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. In particular, the compounds of the invention inhibit TYK2 which is a member of the Janus kinase (JAK) family of non-receptor protein kinases.

Description

Technical Field

[0001] The present invention provides compounds that modulate the activity of kinases, such as tyrosine kinase 2 (TYK2). Background Art

[0002] A wide variety of medical conditions that affect millions of people are caused or exacerbated by unregulated protein kinase activity. For example, aberrant 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 diseases, eye diseases, infectious diseases, and hormone-related diseases. However, for many of these conditions, there are no effective inhibitors or activators for the specific kinase that causes the condition or its symptoms. As a result, patients continue to suffer from a range of conditions due to a lack of suitable drugs for their conditions. Summary of the invention

[0003] Janus tyrosine kinase (JAK) family members are regulators of multiple signal transduction pathways initiated by membrane type I and type II cytokine receptors. There are 4 JAK family members, including JAK1, JAK2, JAK3 and TYK2 (Schwartz et al., 2017). Such an association is produced with the cytokine response mediated by signal transduction and activator of transcription (STAT) signal transduction. The JAK-STAT signal transduction pathway is an interaction chain between proteins in cells and is involved in processes such as immunity, cell division, cell death and tumor formation (Aaronson et al. Science 2002). The binding of type I and type II cytokine receptor ligands (such as interferons and interleukins) to cell surface receptors leads to receptor dimerization, which brings the receptor-related JAKs into close proximity (Jalini et al., Genes and Cancer 2011), and triggers a series of downstream changes. There is a lot of evidence to prove the contribution of JAK-dependent cytokines to immunopathology, and clinical benefits can be provided by blocking these cytokines with biologics and small molecule inhibitors. Some examples of this are blocking IL-6 in rheumatoid arthritis or 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 signal transduction pathways ( Figure 1Many 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).

[0005] In addition to the role of the TYK2 signaling cascade in disease, there is already strong genetic evidence pointing to a role for TYK2. Genetic association studies have linked the TYK2 locus to effects on susceptibility to SLE, psoriasis, and multiple sclerosis (MS). This identification has been replicated and expanded in many recent analyses, and TYK2 is now considered a susceptibility gene for a variety of inflammatory and autoimmune diseases, including type 1 diabetes (T1D). Common features of these diseases are alterations in immune function and activation, as well as downstream damage to target organs (Li et al., PLOS One, 2020).

[0006] The use of TYK2 small molecule inhibitors has confirmed several of these hypotheses. Previous work in human-derived PBMCs has demonstrated the ability of TYK2 inhibition to reduce IL-12 / IL-23 signaling in rodents and humans. 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). Preclinical effects in rodents have been applied to humans, showing the efficacy of deucravacitinib in patients with psoriasis (Armstrong et al., Ann of Rheu Dis, 2020). The genetic contribution of TYK2 has also been confirmed preclinically by using TYK2 knockout (KO) or transgenic (TG) animals. For example, type I interferon signaling is reduced in TYK2 KO animals compared to WT mice (Karaghiosoff, Immunity, 2000), and TG animals with the P1104 protective variant of TYK2 are almost completely protected in the experimental autoimmune encephalitis (EAE) mouse model of MS (Gorman et al., Frnt in Immunology, 2019). In summary, this large body of evidence provides supportive data for the role of cytokine signaling and supports the development of safe TYK2 inhibitors for a variety of inflammatory conditions.

[0007] The present invention provides compounds that modulate the activity of protein kinases associated with human diseases, disorders and conditions. In particular, the compounds of the present invention inhibit TYK2, a member of the Janus kinase (JAK) family of non-receptor protein kinases. Altered or unregulated activity of TYK2 promotes inflammation and is associated with autoimmune diseases such as psoriasis, lupus, multiple sclerosis and inflammatory bowel disease. Therefore, embodiments of the present invention can be used as pharmaceutical compositions for treating such autoimmune disorders. The present invention also provides methods for using these compounds to modulate kinase activity in cells and treat disorders such as autoimmune disorders where modulating kinase activity provides therapeutic benefits.

[0008] In one aspect, the compound of the invention is a compound of formula (I):

[0009]

[0010] and pharmaceutically acceptable salts thereof,

[0011] in:

[0012] X is CH or N;

[0013] Y is CH 2 , S or NH;

[0014] L is a single bond, double bond, triple bond, substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, -C(O)NH-, -NHC(O)-, O, NH or S;

[0015] R 1 is alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, methyl, CD 3 or H;

[0016] R 2 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro, cyano, or a 5- or 6-membered substituted or unsubstituted aryl, or a monocyclic or bicyclic heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S and N,

[0017] The substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, thioalkyl, nitro, cyano, -CH 2 -cycloalkyl, -CF 2 -cycloalkyl, -CH(CH 3 )-cycloalkyl, -CH 2 -Aryl, -CF 3 , -CF 2-aryl, -CH(-CH 3 )-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH 2 , hydroxyl, -COOH (and esters thereof), sulfonyl, alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3-6 membered cycloalkyl or heterocycloalkyl, 3-6 membered aryl or heteroaryl, any of which may have one or more substituents;

[0018] R 3 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkyloxy, 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, substituted or unsubstituted aminoalkylaryl; and R 4 Selected from the group consisting of H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, and alkylhydroxy.

[0019] In certain embodiments, Y is NH.

[0020] In certain embodiments, R 1 It is methyl or ethyl.

[0021] In certain embodiments, L is a single bond.

[0022] In certain embodiments, X is CH.

[0023] In certain embodiments, X is N.

[0024] In certain embodiments, R 3 yes:

[0025]

[0026] Where R 4 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro or cyano.

[0027] In certain embodiments, R 3 yes:

[0028]

[0029] In certain embodiments, R 2 yes:

[0030]

[0031] Where L 2 is substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or a bond connecting these groups;

[0032] A or B is independently a 5- or 6-membered substituted or unsubstituted aryl or heteroaryl ring, the heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S and N, wherein the substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halogen, 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 , hydroxyl, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3-6 membered cycloalkyl or heterocycloalkyl, 3-6 membered aryl or heteroaryl, any of which may have one or more substituents.

[0033] In certain embodiments, R 2 It is phenyl.

[0034] In certain embodiments, R 2 yes:

[0035]

[0036] wherein each X is independently N or CH;

[0037] R 5 is selected from the group consisting of: H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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 bicyclic heteroalkyl, substituted or unsubstituted bridged bicyclic heteroalkyl, substituted or unsubstituted spiro bicyclic heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and n is 0, 1, 2 or 3.

[0038] In certain embodiments, R 2 yes:

[0039]

[0040] wherein Z is O or S, and each X is independently N or CH;

[0041] R 5 is selected from the group consisting of: H, halogen, hydroxy, -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 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 、-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.

[0042] In certain embodiments, R 2 yes:

[0043]

[0044] wherein each X is independently N or CH; R 5 is selected from the group consisting of: H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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.

[0045] In certain embodiments, LR2 yes:

[0046]

[0047] wherein each X is independently N or CH;

[0048] Z is independently O or NR 6 ;

[0049] R 5 and R 5 ` is independently H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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 spiro bicycloheteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and n=1, 2 or 3.

[0050] In certain embodiments, LR 2 yes:

[0051]

[0052] Where Z is N or O,

[0053] Each X is independently N or CH;

[0054] R 5 and R5 ` is independently H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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 spiro bicycloheteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0055] n is 0, 1, 2 or 3.

[0056] In certain embodiments, LR 2 yes:

[0057]

[0058] Where R 5 is selected from the group consisting of: H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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 bicyclic heteroalkyl, substituted or unsubstituted bridged bicyclic heteroalkyl, substituted or unsubstituted spirobicyclic heteroalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; and n is 0, 1, 2 or 3. In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:

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[0161] In another aspect, the invention provides pharmaceutical compositions containing one or more compounds of the invention, such as any of the compounds described above.

[0162] In another aspect, the invention provides a method of modulating kinase activity by contacting a cell containing a kinase with one or more compounds of the invention (e.g., any of the above). The compound may inhibit the activity of the kinase. The compound may increase the activity of the kinase. The kinase may be a JAK family kinase. The kinase may be LRRK2, NUAK1, or TYK2.

[0163] In another aspect, the invention provides a method of treating a condition in a subject by administering to the subject a compound of the invention, such as any of the compounds described above. The condition may be characterized by elevated kinase activity. The condition may be characterized by altered kinase activity. The kinase may be a JAK family kinase. The kinase may be LRRK2, NUAK1, or TYK2. The condition may 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 disease, an eye disease, an infectious disease, or a hormone-related disease.

[0164] In another aspect, the present invention provides the use of a compound of the present invention (eg, any one of the above) for preparing a medicament. In an embodiment of the use, the medicament can be used to treat a condition of a subject.

[0165] In an embodiment of this use, the disorder is characterized by increased activity 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.

[0166] In embodiments of this use, the disorder 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 disease, an eye disease, an infectious disease, or a hormone-related disease. BRIEF DESCRIPTION OF THE DRAWINGS

[0167] Figure 1 An overview of the JAK and TYK2 signaling pathways is provided. DETAILED DESCRIPTION

[0168] Chemical Definition

[0169] The expression alkyl refers to a group of straight-chain or branched saturated hydrocarbon radicals having 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 1-8 In 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, an alkyl group has 1 carbon atom (“C 1 In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 C 1-6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butyl (C 5 ), tert-amyl (C 5 ) and n-hexyl (C 6 Other examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ) etc. Unless otherwise specified, an alkyl group is independently optionally substituted at each occurrence, i.e., unsubstituted (“unsubstituted alkyl”) or substituted (“substituted alkyl”) with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In certain embodiments, an alkyl group is an unsubstituted C 1-10 Alkyl (e.g. -CH 3 In certain embodiments, the alkyl group is a substituted C 1-10 Alkyl. Common alkyl abbreviations include Me(-CH 3 )、Et(-CH 2 CH 3 )、iPr(-CH(CH 3 ) 2 )、nPr(-CH 2 CH 2 CH 3 )、n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ).

