post-traumatic brain injury and small vessel cerebrovascular disease, dementia, vascular dementia, dementia with Lewy bodies, frontotemporal dementia and parkinsonism linked to chromosomes 1-17, frontotemporal dementia including Pick's disease, progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, thalamic degeneration, HIV dementia, schizophrenia with dementia and Korsakoff psychosis, which within the meaning of the definition are also considered CNS disorders of the central and peripheral nervous system complications of malignant, infectious, or autoimmune processes; may be or include nociception, cerebral infarction, seizures, cerebral ischemia, head injury, spinal cord trauma, myelopathic muscular atrophy, Shy-Drager syndrome, Reye's syndrome, progressive multifocal leukoencephalopathy, normal pressure hydrocephalus, sclerosing panencephalitis, frontal lobe dementia, acute poliomyelitis (polio), acute poliomyelitis neuropathy, viral encephalitis, allergic encephalomyelitis, epileptic encephalopathy, Creutzfeldt-Jakob disease, kuru, bovine spongiform encephalopathy (mad cow disease), scrapie, epilepsy, cerebral amyloid angiopathy, depression, mania, bipolar disorder, hereditary cerebellar ataxia, peripheral neuropathy, Nasu-Hakola syndrome, or Machado-Joseph disease.

[0118] The disease, disorder, or condition may be an inflammatory or immunological disease or disorder, for example, general inflammation (of the eyes, nose, lungs, and gastrointestinal tract), mastocytosis / mast cell disorders (skin, systemic, mast cell activation syndrome, and pediatric mast cell disease), mastitis (breast), vaginitis, vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis), Wegener's granulomatosis, myositis (including polymyositis, dermatomyositis), basophil-related diseases including basophilic leukemia and basophilia, and Churg-Strauss syndrome, eosinophil-related diseases such as eosinophilic granuloma, lupus erythematosus (e.g., systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and discoid lupus erythematosus), chronic thyroiditis, Hashimoto's thyroiditis, Graves' disease, type 1 diabetes, complications resulting from diabetes mellitus, other immune disorders, eosinophilia The condition may be or may include fasciitis, hyper-IgE syndrome, Addison's disease, antiphospholipid syndrome, immunodeficiency syndrome, acquired immunodeficiency syndrome (AIDS), leprosy, Sézary syndrome, paraneoplastic syndromes and other autoimmune disorders, fever, neurological diseases selected from myositis, polymyositis, bursitis, Evans syndrome, diseases mediated by leukotriene B4, idiopathic hypoparathyroidism, nephrotic syndrome lupus, or immunosuppression.

[0119] The disease, disorder, or condition may be or include cardiovascular diseases or disorders such as congestive heart failure, myocardial infarction, ischemic disease of the heart, atrial and ventricular arrhythmias of all kinds, hypertension, brain trauma, occlusive vascular disease, stroke, cerebrovascular disease, atherosclerosis, restenosis, coronary and peripheral effects are circulatory, inflammatory and autoimmune cardiomyopathies including pericarditis, myocarditis, myocardial sarcoid, endocarditis, valvular heart disease, and aortitis, including infectious (e.g., syphilitic) forms, hypertensive vascular disease, peripheral vascular disease, and disorders of the proximal and peripheral veins, including atherosclerosis, vasculitic syndromes, phlebitis, and thrombosis, including complications of deep vein thrombosis and varicose veins, aortic aneurysms, periarteritis nodosa, cardiac fibrosis, post-myocardial infarction, idiopathic cardiomyopathies, or angioplasty.

[0120] The disease, disorder, or condition may be an oncological disease or disorder, for example, general cancers (tumors of the prostate, breast, lung, ovary, pancreas, intestine and colon, abdomen, stomach (and any other cancer of the digestive system), liver, pancreas, peritoneum, endocrine glands (adrenal gland, parathyroid gland, pituitary gland, testis, ovary, thymus, thyroid), eye, head, neck, nervous system (central and peripheral), lymphatic system, blood, pelvis, skin, bone, soft tissue, spleen, breast, genitourinary tract, and brain), breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid carcinoma, melanoma, ovarian cancer, Pancreatic cancer, neuroblastoma, malignancies affecting the bone marrow (including leukemia) and lymphoproliferative system, such as Hodgkin's lymphoma and non-Hodgkin's lymphoma, B-cell lymphoma, follicular lymphoma, metastatic disease and tumor recurrence, and paraneoplastic syndromes, as well as hypergammaglobulinemia, lymphoproliferative diseases, disorders, and / or conditions, paraproteinemia, purpura (including idiopathic thrombocytopenic purpura), Waldenstrom's macroglobulinemia, The tumor may be or may include: myeloid leukemia, acute or chronic myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specific cell type, leukemias of unclassified cell type, other and unclassified lymphoid tumors, malignant neoplasms of hematopoietic and related tissues, e.g., diffuse large cell lymphoma, T-cell lymphoma, or cutaneous T-cell lymphoma), myeloid leukemia, including, e.g., acute or chronic myeloid leukemia, or corneal vitiligo.

[0121] The disease, disorder, or condition may be associated with another disease or disorder, such as pain, migraine, sleep disorders, fever, sepsis, idiopathic thrombocytopenia, or idiopathic thrombocytopenia. pupura), postoperative adhesions, flushing, ischemic / reperfusion injury of the heart, brain, peripheral limbs, bacterial infection, viral infection, fungal infection, thrombosis, endotoxic shock, septic shock, thermoregulation including fever, Raynaud's disease, gangrene, diseases requiring anticoagulation therapy, congestive heart failure, impaired mucus secretion, pulmonary hypotension, prostanoid-induced smooth muscle contraction associated with dysmenorrhea and preterm labor, premature labor, reperfusion injury, bum, thermal injury, hemorrhagic or traumatic shock, menstrual pain, menstrual cramps, dysmenorrhea, periodontitis, rickettsial infections, protozoal diseases, reproductive diseases, toothache, pain after tooth extraction, shingles, herpes simplex, retroperitoneal fibrosis, or various radiation injuries.

[0122] In certain embodiments, the disease is selected from the group consisting of inflammatory diseases, autoimmune diseases, allergic diseases, and eye disorders, hi certain embodiments, the disease is selected from the group consisting of pruritus, eczema, asthma, rhinitis, dry eye, eye inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis, and uveitis.

[0123] The method may include modulating the activity of one or more kinases in a subject, such as any of the kinases described above. The method may include inhibiting a kinase. The method may include activating a kinase, such as stimulating or enhancing the activity of a kinase. The method may include modulating the activity of a single kinase, or preferentially modulating the activity of a particular kinase over other kinases. The method may include modulating the activity of multiple kinases, or preferentially modulating the activity of two or more particular kinases over other kinases.

[0124] The method may include providing a compound of the invention. The method may include providing a plurality of compounds of the invention.

[0125] The method may include contacting a cell containing a kinase with one or more compounds of the present invention. For example, but not limited to, contacting a cell with a compound may include exposing the cell to the compound in a formulation such as any of those described above; delivering the compound to the inside of the cell; providing the compound to a subject and allowing the cells in the subject to be exposed to the compound. The contacting may be performed in vivo or in vitro. In vitro contacting may include exposing cells or tissues isolated from a subject. The method may include contacting a cell with a single compound of the present invention. The method may include contacting a cell with multiple compounds of the present invention.

[0126] The method may include administering a composition to a subject. The compositions may be provided by any suitable administration route. For example, but not limited to, the compositions may be administered bucally, by injection, into the skin, into the intestine, into an artery, intravenously, intranasally, for example, by inhalation, into the eye, orally, parenterally, pulmonary, rectally, subcutaneously, systemically, topically, for example, into the skin or eye, transdermally, or using or with an implantable medical device (e.g., a stent or a drug-eluting stent or balloon equivalent). The method may include diagnosing a disease, disorder, or condition in a subject using the composition of the present invention. For example, a radiolabeled form of the compound may be used in positron emission tomography (PET) to identify the anatomical location of abnormal kinase activity. PET is known in the art and is described, for example, in Wadsak Wolfgang, Mitterhauser Markus (2010), "Basics and principles of radiopharmaceuticals for PET / CT", European Journal of Radiology, 73 (3): 461-469. doi:10.1016 / j.ejrad.2009.12.022; Bailey, DL; DW Townsend; PE Valk; MN Maisey (2005), Positron Emission Tomography: Basic Sciences. Secaucus, NJ: Springer-Verlag, ISBN 1-85233-798-2; and Carlson, Neil (January 22, 2012). Physiology of Behavior. Methods and Strategies of Research, 11th edition, Pearson, p. 151, ISBN No. 0205239390, the contents of each of which are incorporated herein by reference. The present invention can encompass administering one or more compositions of the present invention for both diagnostic and therapeutic purposes. [Example]

[0127] Example 1: Synthesis of N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0128] Step 1: 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one [ka]

[0129] To a solution of 6-chloro-2,7-naphthyridin-1-ol (1 g; 5.53 mmol; 1.00 equiv.) in DMF (15 mL) under a nitrogen atmosphere was added NBS (1 g; 5.61 mmol; 1.00 equiv.) at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by LCMS. The precipitated solid was collected by filtration and washed with water, then dried under reduced pressure to give 4-bromo-6-chloro-2,7-naphthyridin-1(2H)-one (1.16 g, 81%) as a white solid. LCMS (ESI) m / z 258.9, [M+H] + .

[0130] Step 2: 4-bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one [ka]

[0131] To a mixture of 4-bromo-6-chloro-2,7-naphthyridin-1(2H)-one (1.16 g; 4.47 mmol; 1.00 equiv.) and CsCO (2.9 g; 8.89 mmol; 2.00 equiv.) in THF (20 mL) under a nitrogen atmosphere was added TBAI (166 mg; 0.449 mmol; 0.10 equiv.) at 0° C. To the reaction mixture was added (2-(chloromethoxy)ethyl)-trimethylsilane (1.31 g; 7.89 mmol; 1.76 equiv.), and the reaction mixture was stirred at room temperature for 1 hour. The desired product was observed by LCMS. The precipitated solid was collected by filtration and washed with THF (20 mL) and dried under reduced pressure to give 4-bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one as a white solid (1.08 g, 62%). LCMS (ESI) m / z 389.0, [M+H] + .

[0132] Step 3: 6-chloro-4-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one [ka]

[0133] To a stirred mixture of 4-bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one (160 mg; 0.411 mmol; 1.00 equiv.) and phenylboronic acid (40 mg; 0.327 mmol; 0.80 equiv.), Pd(PPh3)4 (47.6 mg; 0.041 mmol; 0.10 equiv.) in DME / water (5:1, 6 mL) was added Na2CO3 (87.4 mg; 0.824 mmol; 2.00 equiv.) at room temperature, and the reaction mixture was stirred at 100 °C under nitrogen for 3 h. The desired product was observed by LCMS. The reaction was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using EtOAc in petroleum ether (10-30%) as the eluent to give 6-chloro-4-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one as a yellow solid (78 mg, 49%). LCMS (ESI) m / z 387.1, [M+H] + .

[0134] Step 4: N-(8-oxo-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0135] A mixture of 6-chloro-4-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one (58 mg; 0.150 mmol; 1.00 equiv), Pd(dba) (13.8 mg; 0.015 mmol; 0.10 equiv), XantPhos (17.4 mg; 0.030 mmol; 0.20 equiv), CsCO (98.0 mg; 0.301 mmol; 2.00 equiv), and cyclopropane-carboxamide (38.3 mg; 0.450 mmol; 3.00 equiv) in dioxane (3 mL) was stirred at 110 °C for 2 h. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column using EtOAc in petroleum ether (10-30%) as eluent to give N-(8-oxo-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (60 mg, 92%). LCMS (ESI) m / z 436.2, [M+H] + .

[0136] Step 5: N-(8-oxo-5-phenyl-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0137] To a solution of N-(8-oxo-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (80 mg; 0.183 mmol; 1.00 equiv) in MeOH (0.5 mL) was added a solution of HCl in dioxane (4 M, 2 mL). The reaction mixture was stirred under nitrogen at room temperature for 1 hour. The desired product was observed by LCMS. The mixture was concentrated under reduced pressure to give N-(8-oxo-5-phenyl-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (50 mg, 89%). LCMS (ESI) m / z 306.1, [M+H]+ .

[0138] Step 6: N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0139] N-(8-oxo-5-phenyl-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.162 mmol; 1.00 equiv) was dissolved in POCl (2 mL). The resulting mixture was stirred at 100 °C for 1 h. The desired product was observed by LCMS. The solvent was concentrated under reduced pressure to give N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (35 mg, 66%). LCMS (ESI) m / z 324.1, [M+H] + .

[0140] Step 7: N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0141] N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (35 mg; 0.108 mmol; 1.00 equiv.) was dissolved in a solution of methylamine in THF (2 M, 2 mL), and the reaction mixture was stirred at 60 °C under nitrogen for 12 h. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as the eluent to give N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (5.2 mg, 15%). LCMS (ESI) m / z 319.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.39 (s, 1H), 8.35 (s, 1H), 8.02 - 7.90 (m, 2H), 7.55 - 7.30 (m, 5H), 3.02 (d, J = 4.4 Hz, 3H), 2.07 - 1.95 (m, 1H), 0.84 - 0.6 (m, 4H).

[0142] Example 2: Synthesis of N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0143] Step 1: 6-chloro-4-methylnicotinamide [ka]

[0144] To a stirred solution of 6-chloro-4-methylnicotinic acid (50.0 g; 0.292 mol; 1.00 equiv.) in CHCl (1 L) was added HATU (170 g; 0.447 mol; 1.50 equiv.). The reaction was stirred at room temperature for 20 min. To this mixture was added NHCl (155 g; 2.92 mol; 10.0 equiv.) and DIPEA (113 g; 0.875 mol; 3.00 equiv.) and stirred at room temperature under a nitrogen atmosphere for 2 h. The desired product was observed by LCMS. The resulting mixture was diluted with water (1 L) and extracted with CHCl (200 mL × 5). The organic layer was washed with saturated NaCl solution and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using EtOAc in petroleum ether (25-60%) as the eluent to give 6-chloro-4-methylnicotinamide as a brown solid (33 g, 66%). LCMS (ESI) m / z 171.0, [M+H] + .

[0145] Step 2: (Z)-6-chloro-N-((dimethylamino)methylene)-4-methylnicotinamide [ka]

[0146] To a stirred mixture of 6-chloro-4-methylnicotinamide (51 g; 300 mmol; 1.00 equiv.) in methyltetrahydrofuran (300 mL) was added DMF-DMA (53.5 g; 449 mmol; 1.50 equiv.). The resulting mixture was stirred at 80° C. under a nitrogen atmosphere for 1 hour. The desired product was observed by LCMS. The mixture was cooled and concentrated under reduced pressure to give (Z)-6-chloro-N-((dimethylamino)methylene)-4-methylnicotinamide as a brown solid (65.0 g, crude). The crude product was used directly in the next step without further purification. LCMS (ESI) m / z 226.1, [M+H] + .

[0147] Step 3: 6-chloro-2,7-naphthyridin-1(2H)-one [ka]

[0148] To a solution of (Z)-6-chloro-N-((dimethylamino)methylene)-4-methylnicotinamide (60.0 g; 266 mmol; 1.00 equiv) in THF (387 mL) was slowly added t-BuOK (1.0 M in THF, 400 mL) at 0° C., and the reaction mixture was stirred at 80° C. under a nitrogen atmosphere for 0.5 h. The desired product was detected by LCMS. The precipitated solid was collected by filtration and washed with THF (2×20 mL) to give the crude product. The crude product was diluted with water (500 mL) and acidified to pH=6 with a solution of HCl (1 M), and the precipitated solid was collected by filtration and washed with water. The solid was dried in vacuo to give 6-chloro-2,7-naphthyridin-1(2H)-one as a brown solid (40 g, 83%). LCMS (ESI) m / z 181.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 9.09 (s, 1H), 7.76 (s, 1H), 7.52 -7.40 (m, 1H), 6.53 (d, J = 7.2 Hz, 1H).

[0149] Step 4: N-(8-hydroxy-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0150] To a stirred mixture of 6-chloro-2,7-naphthyridin-1(2H)-one (8.5 g, 47.1 mmol, 1.00 equiv) in 1,4-dioxane (500 mL), Pd(dba) (4.25 g, 4.64 mmol, 0.10 equiv), XantPhos (5.44 g, 9.40 mmol, 0.20 equiv), cyclopropanecarboxamide (16.2 g, 190 mmol, 4.00 equiv), and CsCO (30.6 g, 93.9 mmol, 2.00 equiv) were added under a nitrogen atmosphere. The reaction was stirred at 110 °C for 3 h. The desired product was observed by LCMS. The reaction was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column using EtOAc / petroleum ether (30-100%) and MeOH / CHCl (2-20%) as eluents to give 8.3 g of crude product. The crude was dissolved in a mixed solvent of CHCl / EtOAc (2:1, 450 mL) and stirred overnight, then filtered, the filter cake washed with CHCl (200 mL), and dried overnight to give N-(8-hydroxy-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (6.5 g, 60%). LCMS (ESI) m / z 230.1, [M+H] + .

[0151] Step 5: N-(8-chloro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0152] N-(8-hydroxy-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.4 g, 19.2 mmol, 1.00 equiv) was dissolved in POCl (55 mL). The reaction was stirred at 100 °C for 30 min. The reaction was cooled and then concentrated in vacuo. The residue was diluted with CHCl (300 mL) and neutralized to pH 7 with saturated NaHCO solution. The organic phase was concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using EtOAc / CHCl (20-50%) to give N-(8-chloro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as an off-white solid (1.85 g, 39%). LCMS (ESI) m / z 248.1, [M+H] + .

[0153] Step 6: N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0154] To a stirred mixture of N-(8-chloro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (920 mg, 3.71 mmol, 1.00 equiv) in NMP (10 mL) was added methanamine hydrochloride (1.0 g; 14.8 mmol; 4.00 equiv) and DIPEA (2.4 g, 18.6 mmol, 5.00 equiv) under N. The reaction was stirred at 100 °C for 18 h. The desired product was observed by LCMS. The mixture was diluted with EtOAc (100 mL) and washed with brine (25 mL × 5). The organic layer was concentrated under reduced pressure and purified by flash chromatography on a pre-packed C18 column using 10-40% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as an off-white solid (850 mg, 94%). 10 mg of this product was further purified by flash chromatography on a pre-packed C18 column using 20%-60% MeCN in water (10 M NH4HCO3) to give N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.5 mg, 45%). LCMS (ESI) m / z 243.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.30 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 6.0 Hz, 1H), 7.87 - 7.80 (m, 1H), 6.74 (d, J = 6.0 Hz, 1H), 2.96 (d, J = 4.4 Hz, 3H), 2.09 - 2.00 (m, 1H), 0.88 - 0.78 (m, 4H).

[0155] Example 3 Synthesis of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0156] To a stirred mixture of N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 2, Step 6) (1.9 g, 7.84 mmol, 1.00 equiv) in DMF (12 mL) at 0 °C under a nitrogen atmosphere was added NBS (1.40 g, 7.84 mmol, 1.00 equiv) at 0 °C. The reaction was then warmed to room temperature for 1 h. The desired product was observed by LCMS. The resulting mixture was diluted with EtOAc (150 mL) and washed with brine (50 mL × 5). The organic layer was dried, concentrated under reduced pressure, and purified by flash chromatography on a silica gel column using 2-10% MeOH in CHCl to give 2.5 g of crude product. The crude product was then purified by reverse-phase preparative HPLC (Prep-C18, 5 μM OBD column, 19 × 250 mm water; gradient elution with 40–50% MeCN in water over 8 min, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (327 mg, 13%). LCMS (ESI) m / z 321.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.32 (s, 1H), 8.44 (s, 1H), 8.16 (s, 1H), 8.14 - 8.09 (m, 1H), 2.95 (d, J = 4.4 Hz, 3H), 2.12 - 2.04 (m, 1H), 0.92 - 0.82 (m, 4H).

[0157] Example 4: Synthesis of N-(8-(methylamino)-5-(pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0158] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (35.0 mg; 0.109 mmol; 1.00 equiv.) in 1,4-dioxane (1.5 mL) was added 2-(tributylstannyl)pyridine (80.2 mg; 0.218 mmol; 2.00 equiv.), CuI (4.1 mg; 0.022 mmol; 0.20 equiv.), Pd(PPh3)4 (25.2 mg; 0.022 mmol; 0.20 equiv.), and LiCl (11.6 mg; 0.273 mmol; 2.50 equiv.). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 3 h. The resulting mixture was diluted with EtOAc (50 mL). The organic layer was washed with brine (5 × 3 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as the eluent to give N-(8-(methylamino)-5-(pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.6 mg, 13%). LCMS (ESI) m / z 320.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 8.70 - 8.66 (m, 1H), 8.27 - 8.19 (m, 1H), 8.15 (s, 1H), 7.93 - 7.87 (m, 1H), 7.61 - 7.57 (m, 1H), 7.39 - 7.33 (m, 1H), 3.04 (d, J = 4.4 Hz, 3H), 2.06 - 1.99 (m, 1H), 0.82 - 0.78 (m, 4H).

[0159] Example 5: Synthesis of N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0160] Step 1: 3-Methoxy-2-(tributylstannyl)pyridine [ka]

[0161] To a solution of 2-bromo-3-methoxypyridine (500 mg; 2.65 mmol; 1.00 equiv.) in 1,4-dioxane (5 mL) was added Pd(dba) (244.8 mg; 0.267 mmol; 0.10 equiv.), tricyclohexylphosphane (167.7 mg; 0.598 mmol; 0.22 equiv.), and LiCl (566.8 mg; 13.3 mmol; 5.00 equiv.). To this mixture was added 1,1,1,2,2,2-hexabutyldistannane (2.32 g; 4.01 mmol; 1.50 equiv.). The reaction was stirred at 110 °C for 1 h. The mixture was allowed to cool to room temperature. The desired product was detected by LCMS. The resulting mixture was diluted with CHCl (100 mL) and washed with saturated NaCl solution (3 × 5 mL). The organic layer was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on a neutral AlO column using 1-10% EtOAc in petroleum ether as eluent to give 3-methoxy-2-(tributylstannyl)pyridine as a yellow oil (1.0 g, 93%). LCMS (ESI) m / z 400.2, [M+H] + .

[0162] Step 2: N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0163] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.16 mmol; 1.00 equiv.) in 1,4-dioxane (2 mL), 3-methoxy-2-(tributylstannyl)pyridine (312 mg; 0.78 mmol; 5.00 equiv.), CuI (6 mg; 0.03 mmol; 0.20 equiv.), Pd(PPh3)4 (36 mg; 0.03 mmol; 0.20 equiv.), and LiCl (16 mg; 0.37 mmol; 2.50 equiv.) were added. The reaction was stirred at 110 °C under a nitrogen atmosphere for 5 h. The resulting mixture was diluted with EtOAc (60 mL) and washed with saturated NaCl solution (2 × 5 mL) and dried over anhydrous Na2SO4. After filtration, the organic filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using 2-10% MeOH in CHCl as the eluent to give the crude product. The crude product was purified by flash chromatography on a pre-packed C column using 20-60% MeCN in water (10 mmol / L NHHCO) to give N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (22.8 mg, 41%). LCMS (ESI) m / z 350.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 9.35 (s, 1H), 8.27 - 8.23 ​​(m, 1H), 8.03 - 7.97 (m, 3H), 7.60 - 7.55 (m, 1H), 7.43 - 7.37 (m, 1H), 3.71 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 2.03 - 1.95 (m, 1H), 0.79 - 0.71 (m, 4H).

[0164] Example 6: Synthesis of N-(5-(1-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0165] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg; 0.062 mmol; 1.00 equiv.) in a DME / water mixture (5:1, 1.2 mL) was added (1-methyl-1H-pyrazol-5-yl)boronic acid (11.8 mg; 0.094 mmol; 1.5 equiv.), Pd(PPh3)4 (7.2 mg; 0.006 mmol; 0.10 equiv.), and Na2CO3 (13.2 mg, 0.125 mmol; 2.00 equiv.). The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 3-10% MeOH in CHCl as the eluent to give N-(5-(1-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropane-carboxamide as a yellow solid (16 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (0.05% formic acid) as the eluent to give N-(5-(1-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.8 mg, 23%). LCMS (ESI) m / z 323.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.39 (s, 1H), 8.20 - 8.11 (m, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.30 (d, J = 1.6 Hz, 1H), 3.64 (s, 3H), 2.97 (d, J = 4.4 Hz, 3H), 2.10 - 1.98 (m, 1H), 0.90 - 0.78 (m, 4H).

[0166] Examples 7-25: The examples in Table 1 were prepared using similar experimental procedures to those used to prepare Example 6, using N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 3) as a common intermediate and the appropriate boronic ester or boronic acid.

[0167] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0168] Example 26: Synthesis of N-(8-(methylamino)-5-(5-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0169] To a stirred mixture of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 84, Step 1) (60 mg; 0.163 mmol; 1.00 equiv.) in a 1,4-dioxane / water mixture (10:1, 1.1 mL) was added 4-bromo-5-methylthiazole (43.5 mg; 0.244 mmol; 1.5 equiv.), Pd(dppf)Cl (11.9 mg; 0.016 mmol; 0.10 equiv.), and NaCO (34.5 mg; 0.325 mmol; 2.00 equiv.). The reaction mixture was stirred at 40° C. under a nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2%-10%) as the eluent to give N-(8-(methylamino)-5-(5-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15 mg, crude). The crude product was then purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-(5-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.9 mg, 9%). LCMS (ESI) m / z 340.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 9.38 (s, 1H), 9.03 (s, 1H), 8.12 (s, 1H), 8.10 - 8.03 (m, 1H), 7.99 (s, 1H), 3.03 (d, J = 4.4 Hz, 3H), 2.35 (s, 3H), 2.10 - 1.98 (m, 1H), 0.88 - 0.72 (m, 4H).

[0170] Example 27: Synthesis of N-(5-methyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0171] To a solution of N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 equiv.) and KPO (53 mg; 0.250 mmol; 2.00 equiv.) in dioxane / water (5:1, 4.8 mL) was added Pd(DtBPF)Cl (8 mg; 0.012 mmol; 0.10 equiv.) and trimethyl-1,3,5,2,4,6-trioxatriborinane (19 mg; 0.151 mmol; 1.22 equiv.). After stirring at 90 °C under a nitrogen atmosphere for 2 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (2-6%) in CHCl as the eluent to give N-(8-amino-5-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (crude). The residue was purified by flash chromatography on a pre-packed C column using 20%-60% MeCN in water (10 mmol / L NHHCO) to give N-(8-amino-5-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (15.0 mg, 46.9%). LCMS (ESI) m / z 257.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.30 (s, 1H), 8.27 (s, 1H), 7.83 (s, 1H), 7.69 - 7.65 (m, 1H), 2.93 (d, J = 4.4 Hz, 3H), 2.22 (s, 3H), 2.10 - 2.03 (m, 1H), 0.88 - 0.81 (m, 4H).

[0172] Examples 28-38: The examples in Table 2 were prepared using similar experimental procedures to those used to prepare Example 27, using -[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide as a common intermediate and the appropriate boronic ester or acid or alkene.

[0173] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0174] Example 39: Synthesis of N-(5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0175] To a stirred solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropane-carboxamide (40 mg; 0.125 mmol; 1.00 equiv.) in dioxane / water (5:1, 1.2 mL) under N was added Pd(DtBPF)Cl (8.1 mg; 0.012 mmol; 0.10 equiv.), KPO (52.9 mg; 0.249 mmol; 2.00 equiv.), and 4-methyl-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (72.8 mg; 0.249 mmol; 2.00 equiv.) at room temperature. The reaction was stirred at 90 °C for 2 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (1%-10%) as an eluent to give N-(5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg, crude). The crude product was purified by flash chromatography on a pre-packed C18 column using 10% to 70% MeCN in water (10 mmol / L NH4HCO3) to give N-(5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (6.1 mg, 12%). LCMS (ESI) m / z 407.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.39 (s, 1H), 8.24 - 8.11 (m, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.50 (s, 1H), 4.84 - 4.75 (m, 1H), 3.93 - 3.81 (m, 1H), 3.41 - 3.29 (m, 1H), 3.03 (d, J = 4.4 Hz, 3H), 2.40 - 2.26 (m, 1H), 2.05 - 1.70 (m, 6H), 1.54 - 1.30 (m, 3H), 0.88 - 0.70 (m, 4H).

[0176] Example 40: Synthesis of N-(5-(4-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0177] To a stirred mixture of N-(5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (68 mg; 0.167 mmol; 1.00 equiv) in MeOH (1 mL) was added a solution of HCl in dioxane (4 M, 5 mL) at room temperature under nitrogen. The reaction was stirred at room temperature for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 10% to 70% MeCN in water (10 mmol / L NH4HCO3) to give N-(5-(4-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (10.5 mg, 19%). LCMS (ESI) m / z 323.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.64 (s, 1H), 10.92 (s, 1H), 9.36 (s, 1H), 8.34 - 8.00 (m, 1H), 7.93 (s, 2H), 7.69 - 7.35 (m, 1H), 3.01 (d, J = 4.4 Hz, 3H), 2.05 - 1.97 (m, 1H), 1.92 (s, 3H), 0.83 - 0.74 (m, 4H).

[0178] Example 41 and Example 42: Synthesis of 2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4-yl)benzamide and N-(5-(2-cyanophenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0179] To a stirred solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropane-carboxamide (100 mg; 0.311 mmol; 1.00 equiv.) in 1,4-dioxane / water (10:1, 1.1 mL) was added (2-cyanophenyl)boronic acid (68.6 mg; 0.467 mmol; 1.5 equiv.), Pd(dppf)Cl (22.8 mg; 0.031 mmol; 0.10 equiv.), and KPO (132.2 mg; 0.622 mmol; 2.00 equiv.). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 25-60% EtOAc in petroleum ether as the eluent to give 2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4-yl)benzamide (50 mg, crude) and N-(5-(2-cyanophenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15 mg, crude) separately. These two crude products were each purified by flash chromatography on a pre-packed C18 column using 20-60% MeCN in water (10 mmol / L NH4HCO3) to give 2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4-yl)benzamide as a white solid (28.8 mg, 26%) and N-(5-(2-cyanophenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.3 mg, 4%). Analytical data for 2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4-yl)benzamide: LCMS (ESI) m / z 362.2, [M+H]. + . 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.34 (s, 1H), 8.04 (s, 1H), 7.96 - 7.90 (m, 1H), 7.83 (s, 1H), 7.60 - 7.42 (m, 4H), 7.31 (dd, J = 7.6, 1.2 Hz, 1H), 7.13 (s, 1H), 3.00 (d, J = 4.4 Hz, 3H), 2.05 - 1.96 (m, 1H), 0.82 - 0.70 (m, 4H). Analytical data for N-(5-(2-cyanophenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: LCMS (ESI) m / z 344.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.42 (s, 1H), 8.25 - 8.15 (m, 1H), 8.04 - 7.96 (m, 3H), 7.88 - 7.79 (m, 1H), 7.68 - 7.54 (m, 2H), 3.04 (d, J = 4.4 Hz, 3H), 2.05 - 1.95 (m, 1H), 0.81 - 0.70 (m, 4H).

[0180] Example 43: Synthesis of N-(5-benzyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0181] To a stirred solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.) in THF / water (10:1, 2.2 mL) was added potassium benzyltrifluoroborate (61.8 mg; 0.312 mmol; 2.00 equiv.), Pd(OAc) (3.5 mg; 0.016 mmol; 0.10 equiv.), X-Phos (14.8 mg; 0.031 mmol; 0.20 equiv.), and CsCO (101.4 mg; 0.312 mmol; 2.00 equiv.). The reaction mixture was stirred at 85 °C under a nitrogen atmosphere for 12 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0-10% MeOH in CHCl as the eluent to give N-(5-benzyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropane-carboxamide (15 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) to give N-(5-benzyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (3.9 mg, 8%). LCMS (ESI) m / z 333.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.31 (s, 1H), 8.37 (s, 1H), 7.93 (s, 1H), 7.83 - 7.75 (m, 1H), 7.30 - 7.21 (m, 4H), 7.19 - 7.10 (m, 1H), 3.99 (s, 2H), 2.96 (d, J = 4.4 Hz, 3H), 2.10 - 2.00 (m, 1H), 0.90 - 0.75 (m, 4H).

[0182] Example 44: Synthesis of N-(5-(hydroxymethyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0183] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 equiv.) in 1,4-dioxane (10 mL) was added Pd(PPh3)4 (36.1 mg; 0.031 mmol; 0.10 equiv.) and (tributylstannyl)methanol (300.9 mg; 0.937 mmol; 3.00 equiv.). The reaction was stirred at 95 °C for 2.5 h. The mixture was then cooled to 95 °C for 2.5 h. It was allowed to cool to room temperature. The desired product was observed by LCMS. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 20% ​​to 70% MeCN in water (10 mmol / L NH4HCO3) as eluent to give N-(5-(hydroxymethyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (60 mg, 70%). LCMS (ESI) m / z 273.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.32 (s, 1H), 8.44 (s, 1H), 7.92 (s, 1H), 7.88 - 7.80 (m, 1H), 4.87 (t, J = 5.0 Hz, 1H), 4.56 (d, J = 5.0 Hz, 2H), 2.96 (d, J = 4.4 Hz, 3H), 2.12 - 2.01 (m, 1H), 0.91 - 0.78 (m, 4H).

[0184] Example 45: Synthesis of N-(8-(methylamino)-5-(phenoxymethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0185] To a solution of N-(5-(hydroxymethyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg; 0.110 mmol; 1.00 equiv.) in THF (5 mL), phenol (104 mg; 1.10 mmol; 10.0 equiv.), PPh3 (55.7 mg; 0.212 mmol; 1.93 equiv.) were added at room temperature. To the reaction mixture, DIAD (43.3 mg; 0.214 mmol; 1.94 equiv.) was added and stirred at room temperature for 1 hour. The desired product was detected by LCMS. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2–10%) as the eluent to give N-(8-(methylamino)-5-(phenoxymethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (10 mg, crude). The crude product was purified by reverse-phase preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm, waters; gradient elution with 38%–48% MeCN in water over a 10-minute period, where both water and MeCN contained 10 mmol / L NHHCO, flow rate: 60 mL / min, detector UV wavelength: 220 nm) to give N-(8-(methylamino)-5-(phenoxymethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (1.4 mg, 3%). LCMS (ESI) m / z 349.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.35 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 8.04 - 7.97 (m, 1H), 7.35 - 7.25 (m, 2H), 7.08 - 7.00 (m, 2H), 6.99 - 6.90 (m, 1H), 5.13 (s, 2H), 2.98 (d, J = 4.4 Hz, 3H), 2.10 - 2.00 (m, 1H), 0.86 - 0.75 (m, 4H).

[0186] Example 46: Synthesis of N-(8-(methylamino)-5-(4-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0187] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg; 0.093 mmol; 1.00 equiv.) in 1,4-dioxane / water (5:1, 1.8 mL) was added XPhos (4.4 mg; 0.009 mmol; 0.10 equiv.), XPhos Pd G3 (CAS: 1445085-55-1) (8.1 mg; 0.010 mmol; 0.10 equiv.), KPO (60 mg; 0.283 mmol; 2.00 equiv.), and (4-(methylsulfonyl)phenyl)boronic acid (19 mg; 0.095 mmol; 1.00 equiv.). The resulting solution was stirred at 90 °C under a nitrogen atmosphere for 2 h. The reaction was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with methanol (5-10%) in dichloromethane to give 50 mg of crude product. This crude was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(4-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (30.0 mg, 81%). LCMS (ESI) m / z 397.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.41 (s, 1H), 8.37 (s, 1H), 8.15 - 8.12 (m, 1H), 8.05 - 8.02 (m, 2H), 8.01 (s, 1H), 7.73 - 7.69 (m, 2H), 3.30 (s, 3H), 3.03 (d, J = 4.4 Hz, 3H), 2.06 - 1.98 (m, 1H), 0.82 - 0.76 (m, 4H).

[0188] Example 47: Synthesis of N-(8-(methylamino)-5-(2-(methylthio)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0189] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropane-carboxamide (50 mg; 0.156 mmol; 1.00 equiv.) in DME / water (5:1, 1.2 mL), (2-(methylthio)phenyl)boronic acid (78.5 mg; 0.467 mmol; 3.00 equiv.), Pd(PPh3)4 (18.0 mg; 0.016 mmol; 0.10 equiv.), and Na2CO3 (49.5 mg; 0.467 mmol; 3.00 equiv.) were added at room temperature. The reaction was stirred under nitrogen at 100 °C for 3 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (2–8%) in CHCl2 as the eluent to give 50 mg of crude product. The crude product was purified by flash chromatography on a pre-packed C18 column using 20-60% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(2-(methylthio)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (3.9 mg, 6%). LCMS (ESI) m / z 365.1, [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.36 (s, 1H), 8.00 - 7.96 (m, 1H), 7.79 (s, 2H), 7.46 - 7.41 (m, 1H), 7.38 - 7.35 (m, 1H), 7.27 - 7.22 (m, 1H), 7.18 - 7.14 (m, 1H), 3.01 (d, J = 4.4 Hz, 3H), 2.31 (s, 3H), 2.02 - 1.93 (m, 1H), 0.78 - 0.69 (m, 4H).

[0190] Example 48: Synthesis of N-(8-(methylamino)-5-(2-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0191] To a solution of N-(8-(methylamino)-5-(2-(methylthio)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (14 mg; 0.038 mmol; 1.00 equiv.) in CHCl (1 mL) was added m-CPBA (13.3 mg; 0.077 mmol; 2.00 equiv.) at 0° C. The reaction was stirred under nitrogen at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure and purified by flash chromatography on a silica gel column using 2-10% MeOH in CHCl as the eluent to give N-(8-(methylamino)-5-(2-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (8 mg, crude) and N-(8-(methylamino)-5-(2-(methylsulfinyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (5 mg, crude), separately. These two crude products were each purified by flash chromatography on a pre-packed C18 column using 20–60% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(2-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (3.7 mg, 24%) and N-(8-(methylamino)-5-(2-(methylsulfinyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (0.8 mg, 5%). Analytical data for N-(8-(methylamino)-5-(2-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: LCMS (ESI) m / z 397.1, [M+H]. + . 1H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.36 (s, 1H), 8.16 - 8.12 (m, 1H), 8.08 - 8.01 (m, 1H), 7.90 (s, 1H), 7.83 -7.70 (m, 2H), 7.65 (s, 1H), 7.43 - 7.38 (m, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.88 (s, 3H), 2.00 - 1.93 (m, 1H), 0.76 - 0.69 (m, 4H). Analytical data for N-(8-(methylamino)-5-(2-(methylsulfinyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: LCMS (ESI) m / z 381.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (d, J = 18.0 Hz, 1H), 9.39 (d, J = 5.6 Hz, 1H), 8.17 - 8.08 (m, 1H), 7.99 - 7.61 (m, 5H), 7.35 - 7.30 (m, 1H), 3.02 (d, J = 4.4, 3H), 2.56 - 2.25 (m, 3H), 2.02 - 1.94 (m, 1H), 0.79 - 0.74 (m, 4H).

[0192] Example 49: Synthesis of N-(5-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0193] Step 1: 3-bromo-2-methoxybenzamide [ka]

[0194] To a stirred solution of 3-bromo-2-methoxybenzoic acid (5.00 g; 21.6 mmol; 1.00 equiv.) and DMF (0.321 g; 4.33 mmol; 0.20 equiv.) in CHCl (50 mL) was added dropwise a solution of oxalyl chloride (2 M) in CHCl (13.0 mL; 26.0 mmol; 1.20 equiv.) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was then concentrated under reduced pressure. This crude product was added dropwise to a stirred solution of NH(g) (7 M) in MeOH (9.27 mL; 64.9 mmol; 3.00 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure to give 3-bromo-2-methoxybenzamide as a brown solid (4.98 g, 73%). LCMS (ESI) m / z 230.0, [M+H] + .

[0195] Step 2: 3-(3-bromo-2-methoxyphenyl)-1H-1,2,4-triazole [ka]

[0196] 3-Bromo-2-methoxybenzamide (4.98 g; 21.7 mmol; 1.00 equiv.) was dissolved in DMF-DMA (25.9 g; 217 mmol; 10.0 equiv.). The resulting mixture was stirred under nitrogen at 95° C. for 0.5 h. The resulting mixture was concentrated under reduced pressure to give the crude intermediate. The crude intermediate was dissolved in EtOH (10 mL) and then added dropwise at 0° C. to a pre-treated cold solution containing a mixture of AcOH / EtOH (30 mL / 120 mL) and hydrazine hydrate (80%) (10.6 mL; 217 mmol; 10.0 equiv.) at 0° C. The resulting reaction was stirred at room temperature for 4 h. The desired product was observed by LCMS. The reaction mixture was concentrated under reduced pressure. The resulting mixture was then added to water (300 mL) and the precipitated solid was collected by filtration and washed with water (3×15 mL) and dried under reduced pressure to give 3-(3-bromo-2-methoxyphenyl)-1H-1,2,4-triazole as a white solid (5.30 g, 96%). LCMS (ESI) m / z 254.0, [M+H] + .

[0197] Step 3: 3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole [ka]

[0198] A mixture of 3-(3-bromo-2-methoxyphenyl)-1H-1,2,4-triazole (5.30 g; 20.9 mmol; 1.00 equiv.) and KCO (8.65 g; 62.6 mmol; 3.00 equiv.) in DMF (50 mL) was stirred under a nitrogen atmosphere for 30 min. To this stirred mixture, MeI (3.26 g; 22.9 mmol; 1.10 equiv.) in DMF (10 mL) was added dropwise at 0 °C. The final reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 h. The desired product was observed by LCMS. The residue was purified by flash chromatography on a silica gel column using 20% ​​to 80% EtOAc in petroleum ether as the eluent to give 3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole as a tan oil (1.06 g, 19%). LCMS (ESI) m / z 268.0, [M+H] + . 1 H NMR (400 MHz, methanol-d₄) δ 8.46 (s, 1H), 7.80 (dd, J = 10.4, 2.4 Hz, 1H), 7.66 (dd, J = 10.4, 2.4 Hz, 1H), 7.12 (t, J = 10.4 Hz, 1H), 4.00 (s, 3H), 3.76 (s, 3H).

[0199] Step 4: 3-(2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-1,2,4-triazole [ka]

[0200] A mixture of 3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole (300 mg; 1.12 mmol; 1.00 equiv.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (852 mg; 3.36 mmol; 3.00 equiv.), Pd(dppf)Cl.CHCl (91.7 mg; 0.113 mmol; 0.10 equiv.), and KOAc (221 mg; 2.25 mmol; 2.01 equiv.) in 1,4-dioxane (5 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. A mixture of petroleum ether / EtOAc (10:1, 33 mL) was added, resulting in the formation of a solid. The mixture was stirred at room temperature for 2 hours. The precipitated solid was filtered through filter paper and dried under reduced pressure to give 3-(2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-1,2,4-triazole as a brown solid (528 mg, crude). LCMS (ESI) m / z 316.2, [M+H] + .

[0201] Step 5: N-(5-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0202] A mixture of NaCO (49.7 mg; 0.469 mmol; 3.00 equiv.), 3-(2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-1,2,4-triazole (crude, 57% purity) (256.3 mg; 0.468 mmol; 3.00 equiv.), N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.), and Pd(PPh) (18.1 mg; 0.016 mmol; 0.10 equiv.) in DME / water (5:1, 1.2 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (2-5%) in CHCl as the eluent to give N-(5-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (50 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20%-50% MeCN in water (0.05% formic acid) as the eluent to give N-(5-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide formate as a white solid (35.5 mg, 53%). LCMS (ESI) m / z 430.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.38 (s, 1H), 8.55 (s, 1H), 8.02 - 7.91 (m, 3H), 7.89 - 7.84 (m, 1H), 7.30 (s, 1H), 7.29 (s, 1H), 3.94 (s, 3H), 3.35 (s, 3H) 3.03 (d, J = 4.4 Hz, 3H), 2.04 - 1.93 (m, 1H)), 0.78 - 0.71 (m, 4H).

[0203] Example 50: Synthesis of N-(8-(methylamino)-5-(pyrimidin-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0204] A mixture of CuI (3.6 mg; 0.019 mmol; 0.15 equiv.), N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 equiv.), and Pd(PPh3)2Cl2 (18.4 mg; 0.026 mmol; 0.21 equiv.) in 1,4-dioxane (4 mL) was stirred at room temperature. To this mixture was added 4-(tributylstannyl)pyrimidine (138.8 mg; 0.376 mmol; 3.00 equiv.). The reaction was stirred under nitrogen at 120° C. for 5 hours. Additional 4-(tributylstannyl)pyrimidine (138.8 mg; 0.376 mmol; 3.00 equiv.) was then added. The reaction was stirred at 120° C. overnight. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (1-5%) in CHCl as the eluent to give the crude product (30 mg). The crude product was purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(8-(methylamino)-5-(pyrimidin-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (15.1 mg, 37%). LCMS (ESI) m / z 321.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.41 (s, 1H), 9.23 (s, 1H), 8.99 (s, 1H), 8.83 (d, J = 5.2 Hz, 1H), 8.42 - 8.32 (m, 2H), 7.78 (d, J = 4.8 Hz, 1H), 3.06 (d, J = 4.0 Hz, 3H), 2.09 - 2.00 (m, 1H), 0.87 - 0.78 (m, 4H).

[0205] Example 51: Synthesis of N-(8-(methylamino)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0206] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg; 0.093 mmol; 1.00 equiv.), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (77.9 mg; 0.28 mmol; 3.00 equiv.), Pd(PPh3)4 (10.8 mg; 0.009 mmol; 0.10 equiv.), and Na2CO3 (53.5 mg; 0.505 mmol; 5.40 equiv.) in DME / water (5:1, 3.0 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 3-20% MeOH in CHCl as the eluent to give N-(8-(methylamino)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a brown solid (26.9 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(8-(methylamino)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (10.6 mg, 28%). LCMS (ESI) m / z 393.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.38 (s, 1H), 8.19 - 8.14 (m, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.65 (d, J = 1.6 Hz, 1H), 6.35 (d, J = 1.6 Hz, 1H), 5.04 - 4.99 (m, 1H), 3.88 - 3.79 (m, 1H), 3.29 - 3.25 (m, 1H), 3.03 (d, J = 4.4 Hz, 3H), 2.40 - 2.29 (m, 1H), 2.05 - 1.96 (m, 1H), 1.93 - 1.79 (m, 2H), 1.54 - 1.36 (m, 3H), 0.83 - 0.78 (m, 4H).

[0207] Example 52: Synthesis of N-(8-(methylamino)-5-(1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0208] To a solution of N-(8-(methylamino)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (53.3 mg; 0.136 mmol; 1.00 equiv) in MeOH (1 mL) was added a solution of HCl in dioxane (4 M, 4 mL). The reaction was stirred at room temperature for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 20-40% MeCN in water (10 mmol / L NH4HCO3) as eluent to give N-(8-(methylamino)-5-(1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropane-carboxamide as a white solid (26.2 mg, 62%). LCMS (ESI) m / z 309.1, [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 10.88 (s, 1H), 9.36 (s, 1H), 9.11 - 8.43 (m, 1H),8.27 - 7.53 (m, 3H), 6.58 - 6.41 (m, 1H), 3.01 (d, J = 4.4 Hz, 3H), 2.08 - 2.00 (m, 1H), 0.86 - 0.78 (m, 4H).

[0209] Example 53: Synthesis of N-(5-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0210] Step 1: 3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole and 5-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole [ka]

[0211] To a stirred mixture of 3-(3-bromophenyl)-1H-1,2,4-triazole (1 g; 4.46 mmol; 1.00 equiv.) in DMF (10 mL) was added KCO (1.88 g; 13.63 mmol; 3.00 equiv.) at 0 °C, followed by dropwise addition of a solution of CHI (697 mg; 4.91 mmol; 1.10 equiv.) in DMF (1 mL). The reaction mixture was added to a saturated NHCl solution (30 mL). The resulting mixture was extracted with EtOAc (15 mL × 2). The combined organic layers were washed with a saturated NaCl solution (5 mL × 2) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 30-70% EtOAc in petroleum ether as the eluent to give 3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole as a yellow oil (732 mg, 68%) and 5-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole as a yellow oil (70 mg, 6%). LCMS (ESI) m / z 238.0, [M+H] + HNMR for 3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole: 1 H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.13 - 8.09 (m, 1H), 8.00 - 7.95 (m, 1H), 7.64 - 7.59 (m, 1H), 7.57 - 7.40 (m, 1H), 3.94 (s, 3H). H NMR for 5-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole: 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.98 - 7.95 (m, 1H), 7.82 - 7.74 (m, 2H), 7.56 - 7.51 (m, 1H), 3.99 (s, 3H).