[0170] The expression heteroalkyl refers to an alkyl group as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or 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 ("heteroalkyl") having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1-10In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroalkyl”). 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 (“heteroalkyl”). 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 (“heteroalkyl”). 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 (“heteroalkyl”). 1-10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1-4 In 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, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC 2-6 alkyl").

[0171] The expression alkenyl refers to a straight or branched hydrocarbon radical ("C-carbon"). having 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 2-4In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). 2-4 Examples of alkenyl groups include vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadiene (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups and pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ) and the like. Other examples of alkenyl groups include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ) etc. Unless otherwise specified, alkenyl groups are independently optionally substituted at each occurrence, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted (“substituted alkenyl”) with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In certain embodiments, alkenyl groups are unsubstituted C 2-10 In certain embodiments, an alkenyl group is a substituted C 2-10 Alkenyl.

[0172] As used herein, the term "heteroalkenyl" refers to an alkenyl group as defined herein that further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or 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 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl"). 2-10 In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-9 In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-8In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms (“heteroC 2-7 In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroC 2-6 In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-5 In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-4 In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC 2-3 In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC 2-6 ("alkenyl").

[0173] The expression cycloalkyl refers to a saturated or partially unsaturated (e.g., cycloalkenyl) cyclic group containing one or more rings, such as 2 or 3 rings, and containing 3 to 14 ring carbon atoms, such as 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms. In addition, the expression cycloalkyl refers to a group in which one or more hydrogen atoms are replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH 2 , =NH, N 3 or NO 2 The cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decahydronaphthyl, bicyclo[4.3.0]nonyl, tetrahydronaphthyl, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl.

[0174] The expressions cycloheteroalkyl or heterocycloalkyl refer to cycloalkyl groups as defined above in which one or more (e.g. 1, 2 or 3) of the ring carbon atoms have been replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms or SO groups or SO 2 Cycloheteroalkyl or heterocycloalkyl groups may have 1 or 2 rings containing 3 to 10 (e.g. 3, 4, 5, 6 or 7) ring atoms (e.g. C, O, N or S). Cycloheteroalkyl or heterocycloalkyl groups include cycloheteroalkenyl or heterocycloalkenyl groups. In addition, the expression cycloheteroalkyl or heterocycloalkyl refers to cycloheteroalkyl or heterocycloalkyl groups replaced by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH 2 , =NH, N 3 or NO 2Examples are piperidinyl, proline, imidazolidinyl, piperazinyl, morpholinyl, hexamethylenetetraminyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrofuranyl or 2-pyrazolinyl groups as well as lactams, lactones, cyclic imides and cyclic anhydrides.

[0175] The expression alkylcycloalkyl refers to a group containing a cycloalkyl group according to the above definition as well as an alkyl, alkenyl or alkynyl group, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl. The alkylcycloalkyl group preferably comprises a cycloalkyl group containing one or two rings having 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms and one or two alkyl or alkynyl groups having 1 or 2 to 6 carbon atoms.

[0176] The expression heteroalkylcycloalkyl refers to an alkylcycloalkyl group as defined above in which one or more (e.g. 1, 2 or 3) carbon atoms have been replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms or SO groups or SO 2 Group replacement. The heteroalkylcycloalkyl group preferably contains 1 or 2 rings with 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms, and 1 or 2 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, and these cyclic groups are saturated or mono-, di- or tri-unsaturated.

[0177] The expression aryl refers to an aromatic group containing one or more rings (e.g. 2 or 3 rings) containing 6 to 14 ring carbon atoms, e.g. 6 to 10 ring carbon atoms. In addition, the term aryl refers to an aromatic group substituted by a fluorine, chlorine, bromine or iodine atom or by a CH 3 , OH, SH, NH 2 、N 3 or NO 2 Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilino, 3-nitrophenyl or 4-hydroxyphenyl.

[0178] The expression heteroaryl refers to an aromatic group containing one or more rings, for example 2 or 3 rings, containing 5 to 14 ring atoms, for example 5 to 10 ring atoms, and containing one or more (for example 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms. In addition, the expression heteroaryl refers to an aromatic group containing one or more rings, for example 2 or 3 rings, containing 5 to 14 ring atoms, for example 5 to 10 ring atoms, and containing one or more (for example 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms. 3 , OH, SH, N 3 NH 2 or NO 2Examples 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, quinolyl, isoquinolyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3'-bifuranyl, pyrazolyl (e.g. 3-pyrazolyl) and isoquinolyl groups.

[0179] The expression aralkyl refers to a group containing an aryl group according to the above definition and an alkyl, alkenyl, alkynyl and / or cycloalkyl group, for example an aryl-alkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl group. Specific examples of aralkyl are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1H-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, isopropylbenzene, 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 or 2 to 6 carbon atoms and / or a cycloalkyl group containing 5 or 6 ring carbon atoms.

[0180] The expression heteroaralkyl refers to an aralkyl group as defined above, in which one or more (e.g. 1, 2, 3 or 4) carbon atoms have been replaced by oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atoms, that is to say a group containing an aryl or heteroaryl group as defined above and an alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl group. The heteroaralkyl group preferably contains one or two aromatic ring systems having 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms and / or a cycloalkyl group having 5 or 6 ring carbon atoms, in which 1, 2, 3 or 4 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms.

[0181] Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkylheterocycloalkyl, arylalkenylheterocycloalkyl, arylalkynylheterocycloalkyl, arylalkylheterocycloalkenyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl, heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl, heteroarylheterocycloalkenyl, heteroarylalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylalkylheterocycloalkenyl, heteroarylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylheterocycloalkyl groups, which cyclic groups are saturated or mono-, di- or tri-unsaturated. Specific examples are tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridyl, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl groups.

[0182] As mentioned above, the expressions cycloalkyl, cycloheteroalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl also refer to radicals replaced by fluorine, chlorine, bromine or iodine atoms or by CH 3 , OH, =O, SH, =S, NH 2 , =NH, N 3 or NO 2 Group substituted group.

[0183] The expression carbocyclyl or carbocycle refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms 10 ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 In 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 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) etc. Exemplary C 3-8 Carbocyclyl groups include but are not limited to the above C 3-6 Carbocyclyl groups and cycloheptyl (C 7), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (G), cyclooctenyl (G), bicyclo[2.2.1]heptyl (C 7 ), bicyclo[2.2.2]octanyl (G), etc. Exemplary C 3-10 Carbocyclyl groups include, but are not limited to, the above-mentioned G carbocyclyl groups and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10 ) etc. As shown in the foregoing examples, in certain embodiments, the carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged or spirocyclic system, such as a bicyclic system ("bicyclic carbocyclyl"), and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes a ring system in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such cases, the carbon number continues to represent the carbon number in the carbocyclyl system. Unless otherwise indicated, the carbocyclyl group is optionally substituted independently in each case, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, a carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0184] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("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) 5-6 Examples of cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). C 3-6 Examples of the cycloalkyl group include the above-mentioned C 5-6Cycloalkyl groups and cyclopropyl (C 3 ) and cyclobutyl (C 4 ). C 3-8 Examples of the cycloalkyl group include the above-mentioned C 3-6 Cycloalkyl groups and cycloheptyl (C 7 ) and cyclooctyl (C 8 Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, a cycloalkyl group is a substituted C 3-10 Cycloalkyl.

[0185] The expressions heterocyclyl or heterocycle refer to radicals of 3 to 14 membered non-aromatic ring systems having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-14 membered heterocyclyl"). In heterocyclyl radicals containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom if valence permits. Heterocyclyl radicals may be monocyclic ("monocyclic heterocyclyl") or fused, bridged or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or may be partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclyl groups, wherein the point of attachment is on the carbocyclyl or heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such a case, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Unless otherwise indicated, heterocyclyl is independently optionally substituted in each case, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") by one or more substituents. In certain embodiments, heterocyclyl groups are unsubstituted 3-10 membered heterocyclyls. In certain embodiments, heterocyclyl groups are substituted 3-10 membered heterocyclyls.

[0186] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“5-10 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-8 membered heterocyclyl”). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0187] Exemplary 3-membered heterocyclic groups containing one heteroatom include but are not limited to aziridine, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include but are not limited to azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include but are not limited to tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include but are not limited to dioxolane, oxasulfuranyl, disulfolanyl and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include but are not limited to triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include but are not limited to piperidinyl, tetrahydropyranyl, dihydropyridinyl and sulfide cyclopentyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. 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. 6Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0188] The expression optionally substituted means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permitted substituent, for example, which upon substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, or other reaction. Heteroatoms such as nitrogen may have substituents, such as any suitable substituents described herein, which satisfy the valence of the heteroatoms and result in the formation of a stable moiety.