[0212] Step 2: 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole [ka]

[0213] A mixture of 3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole (200 mg; 0.84 mmol; 1.00 equiv.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (640 mg; 2.52 mmol; 3.00 equiv.), Pd(dppf)Cl2 (69 mg; 0.09 mmol; 0.10 equiv.), and KOAc (165 mg; 1.68 mmol; 2.00 equiv.) in 1,4-dioxane (4 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The solvent was concentrated under reduced pressure. The residue was dissolved in a mixture of petroleum ether / EtOAc (10:1, 30 mL). The resulting mixture was filtered, and the filter cake was washed with a mixture of petroleum ether / EtOAc (10:1, 20 mL). The filtrate was concentrated under reduced pressure to give 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole as a brown solid (350 mg, crude). LCMS (ESI) m / z 286.2, [M+H] + .

[0214] Step 3: N-(5-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0215] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.12 mmol; 0.10 equiv.), 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole (106.8 mg; 0.374 mmol; 3.00 equiv.), Pd(PPh3)4 (14 mg; 0.01 mmol; 0.10 equiv.), Na2CO3 (40 mg; 0.37 mmol; 3.00 equiv.) in DME / water (5:1, 2.4 mL) was stirred at 100 °C under a nitrogen atmosphere for 3 h. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (2-6%) in CHCl as the eluent to give N-(5-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude). The residue was purified by flash chromatography on a pre-packed C column using 20-60% MeCN in water (10 mmol / L NHHCO) to give N-(5-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (8.3 mg, 2%). LCMS (ESI) m / z 400.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.44 (s, 1H), 8.54 (s, 1H), 8.35 - 8.31 (m, 1H), 8.31 (s, 1H), 8.05 - 8.01 (m, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.61 - 7.55 (m, 1H), 7.47 - 7.42 (m, 1H), 3.93 (s, 3H), 3.05 (d, J = 4.4 Hz, 3H), 2.04 - 1.95 (m, 1H), 0.79 - 0.72 (m, 4H).

[0216] Example 54: Synthesis of N-(5-(3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0217] Step 1: 1-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole [ka]

[0218] A mixture of 5-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole (70 mg; 0.295 mmol; 1.00 equiv.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (225 mg; 0.885 mmol; 3.00 equiv.), Pd(dppf)Cl2 (21.5 mg; 0.029 mmol; 0.10 equiv.), and KOAc (57.8 mg; 0.589 mmol; 2.00 equiv.) in 1,4-dioxane (4 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. Upon completion, the reaction was concentrated under reduced pressure. The residue was dissolved in a mixture of petroleum ether / EtOAc (10:1, 20 mL). The resulting mixture was filtered, and the filter cake was washed with a mixture of petroleum ether / EtOAc (10:1, 10 mL). The filtrate was concentrated under reduced pressure to give 1-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole (100 mg, crude). The crude product was purified by flash chromatography on a silica gel column using 30% to 60% EtOAc in petroleum ether as the eluent to give 1-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole as a brown solid (40 mg, 47%). LCMS (ESI) m / z 286.2, [M+H] + .

[0219] Step 2: N-(5-(3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0220] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.12 mmol; 0.10 equiv.), 1-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole (35.6 mg; 1.24 mmol; 1.00 equiv.), Pd(PPh3)4 (14 mg; 0.01 mmol; 0.10 equiv.), and Na2CO3 (39.7 mg; 0.37 mmol; 3.00 equiv.) in DME / water (5:1, 2.4 mL) was stirred at 100 °C under a nitrogen atmosphere for 3 h. After cooling, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (2-6%) in CHCl as the eluent to give N-(5-(3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (25 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20%-60% MeCN in water (10 mmol / L NHHCO) to give N-(5-(3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (16.7 mg, 29%). LCMS (ESI) m / z 400.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.40 (s, 1H), 8.39 (s, 1H), 8.07 - 8.02 (m, 1H), 8.01 (s, 1H), 8.01 (s, 1H), 7.82 - 7.76 (m, 2H), 7.70 - 7.65 (m, 1H), 7.61 - 7.57 (m, 1H), 4.02 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 2.05 - 1.98 (m, 1H), 0.80 - 0.74 (m, 4H).

[0221] Example 55: Synthesis of N-(8-(methylamino)-5-(pyrrolidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0222] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 equiv.), Pd-PEPPSI-IHeptCl (CAS: 1814936-54-3) (12.2 mg; 0.013 mmol; 0.10 equiv.), CsCO (122.3 mg; 0.375 mmol; 3.00 equiv.), and pyrrolidine (17.8 mg; 0.250 mmol; 2.00 equiv.) in 1,4-dioxane (4 mL) was stirred at 100° C. under nitrogen for 16 hours. The mixture was allowed to cool to room temperature. The desired product was observed by LCMS. The residue was purified by flash chromatography on a silica gel column using MeOH (2-10%) in CHCl as the eluent to give N-(8-(methylamino)-5-(pyrrolidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropane-carboxamide (40 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20%-50% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(8-(methylamino)-5-(pyrrolidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (23.5 mg, 60%). LCMS (ESI) m / z 312.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.28 (s, 1H), 8.48 (s, 1H), 7.71 (s, 1H), 7.52 - 7.41 (m, 1H), 3.12 - 3.04 (m, 4H), 2.92 (d, J = 4.4 Hz, 3H), 2.11 - 2.01 (m, 1H), 1.98 - 1.85 (m, 4H), 0.91 - 0.78 (m, 4H).

[0223] Example 56: Synthesis of N-(8-(methylamino)-5-(piperidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0224] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 equiv.) in dioxane (2.00 mL), Pd-PEPPSI-IHeptCl (12.1 mg; 0.012 mmol; 0.10 equiv.), CsCO (121.7 mg; 0.374 mmol; 3.00 equiv.), and piperidine (21.2 mg; 0.249 mmol; 2.00 equiv.) were added at room temperature. The reaction was stirred under nitrogen at 100° C. for 16 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (1-9%) in CHCl as the eluent to give N-(8-(methylamino)-5-(piperidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropane-carboxamide (30 mg, crude). The residue was purified by flash chromatography on a pre-packed C column using 10%-70% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-(piperidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (21.9 mg, 54%). LCMS (ESI) m / z 326.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.28 (s, 1H), 8.46 (s, 1H), 7.68 (s, 1H), 7.61 - 7.53 (m, 1H), 2.92 (d, J = 4.4 Hz, 3H), 2.90 - 2.77 (m, 4H), 2.10 - 2.09 (m, 1H), 1.73 - 1.64 (m, 4H), 1.60 - 1.50 (m, 2H), 0.90 - 0.79 (m, 4H).

[0225] Example 57: Synthesis of N-(8-(methylamino)-5-(1H-pyrazol-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0226] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.), CuI (29.6 mg; 0.158 mmol; 1.00 equiv.), KCO (43.1 mg; 0.312 mmol; 2.00 equiv.), and (1R,2R)-N 1 ,N 2 To a mixture of 1H-dimethylcyclohexane-1,2-diamine (40 mg; 0.281 mmol; 1.80 equiv.) in DMF (5 mL, deoxygenated before use) was added 1H-pyrazole (13.0 mg; 0.191 mmol; 1.23 equiv.). The reaction was stirred under nitrogen at 120 °C for 16 h. The mixture was allowed to cool to room temperature. The desired product was observed by LCMS. The resulting mixture was diluted with EtOAc (70 mL) and then washed with saturated NaCl solution (5 × 10 mL). The organic phase was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2–10%) as eluent to give N-(8-(methylamino)-5-(1H-pyrazol-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude). The crude product was purified by flash chromatography on a pre-packed C18 column using 20%-50% MeCN in water (0.05% formic acid) as eluent to give N-(8-(methylamino)-5-(1H-pyrazol-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (10.6 mg, 22%). LCMS (ESI) m / z 309.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.40 (s, 1H), 8.25 - 8.18 (m, 1H), 8.05 (s, 1H), 8.04 (s, 1H), 7.97 (d, J = 2.4 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 6.52 (t, J = 2.1 Hz, 1H), 3.03 (d, J = 4.3 Hz, 3H), 2.07 - 1.96 (m, 1H), 0.82 - 0.75 (m, 4H).

[0227] Example 58: Synthesis of N-(5-(1,1-dioxidoisothiazolidin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0228] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 equiv), isothiazolidine 1,1-dioxide (15.1 mg; 0.124 mmol; 1.00 equiv), Pd-PEPPSI-IPentCl (10.9 mg; 0.012 mmol; 0.10 equiv), and CsCO (81.5 mg; 0.25 mmol; 2.00 equiv) in 1,4-dioxane (2 mL) was stirred at 120 °C under a nitrogen atmosphere for 12 h. The reaction was monitored by LCMS. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-10%) as the eluent to give N-(5-(1,1-dioxidoisothiazolidin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (12 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) to give N-(5-(1,1-dioxidoisothiazolidin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.5 mg, 10%). LCMS (ESI) m / z 362.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.34 (s, 1H), 8.38 (s, 1H), 8.14 (q, J = 4.4 Hz, 1H), 8.04 (s, 1H), 3.65 (t, J = 6.6 Hz, 2H), 3.45 (t, J = 7.4 Hz, 2H), 2.99 (d, J = 4.4 Hz, 3H), 2.50 - 2.42 (m, 2H), 2.12 - 2.02 (m, 1H), 0.92 - 0.79 (m, 4H).

[0229] Example 59: Synthesis of N-(8-(methylamino)-5-(1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0230] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.12 mmol; 1.00 equiv.) and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (51 mg; 0.18 mmol; 1.50 equiv.) in dioxane (6 mL) was added CsCO (81.5 mg; 0.25 mmol; 2.00 equiv.), Ephos Pd G4 (CAS: 2132978-44-8) (11.4 mg; 0.012 mmol; 0.10 equiv.), and EPhos (CAS: 2118959-55-8) (6.6 mg; 0.012 mmol; 0.10 equiv.). After stirring at 120° C. under nitrogen atmosphere for 12 h, the reaction was monitored by LCMS. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2–6%) as eluent to give N-(8-(methylamino)-5-(1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (50 mg, crude). The residue was purified by flash chromatography on a pre-packed C18 column using 20% ​​to 60% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (43.9 mg, 91%). LCMS (ESI) m / z 375.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.40 (s, 1H), 9.03 (s, 1H), 8.86 (d, J = 5.2 Hz, 1H), 8.19 - 8.14 (m, 1H), 8.12 (s, 1H), 7.95 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 4.91 (s, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.04 - 1.96 (m, 1H), 0.79 - 0.71 (m, 4H).

[0231] Example 60: Synthesis of N-(8-(methylamino)-5-(4-oxopyridin-1(4H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0232] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 equiv.) and pyridin-4-ol (177.9 mg; 1.871 mmol; 6.00 equiv.) in DMSO (5 mL) was added dimethylglycine (28.9 mg; 0.280 mmol; 0.90 equiv.), CsCO (203.9 mg; 0.626 mmol; 2.01 equiv.), and CuI (29.6 mg; 0.155 mmol; 0.50 equiv.). After stirring at 120 °C under a nitrogen atmosphere for 18 h, the desired product was observed by LCMS. The resulting mixture was purified by flash chromatography on a pre-packed C18 column using 10-30% MeCN in water (10 mmol / L NH4HCO3) as the eluent to give N-(8-(methylamino)-5-(4-oxopyridin-1(4H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (13.1 mg, 12%). LCMS (ESI) m / z 336.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 9.42 (s, 1H), 8.36 - 8.25 (m, 1H), 8.14 (s, 1H), 7.95 (s, 1H), 7.68 (d, J = 7.6 Hz, 2H), 6.21 (d, J = 7.6 Hz, 2H), 2.99 (d, J = 4.4 Hz, 3H), 2.09 - 2.00 (m, 1H), 0.90 - 0.70 (m, 4H).

[0233] Example 61 and Example 62: Synthesis of N-(8-(methylamino)-5-(2-oxopyridin-1(2H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and N-(8-(methylamino)-5-(pyridin-2-yloxy)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0234] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 equiv.) and pyridin-2-ol (178 mg; 1.872 mmol; 6.00 equiv.) in DMSO (3 mL) was added CuI (29.5 mg; 0.155 mmol; 0.50 equiv.) and CsCO (203.9 mg; 0.626 mmol; 2.01 equiv.), dimethylglycine (29 mg; 0.281 mmol; 0.90 equiv.). After stirring at 120 °C under a nitrogen atmosphere for 3 days, the reaction yielded two peaks with the desired product masses (17% and 21%). The resulting mixture was purified by flash chromatography on a prepacked C18 column using 10–30% MeCN in water (10 mmol / L NH4HCO3) as the eluent to give 8 mg of a less polar peak and 20 mg of a more polar peak. This smaller peak was then purified by reverse-phase preparative HPLC (Prep-C18, XBridge Prep Phenyl OBD column, 19 × 250 mm water; gradient elution with 18–20% MeCN in water over a 10 min period, where both the water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 25 mL / min, detector UV wavelength: 254 nm) to give N-(8-(methylamino)-5-(2-oxopyridin-1(2H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (3.4 mg, 3%). The more polar peak was purified by reverse-phase preparative HPLC (Prep-C18, XBridge Shield RP18 OBD column, 30 × 150 mm, waters; gradient elution with 30–40% MeCN in water over an 8-minute period, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give N-(8-(methylamino)-5-(pyridin-2-yloxy)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (6.5 mg, 6%). LCMS (ESI) m / z 336.1, [M+H] +HNMR for N-(8-(methylamino)-5-(2-oxopyridin-1(2H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: 1 H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.40 (s, 1H), 8.28 - 8.16 (m, 1H), 7.94 (s, 1H), 7.77 (s, 1H), 7.65 - 7.54 (m, 2H), 6.51 (d, J = 9.2 Hz, 1H), 6.34 (t, J = 6.6 Hz, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.09 - 1.98 (m, 1H), 0.85 - 0.72 (m, 4H). HNMR for N-(8-(methylamino)-5-(pyridin-2-yloxy)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.37 (s, 1H), 8.08 (s, 1H), 8.03 (dd, J = 4.8, 1.2 Hz, 1H), 7.91 - 7.80 (m, 3H), 7.15 - 7.06 (m, 2H), 2.99 (d, J = 4.4 Hz, 3H), 2.09 - 2.00 (m, 1H), 0.85 - 0.74 (m, 4H).

[0235] Example 63: Synthesis of N-(8-(methylamino)-5-(thiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0236] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.) in dioxane (2 mL), Pd(PPh3)2Cl2 (21.9 mg; 0.031 mmol; 0.20 equiv.), CuI (4.5 mg; 0.024 mmol; 0.15 equiv.), and 2-(tributylstannyl)thiazole (116.5 mg; 0.311 mmol; 2.00 equiv.) were added at room temperature under a N2 atmosphere. The reaction was stirred at 100 °C for 16 h. The desired product was observed by LCMS. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-8%) as the eluent to give N-(8-(methylamino)-5-(thiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg, crude). The residue was purified by flash chromatography on a pre-packed C column using 15-70% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-(thiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (17.7 mg, 34%). LCMS (ESI) m / z 326.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.40 (s, 1H), 9.29 (s, 1H), 8.46 (s, 1H), 8.38 - 8.33 (m, 1H), 7.96 (d, J = 3.2 Hz, 1H), 7.73 (d, J = 3.2 Hz, 1H), 3.04 (d, J = 4.4 Hz, 3H), 2.11 - 2.02 (m, 1H), 0.88 - 0.78 (m, 4H).

[0237] Example 64: Synthesis of N-(8-(methylamino)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0238] Step 1: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole [ka]

[0239] To a stirred solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg; 2.57 mmol; 1.00 equiv.) in DMF (7 mL) was added NaH (60%) (256 mg; 6.40 mmol; 2.50 equiv.) at 0°C and stirred at room temperature for 0.5 h. To the resulting mixture was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (597 mg; 2.57 mmol; 1.00 equiv.) and stirred at room temperature under a nitrogen atmosphere for 2 h. Two peaks with the desired product mass were present. The reaction mixture was quenched with sat. NH4Cl solution (0.2 mL) at 0°C. The resulting mixture was diluted with EtOAc (100 mL) and washed with sat. NaCl solution (3 × 10 mL). The organic phase was concentrated under reduced pressure to give 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole as a yellow solid (507 mg, crude). This crude product was used directly in the next step without further purification. LCMS (ESI) m / z 277.1, [M+H] + .

[0240] Step 2: N-(8-(methylamino)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0241] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (129 mg; 0.46 mmol; 3.00 equiv.), Pd(PPh3)4 (18 mg; 0.015 mmol; 0.01 equiv.), Na2CO3 (50 mg; 0.47 mmol; 3.00 equiv.) in DME / water (5:1, 0.4 mL, deoxygenated prior to use) was stirred at 100 °C under a nitrogen atmosphere for 3 h. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-6%) petroleum ether as eluent to give N-(8-(methylamino)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg, crude). The residue was purified by flash chromatography on a pre-packed C column using 20%-60% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (30.6 mg, 50%). LCMS (ESI) m / z 391.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.37 (s, 1H), 8.83 (s, 1H), 8.20 (s, 1H), 8.06 - 8.00 (m, 1H), 7.96 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 5.17 (q, J = 9.2 Hz, 2H), 3.01 (d, J = 4.4 Hz, 3H), 2.08 - 2.00 (m, 1H), 0.86 - 0.78 (m, 4H).

[0242] Example 65: Synthesis of N-(8-(methylamino)-5-(thiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0243] A mixture of 4-(tributylstannyl)thiazole (175 mg; 0.468 mmol; 3.00 equiv.), N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.), Pd(PPh3)2Cl2 (13.5 mg; 0.019 mmol; 0.12 equiv.), and CuI (2.7 mg; 0.014 mmol; 0.09 equiv.) in dioxane (2 mL, deoxygenated before use) was stirred at 100 °C under a nitrogen atmosphere for 8 h. The desired product was detected by LCMS. The reaction was concentrated under reduced pressure and purified by flash chromatography on a silica gel column using MeOH / CHCl2 (1–6%) to give the crude product. The crude product was purified by flash chromatography on a pre-packed C18 column using 10-37% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(thiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a pale yellow solid (8.3 mg, 16%). LCMS (ESI) m / z 326.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.38 (s, 1H), 9.26 (d, J = 2.0 Hz, 1H), 8.72 (s, 1H), 8.25 (s, 1H), 8.10 - 8.04 (m, 1H), 7.78 (d, J = 2.0 Hz, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.07 - 2.00 (m, 1H), 0.85 - 0.78 (m, 4H).

[0244] Example 66: Synthesis of N-(8-(methylamino)-5-(5-methylthiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0245] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40.0 mg; 0.125 mmol; 1.00 equiv.) and 5-methyl-2-(tributylstannyl)thiazole (241 mg; 0.625 mmol; 5.00 equiv.), CuI (4.7 mg; 0.025 mmol; 0.20 equiv.), and Pd(PPh3)2Cl2 (34.9 mg; 0.050 mmol; 0.40 equiv.) in dioxane (2 mL, deoxygenated before use) was stirred at 100 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl2 (2–10%) as eluent to give the desired crude product. The crude product was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as eluent to give N-(8-(methylamino)-5-(5-methylthiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (23.9 mg, 56%). LCMS (ESI) m / z 340.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.39 (s, 1H), 9.24 (s, 1H), 8.37 (s, 1H), 8.33 - 8.28 (m, 1H), 7.63 (s, 1H), 3.03 (d, J = 4.4 Hz, 3H), 2.50 (s, 3H), 2.09 - 2.01 (m, 1H), 0.87 - 0.78 (m, 4H).

[0246] Example 67: Synthesis of N-(5-(3,6-dihydro-2H-pyran-4-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0247] To a mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (98 mg; 0.466 mmol / L; 3.00 equiv.) in DME / water (5:1, 1.2 mL, deoxygenated before use), Pd(PPh3)4 (18.1 mg; 0.015 mmol / L; 0.10 equiv.) and Na2CO3 (33 mg; 0.311 mmol / L; 2.00 equiv.) was added and stirred at 100 °C under a nitrogen atmosphere for 2 h. The desired product was observed by LCMS. The solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (2-10%) in CHCl as the eluent to give the desired crude product. The crude product was purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(5-(3,6-dihydro-2H-pyran-4-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (35 mg, 69%). LCMS (ESI) m / z 325.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.32 (s, 1H), 8.36 (s, 1H), 7.93 - 7.85 (m, 1H), 7.83 (s, 1H), 5.79 (s, 1H), 4.23 (d, J = 2.4 Hz, 2H), 3.85 (t, J = 5.2 Hz, 2H), 2.97 (d, J = 4.4 Hz, 3H), 2.40 - 2.31 (m, 2H), 2.11 - 2.00 (m, 1H), 0.91 - 0.77 (m, 4H).

[0248] Example 68: Synthesis of N-(8-(methylamino)-5-(tetrahydro-2H-pyran-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0249] To a solution of N-(5-(3,6-dihydro-2H-pyran-4-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 67) (30 mg; 0.092 mmol; 1.00 equiv) in MeOH (30 mL) was added 10% Pd / C (30 mg; 100% w / w) under a nitrogen atmosphere. The mixture was hydrogenated at 40° C. under a hydrogen atmosphere (2 atm) for 4 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2-9% MeOH in CHCl as the eluent to give N-(8-(methylamino)-5-(tetrahydro-2H-pyran-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15 mg, crude). The crude product was purified by flash chromatography on a pre-packed C18 column using 15-50% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(tetrahydro-2H-pyran-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.1 mg, 13%). LCMS (ESI) m / z 327.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.32 (s, 1H), 8.45 (s, 1H), 7.90 (s, 1H), 7.75 - 7.70 (m, 1H), 4.02 - 3.94 (m, 2H), 3.55 - 3.45 (m, 2H), 3.06 - 2.97 (m, 1H), 2.94 (d, J = 4.4 Hz, 3H), 2.10 - 2.02 (m, 1H), 1.81 - 1.68 (m, 4H), 0.91 - 0.78 (m, 4H).

[0250] Example 69: Synthesis of N-(5-(cyclohex-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0251] To a mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.) in a DME / water mixture (5:1, 2.4 mL), Pd(PPh3)4 (18.0 mg; 0.016 mmol; 0.10 equiv.), Na2CO3 (49.5 mg; 0.467 mmol; 3.00 equiv.), and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97.5 mg; 0.469 mmol; 3.00 equiv.) were added at room temperature. The reaction was stirred at 100 °C under a nitrogen atmosphere for 3 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (1-10%) as the eluent to give N-(5-(cyclohex-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (65 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 15%-60% MeCN in water (10 mmol / L NHHCO) to give N-(5-(cyclohex-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (6.1 mg, 12%). LCMS (ESI) m / z 323.2, [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.16 (s, 1H), 8.36 (s, 1H), 7.70 (s, 1H), 5.78–5.71 (m, 1H), 3.06 (s, 3H), 2.34–2.22 (m, 4H), 1.97–1.90 (m, 1H), 1.89–1.75 (m, 4H), 1.06–1.01 (m, 2H), 0.95–0.89 (m, 2H).

[0252] Example 70: Synthesis of N-(5-cyclohexyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0253] To a mixture of N-(5-(cyclohex-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 69) (60 mg; 0.186 mmol; 1.00 equiv) in MeOH (30 mL) was added 10% Pd / C (60 mg; 100% w / w) under a nitrogen atmosphere. The mixture was hydrogenated at 40 °C under a hydrogen atmosphere (2 atm) for 4 h. The reaction was filtered through a Celite pad and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (1-9%) as the eluent to give N-(5-cyclohexyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude). The crude product was purified by flash chromatography on a pre-packed C18 column using 15% to 70% MeCN in water (10 mmol / L NH4HCO3) to give N-(5-cyclohexyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.8 mg, 8%). LCMS (ESI) m / z 325.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.30 (s, 1H), 8.44 (s, 1H), 7.87 (s, 1H), 7.68 - 7.63 (m, 1H), 2.93 (d, J = 4.4 Hz, 3H), 2.78 - 2.69 (m, 1H), 2.10 - 2.02 (m, 1H), 1.89 - 1.71 (m, 5H), 1.51 - 1.20 (m, 5H), 0.91 - 0.78 (m, 4H).