[0189] For example, but not limited to, optional substituents include fluorine, chlorine, bromine, and iodine atoms, as well as CF 3 ,CN,OH,=O,SH,=S,NH 2 , =NH, N 3 and NO 2 The optional substituents also include C 1 -C 10 Alkyl, C 2 -C 10 Alkenyl, C 1 -C 10 Heteroalkyl, C 3 -C 16 Cycloalkyl, C 2 -C 17 Heterocycloalkyl, C 4 -C 20 Alkylcycloalkyl, C 2 -C 19 Heteroalkylcycloalkyl, C 6 -C 18 Aryl, C 1-17 Heteroaryl, C 7 -C 20 Arylalkyl or C 2 -C 19 Heteroarylalkyl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 1 -C 6 Heteroalkyl, C 3 -C 10 Cycloalkyl, C 2 -C 9 Heterocycloalkyl, C 7 -C 12 Alkylcycloalkyl, C 2-C 11 Heteroalkylcycloalkyl, C 6 -C 10 Aryl, C 1 -C 9 Heteroaryl, C 7 -C 12 Aralkyl, C 2 -C 11 Heteroarylalkyl and C 1 -C 10 A haloalkyl group.

[0190] Exemplary substituents are F, Cl, Br, OH, SH, =O, NH 2 , amino, C 1-4 Alkyl, C 1-4 Heteroalkyl, cyclopropyl, SF 5 ,NO,NO 2 .

[0191] Other exemplary substituents are F, Cl, Br, OH, SH, =O, NH 2 , C 1-4 Alkyl (e.g. methyl, ethyl, n-butyl), NMe 2 ,CONH 2 , CH 2 NMe 2 NHSO 2 Me, C(CH 3 )2CN, COMe, OMe, SMe, COOMe, COOEt, CH 2 COOH、OCH 2 COOH, COOH, SOMe, SO 2 Me, cyclopropyl, SO 2 NH 2 、SO 2 NHMe、SO 2 CH 2 CH 2 OH, NHCH 2 CH 2 OH, CH 2 CH 2 OCH 3 , SF 5 、SO 2 NMe 2 ,NO,NO 2 、OCF 3 、SO 2 CF 3 , CN or CF 3 .

[0192] Other exemplary substituents are F, Cl, Br, Me, OMe, CN or CF 3 .

[0193] The term halogen preferably refers to F, Cl, Br or I.

[0194] 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.

[0195] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, the rings may be bonded to each other via single or double bonds or the rings may be cyclized.

[0196] Other optional substituents include, but are not limited to, halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -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 , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa 、-OC(O)R aa 、-OCO 2 R 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 CO 2 R aa 、-NR bbC(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 SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(O)R aa 、例如-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) 2 R aa 、-OP(O) 2 R aa 、-P(O)(R aa ) 2、-OP(O)(R aa ) 2 、-OP(O)(OR cc ) 2 、-P(O) 2 N(R bb ) 2 、-OP(O) 2 N(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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd or the two geminal hydrogen atoms on the carbon atom are replaced by groups =O, =S, =NN(R bb ) 2 , =NNR bb C(O)R aa , =NNR bb C(O)OR aa , =NNR bb S(O) 2 R aa , =NR bb or = NOR cc Replacement; where:

[0197] R aaIn each case, independently selected from 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered cycloalkyl, 3-14 membered cycloheteroalkyl, 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R dd Group substitution;

[0198] R bb is independently selected at each occurrence from hydrogen, -OH, -OR aa 、-N(R cc ) 2 、-CN、-C(O)R aa 、-C(O)N(R cc ) 2 , -CO 2 R aa 、-SO 2 R aa 、-C(NR cc )OR aa 、-C(NR cc )N(R cc ) 2 、-SO 2 N(R cc ) 2 、-SO 2 R cc 、-SO 2 OR cc 、-SOR aa 、-C(S)N(R cc ) 2 、-C(O)SR cc 、-C(S)SR cc 、-P(O) 2 R aa 、-P(O)(R aa ) 2 、-P(O) 2 N(R cc ) 2 、-P(O)(NRcc ) 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 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, heteroalkyl, alkenyl, cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, carbocyclyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0199] R cc is independently selected at each occurrence from hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 Alkenyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R aa The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0200] R dd is independently selected at each occurrence from halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -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 , -CO 2 H, -CO 2 R ee 、-OC(O)R ee 、-OCO2 R ee ,-C(O)N(R ff ) 2 ,-OC(O)N(R ff ) 2 ,-NR ff C(O)R ee ,-NR ff CO 2 R 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 SO 2 R ee ,-SO 2 N(R ff ) 2 ,-SO 2 R ee ,-SO 2 OR ee ,-OSO 2 R ee ,-S(O)R ee ,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) 2 R 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 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may be linked to form =O or =S;

[0201] R ee In each case, independently selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution;

[0202] R ff is independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, or two R ff The groups are connected to form a 3-14 membered heterocyclic or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently substituted by 0, 1, 2, 3, 4 or 5 R gg Group substitution; and

[0203] R gg is independently in each case halogen, -CN, -NO 2 、-N 3 、-SO 2 H, -SO 3 H, -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 - 、-NH 2 (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), -CO 2 H, -CO 2 (C 1-6 Alkyl), -OC(O)(C 1-6 Alkyl), -OCO 2 (C 1-6 Alkyl), -C(O)NH 2 、-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), -NHCO 2 (C 1-6 alkyl), -NHC(O)N(C 1-6 alkyl) 2 、-NHC(O)NH(C 1-6 Alkyl), -NHC(O)NH 2 、-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)NH 2 、-OC(NH)N(C 1-6 alkyl) 2 、-OC(NH)NH(C 1-6 Alkyl), -OC(NH)NH 2 、-NHC(NH)N(C 1-6 alkyl) 2、-NHC(NH)NH 2 、-NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 alkyl) 2 、-SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 ,-SO 2 C 1-6 Alkyl, -SO 2 OC 1-6 Alkyl, -OSO 2 C 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)NH 2 、-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 Carbocyclic group, C 3-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may be linked to form =O or =S; where X - It is a counter ion.

[0204] Compound

[0205] In certain aspects, the present invention provides compounds of formula (I):

[0206]

[0207] and pharmaceutically acceptable salts thereof,

[0208] in:

[0209] X is CH or N;

[0210] Y is CH 2 , S or NH;

[0211] L is a single bond, double bond, triple bond, substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, -C(O)NH-, -NHC(O)-, O, NH or S;

[0212] R 1 is alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, methyl, CD 3 or H;

[0213] R 2 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro, cyano, or a 5- or 6-membered substituted or unsubstituted aryl, or a monocyclic or bicyclic heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S and N,

[0214] The substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, thioalkyl, nitro, cyano, -CH 2 -cycloalkyl, -CF 2 -cycloalkyl, -CH(CH 3 )-cycloalkyl, -CH 2 -Aryl, -CF 3 , -CF 2 -aryl, -CH(-CH 3 )-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH 2 , hydroxyl, -COOH (and esters thereof), sulfonyl, alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3-6 membered cycloalkyl or heterocycloalkyl, 3-6 membered aryl or heteroaryl, any of which may have one or more substituents;

[0215] R 3 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkyloxy, 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, substituted or unsubstituted aminoalkylaryl; and R 4 Selected from the group consisting of H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, and alkylhydroxy.

[0216] In certain embodiments, Y is NH.

[0217] In certain embodiments, R 1 It is methyl or ethyl.

[0218] In certain embodiments, L is a single bond.

[0219] In certain embodiments, X is CH.

[0220] In certain embodiments, X is N.

[0221] In certain embodiments, R 3 yes:

[0222]

[0223] Where R 4 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro or cyano.

[0224] In certain embodiments, R 3 yes:

[0225]

[0226] In certain embodiments, R 2 yes:

[0227]

[0228] Where L 2 is substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or a bond connecting these groups;

[0229] A or B is independently a 5- or 6-membered substituted or unsubstituted aryl or heteroaryl ring, the heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S and N, wherein the substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, -CH2 -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 , hydroxyl, -COOH (and esters thereof), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3-6 membered cycloalkyl or heterocycloalkyl, 3-6 membered aryl or heteroaryl, any of which may have one or more substituents.

[0230] In certain embodiments, R 2 It is phenyl.

[0231] In certain embodiments, R 2 yes:

[0232]

[0233] wherein each X is independently N or CH;

[0234] R 5 is selected from the group consisting of: H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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 bicyclic heteroalkyl, substituted or unsubstituted bridged bicyclic heteroalkyl, substituted or unsubstituted spiro bicyclic heteroalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, and n is 0, 1, 2 or 3.

[0235] In certain embodiments, R 2 yes:

[0236]

[0237] wherein Z is O or S, and each X is independently N or CH;

[0238] R 5 is selected from the group consisting of: H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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.

[0239] In certain embodiments, R 2 yes:

[0240]

[0241] wherein each X is independently N or CH; R 5 is selected from the group consisting of: H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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.

[0242] In certain embodiments, LR 2 yes:

[0243]

[0244] wherein each X is independently N or CH;

[0245] Z is independently O or NR 6 ;

[0246] R 5 and R 5 ` is independently H, halogen, hydroxy, -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, -OR6 、-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 、-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 spiro bicycloheteroalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and n=1, 2 or 3.

[0247] In certain embodiments, LR 2 yes:

[0248]

[0249] Where Z is N or O,

[0250] Each X is independently N or CH;

[0251] R 5 and R 5 ` is independently H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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 spiro bicycloheteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0252] n is 0, 1, 2 or 3.

[0253] In certain embodiments, LR 2 yes:

[0254]

[0255] Where R 5 is selected from the group consisting of: H, halogen, hydroxy, -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 、-(CH 2 ) n S(O)R 6 、-(CH 2 ) 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.