[0254] Example 71: Synthesis of N-(8-(methylamino)-5-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0255] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.) in a dioxane / water mixture (5:1, 2.4 mL) was added Pd(DtBPF)Cl (10.2 mg; 0.016 mmol; 0.10 equiv.), KPO (66.1 mg; 0.311 mmol; 2.00 equiv.), and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (72 mg; 0.467 mmol; 3.00 equiv.) at room temperature. The reaction was stirred under nitrogen at 90 °C under a N atmosphere for 2 hours. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (1-9%) in CHCl as the eluent to give N-(8-(methylamino)-5-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 10%-70% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (5.2 mg, 12%). LCMS (ESI) m / z 269.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.33 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 8.02 - 7.95 (m, 1H), 6.92 (dd, J = 17.6, 11.2 Hz, 1H), 5.66 (dd, J = 17.6, 1.2 Hz, 1H), 5.25 (dd, J = 11.2, 1.2 Hz, 1H), 2.98 (d, J = 4.4 Hz, 3H), 2.09 - 2.03 (m, 1H), 0.89 - 0.80 (m, 4H).

[0256] Example 72: Synthesis of N-(5-ethyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0257] To a solution of N-(8-(methylamino)-5-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 71) (43 mg; 0.160 mmol; 1.00 equiv) in MeOH (10 mL) was added 10% Pd / C (17 mg; 40% w / w) under a nitrogen atmosphere. The mixture was hydrogenated at 40° C. under a hydrogen atmosphere (2 atm) for 2 h. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (1-9%) in CHCl as the eluent to give N-(5-ethyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (35 mg, crude). The crude product was purified by flash chromatography on a pre-packed C18 column using 10% to 70% MeCN in water (10 mmol / L NH4HCO3) to give N-(5-ethyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (20.8 mg, 48%). LCMS (ESI) m / z 271.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.31 (s, 1H), 8.35 (s, 1H), 7.84 (s, 1H), 7.71 - 7.65 (m, 1H), 2.94 (d, J = 4.4 Hz, 3H), 2.70 - 2.63 (m, 2H), 2.10 - 2.02 (m, 1H), 1.19 (t, J = 7.6 Hz, 3H), 0.90 - 0.80 (m, 4H).

[0258] Example 73: Synthesis of N-(8-(methylamino)-5-(prop-1-en-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0259] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (70 mg; 0.218 mmol; 1.00 equiv.) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36 mg; 0.214 mmol; 1.00 equiv.) in a 7:1 1,4-dioxane / water mixture (2.4 mL) was added Pd(DtBPF)Cl (14 mg; 0.021 mmol; 0.10 equiv.) and KPO (91 mg; 0.429 mmol; 2.00 equiv.). The mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with methanol (5-10%) in dichloromethane as the eluent to give the crude desired product. The crude product was further purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(prop-1-en-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (5.0 mg). LCMS (ESI) m / z 283.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.32 (s, 1H), 8.39 (s, 1H), 7.86 (s, 1H), 7.85 - 7.82 (m, 1H), 5.31 - 5.28 (m, 1H), 5.00 - 4.97 (m, 1H), 2.96 (d, J = 4.4 Hz, 3H), 2.08 (s, 3H), 2.06 - 2.00 (m, 1H), 0.88 - 0.78 (m, 4H).

[0260] Example 74: Synthesis of N-(5-isopropyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0261] To a stirred mixture of N-(8-(methylamino)-5-(prop-1-en-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 73) (60 mg; 0.213 mmol; 1.00 equiv) in MeOH (10 mL) was added 10% Pd / C (60 mg; 100% w / w). The reaction was stirred at 40° C. under a hydrogen atmosphere (2 atm) for 12 h. The desired product was observed by LCMS. The reaction was concentrated under reduced pressure and purified by flash chromatography on a silica gel column using MeOH / CHCl (2-8%) to give the desired crude product. The crude material was further purified by reverse-phase preparative HPLC (Prep-C18, 5 μM OBD column, 19 × 250 mm water; gradient elution with 35–48% MeCN in water over 8 min, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give N-(5-isopropyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (11.4 mg, 18%). LCMS (ESI) m / z 285.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.31 (s, 1H), 8.45 (s, 1H), 7.91 (s, 1H), 7.71 - 7.66 (m, 1H), 3.21 - 3.12 (m, 1H), 2.94 (d, J = 4.4 Hz, 3H), 2.10 - 2.02 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H), 0.89 - 0.80 (m, 4H).

[0262] Example 75: Synthesis of N-(5-(2,5-dihydrofuran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0263] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.18 mmol; 1.00 equiv.) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44 mg; 0.22 mmol; 1.20 equiv.), Pd(DtBPF)Cl (12 mg; 0.01 mmol; 0.10 equiv.), KPO (79 mg; 0.37 mmol; 2.00 equiv.) in dioxane / water (5:1, 7.2 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2-6% MeOH in CHCl as the eluent to give N-(5-(2,5-dihydrofuran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg, crude). 10 mg of this crude product was then purified by flash chromatography on a pre-packed C column using 20%-60% MeCN in water (10 mmol / L NHHCO) to give N-(5-(2,5-dihydrofuran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (3.1 mg, 5%). LCMS (ESI) m / z 311.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.35 (s, 1H), 8.68 (s, 1H), 8.08 - 8.03 (m, 1H), 7.94 (s, 1H), 6.21 - 6.19 (m, 1H), 4.94 - 4.89 (m, 2H), 4.82 - 4.77 (m, 2H), 2.98 (d, J = 4.4 Hz, 3H), 2.11 - 2.03 (m, 1H), 0.90 - 0.79 (m, 4H).

[0264] Example 76: Synthesis of N-(8-(methylamino)-5-(tetrahydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0265] To a solution of N-(5-(2,5-dihydrofuran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 75) (68 mg; 0.21 mmol; 1.00 equiv) in MeOH (100 mL) was added Pd / C (68 mg, 10% w / w) under a nitrogen atmosphere. The mixture was hydrogenated at 30-40° C. under a hydrogen atmosphere (2 atm) for 2 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 20% ​​to 60% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(tetrahydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (24.9 mg, 36%). LCMS (ESI) m / z 313.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.32 (s, 1H), 8.44 (s, 1H), 7.94 (s, 1H), 7.79 - 7.74 (m, 1H), 4.11 - 4.05 (m, 1H), 3.98 - 3.91 (m, 1H), 3.89 - 3.82 (m, 1H), 3.65 - 3.53 (m, 2H), 2.95 (d, J = 4.4 Hz, 3H), 2.35 - 2.24 (m, 1H), 2.10 - 1.99 (m, 2H), 0.91 - 0.80 (m, 4H).

[0266] Example 77: Synthesis of N-(5-(5,6-dihydro-2H-pyran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0267] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 equiv.) and 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (52.0 mg; 0.248 mmol; 2.00 equiv.) was added to Pd(DtBPF)Cl (8.12 mg; 0.012 mmol; 0.10 equiv.) and KPO (52.9 mg; 0.249 mmol; 2.00 equiv.) in dioxane / water (5:1, 2.4 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-7%) to give 65 mg of crude desired product. The crude product was purified by flash chromatography on a pre-packed C column using 10-40% MeCN in water (10 mmol / L NHHCO) to give N-(5-(5,6-dihydro-2H-pyran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (3.5 mg, 8%). LCMS (ESI) m / z 325.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.30 (s, 1H), 8.36 (s, 1H), 7.90 - 7.85 (m, 1H), 7.81 (s, 1H), 5.86 - 5.83 (m, 1H), 4.18 (s, 2H), 3.83 - 3.77 (m, 2H), 2.96 (d, J = 4.4 Hz, 3H), 2.31 - 2.22 (m, 2H), 2.09 - 2.01 (m, 1H), 0.89 - 0.79 (m, 4H).

[0268] Example 78: Synthesis of N-(8-(methylamino)-5-(tetrahydro-2H-pyran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0269] To a stirred mixture of N-(5-(5,6-dihydro-2H-pyran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 77) (50 mg; 0.154 mmol; 1.00 equiv) in MeOH (50 mL) under a nitrogen atmosphere was added 10% Pd / C (50 mg; 100% w / w). The reaction was stirred at 40° C. under a hydrogen atmosphere (2 atm) overnight. The desired product was observed by LCMS. The reaction was concentrated under reduced pressure and purified by flash chromatography on a silica gel column using MeOH / CHCl (2-8%) to give 31.0 mg of crude product, which was purified by reverse-phase preparative HPLC (Prep-C18, 5 μM OBD column, 19×250 mm water; gradient elution with 37% MeCN in water over 8 min, where both water and MeCN contained 0.1% formic acid, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give N-(8-(methylamino)-5-(tetrahydro-2H-pyran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (6.1 mg, 12%). LCMS (ESI) m / z 327.2, [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.28 (s, 1H), 8.61 (s, 1H), 7.75 (s, 1H), 4.09–3.92 (m, 2H), 3.64–3.50 (m, 2H), 3.27–3.19 (m, 1H), 3.12 (s, 3H), 2.16–2.08 (m, 1H), 2.00–1.75 (m, 4H), 1.08–1.04 (m, 2H), 0.98–0.93 (m, 2H).

[0270] Example 79: Synthesis of (E)-N-(5-((dihydrofuran-3(2H)-ylidene)methyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0271] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.187 mmol; 1.00 equiv.), (E)-2-((dihydrofuran-3(2H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (47.3 mg; 0.225 mmol; 1.21 equiv.), Pd(DtBPF)Cl (12.2 mg; 0.019 mmol; 0.10 equiv.), and KPO (79.7 mg; 0.375 mmol; 2.01 equiv.) in 1,4-dioxane / water (5:1, 2.4 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-10%) as eluent to give the crude desired product. The crude product was further purified by reverse-phase preparative HPLC (XBridge Shield RP18 OBD column, 30 × 150 mm, waters; gradient elution with 30-40% MeCN in water over an 8-minute period, where both water and MeCN contained 10 mmol / L NHHCO, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give (E)-N-(5-((dihydrofuran-3(2H)-ylidene)methyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (50 mg, 82%). LCMS (ESI) m / z 325.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.33 (s, 1H), 8.36 (s, 1H), 7.97 - 7.90 (m, 1H), 7.79 (s, 1H), 6.54 (s, 1H), 4.41 - 4.33 (m, 2H), 3.86 - 3.77 (m, 2H), 2.98 (d, J = 4.4 Hz, 3H), 2.79 - 2.63 (m, 2H), 2.10 - 2.02 (m, 1H), 0.88 - 0.80 (m, 4H).

[0272] Example 80: Synthesis of N-(8-(methylamino)-5-((tetrahydrofuran-3-yl)methyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0273] To a solution of (E)-N-(5-((dihydrofuran-3(2H)-ylidene)methyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 79) (40 mg; 0.123 mmol; 1.00 equiv) in MeOH (20 mL) was added 10% Pd / C (40 mg, 100% w / w). The mixture was hydrogenated at room temperature under a hydrogen atmosphere (2 atm) for 2 hours. The reaction was monitored by LCMS. After filtration, the filtrate was concentrated under reduced pressure to give N-(8-(methylamino)-5-((tetrahydrofuran-3-yl)methyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (60 mg, crude). The crude product was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as the eluent to give N-(8-(methylamino)-5-((tetrahydrofuran-3-yl)methyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (15.6 mg, 38%). LCMS (ESI) m / z 327.2, [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.31 (s, 1H), 8.36 (s, 1H), 7.85 (s, 1H), 7.76 - 7.70 (m, 1H), 3.83 - 3.75 (m, 1H)), 3.70 - 3.57 (m, 2H)), 3.41 - 3.34 (m, 1H), 2.94 (d, J = 4.4 Hz, 3H), 2.72 - 2.64 (m, 2H), 2.57 - 2.52 (m, 1H), 2.09 - 2.02 (m, 1H), 1.92 - 1.84 (m, 1H), 1.60 - 1.51 (m, 1H), 0.91 - 0.80 (m, 4H).

[0274] Example 81: Synthesis of N-(8-(methylamino)-5-(2-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0275] Step 1: N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0276] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (500 mg; 1.557 mmol; 1.00 equiv.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.96 g; 15.59 mmol; 10.00 equiv.), Pd(dppf)Cl2 (128 mg; 0.175 mmol; 0.10 equiv.), and KOAc (306 mg; 3.118 mmol; 2.00 equiv.) in 1,4-dioxane (24 mL) was stirred at 100 °C under a nitrogen atmosphere for 3 h. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in a mixture of petroleum ether / EtOAc (10:1, 200 mL), and a precipitate formed. The solid was collected by filtration and washed with a mixture of petroleum ether / EtOAc (10:1, 20 mL). The solid was dried under reduced pressure to give N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a brown solid (916 mg, crude). LCMS (ESI) m / z 369.2, [M+H] + .

[0277] Step 2: N-(8-(methylamino)-5-(2-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0278] A mixture of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.272 mmol; 1.00 equiv.), 4-bromo-2-methylthiazole (48.3 mg; 0.272 mmol; 1.00 equiv.), Pd(DtBPF)Cl (CAS: 95408-45-0) (17.7 mg; 0.027 mmol; 0.10 equiv.), and KPO (115 mg; 0.544 mmol; 2.00 equiv.) in dioxane / water (6:1, 2.9 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-10%) as the eluent to give the crude product. This crude product was further purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(8-(methylamino)-5-(2-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (20.7 mg, 21%). LCMS (ESI) m / z 340.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.37 (s, 1H), 8.72 (s, 1H), 8.23 ​​(s, 1H), 8.07 - 8.01 (m, 1H), 7.51 (s, 1H), 3.01 (d, J = 4.4, 3H), 2.73 (s, 3H), 2.08 - 2.00 (m, 1H), 0.86 - 0.77 (m, 4H).

[0279] Example 82: Synthesis of N-(5-(isothiazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0280] A mixture of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 81, Step 1) (100 mg; 0.272 mmol; 1.00 equiv.), 3-bromoisothiazole (44.5 mg; 0.272 mmol; 1.00 equiv.), Pd(dppf)Cl.CHCl (22.1 mg; 0.027 mmol; 0.10 equiv.), and KPO (115 mg; 0.544 mmol; 2.00 equiv.) in 1,4-dioxane / water (5:1, 3.0 mL) was stirred at 40° C. under a nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-10%) as the eluent to give the crude desired product. The crude product was further purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(5-(isothiazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (8.6 mg, 10%). LCMS (ESI) m / z 326.1, [M+H]. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.39 (s, 1H), 9.17 (d, J = 4.4 Hz, 1H), 9.14 (s, 1H), 8.42 (s, 1H), 8.23 ​​- 8.17 (m, 1H), 7.72 (d, J = 4.4 Hz, 1H), 3.03 (d, J = 4.4 Hz, 3H), 2.08 - 2.01 (m, 1H), 0.86 - 0.78 (m, 4H).

[0281] Examples 83 and 84: Each compound in Table 3 below was prepared using a procedure similar to that for preparing Example 82, using N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a common intermediate and the appropriate aromatic halide:

[0282] [Table 3]

[0283] Example 85: Synthesis of N-(8-(methylamino)-5-(2-oxo-2,5-dihydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0284] To a stirred mixture of a solution of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 81, Step 1) (71 mg; 0.193 mmol; 1.00 equiv.) in dioxane / water (5:1, 4.8 mL, deoxygenated prior to use), Pd(DtBPF)Cl (12.6 mg; 0.019 mmol; 0.10 equiv.), KPO (81.8 mg; 0.385 mmol; 2.00 equiv.), and 3-bromofuran-2(5H)-one (94.3 mg; 0.579 mmol; 3.00 equiv.) were added at room temperature. The reaction was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-8%) as the eluent to give N-(8-(methylamino)-5-(2-oxo-2,5-dihydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (20 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20%-60% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.5 mg, 9%). Another residue was purified by flash chromatography on a pre-packed C18 column using 20% ​​to 60% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(2-oxo-2,5-dihydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (2.1 mg, 3%). LCMS (ESI) m / z 325.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.01 (s, 1H), 9.37 (s, 1H), 8.30 (s, 1H), 8.17 - 8.13 (m, 1H), 8.11 (s, 1H), 7.89 - 7.85 (m, 1H), 5.13 - 5.09 (m, 2H), 3.01 (d, J = 4.4 Hz, 3H), 2.09 - 2.00 (m, 1H), 0.89 - 0.78 (m, 4H).

[0285] Example 86: Synthesis of N-(8-(methylamino)-5-(2-oxotetrahydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0286] To a solution of N-(8-(methylamino)-5-(2-oxo-2,5-dihydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 85) (46 mg; 0.142 mmol; 1.00 equiv) in MeOH (20 mL) was added 10% Pd / C (46 mg; 100% w / w) at room temperature under a nitrogen atmosphere. The mixture was hydrogenated at 40° C. under a hydrogen atmosphere (2 atm) for 16 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 20% ​​to 60% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(2-oxotetrahydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (1.8 mg, 4%). LCMS (ESI) m / z 327.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.35 (s, 1H), 8.23 ​​(s, 1H), 7.95 - 7.91 (m, 1H), 7.91 (s, 1H), 4.54 - 4.37 (m, 2H), 4.18 (t, J = 10.0 Hz, 1H), 2.96 (d, J = 4.4 Hz, 3H), 2.68 - 2.56 (m, 1H), 2.46 - 2.35 (m, 1H), 2.11 - 2.02 (m, 1H), 0.90 - 0.80 (m, 4H).

[0287] Example 87: Synthesis of N-(5-(1-(cyanomethyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0288] Step 1: 2-(3-Bromo-1H-pyrazol-1-yl)acetonitrile. [ka]

[0289] A mixture of 3-bromo-1H-pyrazole (150 mg; 1.02 mmol; 1.00 equiv.), 2-bromoacetonitrile (159.1 mg; 1.327 mmol; 1.5 equiv.), and CsCO (665 mg; 2.04 mmol; 2.00 equiv.) in DMF (5 mL) was stirred at room temperature for 6 h. The reaction was monitored by LCMS. The reaction was diluted with EtOAc (80 mL) and washed with brine (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 20–50% MeCN in water (10 mmol / L NH4HCO3) to give 2-(3-bromo-1H-pyrazol-1-yl)acetonitrile as a brown solid (140 mg, 74%). LCMS (ESI) m / z 186.0, [M+H] + .

[0290] Step 2: N-(5-(1-(cyanomethyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0291] A mixture of 2-(3-bromo-1H-pyrazol-1-yl)acetonitrile (100 mg; 0.540 mmol; 2.00 equiv.), N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 81, Step 1) (100 mg, 0.272 mmol, 1.00 equiv.), Pd(DtBPF)Cl (17.7 mg; 0.027 mmol; 0.10 equiv.), and KPO (115.3 mg; 0.544 mmol; 2.00 equiv.) in 1,4-dioxane / water (10:1, 2.2 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-10%) as the eluent to give N-(5-(1-(cyanomethyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (10 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) to give N-(5-(1-(cyanomethyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (2.7 mg, 3%). LCMS (ESI) m / z 348.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.38 (s, 1H), 8.82 (s, 1H), 8.22 (s, 1H), 8.10 - 7.89 (m, 2H), 6.62 (s, 1H), 5.54 (s, 2H), 3.02 (d, J = 4.4 Hz, 3H), 2.15 - 1.98 (m, 1H), 0.97 - 0.70 (m, 4H).

[0292] Example 88: Synthesis of N-(8-(methylamino)-5-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0293] N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 81, Step 1) (150 mg; 0.407 mmol; 1.00 equiv.), 1,1,1-trifluoro-2-iodoethane (256.7 mg; 1.22 mmol; 3.00 equiv.), XPhos Pd A mixture of G3 (34.5 mg; 0.040 mmol; 0.10 equiv.), XPhos (19.4 mg; 0.040 mmol; 0.10 equiv.), and KPO (259.2 mg; 1.22 mmol; 3.00 equiv.) in 1,4-dioxane / water (10:1, 2.2 mL, deoxygenated before use) was stirred at 90 °C under a nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2–10% MeOH in CHCl as eluent to give N-(8-(methylamino)-5-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude). The crude product was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (10.1 mg, 4%). LCMS (ESI) m / z 325.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.34 (s, 1H), 8.38 (s, 1H), 8.10 - 7.98 (m, 2H), 3.75 - 3.60 (m, 2H), 2.97 (d, J = 4.4 Hz, 3H), 2.12 - 2.01 (m, 1H), 0.95 - 0.80 (m, 4H).

[0294] Example 89: Synthesis of N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide [ka]

[0295] Step 1: N-(8-hydroxy-2,7-naphthyridin-3-yl)acetamide [ka]

[0296] A mixture of Pd(dba) (250 mg; 0.273 mmol; 0.10 equiv.) and XantPhos (325 mg; 0.562 mmol; 0.20 equiv.), 6-chloro-2,7-naphthyridin-1-ol (500 mg; 2.77 mmol; 1.00 equiv.), acetamide (650 mg; 11.0 mmol; 4.00 equiv.), and CsCO (1.8 g; 5.53 mmol; 2.00 equiv.) in dioxane (12 mL) was stirred at 110 °C under a nitrogen atmosphere for 2 h. The desired product was observed by LCMS. The reaction was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column using 30–100% EtOAc in petroleum ether and 2–20% MeOH in CHCl as eluents to give the crude product. The crude product was diluted with abundant CH2Cl2 (20 mL), then filtered, the filter cake washed with abundant CH2Cl2, and dried to give N-(8-hydroxy-2,7-naphthyridin-3-yl)acetamide as a yellow solid (560 mg, 99%). LCMS (ESI) m / z 204.1, [M+H] + .

[0297] Step 2: N-(8-chloro-2,7-naphthyridin-3-yl)acetamide [ka]

[0298] N-(8-Hydroxy-2,7-naphthyridin-3-yl)acetamide (250 mg; 1.23 mmol; 1.00 equiv) was dissolved in POCl3 (6 mL) under a nitrogen atmosphere. The reaction was stirred at 100 °C for 30 min. The desired product was monitored by LCMS. The reaction was cooled to room temperature and concentrated in vacuo. The resulting mixture was diluted with 100 mL of CHCl2 and neutralized to pH 7 with saturated NaHCO3 solution. The organic phase was concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using 10-30% EtOAc in CHCl2 to give N-(8-chloro-2,7-naphthyridin-3-yl)acetamide as a pale yellow solid (80 mg, 29%). LCMS (ESI) m / z 222.0, [M+H] + .

[0299] Step 3: N-(8-(methylamino)-2,7-naphthyridin-3-yl)acetamide [ka]

[0300] N-(8-chloro-2,7-naphthyridin-3-yl)acetamide (80 mg; 0.361 mmol; 1.00 equiv) was added to a solution of methylamine in THF (2 M, 4 mL). The reaction was stirred at 60° C. overnight. The progress of the reaction was monitored by LCMS. To the mixture was added additional methylamine in THF (2 M, 4 mL). The reaction was stirred at 60° C. overnight. Upon completion, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2-14% MeOH in CHCl to afford N-(8-(methylamino)-2,7-naphthyridin-3-yl)acetamide as an off-white solid (75 mg, 96%). LCMS (ESI) m / z 217.1, [M+H] + .

[0301] Step 4: N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide [ka]

[0302] To a stirred mixture of N-(8-(methylamino)-2,7-naphthyridin-3-yl)acetamide (141 mg; 0.652 mmol; 1.00 equiv) in DMF (4 mL) at 0 °C under a nitrogen atmosphere was added NBS (116 mg; 0.652 mmol; 1.00 equiv). The reaction was then stirred at room temperature for 1 h. Upon completion, the mixture was diluted with EtOAc (80 mL) and washed with brine (20 mL × 5). The organic layer was dried, concentrated under reduced pressure, and purified by flash chromatography on a silica gel column using 2-6% MeOH in CHCl to give N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide as an off-white solid (166 mg, 86%). LCMS (ESI) m / z 295.0, [M+H] + .

[0303] Step 5: N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide [ka]

[0304] A mixture of LiCl (16.7 mg; 0.394 mmol; 2.50 equiv.), CuI (6.1 mg; 0.032 mmol; 0.20 equiv.), and Pd(PPh3)4 (37 mg; 0.032 mmol; 0.20 equiv.) in dioxane (2.5 mL, deoxygenated before use) was added to N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide (47 mg; 0.159 mmol; 1.00 equiv.) and 3-methoxy-2-(tributylstannyl)pyridine (319 mg; 0.341 mmol; 5.00 equiv.). The reaction mixture was stirred at 110 °C under a nitrogen atmosphere for 1 hour. The desired product was observed by LCMS. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (2-20%) to give the crude desired product. This crude product was further purified by flash chromatography on a pre-packed C column using 10-30% MeCN in water (10 mmol / L NHHCO) to give N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide as a white solid (31.5 mg, 61%). LCMS (ESI) m / z 324.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.34 (s, 1H), 8.28 - 8.24 (m, 1H), 8.01 (s, 1H), 8.00 - 7.97 (m, 2H), 7.60 - 7.56 (m, 1H), 7.44 - 7.39 (m, 1H), 3.73 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H), 2.05 (s, 3H).

[0305] Example 90: Synthesis of N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)acetamide [ka]

[0306] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide (Example 89, Step 4) (40 mg; 0.136 mmol; 1.00 equiv) in dioxane / water (10:1, 2.2 mL) was added phenylboronic acid (33 mg, 0.272 mmol; 2.00 equiv), Pd(DtBPF)Cl (8.8 mg; 0.014 mmol; 0.10 equiv), and KPO (57.5 mg, 0.272 mmol; 0.20 equiv) under a nitrogen atmosphere. The reaction was stirred at 90 °C for 2 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH (1-8%) in CHCl as eluent to give the crude product. The crude product was further purified by flash chromatography on a pre-packed C18 column using 10-43% MeCN in water (10 mmol / L NH4HCO3) as eluent to give N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)acetamide as an off-white solid (12.0 mg, 30%). LCMS (ESI) m / z 293.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 9.37 (s, 1H), 8.36 (s, 1H), 7.99 - 7.96 (m, 1H), 7.95 (s, 1H), 7.52 - 7.37 (m, 5H), 3.01 (d, J = 4.4 Hz, 3H), 2.07 (s, 3H).

[0307] Example 91: 4-(3-methoxypyridin-2-yl)-N 1 -methyl-N 6 Synthesis of -(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine [ka]

[0308] Step 1: 6-chloro-4-iodo-2,7-naphthyridin-1-ol [ka]

[0309] A mixture of 6-chloro-2,7-naphthyridin-1-ol (1 g; 5.53 mmol; 1.00 equiv.) and 1-iodopyrrolidine-2,5-dione (1.87 g; 8.30 mmol; 1.50 equiv.) in DMF (10 mL) was stirred at room temperature under a nitrogen atmosphere for 5 hours. The resulting mixture was quenched by the dropwise addition of water (50 mL) and stirred at room temperature for 30 minutes, resulting in the formation of a large amount of precipitate. The mixture was filtered, and the solid was washed with water (10 mL). The solid was dried under reduced pressure to give 6-chloro-4-iodo-2,7-naphthyridin-1-ol as a yellow solid (1.05 g, 61%). LCMS (ESI) m / z 306.9, [M+H] + .

[0310] Step 2: 6-chloro-4-(3-methoxypyridin-2-yl)-2,7-naphthyridin-1(2H)-one [ka]

[0311] A mixture of 6-chloro-4-iodo-2,7-naphthyridin-1-ol (600 mg; 1.96 mmol; 1.00 equiv.), 3-methoxy-2-(tributylstannyl)pyridine (2.34 g; 5.874 mmol; 3.00 equiv.), Pd(PPh3)2Cl2 (137 mg; 0.196 mmol; 0.10 equiv.), and CuI (74.5 mg; 0.392 mmol; 0.20 equiv.) in dioxane (5 mL) was stirred at 60 °C under a nitrogen atmosphere for 18 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was purified by flash chromatography on a silica gel column using MeOH / CH2Cl2 (2-10%) as eluent to give 6-chloro-4-(3-methoxypyridin-2-yl)-2,7-naphthyridin-1(2H)-one as a yellow solid (240 mg, 42%). LCMS (ESI) m / z 288.0, [M+H] + .

[0312] Step 3: 4-(3-methoxypyridin-2-yl)-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one [ka]

[0313] A mixture of 6-chloro-4-(3-methoxypyridin-2-yl)-2,7-naphthyridin-1(2H)-one (330 mg; 1.14 mmol; 1.00 equiv.), pyridin-2-amine (216 mg; 2.29 mmol; 2.00 equiv.), Pd(dba) (105 mg; 0.115 mmol; 0.10 equiv.), XantPhos (132 mg; 0.229 mmol; 0.20 equiv.), and CsCO (934 mg; 2.87 mmol; 2.50 equiv.) in dioxane (5 mL) was stirred at 110 °C under a nitrogen atmosphere overnight. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and purified by flash chromatography on a silica gel column using MeOH / CHCl (5-20%) as eluent to give 4-(3-methoxypyridin-2-yl)-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one as a white solid (350 mg, 88%). LCMS (ESI) m / z 346.1, [M+H] + .

[0314] Step 4: 8-chloro-5-(3-methoxypyridin-2-yl)-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine [ka]

[0315] 4-(3-Methoxypyridin-2-yl)-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one (200 mg; 0.579 mmol; 1.00 equiv.) and POCl3 (5 mL) were mixed in a reaction flask. The resulting mixture was stirred at 100°C for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to give 8-chloro-5-(3-methoxypyridin-2-yl)-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine as a brown solid (200 mg; 95%). LCMS (ESI) m / z 364.1, [M+H] + .

[0316] Step 5: 4-(3-methoxypyridin-2-yl)-N 1 -methyl-N 6 -(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine [ka]

[0317] A mixture of 8-chloro-5-(3-methoxypyridin-2-yl)-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine (200 mg; 0.551 mmol; 1.00 equiv.), methanamine hydrochloride (184 mg; 2.73 mmol; 5.00 equiv.), and DIPEA (706 mg; 5.47 mmol; 2.00 equiv.) in NMP (5 mL) was stirred at 100 °C for 16 h. The reaction was monitored by LCMS. The mixture was cooled and concentrated. The resulting residue was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as eluent to give 4-(3-methoxypyridin-2-yl)-N 1 -methyl-N 6 4-(3-Methoxypyridin-2-yl)-N-(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine was obtained as a yellow solid (60 mg, crude). The crude product was purified by reverse-phase preparative HPLC (Prep-C18, XBridge Prep OBD C18 column, 30 × 150 mm, waters; gradient elution with 35–45% MeCN in water over a 10 min period, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 220 nm) to give 4-(3-methoxypyridin-2-yl)-N-( ... 1 -methyl-N 6 -(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine was obtained as a yellow solid (35.2 mg, 17%). LCMS (ESI) m / z 359.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.78 (s, 1H), 9.29 (s, 1H), 8.28 (d, J = 4.4 Hz, 1H), 8.06 - 8.03 (m, 1H), 8.00 (s, 1H), 7.96 (s, 1H), 7.92 - 7.87 (m, 1H), 7.68 - 7.59 (m, 2H), 7.48 - 7.34 (m, 2H), 6.86 - 6.78 (m, 1H), 3.74 (s, 3H), 3.02 (d, J = 4.4 Hz, 3H).

[0318] Example 92: N 1 -methyl-4-phenyl-N 6 Synthesis of -(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine [ka]

[0319] Step 1: 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one [ka]

[0320] A mixture of 6-chloro-4-iodo-2,7-naphthyridin-1-ol (Example 91, Step 1) (400 mg; 1.305 mmol; 1.00 equiv), phenylboronic acid (477 mg; 3.91 mmol; 3.00 equiv), Pd(PPh3)4 (151 mg; 0.131 mmol; 0.10 equiv), and Na2CO3 (748 mg; 7.06 mmol; 5.41 equiv) in a DME / water mixture (5:1, 12 mL) was stirred at 100° C. under a nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature, and the crude product was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using an eluent of MeOH / CH2Cl2 (2-10%) to give 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one as a yellow solid (228 mg, 68%). LCMS (ESI) m / z 257.0, [M+H] + .

[0321] Step 2: 4-phenyl-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one [ka]

[0322] A mixture of 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one (200 mg; 0.779 mmol; 1.00 equiv.), pyridin-2-amine (220 mg; 2.33 mmol; 3.00 equiv.), Pd(dba) (71.4 mg; 0.078 mmol; 0.10 equiv.), XantPhos (90.2 mg; 0.156 mmol; 0.20 equiv.), and CsCO (507.8 mg; 1.55 mmol; 2.00 equiv.) in 1,4-dioxane (10 mL) was stirred at 100 °C under a nitrogen atmosphere for 2 h. The desired product was observed by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2-10% MeOH in CH2Cl2 as eluent to give 4-phenyl-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one (98 mg, 40%). LCMS (ESI) m / z 315.1, [M+H] + .

[0323] Step 3: 8-chloro-5-phenyl-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine [ka]

[0324] 4-Phenyl-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one (98 mg; 0.312 mmol; 1.00 equiv) was mixed with POCl (4 mL), and the mixture was stirred at 100 °C under a nitrogen atmosphere for 1 hour. Upon completion, the mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CHCl (50 mL). The mixture was basified with saturated NaHCO solution to pH 7. The resulting mixture was extracted with CHCl (2 × 40 mL). The combined organic layers were washed with saturated NaCl solution (1 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 20-80% EtOAc in petroleum ether as eluent to give 8-chloro-5-phenyl-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine as a pale yellow solid (43.2 mg, 41%). LCMS (ESI) m / z 333.1, [M+H] + .

[0325] Step 4: N 1 -methyl-4-phenyl-N 6 -(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine [ka]

[0326] A mixture of 8-chloro-5-phenyl-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine (43.2 mg; 0.130 mmol; 1.00 equiv.), methanamine hydrochloride (18 mg; 0.267 mmol; 2.05 equiv.), and DIPEA (83.9 mg; 0.649 mmol; 5.00 equiv.) in NMP (2 mL) was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction was cooled to room temperature. The resulting mixture was purified by flash chromatography on a pre-packed C18 column using 20–50% MeCN in water (10 mmol / L NH4HCO3) as the eluent to give N 1 -methyl-4-phenyl-N6 -(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine was obtained as a white solid (20.0 mg, 47%). LCMS (ESI) m / z 328.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.32 (s, 1H), 8.42 (s, 1H), 8.10 - 8.06 (m, 1H), 7.97 - 7.91 (m, 1H), 7.88 (s, 1H), 7.67 - 7.61 (m, 1H), 7.55 - 7.49 (m, 4H), 7.44 - 7.35 (m, 2H), 6.87 - 6.82 (m, 1H), 3.01 (d, J = 4.4 Hz, 3H).

[0327] Example 93: N 6 -(cyclopropylmethyl)-N 1 Synthesis of 1,6-methyl-4-phenyl-2,7-naphthyridine-1,6-diamine [ka]

[0328] Step 1: 6-((cyclopropylmethyl)amino)-4-phenyl-2,7-naphthyridin-1(2H)-one [ka]

[0329] A mixture of 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one (Example 92, Step 1) (261 mg; 1.02 mmol; 1.00 equiv.), cyclopropylmethanamine (725 mg; 10.1 mmol; 10.0 equiv.), and DIPEA (329 mg; 2.55 mmol; 2.50 equiv.) in NMP (5 mL) was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction was cooled to room temperature. The resulting mixture was purified by flash chromatography on a pre-packed C18 column using 20–50% MeCN in water (10 mmol / L NH4HCO3) as the eluent to afford 6-((cyclopropylmethyl)amino)-4-phenyl-2,7-naphthyridin-1(2H)-one as a pale yellow solid (145 mg, 48%). LCMS (ESI) m / z 292.1, [M+H] + .

[0330] Step 2: 8-chloro-N-(cyclopropylmethyl)-5-phenyl-2,7-naphthyridin-3-amine [ka]

[0331] 6-((cyclopropylmethyl)amino)-4-phenyl-2,7-naphthyridin-1(2H)-one (145 mg; 0.498 mmol; 1.00 equiv) was dissolved in POCl (4 mL) and stirred at 100 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CHCl (55 mL). The mixture was basified with saturated NaHCO solution to pH 7. The resulting mixture was extracted with CHCl (2 × 40 mL). The combined organic layers were washed with saturated NaCl solution (1 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using EtOAc / petroleum ether (10-80%) as the eluent to give 8-chloro-N-(cyclopropylmethyl)-5-phenyl-2,7-naphthyridin-3-amine as a yellow solid (84.7 mg, 54%). LCMS (ESI) m / z 310.1, [M+H] + .

[0332] Process 3: N 6 -(cyclopropylmethyl)-N 1 -Methyl-4-phenyl-2,7-naphthyridine-1,6-diamine [ka]

[0333] A mixture of 8-chloro-N-(cyclopropylmethyl)-5-phenyl-2,7-naphthyridin-3-amine (74.7 mg; 0.241 mmol; 1.00 equiv.), methylamine hydrochloride (48.6 mg; 0.72 mmol; 2.99 equiv.), and DIPEA (155 mg; 1.20 mmol; 4.99 equiv.) in NMP (3 mL) was stirred at 120 °C under a nitrogen atmosphere for 12 h. The reaction mixture was cooled to room temperature, and the resulting mixture was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as eluent to give N 6 -(cyclopropylmethyl)-N1 33.5 mg, 45% yield of 4-methyl-4-phenyl-2,7-naphthyridine-1,6-diamine as a white solid (45%). LCMS (ESI) m / z 305.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 7.66 (s, 1H), 7.65 - 7.62 (m, 1H), 7.49 - 7.44 (m, 2H), 7.41 - 7.34 (m, 3H), 6.91 - 6.86 (m, 1H), 6.41 (s, 1H), 3.13 - 3.08 (m, 2H), 2.96 (d, J = 4.4 Hz, 3H), 1.04 - 0.93 (m, 1H), 0.44 - 0.38 (m, 2H), 0.19 - 0.14 (m, 2H).

[0334] Example 94: N 1 -methyl-4-phenyl-N 6 Synthesis of -(2,2,2-trifluoroethyl)-2,7-naphthyridine-1,6-diamine [ka]

[0335] Step 1: 4-phenyl-6-((2,2,2-trifluoroethyl)amino)-2,7-naphthyridin-1(2H)-one [ka]

[0336] A mixture of 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one (Example 92, Step 1) (100 mg; 0.390 mmol; 1.00 equiv), 2,2,2-trifluoroethan-1-amine (77.2 mg; 0.779 mmol; 2.00 equiv), Pd-PEPPSI-IHeptCl (37.9 mg; 0.039 mmol; 0.10 equiv), and t-BuOK (87.4 mg; 0.779 mmol; 2.00 equiv) in 1,4-dioxane (10 mL) was stirred at 90° C. under a nitrogen atmosphere for 16 hours. The reaction was cooled to room temperature, and the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CH2Cl2 (2-10%) as eluent to give 4-phenyl-6-((2,2,2-trifluoroethyl)amino)-2,7-naphthyridin-1(2H)-one as an off-white solid (80.6 mg, 64%). LCMS (ESI) m / z 320.1, [M+H] + .

[0337] Step 2: 8-chloro-5-phenyl-N-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-amine [ka]

[0338] 4-Phenyl-6-((2,2,2-trifluoroethyl)amino)-2,7-naphthyridin-1(2H)-one (80.6 mg; 0.252 mmol; 1.00 equiv) was dissolved in POCl (3 mL). The reaction mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CHCl (50 mL). The mixture was basified with saturated NaHCO solution to pH 7. The resulting mixture was extracted with CHCl (2 × 40 mL). The combined organic layers were washed with saturated NaCl solution (1 × 5 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 20-80% EtOAc in petroleum ether as eluent to give 8-chloro-5-phenyl-N-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-amine as a yellow solid (76.6 mg, 89%). LCMS (ESI) m / z 338.1, [M+H] + .

[0339] Process 3: N 1 -methyl-4-phenyl-N 6 -(2,2,2-trifluoroethyl)-2,7-naphthyridine-1,6-diamine [ka]

[0340] A mixture of 8-chloro-5-phenyl-N-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-amine (66.6 mg; 0.197 mmol; 1.00 equiv.), methanamine hydrochloride (39.9 mg; 0.591 mmol; 3.00 equiv.), and DIPEA (127 mg; 0.984 mmol; 4.99 equiv.) in NMP (3 mL) was stirred at 120 °C under a nitrogen atmosphere for 12 h. The reaction was cooled to room temperature. The resulting mixture was purified by flash chromatography on a pre-packed C18 column using 20–50% MeCN in water (10 mmol / L NH4HCO3) as the eluent to give the N1 -methyl-4-phenyl-N 6 -(2,2,2-trifluoroethyl)-2,7-naphthyridine-1,6-diamine was obtained as a white solid (41.3 mg, 63%). LCMS (ESI) m / z 333.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 7.74 (s, 1H), 7.73 - 7.70 (m, 1H), 7.51 - 7.45 (m, 2H), 7.41 - 7.36 (m, 4H), 6.64 (s, 1H), 4.25 - 4.14 (m, 2H), 2.98 (d, J = 4.4 Hz, 3H).

[0341] Example 95: Synthesis of N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0342] Step 1: N-(8-hydroxy-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0343] To a stirred mixture of 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one (Example 92, Step 1) (1.1 g; 4.29 mmol; 1.00 equiv.) in dioxane (30 mL) was added cyclopropanecarboxamide (1.46 g; 17.1 mmol; 4.00 equiv.), Pd(dba) (394.4 mg; 0.429 mmol; 0.10 equiv.), XantPhos (495 mg; 0.859 mmol; 0.20 equiv.), and CsCO (2.8 g; 8.58 mmol; 2.00 equiv.) under a nitrogen atmosphere. The reaction was stirred under nitrogen at 130 °C overnight. Upon completion, the reaction was concentrated under reduced pressure and purified by flash chromatography on a silica gel column using MeOH / CHCl (3-15%) to give N-(8-hydroxy-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a pale yellow solid (560 mg, crude). The crude product was diluted with water (20 mL), then filtered, the filter cake washed with water, and dried to give N-(8-hydroxy-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (180 mg, 13%). LCMS (ESI) m / z 306.1, [M+H] + .

[0344] Step 2: N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0345] N-(8-hydroxy-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (116 mg; 0.380 mmol; 1.00 equiv) was dissolved in phosphorus oxychloride (3 mL). The reaction was stirred under nitrogen at 100 °C for 1 h. Upon completion, the reaction was concentrated under reduced pressure. The resulting mixture was diluted with CHCl (50 mL). The resulting mixture was washed with saturated NaHCO solution. The solution was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 20-50% EtOAc in petroleum ether to give the crude product. The crude material was further purified by reverse-phase preparative HPLC (Prep-C18, 5 μM OBD column, 19 × 250 mm, waters; gradient elution with 46–56% MeCN in water over 8 min, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (1.9 mg, 1%). LCMS (ESI) m / z 324.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.52 (s, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 7.62 - 7.51 (m, 5H), 2.10 - 2.03 (m, 1H), 0.85 - 0.78 (m, 4H).

[0346] Example 96: Synthesis of N-(8-ethyl-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0347] Step 1: N-(5-phenyl-8-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0348] To a stirred mixture of N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 95, Step 2) (80 mg; 0.247 mmol; 1.00 equiv.) in dioxane / water (5:1, 6 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (76 mg; 0.493 mmol; 2.00 equiv.), Pd(DtBPF)Cl (16 mg; 0.025 mmol; 0.10 equiv.), and KPO (105 mg; 0.493 mmol; 2.00 equiv.). The reaction was stirred under nitrogen at 90° C. for 2 hours. Upon completion, the reaction was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using EtOAc / CH2Cl2 (10-30%) to give N-(5-phenyl-8-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a pale yellow solid (60 mg, 77%). LCMS (ESI) m / z 316.1, [M+H] + .

[0349] Step 2: N-(8-ethyl-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0350] To a stirred mixture of N-(5-phenyl-8-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.159 mmol; 1.00 equiv) in MeOH (15 mL) was added 10% Pd / C (50 mg; 100% w / w). The reaction was stirred at 40 °C under a hydrogen atmosphere (2 atm) for 4 h. The resulting mixture was filtered, and the filter cake was washed with CHCl / MeOH (1:1, 50 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography on a pre-packed C18 column using 10–50% MeCN in water (10 mmol / L NHHCO) to give N-(8-ethyl-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as an off-white solid (12.5 mg, 24%). LCMS (ESI) m / z 318.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.58 (s, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 7.59 - 7.47 (m, 5H), 3.41 (q, J = 7.2 Hz, 2H), 2.09 - 2.01 (m, 1H), 1.41 (t, J = 7.2 Hz, 3H), 0.82 - 0.78 (m, 4H).

[0351] Example 97: N 1 -methyl-N 6 Synthesis of -(oxetan-3-yl)-4-phenyl-2,7-naphthyridine-1,6-diamine [ka]

[0352] Step 1: 6-chloro-N-methyl-2,7-naphthyridin-1-amine [ka]

[0353] To a stirred mixture of 6-chloro-2,7-naphthyridin-1(2H)-one (Example 2, Step 3) (1 g; 5.53 mmol; 1.00 equiv.) and PyBOP (5.7 g; 10.95 mmol; 2.00 equiv.) in DMA (15 mL) was added methylamine hydrochloride (1.11 g; 16.44 mmol; 3.00 equiv.) and DIEA (3.6 g; 27.85 mmol; 5.00 equiv.). After stirring at 80 °C under a nitrogen atmosphere for 16 h, the reaction was cooled to room temperature. The resulting mixture was diluted with EtOAc (150 mL). The resulting solution was washed with saturated NaCl solution (5 × 10 mL). The EtOAc was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 10–40% EtOAc in CHCl as the eluent to give 1.5 g of crude product. The crude product was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as eluent to give 6-chloro-N-methyl-2,7-naphthyridin-1-amine as an off-white solid (676 mg, 63%). LCMS (ESI) m / z 194.0, [M+H] + .

[0354] Step 2: 6-chloro-4-iodo-N-methyl-2,7-naphthyridin-1-amine [ka]

[0355] To a solution of 6-chloro-N-methyl-2,7-naphthyridin-1-amine (612 mg; 3.16 mmol; 1.00 equiv.) in DMF (12 mL) was slowly added NIS (1.07 g; 4.75 mmol; 1.50 equiv.) at 0 °C. The mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with EtOAc (150 mL) and then washed with saturated NaCl solution (5 × 10 mL). The resulting solution (EtOAc) was dried over NaSO and concentrated under reduced pressure. The residue was diluted with CHCl (15 mL) to precipitate a solid. The solid was collected by filtration and washed with CHCl to give 6-chloro-4-iodo-N-methyl-2,7-naphthyridin-1-amine as a yellow solid (983 mg, 97%). LCMS (ESI) m / z 319.9, [M+H] + .

[0356] Step 3: 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine [ka]

[0357] To a mixture of 6-chloro-4-iodo-N-methyl-2,7-naphthyridin-1-amine (950 mg; 2.97 mmol; 1.00 equiv.) and phenylboronic acid (363 mg; 2.97 mmol; 1.00 equiv.) in dioxane / water (10:1, 13.2 mL) was added KPO (1.26 g; 5.93 mmol; 2.00 equiv.) and Pd(dppf)Cl.CHCl (242 mg; 0.297 mmol; 0.10 equiv.). After stirring at 60 °C under a nitrogen atmosphere for 2 hours, the reaction was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 20-50% EtOAc in petroleum ether as the eluent to give 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine as a yellow solid (620 mg, 77%). LCMS (ESI) m / z 270.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 8.32 - 8.21 (m, 1H), 8.10 (s, 1H), 7.60 - 7.50 (m, 2H), 7.49 - 7.38 (m, 4H), 3.04 (d, J = 4.4 Hz, 3H).

[0358] Step 4: N 1 -methyl-N 6 -(Oxetan-3-yl)-4-phenyl-2,7-naphthyridine-1,6-diamine [ka]

[0359] A mixture of 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine (40 mg; 0.148 mmol; 1.00 equiv.), Pd-PEPPSI-IHeptCl (CAS: 1814936-54-3) (14.4 mg; 0.015 mmol; 0.10 equiv.), t-BuOK (33.3 mg; 0.297 mmol; 2.00 equiv.), and oxetan-3-amine (10.8 mg; 0.148 mmol; 1.00 equiv.) in dioxane (2 mL) was stirred at 90 °C for 2 h. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (1-9%) as eluent to give N-(2-methyl-2-propanol). 1 -methyl-N 6 -(oxetan-3-yl)-4-phenyl-2,7-naphthyridine-1,6-diamine (20 mg, crude) was obtained. The crude product was purified by flash chromatography on a pre-packed C18 column using 10% to 70% MeCN in water (10 mmol / L NH4HCO3) to give N 1 -methyl-N 6 -(Oxetan-3-yl)-4-phenyl-2,7-naphthyridine-1,6-diamine was obtained as an orange solid (6.3 mg, 13%). LCMS (ESI) m / z 307.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 9.11 (s, 1H), 7.71 (s, 1H), 7.69 - 7.64 (m, 1H), 7.53 - 7.45 (m, 3H), 7.42 - 7.35 (m, 3H), 6.41 (s, 1H), 4.95 - 4.85 (m, 1H), 4.79 - 4.73 (m, 2H), 4.45 - 4.40 (m, 2H), 2.96 (d, J = 4.4 Hz, 3H).