[0256] In another preferred embodiment, the compound of formula (I) is selected from the group consisting of:

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272]

[0273]

[0274]

[0275]

[0276]

[0277]

[0278]

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285]

[0286]

[0287]

[0288]

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302]

[0303]

[0304]

[0305]

[0306]

[0307]

[0308]

[0309]

[0310]

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359] Pharmaceutical composition

[0360] The present invention provides a pharmaceutical composition containing one or more of the above compounds 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 drugs for treating one or more diseases mentioned herein.

[0361] The pharmaceutical composition may contain a therapeutically effective amount of one or more compounds of the present invention. The therapeutically effective amount of a compound according to the present invention refers to the amount of the compound that effectively prevents, alleviates or improves disease symptoms or prolongs the survival of the treated subject. The determination of a therapeutically effective amount is within the technical scope of the art.

[0362] The therapeutically effective amount or dosage of the compound according to the present invention can vary within a wide range and can be determined in a manner known in the art. This dosage can be adjusted according to the individual needs in each specific case, including the specific compound used, the route of administration, the disease treated, and the patient treated.

[0363] The compositions of the invention may include a vehicle for delivering one or more compounds of the invention. For example, the composition may contain particles, such as nanoparticles, microparticles, liposomes, micelles, and viral particles.

[0364] Examples of pharmacologically acceptable salts of sufficiently basic compounds of the present invention are salts of physiologically acceptable inorganic 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 or alkaline earth metal salts, such as sodium salts, potassium salts, lithium salts, calcium salts or magnesium salts; ammonium salts; or organic base salts, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumine, piperidine, morpholine, tri-(2-hydroxyethyl)amine, lysine or arginine salts; all of which are also further examples of salts of the present invention. The compounds of the present invention may be solvated, especially hydrated. Hydration / hydration may occur during the production process, or may occur due to the hygroscopicity of the initially anhydrous compound of the present invention. Solvates and / or hydrates may, for example, exist in solid or liquid form.

[0365] It should be understood that certain compounds of the present invention may have tautomeric forms (of which only one may be specifically mentioned or depicted in the following description), different geometric isomers (which are usually represented as cis / trans isomers or more generally as (E) and (Z) isomers) or different optical isomers (which are usually named under the Cahn-Ingold-Prelog or R / S system) due to one or more chiral carbon atoms. All of these tautomeric forms, geometric or optical isomers (as well as racemates and diastereomers) and polymorphic forms are included in the present invention. Since the compounds of the present invention may contain asymmetric C atoms, they may exist as non-chiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention includes all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any mixing ratio.

[0366] According to another embodiment of the present invention, one or more hydrogen atoms of the compounds of this invention can be replaced by deuterium. Deuterium modification improves the metabolic characteristics of the drug, and its intrinsic pharmacology has little or no change. Deuterium substitution at specific molecular positions improves metabolic stability, reduces the formation of toxic metabolites and / or increases the formation of desired active metabolites. Therefore, the present invention also encompasses partially and fully deuterated compounds of the present invention. The term hydrogen also encompasses deuterium.

[0367] The therapeutic use of the compounds according to the present invention, their pharmacologically acceptable salts, solvates and hydrates, as well as preparations and pharmaceutical compositions are also within the scope of the present invention. The pharmaceutical composition according to the present invention may comprise at least one compound of the present invention as an active ingredient, optionally also comprising a carrier substance and / or an adjuvant.

[0368] The invention also relates to prodrugs consisting of a compound according to the invention and at least one pharmacologically acceptable protecting group which is cleaved off under physiological conditions, such as an alkoxy-, arylalkoxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl), a 2-alkyl-, 2-aryl- or 2-arylalkyloxycarbonyl-2-alkyleneethyl group or an acyloxy group, such as ethoxy, benzyloxy, acetyl or acetoxy, or, in particular for compounds according to the invention carrying a hydroxyl group (-OH): a sulfate, a phosphate (-OPO) or a prodrug comprising a compound according to the invention and at least one pharmacologically acceptable protecting group which is cleaved off under physiological conditions, such as an alkoxy-, arylalkoxy-, acyl-, acyloxymethyl group (e.g. pivaloyloxymethyl) group, a 2-alkyl-, 2-aryl- or 2-arylalkyloxycarbonyl-2-alkyleneethyl group or an acyloxy group, such as ethoxy, benzyloxy, acetyl or acetoxy 3 or -OCH 2 OPO 3 ) or esters of amino acids. For example, the composition may contain a prodrug of a hydroxyl group of a compound of the invention.

[0369] As used herein, the term pharmaceutically acceptable ester refers in particular to esters that hydrolyze in vivo, and includes those esters that readily decompose in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, olefinic acids, cycloalkanoic acids, and alkanedioic acids, wherein each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinate.

[0370] 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 present invention.

[0371] As mentioned above, therapeutically useful agents containing a compound of the invention, its solvate, salt or formulation are also included within the scope of the invention. Generally, the compounds of the invention will be administered alone or in combination with any other therapeutic agent by using modes known and acceptable in the art.

[0372] For oral administration, such therapeutically useful agents can be administered by one of the following routes: orally, for example as 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 injections, for example as injectable solutions or suspensions; through the rectum as suppositories; by inhalation or insufflation, for example as powder preparations, as microcrystals or as sprays (e.g. liquid aerosols); transdermally, for example by transdermal delivery systems (TDS), such as plasters containing active ingredients; or intranasally. In order to prepare such tablets, pills, semisolids, coated tablets, dragees and hard capsules, such as gelatin capsules, the therapeutically useful product can be mixed with pharmaceutically inert inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salts, skimmed milk powder, etc. In order to prepare soft capsules, for example, vegetable oil, petroleum, animal oil or synthetic oil, wax, fat, polyol can be used as excipient. In order to prepare liquid solutions, emulsions or suspensions or syrups, for example, water, alcohol, aqueous saline, aqueous dextrose, polyols, glycerol, lipids, phospholipids, cyclodextrins, vegetable oil, petroleum, animal oil or synthetic oil can be used as excipients. Particularly useful are lipids in phosphate buffered saline (pH=7 to 8, such as 7.4), such as phospholipids (e.g., natural origin and / or particle size between 300 and 350nm). For suppositories, for example, vegetable oil, petroleum, animal oil or synthetic oil, wax, fat and polyol can be used as excipients. For aerosol preparations, compressed gases suitable for this purpose, such as oxygen, nitrogen and carbon dioxide, can be used. Pharmaceutically useful medicaments can also contain additives for preservation and stability, such as UV stabilizers, emulsifiers, sweeteners, aromatics, salts that change osmotic pressure, buffers, coating additives and antioxidants.

[0373] Generally, for an adult weighing about 80 kg, oral or parenteral administration, 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 the upper limit may be exceeded when indicated. The daily dosage may be administered in a single dose or divided doses, or for parenteral administration, may be administered as a continuous infusion or subcutaneous injection.

[0374] Methods for preparing compounds

[0375] The present invention also provides methods of preparing compounds of the present invention, such as those described above.Synthetic schemes for preparing specific compounds of formula (I) are provided in the following examples.

[0376] Methods of treating the disease

[0377] The compounds and compositions of the present invention modulate the activity of one or more protein kinases. These compounds and compositions can inhibit, activate or otherwise alter the activity of the kinase. Therefore, these compounds and compositions can be used to diagnose, treat or prevent disorders, such as diseases, disorders or other conditions where modulation of kinase activity provides a therapeutic benefit.

[0378] 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 activity or decreased activity) of one or more kinases. The kinase can be a serine-threonine kinase or a tyrosine kinase, such as a receptor tyrosine kinase or a non-receptor tyrosine kinase. The kinase can be a member of the JAK family. For example, but not limited to, the kinase can be death-associated protein kinase 1 (DAPK1), leucine-rich repeat kinase 2 (LRRK2), NUAK family SNF1-like kinase 1 (NUAK1, also known as AMPK-associated protein kinase 5 or ARK5), spleen tyrosine kinase (SYK) or non-receptor tyrosine protein kinase TYK2 (TYK2), including mutants of any of the foregoing kinases.

[0379] The disease, disorder or condition can be associated with aberrant DAPK1 activity, such as Alzheimer's disease, atherosclerosis, brain damage, 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, epilepsy, tumor metastasis, tumor suppression, ulcerative colitis, or viral infection.

[0380] The disease, disorder or condition can be associated with aberrant LRRK2 activity, such as Alzheimer's disease, Crohn's disease, inflammatory bowel disease, inflammatory disease, leprosy, a 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 Parkinson's disease type VIII.

[0381] The disease, disorder or condition may be associated with aberrant NUAK1 activity, such as cancer (eg, colorectal cancer, gastric cancer, endometrial cancer, or multiple myeloma), diabetes, fibrosis, a neurodegenerative disease, or omphalocele.

[0382] The disease, disorder or condition may be associated with abnormal SYK activity, such as an allergic disorder, anaphylactic shock, aneurysm, arteriosclerosis, asthma, an autoimmune disease, B-cell lymphoma, breast cancer, breast ductal carcinoma in situ (BCIS), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), eosinophilic inflammation, episcleritis, follicular lymphoma, functional gastrointestinal disorder, fungal keratitis, gastric cancer, head and neck cancer, heart attack, hemolytic anemia, heparin-induced thrombocytopenia, immune thrombocytopenic purpura, infection (e.g., 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 erythematosus.

[0383] The disease, disorder or condition may be associated with aberrant TYK2 activity, such as an autoimmune disorder, Crohn's disease, hyperimmunoglobulin E syndrome, inflammatory bowel disease, multiple sclerosis (MS), multiple sclerosis (MS), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE), type 1 diabetes (T1D), or ulcerative colitis.