[0360] Examples 98-100: Each compound in Table 4 was prepared using similar experimental procedures to prepare Example 97, using 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine as a common intermediate and the appropriate amine:

[0361] [Table 4-1]

[0362] Example 101: Synthesis of 1-methyl-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide [ka]

[0363] To a stirred mixture of 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine (Example 97, Step 3) (30 mg; 0.111 mmol; 1.00 equiv.) in 1,4-dioxane (2 mL) was added 1-methylcyclopropane-1-carboxamide (21.9 mg; 0.221 mmol; 2.00 equiv.), Pd(dba) (10.2 mg; 0.011 mmol; 0.10 equiv.), XantPhos (12.9 mg; 0.022 mmol; 0.20 equiv.), and CsCO (72.1 mg; 0.221 mmol; 1.99 equiv.) under a nitrogen atmosphere. The reaction was stirred at 110 °C for 3 h. The desired product was observed by LCMS. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (0-6%) to give the crude product. This crude product was further purified by flash chromatography on a pre-packed C column using 20-55% MeCN in water (10 mmol / L NHHCO) to give 1-methyl-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide as an off-white solid (24.4 mg, 66%). LCMS (ESI) m / z 333.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.40 (s, 1H), 8.31 (s, 1H), 8.03 - 7.98 (m, 1H), 7.94 (s, 1H), 7.52 - 7.36 (m, 5H), 3.02 (d, J = 4.4 Hz, 3H), 1.41 (s, 3H), 1.11 - 1.07 (m, 2H), 0.65 - 0.61 (m, 2H).

[0364] Example 102 was prepared using similar experimental procedures to prepare Example 97.

[0365] [Table 4-2]

[0366] Example 103 and Example 104: Synthesis of 2-fluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (trans isomer: 103, cis isomer: 104) [ka]

[0367] Step 1: 2-Fluorocyclopropane-1-carboxamide [ka]

[0368] To a stirred solution of 2-fluorocyclopropane-1-carboxylic acid (200 mg; 1.92 mmol; 1.00 equiv.) and DMF (28 mg; 0.383 mmol; 0.20 equiv.) in CHCl (6 mL) was added dropwise at 0 °C a solution of oxalyl chloride (2 M) in CHCl (1.15 mL; 2.3 mmol; 1.20 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Upon completion, the resulting mixture was concentrated under reduced pressure. This crude product was added dropwise to a stirred solution of NH (g) in MeOH (7 M, 3 mL) at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CH2Cl2 (1%-9%) as eluent to give 2-fluorocyclopropane-1-carboxamide as an off-white solid (40 mg, 20%). LCMS (ESI) m / z 104.0, [M+H] + .

[0369] Step 2: 2-fluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (cis and trans isomers) [ka]

[0370] To a stirred mixture of 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine (Example 97, Step 3) (40 mg; 0.148 mmol; 1.00 equiv.) in dioxane (2 mL), Pd(dba) (13.6 mg; 0.015 mmol; 0.10 equiv.), XantPhos (17.2 mg; 0.030 mmol; 0.20 equiv.), CsCO (96.6 mg; 0.296 mmol; 2.00 equiv.), and 2-fluorocyclopropane-1-carboxamide (23 mg; 0.223 mmol; 1.50 equiv.) were added at room temperature under a nitrogen atmosphere. The reaction was stirred at 110 °C for 3 hours. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (1–9%) as the eluent to give two separate peaks with the desired product mass. The less polar peak was the minor component (approximately 10 mg) compared to the more polar peak (30 mg). These two peaks were further purified separately by flash chromatography on a pre-packed C column using 10%–50% MeCN in water (10 mmol / L NHHCO) to give 2-fluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide as a white solid (trans isomer) (3.8 mg, 7%) and 2-fluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide as a white solid (cis isomer) (21.5 mg, 43%). LCMS (ESI) m / z 337.1, [M+H] + HNMR for the trans isomer: 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.39 (s, 1H), 8.30 (s, 1H), 8.01 - 7.96 (m, 1H), 7.94 (s, 1H), 7.50 - 7.36 (m, 5H), 4.96 - 4.75 (m, 1H), 3.01 (d, J = 4.4 Hz, 3H), 2.60 - 2.54 (m, 1H), 1.54 - 1.42 (m, 1H), 1.26 - 1.16 (m, 1H). HNMR for cis isomer: 1 H NMR (400 MHz, DMSO-d6) δ 10.97 (s, 1H), 9.39 (s, 1H), 8.34 (s, 1H), 8.01 - 7.96 (m, 1H), 7.94 (s, 1H), 7.53 - 7.37 (m, 5H), 5.01 - 4.78 (m, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.25 - 2.16 (m, 1H), 1.66 - 1.53 (m, 1H), 1.18 - 1.08 (m, 1H).

[0371] Example 105: Synthesis of 2,2-difluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide [ka]

[0372] Step 1: N-(2,4-dimethoxybenzyl)-2,2-difluorocyclopropane-1-carboxamide [ka]

[0373] A mixture of 2,2-difluorocyclopropane-1-carboxylic acid (200 mg; 1.63 mmol; 1.00 equiv.) and HATU (741 mg; 1.94 mmol; 1.19 equiv.) in DMF (2 mL) was stirred at room temperature under a nitrogen atmosphere for 20 minutes. To this reaction mixture, DIPEA (629 mg; 4.86 mmol; 3.00 equiv.) and (2,4-dimethoxyphenyl)methanamine (543 mg; 3.24 mmol; 1.98 equiv.) were added. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. The residue was purified by flash chromatography on a pre-packed C18 column using 20% ​​to 60% MeCN in water (10 mmol / L NH4HCO3) to give N-(2,4-dimethoxybenzyl)-2,2-difluorocyclopropane-1-carboxamide as a yellow solid (393 mg, 88%). LC-MS: (ESI, m / z): [M+H] + = 272.1.

[0374] Step 2: 2,2-difluorocyclopropane-1-carboxamide [ka]

[0375] A mixture of N-(2,4-dimethoxybenzyl)-2,2-difluorocyclopropane-1-carboxamide (393 mg; 1.44 mmol; 1.00 equiv) in trifluoroacetaldehyde (3 mL) was stirred at 70 °C under a nitrogen atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2-6% MeOH in CHCl as eluent to give 2,2-difluorocyclopropane-1-carboxamide as a white solid (170 mg, 97%). LCMS (ESI) m / z 122.0, [M+H] + .

[0376] Step 3: 2,2-difluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide [ka]

[0377] To a solution of 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine (Example 97, Step 3) (50 mg; 0.185 mmol; 1.00 equiv.) and 2,2-difluorocyclopropane-1-carboxamide (27 mg; 0.223 mmol; 1.20 equiv.) in dioxane (4 mL) and CsCO (121.6 mg; 0.373 mmol; 2.00 equiv.), Pd(dba) (14 mg; 0.015 mmol; 0.10 equiv.) and XantPhos (17 mg; 0.02 mmol; 0.20 equiv.) were added. After stirring at 110 °C under a nitrogen atmosphere for 3 hours, the reaction was monitored by LCMS. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2-6% MeOH in CHCl as the eluent to give 2,2-difluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide as a yellow solid (50 mg, crude). The residue was purified by flash chromatography on a pre-packed C column using 20%-60% MeCN in water (10 mmol / L NHHCO) to give 2,2-difluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide as a white solid (24.5 mg, 46%). LCMS (ESI) m / z 355.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.41 (s, 1H), 8.33 (s, 1H), 8.04 - 7.99 (m, 1H), 7.96 (s, 1H), 7.53 - 7.38 (m, 5H), 3.02 (d, J = 4.4 Hz, 3H), 3.00 - 2.94 (m, 1H), 2.05 - 1.91 (m, 2H).

[0378] Example 106: Synthesis of N-(8-(methylamino)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0379] A mixture of KPO (53 mg; 0.250 mmol; 2.00 equiv.), N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 equiv.), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (36.6 mg; 0.150 mmol; 1.20 equiv.), and 1,1′-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (8.1 mg; 0.012 mmol; 0.10 equiv.) in 1,4-dioxane / water (5:1, 2.4 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 h. The mixture was allowed to cool to room temperature, and the solvent was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (1-10%) as the eluent to give the crude product. The crude product was further purified by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(8-(methylamino)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (23.5 mg, 52%). LCMS (ESI) m / z 359.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.92 (s, 1H), 9.41 (s, 1H), 8.36 (s, 1H), 8.28 (dd, J = 4.8, 1.2 Hz, 1H), 8.10 - 7.96 (m, 2H), 7.75 (dd, J = 4.8, 1.2 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 7.06 (dd, J = 8.0, 4.8 Hz, 1H), 3.04 (d, J = 4.4 Hz, 3H), 2.05 - 1.94 (m, 1H), 0.81 - 0.68 (m, 4H).

[0380] Examples 107-119: Each compound in Table 5 was prepared using an analogous experimental procedure to prepare Example 106, using N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a common intermediate and the appropriate boronic ester or acid.

[0381] [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0382] Example 120: Synthesis of 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid [ka]

[0383] Step 1: methyl 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylate [ka]

[0384] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (200 mg; 0.623 mmol; 1.00 equiv.) in a 2:1 DMSO / methanol mixture (9 mL), Pd(dppf)Cl.CHCl (51 mg; 0.063 mmol; 0.10 equiv.) and EtN (189 mg; 1.868 mmol; 3.00 equiv.) were added in a pressure tank. The mixture was pressurized to 20 atm with carbon monoxide and stirred at 130 °C overnight. The reaction mixture was cooled to room temperature. Upon completion, the reaction solution was diluted with EtOAc (100 mL), washed with brine (3 × 20 mL), and dried over NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 60-90% EtOAc in CH2Cl2 as the eluent to give methyl 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylate as a yellow solid (170 mg, 90%). LCMS (ESI) m / z 301.1, [M+H] + .

[0385] Step 2: 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid [ka]

[0386] A mixture of methyl 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylate (150 mg; 0.499 mmol; 1.00 equiv.) and lithium hydroxide monohydrate (42 mg; 1.00 mmol; 2.00 equiv.) in THF / water (3:1, 12 mL) was stirred at room temperature under a nitrogen atmosphere overnight. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (2 mL). The mixture was acidified with 1 M HCl to a pH of approximately 6. The precipitated solid was collected by filtration and washed with water (2 mL). The solid was dried under reduced pressure to give 6-cyclopropanamido-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid as a white solid (140 mg, 97%). 10 mg of this crude product was then further purified by flash chromatography on a pre-packed C18 column using 10-60% MeCN in water (0.05% formic acid) to give 6-cyclopropanamido-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid as a white solid (2.9 mg). LCMS (ESI) m / z 287.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.39 (s, 1H), 9.34 (s, 1H), 8.73 (s, 1H), 8.55 - 8.48 (m, 1H), 3.04 (d, J = 4.4 Hz, 3H), 2.09 - 2.00 (m, 1H), 0.88 - 0.77 (m, 4H).

[0387] Example 121: Synthesis of N-(8-(methylamino)-5-(4-phenoxypiperidine-1-carbonyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0388] A mixture of 6-cyclopropanamide-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (50 mg; 0.175 mmol; 1.00 equiv), 4-phenoxypiperidine (37.2 mg; 0.210 mmol; 1.20 equiv), HATU (100 mg; 0.263 mmol; 1.51 equiv) and DIPEA (67.6 mg; 0.523 mmol; 2.99 equiv) in DMF (3 mL) was stirred at room temperature for 2 h. Upon completion, the reaction mixture was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to afford N-(8-(methylamino)-5-(4-phenoxypiperidine-1-carbonyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (59.1 mg, 75%). LCMS (ESI) m / z 446.2, [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.23 (s, 1H), 8.35 (s, 1H), 8.00 (s, 1H), 7.30 - 7.23 (m, 2H), 7.00 - 6.89 (m, 3H), 4.72 - 4.62 (m, 1H), 4.12 - 3.79 (m, 2H), 3.68 - 3.52 (m, 1H), 3.45 - 3.36 (m, 1H), 3.10 (s, 3H), 2.24 - 1.63 (m, 5H), 1.10 - 0.88 (m, 4H).

[0389] Example 122: Synthesis of N-(8-(methylamino)-5-(piperidine-1-carbonyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0390] A mixture of 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (50 mg; 0.175 mmol; 1.00 equiv.), piperidine (17.9 mg; 0.210 mmol; 1.20 equiv.), HATU (100 mg; 0.263 mmol; 1.50 equiv.), and DIPEA (67.6 mg; 0.523 mmol; 3.00 equiv.) in DMF (3 mL) was stirred at room temperature for 1 h. The desired product was observed by LCMS. The reaction mixture was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(piperidine-1-carbonyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (42.6 mg, 69%). LCMS (ESI) m / z 354.2, [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.23 (s, 1H), 8.30 (s, 1H), 7.95 (s, 1H), 3.86–3.74 (m, 2H), 3.39–3.34 (m, 2H), 3.10 (s, 3H), 1.97–1.90 (m, 1H), 1.81–1.44 (m, 6H), 1.04–0.89 (m, 4H).

[0391] Example 123: Synthesis of 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxamide [ka]

[0392] A mixture of 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (21.3 mg; 0.074 mmol; 1 equiv.), NH4Cl (19.7 mg; 0.371 mmol; 5.00 equiv.), HATU (42.4 mg; 0.112 mmol; 1.50 equiv.) and DIPEA (28.8 mg; 0.223 mmol; 3.00 equiv.) in DMF (1.5 mL) was stirred at room temperature for 1 h. Upon completion, the reaction mixture was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to afford 6-(cyclopropanecarboxamide)-1-(methylamino)-2,7-naphthyridine-4-carboxamide as a white solid (8.6 mg, 40%). LCMS (ESI) m / z 286.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.32 (s, 1H), 8.96 (s, 1H), 8.31 (s, 1H), 8.24 - 8.19 (m, 1H), 7.67 (s, 1H), 7.10 (s, 1H), 3.00 (d, J = 4.4 Hz, 3H), 2.09 - 2.01 (m, 1H), 0.90 - 0.78 (m, 4H).

[0393] Example 124: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-1-(methylamino)-2,7-naphthyridine-4-carboxamide [ka]

[0394] To a stirred mixture of 6-cyclopropanamide-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (26 mg; 0.09 mmol; 1.00 equiv.) in DMF (1 mL) was added HATU (51.8 mg; 0.136 mmol; 1.50 equiv.). The reaction was stirred at room temperature for 20 min. To the reaction mixture was added DIPEA (35.1 mg; 0.272 mmol; 3.00 equiv.) and MeNH2.HCl (7.2 mg; 0.108 mmol; 1.2 equiv.). The reaction was stirred at room temperature for 1 h. Upon completion, the resulting mixture was purified by flash chromatography on a pre-packed C18 column using 20-80% MeCN in water (10 mmol / L NH4HCO3) to afford 6-cyclopropanamido-N-methyl-1-(methylamino)-2,7-naphthyridine-4-carboxamide as a white solid (1.4 mg, 9%). LCMS (ESI) m / z 300.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 9.32 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 8.20 - 8.13 (m, 2H), 3.00 (d, J = 4.4 Hz, 3H), 2.76 (d, J = 4.4 Hz, 3H), 2.07 - 1.99 (m, 1H), 0.86 - 0.77 (m, 4H).

[0395] Example 125: Synthesis of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0396] Step 1: N-(8-(methylamino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0397] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (500 mg; 1.557 mmol; 1.00 equiv.) in DMF (7 mL, deoxygenated before use), CuI (9 mg; 0.047 mmol; 0.03 equiv.), Pd(PPh)Cl (21.9 mg; 0.031 mmol; 0.02 equiv.), PPh (8.2 mg; 0.031 mmol; 0.02 equiv.), piperidine (205 mg; 2.411 mmol; 1.55 equiv.), and ethynyltrimethylsilane (504.6 mg; 5.137 mmol; 3.30 equiv.) were added at room temperature. The reaction was stirred at 90° C. for 16 hours. The reaction mixture was monitored by LCMS. The reaction was diluted with EtOAc (100 mL) and the organic phase was washed with saturated NaCl solution (3 × 10 mL). The organic phase was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 20-60% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (397 mg, 75%). LCMS (ESI) m / z 339.2, [M+H] + .

[0398] Step 2: N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0399] To a stirred mixture of N-(8-(methylamino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (397 mg; 1.17 mmol; 1.00 equiv) in MeOH (10 mL) was added K2CO3 (431 mg; 3.16 mmol; 2.70 equiv) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 2 h. Upon completion, the reaction was diluted with EtOAc (100 mL) and the organic phase was washed with saturated NaCl solution (2 x 10 mL). The organic phase was dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1-9% MeOH in CHCl as the eluent to give N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (300 mg, 96%). 10 mg of the crude product was then purified by flash chromatography on a pre-packed C column using 20-60% MeCN in water (10 mmol / L NHHCO) to give N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (2.9 mg). LCMS (ESI) m / z 267.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.34 (s, 1H), 8.52 (s, 1H), 8.31 - 8.24 (m, 1H), 8.21 (s, 1H), 4.35 (s, 1H), 2.99 (d, J = 4.4 Hz, 3H), 2.11 - 2.03 (m, 1H), 0.91 - 0.80 (m, 4H).

[0400] Example 126: Synthesis of N-(5-(3-bromoisoxazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0401] To a stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (80 mg; 0.300 mmol; 1.00 equiv) in EtOAc / water (5:1, 3.6 mL) was added KHCO (90.3 mg; 0.902 mmol; 3.00 equiv) and hydroxycarbonimidic dibromide (140.1 mg; 0.691 mmol; 2.30 equiv) at room temperature. The reaction was stirred at room temperature for 1 hour. Another portion of KHCO (90.3 mg; 0.902 mmol; 3.00 equiv) and hydroxycarbonimidic dibromide (140.1 mg; 0.691 mmol; 2.30 equiv) was added at room temperature. The reaction was stirred at room temperature for 1.5 hours. The progress of the reaction was monitored by LCMS. The reaction was diluted with EtOAc (50 mL) and the organic phase was washed with saturated NaCl solution (1 × 5 mL). The organic phase was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1-9% MeOH in CHCl as eluent to give N-(5-(3-bromoisoxazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (70 mg, crude). 20 mg of this crude product was then purified by reverse-phase preparative HPLC (Prep-C18, 5 μM OBD column, 30 × 150 mm, waters; gradient elution with 40–48% MeCN in water over an 8-minute period, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give N-(5-(3-bromoisoxazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (4.7 mg). LCMS (ESI) m / z 388.0, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.42 (s, 1H), 8.72 (s, 1H), 8.60 - 8.54 (m, 1H), 8.46 (s, 1H), 7.03 (s, 1H), 3.05 (d, J = 4.4 Hz, 3H), 2.12 - 2.02 (m, 1H), 0.90 - 0.82 (m, 4H).

[0402] Example 127: Synthesis of N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0403] Step 1: 1-Cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one [ka]

[0404] To a stirred mixture of CuI (38.9 mg; 0.204 mmol; 0.04 equiv.) and Pd(PPh3)2Cl2 (71.6 mg; 0.102 mmol; 0.02 equiv.) in THF (10 mL, deoxygenated prior to use) was added cyclopropanecarbonyl chloride (530.6 mg; 5.076 mmol; 1.00 equiv.), Et3N (519.9 mg; 5.138 mmol; 1.01 equiv.), and ethynyltrimethylsilane (500 mg; 5.091 mmol; 1.00 equiv.). The reaction was stirred at room temperature under a N2 atmosphere for 1 h. The desired product was observed by LCMS. The reaction was quenched with saturated NH4Cl solution (20 mL) and then extracted with EtOAc (3 × 20 mL). The combined organic phase was washed with saturated NaCl solution (1 × 5 mL). The solution was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1-10% EtOAc in petroleum ether as eluent to give 1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one as a yellow oil (520 mg, 61%). LCMS (ESI) m / z 167.1, [M+H] + .

[0405] Step 2: N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0406] To a mixture of Pd(PPh)Cl (45.6 mg; 0.062 mmol; 0.10 equiv.), PPh (32.7 mg; 0.124 mmol; 0.20 equiv.), CuI (59.3 mg; 0.312 mmol; 0.50 equiv.), and N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (200 mg; 0.625 mmol; 1.00 equiv.) in DMF (10 mL, deoxygenated prior to use) was added EtN (145.1 mg; 1.43 mmol; 2.30 equiv.) and 1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one (155.6 mg; 0.937 mmol; 1.50 equiv.). To this mixture was added a solution of TBAF in THF (1 M) (0.93 mL; 0.93 mmol; 1.50 equiv.). The reaction mixture was stirred at 90 °C for 3 h. The resulting mixture was diluted with EtOAc (100 mL), and the organic phase was washed with saturated NaCl solution (3 × 10 mL). The organic phase was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1–10% MeOH in CHCl as the eluent to give the crude product. The crude product was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as eluent to give N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (100 mg, 48%). 2.1 mg of the desired product was then removed. LCMS (ESI) m / z 335.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 9.38 (s, 1H), 8.74 - 8.67 (m, 1H), 8.49 (s, 1H), 8.42 (s, 1H), 3.04 (d, J = 4.4 Hz, 3H), 2.25 - 2.15 (m, 1H), 2.13 - 2.02 (m, 1H), 1.27 - 1.08 (m, 4H), 0.93 - 0.80 (m, 4H).

[0407] Example 128: Synthesis of N-(8-(methylamino)-5-propionyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0408] Step 1: (Z)—N-(5-(1-ethoxyprop-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0409] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.) in ethylene glycol (2 mL, deoxygenated prior to use), Pd(OAc) (0.7 mg; 0.003 mmol; 0.02 equiv.), DPPP (2.6 mg; 0.006 mmol; 0.04 equiv.), and EtN (31.6 mg; 0.312 mmol; 2.00 equiv.) were added. The reaction was stirred at 80° C. for 2 minutes, after which (E)-1-ethoxyprop-1-ene (26.9 mg; 0.312 mmol; 2.00 equiv.) was added. The reaction was stirred at 100° C. for 1 hour. The resulting mixture was diluted with EtOAc (50 mL), and the organic phase was washed with saturated NaCl solution (3 × 5 mL). The solution was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1-10% MeOH in CHCl as eluent to give (Z)-N-(5-(1-ethoxyprop-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (17 mg, 33%). LCMS (ESI) m / z 327.2, [M+H] + .

[0410] Step 2: N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0411] To a stirred mixture of a solution of (Z)—N-(5-(1-ethoxyprop-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (17 mg; 0.026 mmol; 1.00 equiv) in DMF (2 mL) was added a solution of HCl solution (0.26 mL, 5%) at 0° C. The reaction was stirred at room temperature overnight. The desired product was observed by LCMS. The product mixture was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) as eluent to give N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (1.9 mg, 24%). LCMS (ESI) m / z 299.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 9.49 (s, 1H), 9.35 (s, 1H), 8.84 (s, 1H), 8.65 - 8.60 (m, 1H), 3.06 (d, J = 4.4 Hz, 3H), 2.96 (q, J = 7.2 Hz, 2H), 2.08 - 2.02 (m, 1H), 1.09 (t, J = 7.2 Hz, 3H), 0.90 - 0.80 (m, 4H).

[0412] Example 129: Synthesis of (E)-N-(8-(methylamino)-5-(prop-1-en-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0413] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.), Pd(OAc) (0.7 mg; 0.003 mmol; 0.02 equiv.), and DPPP (2.6 mg; 0.006 mmol; 0.04 equiv.) in ethylene glycol (2 mL, deoxygenated before use). To this reaction mixture was added EtN (31.6 mg; 0.312 mmol; 2.00 equiv.). The reaction was stirred at 80° C. for 2 minutes, after which (E)-1-ethoxyprop-1-ene (26.9 mg; 0.312 mmol; 2.00 equiv.) was added. The reaction was stirred at 100° C. for 1 hour. The resulting mixture was diluted with EtOAc (50 mL), and the organic phase was washed with saturated NaCl solution (3 × 5 mL). The solution was dried over NaSO, filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1–10% MeOH in CHCl as eluent to give the crude product. The crude product was then purified by reverse-phase preparative HPLC (Prep-C18, 5 μM OBD column, 19 × 150 mm, waters; gradient elution with 22–32% MeCN in water over an 8-minute period, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give (E)-N-(8-(methylamino)-5-(prop-1-en-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (2.6 mg, 35%). LCMS (ESI) m / z 283.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.00 (s, 1H), 9.32 (s, 1H), 8.43 (s, 1H), 8.08 (s, 1H), 7.92 - 7.85 (m, 1H), 6.57 (d, J = 14.8 Hz, 1H), 6.13 - 6.03 (m, 1H), 2.96 (d, J = 4.4 Hz, 3H), 2.10 - 2.02 (m, 1H), 1.89 (dd, J = 6.4, 1.2 Hz, 3H), 0.90 - 0.79 (m, 4H).

[0414] Example 130: Synthesis of N-(8-(methylamino)-5-(2-methyloxazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0415] To a stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.188 mmol; 1.00 equiv) in MeCN (2.5 mL) was added (triphenyl((1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methyl)sulfonamide)-λ 5 -phosphanyl)gold((triphenyl((1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methyl)sulfonamido)-λ 5N-(8-(methylamino)-5-(2-methyloxazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude) was purified by flash chromatography on a silica gel column using 1-9% MeOH in CHCl as the eluent. The crude product was then purified by reverse-phase preparative HPLC (Prep-C18, 5 μM YMC-Actus Triart column, 30 × 150 mm, waters; gradient elution with 19–29% MeCN in water over a 10-minute period, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give N-(8-(methylamino)-5-(2-methyloxazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (2.1 mg, 3%). LCMS (ESI) m / z 324.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.24 (s, 1H), 8.24 - 8.20 (m, 1H), 7.19 (s, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.48 (s, 3H), 2.10 - 2.02 (m, 1H), 0.89 - 0.79 (m, 4H).

[0416] Example 131: Synthesis of N-(5-(1-benzyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0417] Step 1: (1-benzyl-1H-pyrazol-3-yl)boronic acid [ka]

[0418] To a stirred mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (500 mg; 2.577 mmol; 1.00 equiv.) in DMF (5 mL), NaH (206.1 mg; 5.154 mmol; 2.00 equiv., 60%) was added at 0° C. and stirred at room temperature under a nitrogen atmosphere for 30 minutes. To this reaction mixture, (bromomethyl)benzene (528.8 mg; 3.092 mmol; 1.20 equiv.) was added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The desired product was observed by LCMS. The resulting mixture was quenched with saturated NH4Cl solution (0.2 mL). The resulting mixture was purified by flash chromatography on a pre-packed C18 column using 10-40% MeCN in water (10 mmol / L NH4HCO3) as eluent to give (1-benzyl-1H-pyrazol-3-yl)boronic acid as an off-white oil (180 mg, 24%). LCMS (ESI) m / z 203.1, [M+H] + .

[0419] Step 2: N-(5-(1-benzyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0420] To a stirred mixture of (1-benzyl-1H-pyrazol-3-yl)boronic acid (31.4 mg; 0.156 mmol; 1.00 equiv.) in a 5:1 1,4-dioxane / water mixture (1.2 mL), XPhos Pd G3 (13.2 mg; 0.016 mmol; 0.1 equiv.), XPhos (7.4 mg; 0.016 mmol; 0.10 equiv.), K3PO4 (99.1 mg; 0.468 mmol; 3.00 equiv.), and N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 equiv.) were added at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 hours. Upon completion, the mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1-8% MeOH in CHCl as the eluent to give 25 mg of crude product. The crude product was purified by flash chromatography on a pre-packed C column using 10-40% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(5-(1-benzyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as an off-white solid (21.0 mg, 33%). LCMS (ESI) m / z 399.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.35 (s, 1H), 9.00 (s, 1H), 8.21 (s, 1H), 7.96 - 7.92 (m, 1H), 7.90 (d, J = 2.0 Hz, 1H), 7.45 - 7.28 (m, 5H), 6.53 (d, J = 2.0 Hz, 1H), 5.37 (s, 2H), 3.00 (d, J = 4.4 Hz, 3H), 2.08 - 2.02 (m, 1H), 0.90 - 0.80 (m, 4H).

[0421] Example 132: Synthesis of N-(8-(methylamino)-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0422] Step 1: 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine [ka]

[0423] To a stirred mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (100 mg; 0.454 mmol; 1.00 equiv.) in THF (2 mL) was added PPh3 (238.3 mg; 0.908 mmol; 2.00 equiv.), 1-methylpiperidin-4-ol (104.6 mg; 0.908 mmol; 2.00 equiv.), and DIAD (183.7 mg; 0.908 mmol; 2.00 equiv.). The reaction mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction was monitored by LCMS. Upon completion, the resulting mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to give 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine as a white solid (48 mg; 34%). LCMS (ESI) m / z 318.2 [M+H] + .

[0424] Step 2: N-(8-(methylamino)-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0425] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (36 mg; 0.112 mmol; 1.00 equiv.), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine (36 mg; 0.112 mmol; 1.00 equiv.), Pd(DtBPF)Cl (8 mg; 0.011 mmol; 0.10 equiv.), and KPO (48 mg; 0.224 mmol; 2.00 equiv.) in 1,4-dioxane / water (5:1, 1.2 mL) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2-10% MeOH in CHCl as the eluent to give the crude product. This crude product was purified again by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (12.4 mg, 26%). LCMS (ESI) m / z 432.2, [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 9.25 (s, 1H), 8.39 (s, 1H), 7.83 (s, 1H), 7.44 - 7.36 (m, 2H), 7.19 - 7.11 (m, 2H), 4.83 - 4.79 (m, 1H), 3.52 - 3.39 (m, 4H), 3.12 (s, 3H), 2.93 (s, 3H), 2.31 - 2.11 (m, 4H), 1.99 - 1.90 (m, 1H), 0.99 - 0.86 (m, 4H).

[0426] Example 133: Synthesis of N-(8-(methylamino)-5-(5-methyloxazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0427] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.187 mmol; 1.00 equiv.), 5-methyl-2-(tributylstannyl)oxazole (104.3 mg; 0.280 mmol; 1.50 equiv.), Pd(PPh3)4 (43.3 mg; 0.037 mmol; 0.20 equiv.), CuI (7.12 mg; 0.037 mmol; 0.2 equiv.), and LiCl (15.8 mg; 0.373 mmol; 2.00 equiv.) in 1,4-dioxane (3 mL) was stirred at 100 °C for 3 h. Upon completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (0-20%) as the eluent to give N-(8-(methylamino)-5-(5-methyloxazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (36.4 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20-60% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-(5-methyloxazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (5.7 mg, 9%). LCMS (ESI) m / z 324.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.51 (s, 1H), 9.39 (s, 1H), 8.60 (s, 1H), 8.41 - 8.35 (m, 1H), 7.00 (s, 1H), 3.04 (d, J = 4.4 Hz, 3H), 2.38 (s, 3H), 2.09 - 2.04 (m, 1H), 0.90 - 0.81 (m, 4H).

[0428] Example 134: Synthesis of N-(8-(methylamino)-5-(phenylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0429] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 equiv.), aniline (11.6 mg; 0.125 mmol; 1.00 equiv.), EPhos Pd G4 (11.5 mg; 0.013 mmol; 0.10 equiv.), EPhos (7 mg; 0.013 mmol; 0.10 equiv.), and CsCO3 (81.2 mg; 0.250 mmol; 2.00 equiv.) in 1,4-dioxane (1.5 mL) was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction was monitored by LCMS. The reaction was concentrated, and the residue was purified by flash chromatography on a silica gel column using MeOH / CHCl2 (2–10%) as eluent to give the crude product. The crude product was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(phenylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (28.4 mg, 69%). LCMS (ESI) m / z 334.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.34 (s, 1H), 8.26 (s, 1H), 7.88 (s, 1H), 7.84 - 7.81 (m, 1H), 7.42 (s, 1H), 7.07 - 7.01 (m, 2H), 6.60 - 6.49 (m, 3H), 2.98 (d, J = 4.4 Hz, 3H), 2.09 - 1.99 (m, 1H), 0.82 - 0.71 (m, 4H).

[0430] Example 135 and Example 136: Synthesis of (E)-N-(5-(4-methoxystyryl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and (Z)-N-(5-(4-methoxystyryl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0431] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50.0 mg; 0.156 mmol; 1.00 equiv.) in DMF (2 mL), Pd(PPh3)2Cl2 (10.9 mg; 0.016 mmol; 0.10 equiv.), Na2CO3 (33.0 mg; 0.312 mmol; 2.00 equiv.), and 1-methoxy-4-vinylbenzene (20.8 mg; 0.156 mmol; 1.00 equiv.) were added at room temperature. The resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 2 h. The desired product was observed by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1–6% MeOH in CHCl2 as the eluent to give 15 mg of a crude product mixture. The crude product of this mixture was purified by reverse-phase preparative HPLC (Prep-C18, XBridge Shield RP18 OBD column, 30 × 150 mm, water; gradient elution with 35–45% MeCN in water over a 10-minute period, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to give (E)-N-(5-(4-methoxystyryl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (8.9 mg, 15%). LCMS (ESI) m / z 375.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1H), 9.35 (s, 1H), 8.56 (s, 1H), 8.30 (s, 1H), 8.03 - 7.95 (m, 1H), 7.55 - 7.47 (m, 2H), 7.22 (d, J = 16.4 Hz, 1H), 7.04 - 6.95 (m, 3H), 3.79 (s, 3H), 3.01 (d, J = 4.4 Hz, 3H), 2.13 - 2.02 (m, 1H), 0.92 - 0.79 (m, 4H); and (Z)—N-(5-(4-methoxystyryl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide was obtained as a white solid (2.7 mg, 4%). LCMS (ESI) m / z 375.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.81 (s, 1H), 9.33 (s, 1H), 7.99 (s, 1H), 7.95 - 7.92 (m, 1H), 7.84 (s, 1H), 7.26 - 7.20 (m, 2H), 6.89 - 6.81 (m, 2H), 5.78 (d, J = 1.2 Hz, 1H), 5.16 (d, J = 1.2 Hz, 1H), 3.73 (s, 3H), 3.00 (d, J = 4.4 Hz, 3H), 2.00 - 1.91 (m, 1H), 0.79 - 0.72 (m, 4H).

[0432] Example 137: Synthesis of N-(8-(methylamino)-5-(phenylethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0433] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 equiv.), CuI (1.8 mg; 0.009 mmol; 0.02 equiv.), Pd(PPh3)2Cl2 (4.4 mg; 0.006 mmol; 0.02 equiv.), piperidine (26.5 mg; 0.311 mmol; 1.00 equiv.), and PPh3 (1.6 mg; 0.006 mmol; 0.02 equiv.) in DMF (3 mL) was stirred at 90 °C under a nitrogen atmosphere for 12 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2–10% MeOH in CHCl2 as the eluent to give the crude desired product. The product was purified again by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to give N-(8-(methylamino)-5-(phenylethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (20.7 mg, 19.4%). LCMS (ESI) m / z 343.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 9.37 (s, 1H), 8.66 (s, 1H), 8.36 - 8.30 (m, 1H), 8.28 (s, 1H), 7.61 - 7.36 (m, 5H), 3.02 (d, J = 4.4 Hz, 3H), 2.11 - 2.02 (m, 1H), 0.95 - 0.80 (m, 4H).

[0434] Example 138: Synthesis of N-(8-(methylamino)-5-(3-methylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0435] A mixture of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50.0 mg; 0.136 mmol; 1.00 equiv.), 5-bromo-3-methylisothiazole (24.1 mg; 0.135 mmol; 1.00 equiv.), XPhos Pd G3 (11.5 mg; 0.014 mmol; 0.10 equiv.), XPhos (6.5 mg; 0.014 mmol; 0.10 equiv.), and KPO4 (86.4 mg; 0.407 mmol; 3.00 equiv.) in a 7:1 1,4-dioxane / water mixture (2.4 mL) was stirred at 90 °C under a nitrogen atmosphere for 1 h. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (0-20%) as the eluent to give a crude brown solid (30.1 mg). This crude product was purified on a C18 column using 33-62% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(8-(methylamino)-5-(3-methylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (14.9 mg, 32%). LCMS (ESI) m / z 340.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1H), 9.40 (s, 1H), 8.62 (s, 1H), 8.30 - 8.27 (m, 1H), 8.19 (s, 1H), 7.34 (s, 1H), 3.02 (d, J = 4.4 Hz, 3H), 2.48 (s, 3H), 2.09 - 2.04 (m, 1H), 0.90 - 0.78 (m, 4H).

[0436] Examples 139-145: Each compound in Table 6 below was prepared following the same experimental procedure as previously described in Example 138.

[0437] [Table 6-1] [Table 6-2] [Table 6-3]

[0438] Example 146: Synthesis of N-(8-(methylamino)-5-(3-phenylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0439] Step 1: 5-chloro-3-phenylisothiazole [ka]

[0440] To a stirred mixture of CuCl2 (58 mg; 0.426 mmol; 1.50 equiv.) and tert-butylnitrite (44 mg; 0.426 mmol; 1.50 equiv.) in MeCN (1 mL) was added. The reaction mixture was stirred at 60 °C for 2 min. To this mixture, a solution of 3-phenylisothiazol-5-amine (50 mg; 0.284 mmol; 1.00 equiv.) in MeCN (0.5 mL) was added, and the reaction mixture was stirred at 60 °C for 1 h. The reaction was monitored by LCMS. The mixture was acidified to pH 3 with a solution of HCl (1 N). The resulting mixture was extracted with CHCl (2 × 20 mL). The combined organic layers were washed with brine (1 × 5 mL) and dried over anhydrous NaSO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 5-15% EtOAc in petroleum ether as the eluent to give 5-chloro-3-phenylisothiazole as a white solid (30 mg, 75%). LCMS (ESI) m / z 196.0, [M+H] + .

[0441] Step 2: N-(8-(methylamino)-5-(3-phenylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0442] To a solution of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg; 0.081 mmol; 1.00 equiv.) in a 1,4-dioxane / water mixture (5:1, 1.2 mL), 5-chloro-3-phenylisothiazole (16 mg; 0.081 mmol; 1.00 equiv.), XPhos Pd G3 (6.9 mg; 0.008 mmol; 0.10 equiv.), XPhos (3.9 mg; 0.008 mmol; 0.10 equiv.), and K3PO4 (34.6 mg; 0.162 mmol; 2.00 equiv.) were added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 h. The reaction was monitored by LCMS. The residue was purified by flash chromatography on a silica gel column using (MeOH / CHCl: 2-10%) as the eluent to give N-(8-(methylamino)-5-(3-phenylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (28.6 mg, crude). The crude product was purified again by flash chromatography on a pre-packed C column using 20-50% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-(3-phenylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (8.6 mg, 27%). LCMS (ESI) m / z 402.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.10 (s, 1H), 9.43 (s, 1H), 8.72 (s, 1H), 8.36 - 8.34 (m, 1H), 8.33 (s, 1H), 8.11 (s, 1H), 8.10 - 8.07 (m, 2H), 7.56 - 7.45 (m, 3H), 3.05 (d, J = 4.4 Hz, 3H), 2.10 - 2.02 (m, 1H), 0.87 - 0.78 (m, 4H).

[0443] Example 147: Synthesis of N-(5-(1-ethyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0444] Step 1: 3-Bromo-1-ethyl-1H-pyrazole and 5-Bromo-1-ethyl-1H-pyrazole [ka]

[0445] To a stirred solution of 3-bromo-1H-pyrazole (500.2 mg; 3.40 mmol; 1.00 equiv.) and Cs2CO3 (2.21 g; 6.78 mmol; 2.00 equiv.) in DMF (10 mL) was added iodoethane (796.6 mg; 5.10 mmol; 1.50 equiv.). The resulting mixture was stirred at room temperature for 2 h. The desired product (two peaks with the desired product mass) could be detected by LCMS. The resulting mixture was diluted with EtOAc (100 mL). This was followed by a standard aqueous workup with EtOAc. The combined organic layers were washed with brine (5 mL × 3). The resulting EtOAc was dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CH2Cl2 (0-2%) to give 3-bromo-1-ethyl-1H-pyrazole as a yellow oil (340.5 mg, 57%) and 5-bromo-1-ethyl-1H-pyrazole as a yellow oil (60 mg, 10%). LCMS (ESI) m / z 175.0, [M+H] + .

[0446] Step 2: N-(5-(1-ethyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0447] To a stirred solution of 3-bromo-1-ethyl-1H-pyrazole (36.8 mg; 0.21 mmol; 1.30 equiv.) and N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.16 mmol; 1.00 equiv.) in a 1,4-dioxane / water mixture (10:1, 3.3 mL) was added XPhos Pd G3 (13.7 mg; 0.016 mmol; 0.10 equiv.), XPhos (7.7 mg; 0.016 mmol; 0.10 equiv.), and K3PO4 (90 mg; 0.42 mmol; 2.00 equiv.). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 1 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (4-6%) to give the crude product (20 mg). This crude product was further purified by flash chromatography on a pre-packed C column using 50-70% MeCN / water (50-70% and 10 mmol / L NHHCO) to give N-(5-(1-ethyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as an off-white solid (10.2 mg, 30%). LCMS (ESI) m / z 337.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.35 (s, 1H), 9.01 (s, 1H), 8.20 (s, 1H), 7.96 - 7.91 (m, 1H), 7.81 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.00 (d, J = 4.4 Hz, 3H), 2.09 - 2.01 (m, 1H), 1.46 (t, J = 7.2 Hz, 3H), 0.88 - 0.78 (m, 4H).

[0448] Example 148: Synthesis of N-(5-(1-isopropyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0449] Step 1: 3-Bromo-1-isopropyl-1H-pyrazole and 5-Bromo-1-isopropyl-1H-pyrazole [ka]

[0450] To a stirred solution of 3-bromo-1H-pyrazole (500.2 mg; 3.40 mmol; 1.00 equiv.) and CsCO (2.21 g; 6.804 mmol; 2.00 equiv.) in DMF (10 mL) was added 2-iodopropane (867.4 mg; 5.103 mmol; 1.50 equiv.). The resulting mixture was stirred at room temperature for 2 hours. The desired product (two peaks with the desired product mass) was detected by LCMS. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3 × 5 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CH2Cl2 (1-2%) as eluent to give 3-bromo-1-isopropylpyrazole as a yellow oil (370 mg, 57%) and 5-bromo-1-isopropyl-1H-pyrazole as a yellow oil (120 mg, 18%). LCMS (ESI) m / z 189.0, [M+H] + .

[0451] Step 2: N-(5-(1-isopropyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0452] To a stirred solution of 3-bromo-1-isopropylpyrazole (39.8 mg; 0.211 mmol; 1.30 equiv.) and N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.16 mmol; 1.00 equiv.) in a 1,4-dioxane / water mixture (10:1, 3.3 mL) was added XPhos Pd G3 (13.7 mg; 0.016 mmol; 0.10 equiv.), XPhos (7.7 mg; 0.016 mmol; 0.10 equiv.), and K3PO4 (90 mg; 0.42 mmol; 2.00 equiv.). The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 1 h. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (0-5%) as the eluent to give the title compound (20 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 20-60% MeCN in water (10 mmol / L NHHCO) to give N-(5-(1-isopropyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as an off-white solid (7.1 mg, 20%). LCMS (ESI) m / z 351.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.35 (s, 1H), 9.09 (s, 1H), 8.21 (s, 1H), 7.98 - 7.92 (m, 1H), 7.83 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 4.60 - 4.48 (m, 1H), 3.00 (d, J = 4.4 Hz, 3H), 2.09 - 2.01 (m, 1H), 1.50 (d, J = 6.8 Hz, 6H), 0.90 - 0.78 (m, 4H).

[0453] Example 149: Synthesis of N-(5-(1-isobutyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0454] Step 1: 3-Bromo-1-isobutyl-1H-pyrazole and 5-Bromo-1-isobutyl-1H-pyrazole [ka]

[0455] To a stirred solution of 3-bromo-1H-pyrazole (500.2 mg; 3.40 mmol; 1.00 equiv.) and CsCO (2.21 g; 6.80 mmol; 2.00 equiv.) in DMF (10 mL) was added 1-iodo-2-methylpropane (945.2 mg; 5.10 mmol; 1.5 equiv.). The resulting mixture was stirred at room temperature for 2 h. The desired product (two peaks with the desired product mass) was detected by LCMS. The resulting mixture was diluted with EtOAc (100 mL) and washed with brine (3 × 5 mL). The organic layer was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using CHCl in petroleum ether (0-60%) as the eluent to give 3-bromo-1-isobutyl-1H-pyrazole as a yellow oil (150 mg, 21%) and 5-bromo-1-isobutyl-1H-pyrazole as a yellow oil (20 mg, 2%). LCMS (ESI) m / z 203.0, [M+H] + .

[0456] Step 2: N-(5-(1-isobutyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0457] To a stirred solution of 3-bromo-1-isobutyl-1H-pyrazole (42.8 mg; 0.211 mmol; 1.30 equiv) and N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.16 mmol; 1.00 equiv) in a 1,4-dioxane / water mixture (10:1, 3.3 mL) was added XPhos Pd G3 (13.7 mg; 0.016 mmol; 0.10 equiv), XPhos (7.7 mg; 0.016 mmol; 0.10 equiv), and K3PO4 (90 mg; 0.42 mmol; 2.00 equiv). The resulting mixture was stirred at 90°C under a nitrogen atmosphere for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified on a silica gel column using MeOH / CHCl (0-5%) as an eluent to give the title compound (12 mg, crude). The crude product was purified by flash chromatography on a pre-packed C column using 10-37% MeCN in water (10 mmol / L NHHCO) as an eluent to give N-(5-(1-isobutyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as an off-white solid (6.9 mg, 23%). LCMS (ESI) m / z 365.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.35 (s, 1H), 8.94 (s, 1H), 8.18 (s, 1H), 7.98 - 7.90 (m, 1H), 7.79 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 3.95 (d, J = 7.2 Hz, 2H), 3.00 (d, J = 4.4 Hz, 3H), 2.30 - 2.20 (m, 1H), 2.08 - 2.00 (m, 1H), 0.89 (d, J = 6.8 Hz, 6H), 0.84 - 0.77 (m, 4H).

[0458] Example 150: Synthesis of N-(5-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0459] Step 1: 3-((3-bromo-1H-pyrazol-1-yl)methyl)-1-methyl-1H-1,2,4-triazole [ka]

[0460] To a stirred solution of 3-bromo-1H-pyrazole (212.2 mg; 1.442 mmol; 1.20 equiv.) and CsCO (780.3 mg; 2.394 mmol; 2.00 equiv.) in DMF (4 mL) was added 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (200.3 mg; 1.198 mmol; 1.00 equiv.). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The desired product could be detected by LCMS. The resulting mixture was diluted with EtOAc (100 mL). The resulting mixture was washed with brine (3 × 5 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 3-((3-bromo-1H-pyrazol-1-yl)methyl)-1-methyl-1H-1,2,4-triazole as a yellow oil (220 mg, 76%). LCMS (ESI) m / z 242.0, [M+H] + .

[0461] Step 2: N-(5-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0462] To a stirred solution of 3-((3-bromo-1H-pyrazol-1-yl)methyl)-1-methyl-1H-1,2,4-triazole (85.2 mg; 0.352 mmol; 1.30 equiv.) and N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100.2 mg; 0.272 mmol; 1.00 equiv.) in a 5:1 1,4-dioxane / water mixture (2.4 mL) was added XPhos Pd G3 (23.4 mg; 0.027 mmol; 0.10 equiv.), XPhos (13.2 mg; 0.027 mmol; 0.10 equiv.), and KPO (172.8 mg; 0.815 mmol; 3.00 equiv.) were added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 1 h. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (5–20%) as the eluent to give the crude product. The crude product was purified by reverse-phase preparative HPLC (Prep-C18, XBridge Shield RP18 OBD column, 30 × 150 mm, waters; gradient elution with 15–25% MeCN in water over a 10-minute period, where both water and MeCN contained 10 mmol / L NH4HCO3, flow rate: 10 mL / min, detector UV wavelength: 254 nm) to give N-(5-(1-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a yellow solid (2.4 mg, 2%). LCMS (ESI) m / z 404.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.88 (s, 1H), 9.35 (s, 1H), 8.84 (s, 1H), 8.43 (s, 1H), 8.17 (s, 1H), 8.00 - 7.92 (m, 1H), 7.85 (d, J = 2.0 Hz, 1H), 6.50 (d, J = 2.0 Hz, 1H), 5.38 (s, 2H), 3.85 (s, 3H), 3.00 (d, J = 4.4 Hz, 3H), 2.10 - 2.00 (m, 1H), 0.90 - 0.78 (m, 4H).