[0384] The disease, disorder or condition may be or include a respiratory / obstructive airway disease or disorder, such as rhinorrhoea, tracheal stenosis, airway constriction, acute, allergic, atrophic or chronic rhinitis (e.g., caseous rhinitis, hypertrophic rhinitis, purulent rhinitis, sicca), rhinitis medicamentosa, membranous rhinitis (including croup, fibrinous and pseudomembranous rhinitis), adenopathy, perennial allergic rhinitis, seasonal rhinitis (including neurogenic rhinitis (hay fever) and vasomotor rhinitis), hay fever, asthma (e.g., bronchial, atopic, allergic, endogenous, exogenous, exercise-induced, cold air Induced, occupational, bacterial infection-induced and dust-induced asthma, especially chronic or refractory asthma (such as advanced asthma and airway hyperresponsiveness), bronchitis (including chronic, acute, peanut, catarrhal, croup, tuberculous and eosinophilic bronchitis), cardiobronchitis, pneumoconiosis, chronic inflammatory diseases of the lungs leading to interstitial fibrosis (such as interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis or other autoimmune disorders)), acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), Lung disease, airway disease or lung disease (CORD, COAD, COLD or COPD, such as irreversible COPD), chronic sinusitis, conjunctivitis (such as allergic conjunctivitis), cystic fibrosis, extrinsic allergic alveolitis (such as farmer's lung and related diseases), fibroid lung, allergic lung disease, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, nasal congestion, nasal polyposis, otitis media and cough (chronic cough related to inflammation or iatrogenically induced cough), pleurisy, pulmonary congestion, emphysema, bronchiectasis, sarcoidosis, pulmonary fibrosis (including cryptogenic fibrosing alveolitis, antineoplastic therapy and chronic infection) Acute viral infections including colds, and infections caused by respiratory syncytial virus, influenza, coronaviruses (including SARS) and adenoviruses, allergic bronchopulmonary fungal disease, emphysema, diffuse panbronchiolitis, anaphylaxis or hypersensitivity reactions, drug allergies (e.g., to penicillins, cephalosporins), allergic allergies to insect bites and stings, and food-related allergies that may have effects distal to the gut (e.g., migraine, rhinitis, and eczema), anaphylactic shock, or vasospasm.

[0385] The disease, disorder or condition can be or include a bone and joint related disease or disorder, such as osteoporosis, arthritis (including rheumatic, infectious, autoimmune, chronic, malignant), seronegative spondyloarthropathies (such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, end-disease, Behcet's disease, Marie-Strumpell arthritis, inflammatory bowel arthritis and Reiter's disease), systemic sclerosis, osteoarthritis, osteoarthropathy (primary and secondary to, for example, congenital hip dysplasia, cervical and lumbar spondylitis, and low back and neck pain), Still's disease, reactive arthritis and undifferentiated spondyloarthropathies, septic arthritis and other infection-related arthropathy and bone disorders (such as tuberculosis, including Potter's disease and Poncet's syndrome), acute and chronic crystalline synovitis (including urate gout, calcium pyrophosphate deposition disease and calcium apatite-related tendon, bursal and synovial inflammation), primary and secondary Sjögren's syndrome, systemic sclerosis and localized scleroderma. disease, mixed connective tissue disease and undifferentiated connective tissue disease, inflammatory myopathies (including polymyalgia rheumatica), juvenile arthritis (including idiopathic inflammatory arthritis of any joint distribution and related syndromes), other joint diseases (such as intervertebral disc degeneration or temporomandibular joint degeneration), rheumatic fever and its systemic complications, vasculitis (including giant cell arteritis, Takayasu arteritis, polyarteritis nodosa, microscopic polyangiitis and viral infections), hypersensitivity reactions, cryoglobulins, paraproteins, low back pain, familial Mediterranean fever , Muckle-Wells syndrome and familial Hibenian fever-associated vasculitis), Kikuchi disease, drug-induced arthralgia, tendinitis, polychondritis and myopathy, osteoporosis, osteomalacia-like osteoporosis, osteopenia, osteogenesis imperfecta, osteosclerosis, osteofibrosis, osteonecrosis, Paget's disease of bone, hypophosphatemia, Felty's syndrome, Still's disease, loosening of artificial joint implants, muscle or joint sprains or strains, tendinitis, fasciitis, frozen shoulder, cervical shoulder-arm syndrome, or tenosynovitis.

[0386] The disease, disorder or condition may be or include a skin or eye-related disease or disorder, such as glaucoma, ocular hypertension, cataract, retinal detachment, psoriasis (including psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, erythrodermic psoriasis), palmoplantar pustulosis, xeroderma, eczematous diseases (such as atopic dermatitis, ultraviolet radiation dermatitis, contact dermatitis and seborrheic dermatitis), phytodermatitis, photodermatitis, cutaneous eosinophilia, chronic skin ulcers, cutaneous lupus erythematosus, contact hypersensitivity / allergic contact dermatitis (including allergies to poison ivy, sumac, or oak) and eosinophilic folliculitis (Taitung disease), pruritus, drug eruption, urticaria (acute or chronic, allergic or nonallergic), acne, erythema, dermatitis herpetiformis, scleroderma, vitiligo, lichen planus, lichen sclerosus, pyoderma gangrenosum, cutaneous sarcoidosis, pemphigus, pemphigus ocular, pemphigoid, epidermolysis bullosa, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, androgenetic baldness erythema multiforme, cellulitis, infectious and noninfectious panniculitis, cutaneous lymphoma, non-melanoma skin cancer and other dysplastic lesions, blepharitis, iritis, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory conditions affecting the retina, ophthalmitis (including sympathetic ophthalmia), sarcoidosis, xerosis infections including viral, fungal and bacterial, allergic conjunctivitis, increased fibrosis, Keloids, scar formation, post-surgical scars, epidermolysis bullosa, dry eyes, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis and giant papillary conjunctivitis, ocular angiogenesis, corneal damage and scarring, all forms of macular degeneration, macular edema, macular dystrophy, abnormal wound healing, scleritis, superficial scleritis, pachyderma, peripheral ulcerative keratitis, fungal keratitis, herpetic keratitis, invasive aspergillosis, keratoconus, corneal epithelial dystrophy, or severe intraocular inflammation.

[0387] The disease, disorder or condition can be or include a gastrointestinal and abdominal related disease or disorder, such as 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, Moren's ulcer, irritable bowel syndrome, necrotizing enterocolitis, intestinal ischemia, glossitis, gingivitis, periodontitis, esophagitis (including reflux), proctitis, liver fibrosis and Cirrhosis of the liver, pancreatitis, acute and chronic pancreatic fibrosis, pancreatic cirrhosis, pancreatolithiasis, cirrhosis of the liver, hepatitis (congestive, autoimmune, acute, fulminant, chronic, drug-induced, alcoholic, lupus-like, 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 hepatic necrosis (e.g. caused by toxins, viral hepatitis, shock, or hypoxia), or hemolytic uremic syndrome.

[0388] The disease, disorder or condition can be or include a blood disease or disorder, e.g., anemia, coagulation, a myeloproliferative disorder, a bleeding disorder, leukopenia, an eosinophilic disorder, a leukemia (e.g., myeloid), a lymphoma, a plasma cell dyscrasia, a spleen disorder, Band's disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott-Aldrich syndrome.

[0389] The disease, disorder or condition can be or include a metabolic disease or disorder, such as obesity, amyloidosis, amino acid metabolism disorders such as branched chain diseases, hyperaminoacidemia, hyperaminoaciduria, urea metabolism disorders, hyperammonemia, mucopolysaccharidosis such as Maroteaux-Lamy syndrome, storage diseases such as glycogen storage diseases and lipid storage diseases, glycogen storage disease I diseases such as Currie's disease, malabsorption diseases such as intestinal carbohydrate malabsorption, oligosaccharidase deficiencies such as maltase, lactase, sucrase deficiency, fructose metabolism disorders, galactose metabolism disorders, galactosemia, carbohydrate utilization disorders such as diabetes mellitus, hypoglycemia, pyruvate metabolism disorders, hypolipidemia, hypolipoproteinemia, hyperlipidemia, hyperlipoproteinemia, carnitine or carnitine acyltransferase deficiency, porphyrin metabolism disorders, porphyrin, purine metabolism disorders, lysosomal diseases, metabolic diseases of the nervous system and nervous system such as gangliosidosis, neurolipidosis, sulfatide storage disease, leukodystrophy or Lesch-Nyhan syndrome.

[0390] The disease, disorder or condition can be or include cerebellar dysfunction or cerebral metabolic disorders, such as dementia, Alzheimer's disease, Huntington's disease, 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 deficiencies, such as any disorder arising from hyperfunction or hypofunction of certain hormone-secreting endocrine glands, and any combination thereof; Sipple syndrome, pituitary dysfunction and its effects on other endocrine glands (e.g., thyroid, adrenal glands, ovaries and testes), acromegaly, hyperthyroidism and hypothyroidism, euthyroid goiter, euthyroid sick syndrome, thyroiditis and thyroid cancer, adrenal steroid hormone over- or under-secretion, adrenogenetic syndrome, Cushing's syndrome, Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary aldosteronism dystrophies, diabetes insipidus, diabetes mellitus, carcinoid syndrome, disorders caused by parathyroid dysfunction, islet cell dysfunction, diabetes mellitus, disorders of the female endocrine system such as estrogen deficiency, resistant ovary syndrome, myasthenia, myotonia; Duchenne and other muscular dystrophies, myotonic dystrophy Steinert disease, mitochondrial myopathies such as catabolic disorders in muscle, carbohydrate and lipid storage myopathies, glycogenosis, myoglobinuria, malignant hyperthermia, polymyalgia rheumatica, dermatomyositis, polymyositis, primary cardiomyopathy, cardiomyopathy; ectodermal disorders, neurofibromatosis, scleroderma and polyarteritis, Louis-Barr syndrome, von Hippel-Lindau disease, Sturge-Weber syndrome, tuberous sclerosis, amyloidosis, porphyria; male and female sexual dysfunction; confusional states and seizures due to inappropriate secretion of pituitary antidiuretic hormone, Liddle syndrome, Bartter syndrome, Fanconi I syndrome or renal electrolyte depletion.