[0463] Example 151: Synthesis of N-(8-(methylamino)-5-(1-(thiazol-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0464] Step 1: 2-((3-bromo-1H-pyrazol-1-yl)methyl)thiazole [ka]

[0465] A mixture of 3-bromo-1H-pyrazole (395.2 mg; 2.689 mmol; 1.20 equiv.) in DMF (5 mL) was treated with NaH (107.8 mg; 4.492 mmol; 2.00 equiv.) at 0 °C and stirred at room temperature under a nitrogen atmosphere for 0.5 h. To this mixture, 2-(chloromethyl)thiazole (300.0 mg; 2.246 mmol; 1.00 equiv.) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for an additional 2 h. The desired product could be detected by LCMS. The reaction was quenched with sat. NH4Cl solution (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (50 mL × 3). The organic layer was washed with brine (10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified on a silica gel column using 10-50% CH2Cl2 in petroleum ether as the eluent to give 2-((3-bromo-1H-pyrazol-1-yl)methyl)thiazole as a yellow solid (309.0 mg, 56%). LCMS (ESI) m / z 243.9, [M+H] + .

[0466] Step 2: N-(8-(methylamino)-5-(1-(thiazol-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0467] A mixture of 2-((3-bromo-1H-pyrazol-1-yl)methyl)thiazole (66.2 mg; 0.271 mmol; 1.00 equiv.) and N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100.0 mg; 0.272 mmol; 1.00 equiv.) in a 1,4-dioxane / water mixture (5:1, 2.4 mL) was added to XPhos Pd G3 (22.9 mg; 0.027 mmol; 0.10 equiv.) and XPhos (12.9 mg; 0.027 mmol; 0.10 equiv.) and K3PO4 (172.9 mg; 0.815 mmol; 3.00 equiv.). The resulting mixture was stirred at 90°C under a nitrogen atmosphere for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 2-10% MeOH in CHCl as the eluent to give the crude product. The crude product was purified by flash chromatography on a pre-packed C column using 20-60% MeCN in water (10 mmol / L NHHCO) to give N-(8-(methylamino)-5-(1-(thiazol-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (4.5 mg, 4%). LCMS (ESI) m / z 406.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.36 (s, 1H), 8.85 (s, 1H), 8.21 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.79 (d, J = 3.2 Hz, 1H), 7.69 (d, J = 3.2 Hz, 1H), 6.57 (d, J = 2.0 Hz, 1H), 5.75 (s, 2H), 3.00 (d, J = 4.4 Hz, 3H), 2.09 - 2.01 (m, 1H), 0.88 - 0.76 (m, 4H).

[0468] Example 152: Synthesis of N-(5-(1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0469] Step 1: 3-((3-bromo-1H-pyrazol-1-yl)methyl)-5-methyl-1,2,4-oxadiazole [ka]

[0470] To a mixture of 3-bromo-1H-pyrazole (399 mg; 2.72 mmol; 1.20 equiv.) in DMF (5.0 mL) was added CsCO (1.84 g; 5.66 mmol; 2.50 equiv.) at room temperature, followed by the addition of 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (300 mg; 2.26 mmol; 1.00 equiv.) portionwise at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The desired product was detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 25–60% EtOAc in CHCl as the eluent to give 3-((3-bromo-1H-pyrazol-1-yl)methyl)-5-methyl-1,2,4-oxadiazole as an off-white oil (150 mg, 27%). LCMS (ESI) m / z 243.0, [M+H] + .

[0471] Step 2: N-(5-(1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0472] To a mixture of 3-((3-bromo-1H-pyrazol-1-yl)methyl)-5-methyl-1,2,4-oxadiazole (66.0 mg; 0.272 mmol; 1.00 equiv.), N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide) (100 mg; 0.272 mmol; 1.00 equiv.) in a 5:1 1,4-dioxane / water mixture (3 mL), Pd(DtBPF)Cl (17.8 mg; 0.027 mmol; 0.100 equiv.) and KPO (115 mg; 0.542 mmol; 2.00 equiv.) were added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. The desired product was observed by LCMS. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (0-20%) as the eluent to give a yellow crude product (33 mg). This crude product was purified on a C18 column using 25-60% MeCN in water (10 mmol / L NHHCO) as the eluent to give N-(5-(1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (14.6 mg, 13%). LCMS (ESI) m / z 405.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.40 (s, 1H), 8.85 (s, 1H), 8.10 (s, 1H), 7.99 (d, J = 2.0 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 5.54 (s, 2H), 3.03 (d, J = 4.4 Hz, 3H), 2.57 (s, 3H), 2.09 - 2.01 (m, 1H), 0.90 - 0.79 (m, 4H).

[0473] Example 153A: Synthesis of N-(8-(methylamino)-5-(1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0474] Step 1: (tetrahydro-2H-thiopyran-4-yl)methyl methanesulfonate [ka]

[0475] To a stirred solution of (tetrahydro-2H-thiopyran-4-yl)methanol (300.2 mg; 2.269 mmol; 1.00 equiv) and DIPEA (703.8 mg; 5.446 mmol; 2.4 equiv) in CHCl (4 mL) was added methanesulfonic anhydride (830.1 mg; 4.992 mmol; 2.20 equiv) portionwise at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The residue was diluted with CHCl (80 mL) and washed with water (2 × 10 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give (tetrahydro-2H-thiopyran-4-yl)methyl methanesulfonate as a yellow solid (450 mg, 94%). LCMS (ESI) m / z 211.0, [M+H] + .

[0476] Step 2: 3-bromo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazole [ka]

[0477] To a stirred solution of 3-bromo-1H-pyrazole (365.3 mg; 2.483 mmol; 1.49 equiv.) and CsCO (1.08 g; 3.333 mmol; 2.00 equiv.) in DMF (5 mL) was added (tetrahydro-2H-thiopyran-4-yl)methyl methanesulfonate (350.2 mg; 1.664 mmol; 1.00 equiv.). The resulting mixture was stirred at 50 °C under a nitrogen atmosphere overnight. The desired product could be detected by LCMS. The resulting mixture was diluted with CHCl (70 mL). The resulting mixture was washed with saturated NaCl solution (2 × 5 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a pre-packed C18 column using 55-60% MeCN in water (10 mmol / L NH4HCO3) to give 3-bromo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazole as a white solid (190.2 mg, 43%). LCMS (ESI) m / z 261.0, [M+H] + .

[0478] Step 3: N-(8-(methylamino)-5-(1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0479] To a stirred solution of 3-bromo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazole (46.2 mg; 0.176 mmol; 1.30 equiv.) and N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50.2 mg; 0.136 mmol; 1.00 equiv.) in a 5:1 1,4-dioxane / water mixture (2.4 mL) was added XPhos Pd G3 (11.5 mg; 0.014 mmol; 0.10 equiv.), XPhos (6.5 mg; 0.014 mmol; 0.10 equiv.), and KPO (86.2 mg; 0.405 mmol; 2.98 equiv.) were added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 1 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (0–7%) as the eluent to give the crude product. The crude product was further purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (0.05% formic acid) as the eluent to give N-(8-(methylamino)-5-(1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (5.2 mg, 9%). LCMS (ESI) m / z 423.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 9.40 (s, 1H), 9.14 (s, 1H), 8.10 (s, 1H), 7.79 (d, J = 2.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 4.00 (d, J = 7.2 Hz, 2H), 3.04 (d, J = 4.4 Hz, 3H), 2.75 - 2.65 (m, 2H), 2.59 - 2.52 (m, 2H), 2.30 - 2.19 (m, 1H), 2.09 - 2.02 (m, 1H), 1.85 - 1.77 (m, 2H), 1.36 - 1.26 (m, 2H), 0.89 - 0.79 (m, 4H).

[0480] Example 153B: Synthesis of N-(5-(1-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0481] Step 1: 4-((3-bromo-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide [ka]

[0482] A mixture of 3-bromo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazole (50.2 mg; 0.191 mmol; 1.00 equiv.) and m-CPBA (100.2 mg; 0.581 mmol; 3.00 equiv.) in dichloromethane (2 mL) was stirred at room temperature under air for 1 h. After completion of the reaction, the mixture was diluted with CHCl (80 mL) and washed with water (2 × 10 mL). The organic layer was dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 0–5% MeOH in CHCl as the eluent to give 4-((3-bromo-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide as a white solid (50.3 mg, 89%). LCMS (ESI) m / z 293.0, [M+H] + .

[0483] Step 2: N-(5-(1-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0484] To a stirred solution of 4-((3-bromo-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (40.2 mg; 0.137 mmol; 1.00 equiv.) and N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50.1 mg; 0.136 mmol; 0.99 equiv.) in a 5:1 1,4-dioxane / water mixture (2.4 mL) was added XPhos Pd G3 (11.5 mg; 0.014 mmol; 0.10 equiv.), XPhos (6.5 mg; 0.014 mmol; 0.10 equiv.), and KPO (86.5 mg; 0.408 mmol; 2.97 equiv.) were added. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 2 h. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using MeOH / CHCl (5–8%) as the eluent to give the crude product. The crude product was further purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN in water (10 mmol / L NH4HCO3) to give N-(5-(1-((1,1-dioxidetetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a white solid (7.2 mg, 11%). LCMS (ESI) m / z 455.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 9.35 (s, 1H), 9.17 (s, 1H), 8.21 (s, 1H), 7.98 - 7.95 (m, 1H), 7.79 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 4.09 (d, J = 7.2 Hz, 2H), 3.21 - 3.02 (m, 4H), 3.00 (d, J = 4.4 Hz, 3H), 2.63 - 2.56 (m, 1H), 2.10 - 2.03 (m, 1H), 1.87 - 1.80 (m, 2H), 1.73 - 1.62 (m, 2H), 0.89 - 0.79 (m, 4H).

[0485] Example 154: Synthesis of N-(8-(methylamino)-5-(1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [ka]

[0486] Step 1: 2-((3-bromo-1H-pyrazol-1-yl)methyl)pyridine [ka]

[0487] A mixture of 3-bromo-1H-pyrazole (500 mg; 3.40 mmol; 1.00 equiv.), 2-(bromomethyl)pyridine hydrobromide (1.29 g; 5.10 mmol; 1.50 equiv.), and CsCO (3.33 g; 10.2 mmol; 3.00 equiv.) in DMF (10.0 mL) was stirred at room temperature under a nitrogen atmosphere for 3 h. The desired product was observed by LCMS. The residue was dissolved in EtOAc (200 mL) and washed with brine (3 × 20 mL). The organic solution was dried over anhydrous NaSO and then concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 30–60% EtOAc in petroleum ether as the eluent to give 2-((3-bromo-1H-pyrazol-1-yl)methyl)pyridine as a crude yellow oil (600 mg, 73%). LCMS (ESI) m / z 238.0, [M+H] + .

[0488] Step 2: N-(8-(methylamino)-5-(1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide [k...

Claims

1. Compound of formula (I): 【Chemical 2133】 The enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof In equation (I): X is CH; Y is CH ２ , S, or NH; L is a single, double, or triple bond-substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, -C(O)NH-, -NHC(O)-, O, NH, or S; R １ These include alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, methyl, and CD. ３ , or H; R ２ These are H, halo, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, substituted or unsubstituted five- or six-membered monocyclic aryl, substituted or unsubstituted five- or six-membered monocyclic heteroaryl ring, or substituted or unsubstituted bicyclic heteroaryl ring. R ３ H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, aminoalkyl, aminocycloalkyl, aminoheterocycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-phenyl, -NH ２ , -NH-CH-CF ３ , substituted or unsubstituted -C(=O)cycloalkyl, substituted or unsubstituted -NH-C(=O)cycloalkyl, -NH-C(=O)alkyl, substituted or unsubstituted -NH-C(=O)cycloalkyl, or substituted or unsubstituted aminoalkylaryl; R ４ H is: H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, or alkylhydroxyl. Compounds, their enantiomers, diastereomers, or mixtures, or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein Y is NH.

3. R １ The compound according to claim 1, wherein R is methyl or ethyl.

4. The compound according to claim 1, wherein L is a single bond.

5. R ３ but: 【Chemistry 2134】 And here R ４ The compound according to claim 1, wherein is H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, or cyano.

6. R ２ but: 【Chemical 2136】 And here L ２ is a substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or bond connecting A and B; A or B is independently a 5-membered or 6-membered substituted or unsubstituted aryl or heteroaryl ring, where the substitutions are: H, halo, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH ２ -Cycloalkyl, -CF ２ -Cycloalkyl, -CH(CH ３ ) -cycloalkyl, -CH ２ -Aryl, -CF ２ -aryl, -CH(-CH ３ )-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH ２ The compound according to claim 1, selected from the group consisting of hydroxy, -COOH (and its esters), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3- to 6-membered cycloalkyl or heterocycloalkyl, and 3- to 6-membered aryl or heteroaryl, wherein the substitution optionally comprises one or more substituents.

7. R ２ but: 【Chemical 2137】 And here each X is independently either N or CH; R ５ H: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicyclic heterocyclyl, substituted or unsubstituted condensed bicyclic heterocyclyl, substituted or unsubstituted spiro-bicyclic heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ６ , -SR ６ , - NHR ６ ,-NH(CO)R ６ , -C(O)R ６ , -C(O)NHR ６ , -S(O)R ６ ,-S(O)NHR ６ , -S(O)(NH)R ６ , -S(O)(NMe)R ６ ,-(CH ２ ) ｎ S(O)R ６ ,-(CH ２ ) ｎ OR ６ , and -P(O)R ６ R ６’ Selected from the group consisting of, Here R ６ and R ６’ Each of these is independently an alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted condensed bicyclic heterocyclil, substituted or unsubstituted bridged bicyclic heterocyclil, substituted or unsubstituted spiro-bicyclic heterocyclil, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; And n is 0, 1, 2, or 3. The compound according to claim 1.

8. R ２ but: 【Chemical 2138】 Here, Z is either O or S, and each X is independently either N or CH; R ５ H: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicyclic heterocyclyl, substituted or unsubstituted condensed bicyclic heterocyclyl, substituted or unsubstituted spiro-bicyclic heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ６ , -SR ６ , - NHR ６ ,-NH(CO)R ６ , -C(O)R ６ , -C(O)NHR ６ , -S(O)R ６ ,-S(O)NHR ６ , -S(O)(NH)R ６ , -S(O)(NMe)R ６ ,-(CH ２ ) ｎ S(O)R ６ ,-(CH ２ ) ｎ OR ６ , and -P(O)R ６ R ６’ Selected from the group consisting of, Here R ６ and R ６’ Each of these is independently an alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted condensed bicyclic heterocyclil, substituted or unsubstituted bridged bicyclic heterocyclil, substituted or unsubstituted spiro-bicyclic heterocyclil, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; And n is 0, 1, 2, or 3. The compound according to claim 1.

9. R ２ but: 【Chemistry 2139】 And here each X is independently either N or CH; R ５ H: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicyclic heterocyclyl, substituted or unsubstituted condensed bicyclic heterocyclyl, substituted or unsubstituted spiro-bicyclic heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ６ , -SR ６ , - NHR ６ ,-NH(CO)R ６ , -C(O)R ６ , -C(O)NHR ６ , -S(O)R ６ ,-S(O)NHR ６ , -S(O)(NH)R ６ , -S(O)(NMe)R ６ ,-(CH ２ ) ｎ S(O)R ６ ,-(CH ２ ) ｎ OR ６ , and -P(O)R ６ R ６’ Selected from the group consisting of, Here R ６ and R ６’ Each of these is independently an alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted condensed bicyclic heterocyclil, substituted or unsubstituted bridged bicyclic heterocyclil, substituted or unsubstituted spiro-bicyclic heterocyclil, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; And n is 0, 1, 2, or 3. The compound according to claim 1.

10. L-R ２ but: 【Chemistry 2140】 And here each X is independently either N or CH; Z is independent of O or NR ６ And; R ５ and R ５ ’ are each independently H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicyclic heterocyclyl, substituted or unsubstituted fused bicyclic heterocyclyl, substituted or unsubstituted spiro bicyclic heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ６ , -SR ６ , -NHR ６ , -NH(CO)R ６ , -C(O)R ６ , -C(O)NHR ６ , -S(O)R ６ , -S(O)NHR ６ , -S(O)(NH)R ６ , -S(O)(NMe)R ６ , -(CH ２ ) ｎ S(O)R ６ , -(CH ２ ) ｎ OR ６ , or -P(O)R ６ R ６’ where Here R ６ and R ６’ Each of these is independently an alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted condensed bicyclic heterocyclil, substituted or unsubstituted bridged bicyclic heterocyclil, substituted or unsubstituted spiro-bicyclic heterocyclil, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; And n is 0, 1, 2, or 3. The compound according to claim 1.

11. L-R ２ but: 【Chemistry 2141】 And here Z is either N or O, Each X is independently N or CH; R ５ and R ５ Each of these is independently H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicyclic heterocyclyl, substituted or unsubstituted condensed bicyclic heterocyclyl, substituted or unsubstituted spiro-bicyclic heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ６ , -SR ６ , - NHR ６ ,-NH(CO)R ６ , -C(O)R ６ , -C(O)NHR ６ , -S(O)R ６ ,-S(O)NHR ６ , -S(O)(NH)R ６ , -S(O)(NMe)R ６ ,-(CH ２ ) ｎ S(O)R ６ ,-(CH ２ ) ｎ OR ６ , or -P(O)R ６ R ６’ And, Here R ６ and R ６’ Each of these is independently an alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted condensed bicyclic heterocyclil, substituted or unsubstituted bridged bicyclic heterocyclil, substituted or unsubstituted spiro-bicyclic heterocyclil, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3. The compound according to claim 1.

12. L-R ２ but: 【Chemistry 2142】 And here R ５ H: H, halogen, hydroxyl, -CN, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted bridged bicyclic heterocyclyl, substituted or unsubstituted condensed bicyclic heterocyclyl, substituted or unsubstituted spiro-bicyclic heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR ６ , -SR ６ , - NHR ６ ,-NH(CO)R ６ , -C(O)R ６ , -C(O)NHR ６ , -S(O)R ６ ,-S(O)NHR ６ , -S(O)(NH)R ６ , -S(O)(NMe)R ６ ,-(CH ２ ) ｎ S(O)R ６ ,-(CH ２ ) ｎ OR ６ , and -P(O)R ６ R ６’ Selected from the group consisting of, Here R ６ and R ６’ Each of these is independently an alkyl, branched alkyl, haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted condensed bicyclic heterocyclil, substituted or unsubstituted bridged bicyclic heterocyclil, substituted or unsubstituted spiro-bicyclic heterocyclil, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and n is 0, 1, 2, or 3. The compound according to claim 1.

13. The aforementioned compound is: 【Chemistry 2143】 【Chemistry 2144】 【Chemistry 2145】 【Chemical 2146】 【Chemistry 2147】 【Chemical 2148】 【Chemistry 2149】 【Chemical 2150】 【Chemical 2151】 【Chemistry 2152】 【Chemical 2153】 【Chemistry 2154】 【Chemical 2155】 【Chemical 2156】 【Chemistry 2157】 【Chemical 2158】 【Chemistry 2159】 【Chemical 2160】 【Chemistry 2161】 【Chemical 2162】 A compound according to claim 1, selected from the group consisting of the following.

14. The aforementioned compound is: 【Chemical 2163】 【Chemical 2164】 【Chemical 2165】 【Chemical 2166】 【Chemical 2167】 【Chemical 2168】 【Chemical 2169】 【Chemistry 2170】 【Chemistry 2171】 【Chemistry 2172】 【Chemistry 2173】 【Chemistry 2174】 【Chemistry 2175】 【Chemical 2176】 【Chemistry 2177】 【Chemical 2178】 【Chemistry 2179】 【Chemistry 2180】 【Chemistry 2181】 【Chemistry 2182】 【Chemical 2183】 【Chemistry 2184】 【Chemistry 2185】 【Chemical 2186】 【Chemical 2187】 【Chemical 2188】 【Chemical 2189】 【Chemistry 2190】 【Chemical 2191】 【Chemistry 2192】 【Chemistry 2193】 【Chemistry 2194】 【Chemical 2195】 【Chemistry 2196】 【Chemistry 2197】 【Chemical 2198】 【Chemical 2199】 【Chemical 2200】 【Chemical Engineering 2201】 【Chemical 2202】 【Chemical 2203】 【Chemical 2204】 【Chemical 2205】 【Chemical 2206】 【Chemical 2207】 【Chemical 2208】 【Chemical 2209】 【Chemical 2210】 【Chemical Engineering 2211】 【Chemical 2212】 【Chemical 2213】 【Chemical 2214】 【Chemical 2215】 【Chemical 2216】 【Chemical 2217】 【Chemical 2218】 【Chemical 2219】 【Chemical 2220】 【Chemical 2221】 【Chemical 2222】 【Chemical 2223】 【Chemical 2224】 【Chemical 2225】 【Chemical 2226】 【Chemical 2227】 【Chemical Formula 2228】 【Chemical 2229】 【Chemical 2230】 【Chemistry 2231】 【Chemical 2232】 【Chemical formula 2233】 【Chemical 2234】 【Chemical 2235】 【Chemical 2236】 【Chemical 2237】 【Chemical 2238】 【Chemical 2239】 【Chemistry 2240】 【Chemistry 2241】 【Chemistry 2242】 【Chemistry 2243】 【Chemistry 2244】 【Chemistry 2245】 【Chemical 2246】 【Chemistry 2247】 【Chemical 2248】 【Chemistry 2249】 【Chemical 2250】 【Chemistry 2251】 【Chemical 2252】 【Chemical 2253】 【Chemistry 2254】 【Chemistry 2255】 【Chemical 2256】 【Chemistry 2257】 【Chemical 2258】 【Chemistry 2259】 A compound according to claim 1, selected from the group consisting of the following.

15. The compound according to claim 9, wherein Y is NH.

16. The compound according to claim 9, wherein R1 is methyl or ethyl.

17. The compound according to claim 9, wherein L is a single bond.

18. R 3 is: 【Chemistry 2261】 The compound according to claim 9, wherein R4 is selected from the group consisting of H, halo, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, and cyano.

19. The compound according to claim 9, wherein R5 is a substituted or unsubstituted cycloheteralkyl.

20. The compound according to claim 9, wherein R 5 is morpholinyl, piperidinyl, piperazinyl, tetrahydrothiophenyl, or tetrahydropyranil.

21. The compound according to claim 9, wherein R4 is H.

22. R2 is: 【Chemical 2265】 The compound according to claim 9.

23. The compound is 【Chemical Engineering 2301】 A compound according to claim 1, selected from the group consisting of the following.

24. The compound is 【Chemical 2302】 【Chemical 2303】 【Chemical 2304】 【Chemical 2305】 【Chemical 2306】 【Chemical 2307】 【Chemical 2308】 【Chemical 2309】 【Chemical 2310】 【Chemical 2311】 【Chemical 2312】 【Chemical 2313】 A compound according to claim 1, selected from the group consisting of the following.

25. A pharmaceutical composition for use in the treatment of a condition related to TYK2 activity, wherein the pharmaceutical composition comprises a compound according to any one of claims 1 to 24, and the condition is optionally an autoimmune disease, Crohn's disease, hyperimmune globulin E syndrome, inflammatory bowel disease, psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), or ulcerative colitis.

26. A pharmaceutical composition for use in the treatment of diseases or disorders relating to bone or joints, diseases or disorders relating to skin or eyes, diseases or disorders relating to the gastrointestinal tract and abdomen, and / or inflammatory or immunological diseases or disorders, comprising a compound according to any one of claims 1 to 24.

27. ​​(i) The disease or disorder relating to the bone or joint is seronegative spondyloarthritis, primary or secondary Sjögren's syndrome, or vasculitis, wherein the seronegative spondyloarthritis is ankylosing spondylitis and the vasculitis is giant cell arteritis, if applicable; (ii) The disease or disorder relating to the skin or eye is cutaneous lupus erythematosus, urticaria, vitiligo, alopecia areata, or anterior or posterior uveitis; (iii) The disease or disorder relating to the gastrointestinal tract and abdomen is celiac disease, primary biliary cirrhosis, or Behçet's disease; and (iv) The pharmaceutical composition according to claim 26, wherein the inflammatory or immunological disease or disorder is myositis, and optionally the myositis is dermatomyositis.

28. A pharmaceutical composition containing the compound described in Claim 1.

29. The pharmaceutical composition according to claim 28, wherein the composition further contains at least one additional additive.

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