[0391] The disease, disorder or condition may be or include a transplant rejection-related disorder such as acute and chronic allograft rejection following solid organ transplantation (e.g., kidney, heart, liver, lung and corneal transplantation), chronic graft-versus-host disease, skin transplant rejection and bone marrow transplant rejection or immunosuppression.

[0392] The disease, disorder or condition may be or include a urogenital related disorder such as nephritis (interstitial, acute interstitial (allergic) and glomerulonephritis), nephrotic syndrome, cystitis (including acute and chronic (interstitial) cystitis and Huntington's ulcer), acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvovaginitis, vulvovaginal candidiasis, Peyronie's disease and erectile dysfunction, nephropathy, renal fibrosis, pyelonephritis, secondary contractile kidney, steroid-dependent and steroid-resistant nephropathy or Goodpasture's syndrome.

[0393] The disease, disorder or condition may be or include a CNS-related disease or disorder, such as neurodegenerative diseases, Alzheimer's disease and other bone cement disorders (including CJD and nvCJD), amyloidosis and other demyelinating syndromes, cerebral atherosclerosis and vasculitis, temporal arteritis, myasthenia gravis, acute and chronic pain (acute, intermittent or persistent, whether central or peripheral in origin) (including postoperative, visceral pain, headache, migraine, neuralgia (including trigeminal), atypical facial pain, Joint and bone pain, pain due to cancer and tumor invasion), neuropathic pain syndromes (including diabetic, post-herpetic and HIV-related neuropathies), neurosarcoidosis, brain injury, cerebrovascular disease and its consequences, Parkinson's disease, cortical basal degeneration, motor neurone 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, chromosome 17-linked frontotemporal dementia The following are considered to be CNS disorders: dementia with associated Parkinson's syndrome, frontotemporal dementia (including Pick's disease), progressive supranuclear palsy, corticobasal degeneration, Huntington's disease, thalamic degeneration, HIV dementia, schizophrenia with dementia, and Korsakoff's psychosis. Also considered to be CNS disorders within the meaning of this definition are central and peripheral nervous system complications of malignant, infectious, or autoimmune processes, pain, cerebral infarction, seizures, cerebral ischemia, head injury, spinal cord injury, myelopathy, Shy-Drager syndrome, Reye's syndrome syndrome, progressive multifocal leukoencephalopathy, normal pressure hydrocephalus, sclerosing panencephalitis, frontal lobe dementia, acute anterior horn poliomyelitis (poliomyelitis), poliomyelitis neurosis, viral encephalitis, allergic encephalomyelitis, epileptic encephalopathy, Creutzfeldt-Jakob disease, kuru, bovine spongiform encephalopathy (mad cow disease), scrapie, epilepsy, cerebral amyloid angiopathy, depression, mania, manic-depressive psychosis, hereditary cerebellar ataxia, peripheral neuropathy, Nasu-Hakola syndrome, or Machado-Joseph disease.

[0394] The disease, disorder or condition may be or include an inflammatory or immune disease or disorder, such as general inflammation (of the eye, nose, lungs and gastrointestinal tract), mastocytosis / mast cell disorders (cutaneous, 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 basophilic leukocytosis) and eosinophil-related diseases (e.g., Churg-Strauss syndrome), eosinophilic granuloma, lupus erythematosus. lupus (e.g., systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and discoid lupus erythematosus), chronic thyroiditis, Hashimoto's thyroiditis, Graves' disease, type I diabetes, complications caused by diabetes, other immune disorders, eosinophilic fasciitis, hyper-IgE syndrome, Addison's disease, antiphospholipid syndrome, immunodeficiency diseases, acquired immunodeficiency syndrome (AIDS), leprosy, Sezary syndrome, paraneoplastic syndromes and other autoimmune disorders, fever, myositis, a neurological disease selected from polymyositis, bursitis, Evan's syndrome, leukotriene B4-mediated diseases, idiopathic hypoparathyroidism, nephrotic syndrome, lupus, or immunosuppressive.

[0395] The disease, disorder or condition can be or include a cardiovascular disease or disorder, such as congestive heart failure, myocardial infarction, ischemic heart disease, various atrial and ventricular arrhythmias, hypertension, brain trauma, occlusive vascular disease, stroke, cerebrovascular disorders, atherosclerosis, restenosis affecting the coronary arteries and peripheral circulation, pericarditis, myocarditis, inflammatory and autoimmune cardiomyopathy (including cardiomyosacral tumors, endocarditis, valvulitis and aortitis, including infectious (e.g., syphilis), hypertensive vascular disease, peripheral vascular disease and atherosclerosis), vasculitis, disorders of the proximal and peripheral veins (including phlebitis and thrombosis, including deep vein thrombosis and varicose vein complications), aortic aneurysm, periarteritis nodosa, cardiac fibrosis, post-myocardial infarction, idiopathic cardiomyopathy or angioplasty.

[0396] The disease, disorder or condition can be or include a neoplastic disease or disorder, such as common cancers (prostate, breast, lung, ovary, pancreas, intestine and colon, abdomen, stomach (and any other digestive system cancer), liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testis, ovary, thymus, thyroid), eye, head, neck, nervous system (central and peripheral), lymphatic system, blood, pelvis, skin, bone, soft tissue, spleen, chest, genitourinary system and brain tumors), breast cancer, genitourinary cancer, lung cancer, gastrointestinal cancer, epidermoid carcinoma, melanoma, ovarian cancer, pancreatic cancer, neuroblastoma, malignancies affecting the bone marrow (including leukemias) and lymphoproliferative system, such as Hodgkin's lymphoma and non-Hodgkin's lymphoma, B-cell lymphoma, follicular lymphoma, metastatic disease and tumor recurrence, and side effects. Tumor syndromes, as well as hypergammaglobulinemia, lymphoproliferative diseases, disorders and / or conditions, paraproteinemias, purpura (including idiopathic thrombocytopenic purpura), Waldenstrom's macroglobulinemia, Gaucher disease, histiocytosis, retinoblastoma and any other hyperproliferative disease, malignant neoplasms, cachexia, tumor growth, tumor invasion, metastasis, AIDS-related lymphoma, malignant immunoproliferative diseases, multiple myeloma and malignant plasmacytoma, lymphoid leukemia, acute or chronic myeloid leukemia, acute or chronic lymphocytic leukemia, monocytic leukemia, other leukemias of specified cell types, leukemias of unspecified cell types, other and unspecified malignancies of lymphoid, hematopoietic and related tissues, such as diffuse large cell lymphoma, T-cell lymphoma or cutaneous T-cell lymphoma). Myeloid cancers include, for example, acute or chronic myeloid leukemia or corneal leukoma.

[0397] The disease, disorder or condition can be or include another disease or disorder, such as pain, migraine, sleep disorder, fever, sepsis, idiopathic thrombocytopenic purpura, postoperative adhesions, flushing, ischemia / reperfusion injury of the heart, brain, peripheral limbs, bacterial infection, viral infection, fungal infection, thrombosis, endotoxin shock, septic shock, heat regulation (including fever), Raynaud's disease, gangrene, diseases requiring anticoagulant therapy, congestive heart failure, mucus secretion disorders, pulmonary hypotension, prostaglandin-induced smooth muscle contraction associated with dysmenorrhea and premature labor, premature labor, reperfusion injury, burns, thermal injury, hemorrhage or traumatic shock, menstrual pain, menstrual cramps, dysmenorrhea, periodontal disease, rickettsial infections, protozoal diseases, reproductive diseases, toothache, post-extraction pain, herpes zoster, herpes simplex, retroperitoneal fibrosis, or various radiation injuries.

[0398] In certain embodiments, the disease is selected from the group consisting of inflammatory diseases, autoimmune diseases, allergic disorders and eye disorders. In certain embodiments, the disease is selected from the group consisting of pruritus, eczema, asthma, rhinitis, dry eyes, eye inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis and uveitis.

[0399] 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 specific kinase over other kinases. The method may include modulating the activity of multiple kinases or preferentially modulating the activity of two more specific kinases over other kinases.

[0400] The method may comprise providing a compound of the invention. The method may comprise providing a plurality of compounds of the invention.

[0401] The method may include contacting a cell containing a kinase with one or more compounds of the invention. For example, but not limited to, contacting a cell with a compound may include exposing the cell to, for example, a compound in a formulation, such as any of those described above; delivering the compound intracellularly; providing the compound to a subject and allowing 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 invention. The method may include contacting a cell with multiple compounds of the invention.

[0402] The method may include administering the composition to the subject. The composition may be provided by any suitable route of administration. For example, but not limited to, the composition may be administered buccally, by injection, transdermally, enterally, intra-arterially, intravenously, intranasally (e.g., by inhalation), intraocularly, orally, parenterally, pulmonary, rectal, subcutaneously, systemically, topically (e.g., to the skin or eyes), transdermally, or with or on an implantable medical device (e.g., a stent or drug eluting stent or balloon equivalent).

[0403] The method may include using the compositions of the invention to diagnose a disease, disorder or condition in a subject.For example, a radiolabeled form of the compound can be used as a tracer in positron emission tomography (PET) to identify the anatomical location of aberrant 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, page 151, ISBN 0205239390, the contents of each of which are incorporated herein by reference. The present invention may include administering one or more compositions of the present invention for diagnostic and therapeutic purposes.

[0404] Examples

[0405] Example 1: Synthesis of N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0406]

[0407] Step 1: 4-Bromo-6-chloro-2,7-naphthyridin-1(2H)-one

[0408]

[0409] To a solution of 6-chloro-2,7-naphthyridine-1-ol (1 g; 5.53 mmol; 1.00 eq.) in DMF (15 mL) was added NBS (1 g; 5.61 mmol; 1.00 eq.) at 0 ° C under nitrogen 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, washed with water, and then dried in vacuo to give 4-bromo-6-chloro-2,7-naphthyridine-1 (2H) -one (1.16 g, 81%) as a white solid. LCMS (ESI) m / z 258.9, [M+H] + .

[0410] Step 2: 4-Bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one

[0411]

[0412] To 4-bromo-6-chloro-2,7-naphthyridin-1(2H)-one (1.16 g; 4.47 mmol; 1.00 eq.) and Cs 2 CO 3 To a mixture of (2.9 g; 8.89 mmol; 2.00 eq.) in THF (20 mL) was added TBAI (166 mg; 0.449 mmol; 0.10 eq.). To the reaction mixture was added (2-(chloromethoxy)ethyl)-trimethylsilane (1.31 g; 7.89 mmol; 1.76 eq.) 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, washed with THF (20 mL) and dried in vacuo to give 4-bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one (1.08 g, 62%) as a white solid. LCMS (ESI) m / z 389.0, [M+H] + .

[0413] Step 3: 6-Chloro-4-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one

[0414]

[0415] 4-Bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one (160 mg; 0.411 mmol; 1.00 eq.) and phenylboronic acid (40 mg; 0.327 mmol; 0.80 eq.), Pd(PPh 3 ) 4To a stirred mixture of (47.6 mg; 0.041 mmol; 0.10 eq.) in DME / water (5:1, 6 mL) was added Na 2 CO 3 (87.4 mg; 0.824 mmol; 2.00 eq.) and the reaction mixture was stirred at 100 ° C for 3 hours under nitrogen. The desired product was observed by LCMS. The reactants were concentrated in vacuo. The residue was purified by flash chromatography on a silica gel column using EtOAc / petroleum ether (10-30%) as eluent to provide 6-chloro-4-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one (78 mg, 49%) as a yellow solid. LCMS (ESI) m / z 387.1, [M+H] + .

[0416] Step 4: N-(8-oxo-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0417]

[0418] 6-Chloro-4-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2,7-naphthyridin-1(2H)-one (58 mg; 0.150 mmol; 1.00 eq.), Pd 2 (dba) 3 (13.8mg; 0.015mmol; 0.10eq.), XantPhos (17.4mg; 0.030mmol; 0.20eq.), Cs 2 CO 3 A mixture of cyclopropanecarboxamide (98.0 mg; 0.301 mmol; 2.00 eq.) and cyclopropanecarboxamide (38.3 mg; 0.450 mmol; 3.00 eq.) in dioxane (3 mL) was stirred at 110 ° C for 2 hours. The mixture was cooled to room temperature and then concentrated in vacuo. The residue was purified by a silica gel column using EtOAc / petroleum ether (10-30%) as eluent to provide N-(8-oxo-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg, 92%) as a white solid. LCMS (ESI) m / z 436.2, [M+H] + .

[0419] Step 5: N-(8-oxo-5-phenyl-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0420]

[0421] 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 eq.) in MeOH (0.5 mL) was added a solution of HCl in dioxane (4 M, 2 mL). The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The desired product was observed by LCMS. The mixture was concentrated in vacuo to give N-(8-oxo-5-phenyl-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg, 89%) as a yellow solid. LCMS (ESI) m / z 306.1, [M+H] + .

[0422] Step 6: N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0423]

[0424] N-(8-Oxo-5-phenyl-7,8-dihydro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.162 mmol; 1.00 eq.) was dissolved in POCl 3 (2 mL). The resulting mixture was stirred at 100 ° C for 1 hour. The desired product was observed by LCMS. The solvent was concentrated in vacuo to give N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (35 mg, 66%) as a yellow solid. LCMS (ESI) m / z 324.1, [M+H] + .

[0425] Step 7: N-(8-(Methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0426]

[0427] N-(8-Chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (35 mg; 0.108 mmol; 1.00 eq.) 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 hours. After completion, the mixture was concentrated in vacuo. The reaction mixture was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3The residue was purified by flash chromatography on a pre-packed C18 column with 4% paraformaldehyde as eluent to afford N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (5.2 mg, 15%) as a white solid. LCMS (ESI) m / z 319.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.92(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=4.4Hz,3H),2.07-1.95(m,1H),0.84-0.6(m,4H).

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

[0429]

[0430] Step 1: 6-Chloro-4-methylnicotinamide

[0431]

[0432] 6-Chloro-4-methylnicotinic acid (50.0 g; 0.292 mol; 1.00 eq.) was dissolved in CH 2 Cl 2 HATU (170 g; 0.447 mol; 1.50 eq.) was added to the stirred solution in (1 L). The reaction was stirred at room temperature for 20 minutes. NH 4 Cl (155 g; 2.92 mol; 10.0 eq.) and DIPEA (113 g; 0.875 mol; 3.00 eq.) were added and stirred at room temperature under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was diluted with water (1 L) and washed with CH 2 Cl 2 (200 mL × 5) extraction. The organic layer was washed with saturated NaCl solution and then with anhydrous Na 2 SO 4 Dry. 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 (25-60%) as eluent to provide 6-chloro-4-methylnicotinamide (33 g, 66%) as a brown solid. LCMS (ESI) m / z 171.0, [M+H] + .

[0433] Step 2: (Z)-6-Chloro-N-((dimethylamino)methylene)-4-methylnicotinamide

[0434]

[0435] To a stirred mixture of 6-chloro-4-methylnicotinamide (51 g; 300 mmol; 1.00 eq.) in methyltetrahydrofuran (300 mL) was added DMF-DMA (53.5 g; 449 mmol; 1.50 eq.). 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 (65.0 g, crude) as a brown solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z 226.1, [M+H] + .

[0436] Step 3: 6-Chloro-2,7-naphthyridin-1(2H)-one

[0437]

[0438] To a solution of (Z)-6-chloro-N-((dimethylamino)methylene)-4-methylnicotinamide (60.0 g; 266 mmol; 1.00 eq.) in THF (387 mL) was slowly added t-BuOK (1.0 M THF solution, 400 mL) at 0 ° C and the reaction mixture was stirred at 80 ° C under a nitrogen atmosphere for 0.5 hours. The desired product was detected by LCMS. The precipitated solid was collected by filtration and washed with THF (2×20 mL) to obtain a crude product. The crude product was dissolved with water (500 mL), acidified to pH=6 with HCl solution (1 M), and the precipitated solid was collected by filtration and washed with water. The solid was dried in vacuo to obtain 6-chloro-2,7-naphthyridine-1(2H)-one (40 g, 83%) as a brown solid. LCMS (ESI) m / z 181.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.69(s,1H),9.09(s,1H),7.76(s,1H),7.52 -7.40(m,1H),6.53(d,J=7.2Hz,1H).

[0439] Step 4: N-(8-Hydroxy-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0440]

[0441] To a stirred mixture of 6-chloro-2,7-naphthyridin-1(2H)-one (8.5 g, 47.1 mmol, 1.00 eq.) in 1,4-dioxane (500 mL) was added Pd 2 (dba) 3 (4.25 g, 4.64 mmol, 0.10 eq.), XantPhos (5.44 g, 9.40 mmol, 0.20 eq.), cyclopropanecarboxamide (16.2 g, 190 mmol, 4.00 eq.) and Cs 2 CO 3 (30.6 g, 93.9 mmol, 2.00 eq.). The reaction was stirred at 110°C for 3 hours. The desired product was observed by LCMS. The reaction was concentrated in vacuo and purified by using EtOAc / petroleum ether (30-100%) and MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 4% (2-20%) as eluent to afford 8.3 g of crude product. The crude product was purified by washing with CH 2 Cl 2 / EtOAc mixed solvent (2:1, 450 mL) and stirred overnight, then filtered and washed with CH 2 Cl 2 (200 mL) and the filter cake was washed and dried to give N-(8-hydroxy-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (6.5 g, 60%) as a yellow solid. LCMS (ESI) m / z 230.1, [M+H] + .

[0442] Step 5: N-(8-chloro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0443]

[0444] N-(8-Hydroxy-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.4 g, 19.2 mmol, 1.00 eq.) was dissolved in POCl 3 (55 mL). The reaction was stirred at 100 °C for 30 minutes. The reaction was cooled and then concentrated in vacuo. The residue was washed with CH 2 Cl 2 (300 mL) and diluted with saturated NaHCO 3 The solution was neutralized to pH 7. The organic phase was concentrated in vacuo. 2 Cl 2The residue was purified by flash chromatography on a silica gel column (20-50%) to give N-(8-chloro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (1.85 g, 39%) as an off-white solid. LCMS (ESI) m / z 248.1, [M+H] + .

[0445] Step 6: N-(8-(Methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0446]

[0447] In N 2 Methylamine hydrochloride (1.0 g; 14.8 mmol; 4.00 eq.) and DIPEA (2.4 g, 18.6 mmol, 5.00 eq.) were added to a stirred mixture of N-(8-chloro-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (920 mg, 3.71 mmol, 1.00 eq.) in NMP (10 mL). The reaction was stirred at 100 ° C for 18 hours. 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 in vacuo and purified by using 10-40% MeCN / water (10 mmol / L NH 4 HCO 3 ) was purified by flash chromatography on a prepacked C18 column to afford N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (850 mg, 94%) as an off-white solid. The product was purified by using 20%-60% MeCN / water (10 M NH 4 HCO 3 ) was further purified by flash chromatography on a pre-packed C18 column to provide N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.5 mg, 45%) as a white solid. LCMS (ESI) m / z 243.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.91(s,1H),9.30(s,1H),8.16(s,1H),7.95(d,J=6.0Hz,1H),7.87-7.80(m,1H) ,6.74(d,J=6.0Hz,1H),2.96(d,J=4.4Hz,3H),2.09-2.00(m,1H),0.88-0.78(m,4H)

[0448] Example 3

[0449] Synthesis of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0450]

[0451] 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 eq.) in DMF (12 mL) at 0 ° C. was added NBS (1.40 g, 7.84 mmol, 1.00 eq.). The reaction was then warmed to room temperature for 1 hour. 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 in vacuo and purified by using 2-10% MeOH / CH 2 Cl 2 The crude product was then purified by reverse phase preparative HPLC (Prep-C18, 5 μM OBD column, 19×250 mm, waters; gradient elution of 40-50% MeCN / water over an 8 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to obtain N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (327 mg, 13%) as a white solid. LCMS (ESI) m / z 321.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.13(s,1H),9.32(s,1H),8.44(s,1H),8.16(s,1H),8.14-8.09(m,1H),2.95(d,J=4.4Hz,3H),2.12-2.04(m,1H),0.92-0.82(m,4H).

[0452] Example 4: Synthesis of N-(8-(methylamino)-5-(pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0453]

[0454] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (35.0 mg; 0.109 mmol; 1.00 eq.) in 1,4-dioxane (1.5 mL) were added 2-(tributylstannyl)pyridine (80.2 mg; 0.218 mmol; 2.00 eq.), CuI (4.1 mg; 0.022 mmol; 0.20 eq.), Pd(PPh 3 ) 4 (25.2 mg; 0.022 mmol; 0.20 eq.) and LiCl (11.6 mg; 0.273 mmol; 2.50 eq.). The reaction mixture was stirred at 110°C under nitrogen atmosphere for 3 hours. The resulting mixture was diluted with EtOAc (50 mL). The organic layer was washed with brine (5×3 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. 4 HCO 3 The residue was purified by flash chromatography on a pre-packed C18 column with 4% paraformaldehyde as eluent to afford N-(8-(methylamino)-5-(pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.6 mg, 13%) as a white solid. LCMS (ESI) m / z 320.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.94(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=4.4Hz,3H),2.06-1.99(m,1H),0.82-0.78(m,4H).

[0455] Example 5: Synthesis of N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0456]

[0457] Step 1: 3-Methoxy-2-(tributylstannyl)pyridine

[0458]

[0459] To a solution of 2-bromo-3-methoxypyridine (500 mg; 2.65 mmol; 1.00 eq.) in 1,4-dioxane (5 mL) was added Pd 2 (dba) 3 (244.8 mg; 0.267 mmol; 0.10 eq.), tricyclohexylphosphine (167.7 mg; 0.598 mmol; 0.22 eq.), LiCl (566.8 mg; 13.3 mmol; 5.00 eq.). To the mixture was added 1,1,1,2,2,2-hexa-n-butylditin (2.32 g; 4.01 mmol; 1.50 eq.). The reactants were stirred at 110 °C for 1 hour. The mixture was cooled to room temperature. The desired product was detected by LCMS. The resulting mixture was purified by CH 2 Cl 2 (100 mL) and washed with saturated NaCl solution (3×5 mL). 2 SO 4 Dry, filter and remove the solvent under reduced pressure. Neutral Al was purified by eluting with 1-10% EtOAc / petroleum ether as eluent. 2 O 3 The residue was purified by column flash chromatography to provide 3-methoxy-2-(tributylstannyl)pyridine (1.0 g, 93%) as a yellow oil. LCMS (ESI) m / z 400.2, [M+H] + .

[0460] Step 2: N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0461]

[0462] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.16 mmol; 1.00 eq.) in 1,4-dioxane (2 mL) were added 3-methoxy-2-(tributylstannyl)pyridine (312 mg; 0.78 mmol; 5.00 eq.), CuI (6 mg; 0.03 mmol; 0.20 eq.), Pd(PPh 3 ) 4 (36 mg; 0.03 mmol; 0.20 eq.) and LiCl (16 mg; 0.37 mmol; 2.50 eq.). The reaction was stirred at 110°C under nitrogen atmosphere for 5 hours. The resulting mixture was diluted with EtOAc (60 mL) and washed with saturated NaCl solution (2×5 mL), and then washed with anhydrous Na 2 SO 4After filtration, the organic layer filtrate was concentrated under reduced pressure. 2 Cl 2 The residue was purified by silica gel column as eluent to afford the crude product. 4 HCO 3 ) to provide N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (22.8 mg, 41%) as a white solid. LCMS (ESI) m / z 350.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.84(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=4.4Hz,3H),2.03-1.95(m,1H),0.79-0.71(m,4H).

[0463] Example 6: Synthesis of N-(5-(1-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0464]

[0465] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg; 0.062 mmol; 1.00 eq.) in a DME / water mixed solvent (5:1, 1.2 mL) were added (1-methyl-1H-pyrazol-5-yl)boronic acid (11.8 mg; 0.094 mmol; 1.5 eq.), Pd(PPh 3 ) 4 (7.2 mg; 0.006 mmol; 0.10 eq.) and Na 2 CO 3 (13.2 mg, 0.125 mmol; 2.00 eq.). The resulting mixture was stirred at 100° C. under nitrogen atmosphere for 3 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The product was purified by using 3-10% MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column as eluent to provide N-(5-(1-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (16 mg, crude) as a yellow solid. The crude product was purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN / water (0.05% formic acid) as eluent to provide N-(5-(1-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.8 mg, 23%) as a white solid. LCMS (ESI) m / z 323.2, [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.98(s,1H),9.39(s,1H),8.20-8.11(m,1H),8.01(s,1H),7.98(s,1H),7.54(d,J=1.6Hz,1H) ,7.30(d,J=1.6Hz,1H),3.64(s,3H),2.97(d,J=4.4Hz,3H),2.10-1.98(m,1H),0.90-0.78(m,4H).

[0466] Examples 7-25: Using similar experimental procedures used to prepare Example 6, the examples in Table 1 were prepared using N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 3) as a common intermediate and the appropriate boronic acid ester or acid.

[0467] Table 1

[0468]

[0469]

[0470]

[0471]

[0472]

[0473] Example 26: Synthesis of N-(8-(methylamino)-5-(5-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0474]

[0475] 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 eq.) in a mixed solvent of 1,4-dioxane / water (10:1, 1.1 mL) were added 4-bromo-5-methylthiazole (43.5 mg; 0.244 mmol; 1.5 eq.), Pd(dppf)Cl 2 (11.9 mg; 0.016 mmol; 0.10 eq.) and Na 2 CO 3 (34.5 mg; 0.325 mmol; 2.00 eq.). The reaction mixture was stirred at 40 °C under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 2%-10% HCl as eluent to give N-(8-(methylamino)-5-(5-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15 mg, crude). The product was then purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(5-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.9 mg, 9%) as a white solid. LCMS (ESI) m / z 340.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.92(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=4.4Hz,3H),2.35(s,3H),2.10-1.98(m,1H),0.88-0.72(m,4H).

[0476] Example 27: Synthesis of N-(5-methyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0477]

[0478] To N-[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.) and K 3 PO4 To a solution of (53 mg; 0.250 mmol; 2.00 eq.) in dioxane / water (5:1, 4.8 mL) was added Pd(DtBPF)Cl 2 (8 mg; 0.012 mmol; 0.10 eq.) and trimethyl-1,3,5,2,4,6-trioxatriborinane (19 mg; 0.151 mmol; 1.22 eq.). After stirring at 90 °C under nitrogen atmosphere for 2 hours, the resulting mixture was concentrated under reduced pressure. The mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-amino-5-methyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15.0 mg, 46.9%) as a white solid. LCMS (ESI) m / z 257.1, [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.97(s,1H),9.30(s,1H),8.27(s,1H),7.83(s,1H),7.69-7.65(m,1H) ,2.93(d,J=4.4Hz,3H),2.22(s,3H),2.10-2.03(m,1H),0.88-0.81(m,4H).

[0479] Examples 28-38: Using similar experimental procedures used to prepare Example 27, the examples in Table 2 were prepared using -[5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl]cyclopropanecarboxamide as a common intermediate and the appropriate boronic acid or olefin.

[0480] Table 2

[0481]

[0482]

[0483]

[0484] 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

[0485]

[0486] At room temperature in N 2 To a stirred solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.) in dioxane / water (5:1, 1.2 mL) was added Pd(DtBPF)Cl 2 (8.1mg; 0.012mmol; 0.10eq.), K 3 PO 4 (52.9 mg; 0.249 mmol; 2.00 eq.) 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 eq.). The reactants were stirred at 90 ° C for 2 hours. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo. The reaction was carried out by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with 1%-10% (1%-10%) as eluent to afford 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 product was prepared by using 10%-70% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(5-(4-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (6.1 mg, 12%) as a white solid. LCMS (ESI) m / z 407.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.96(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 = 4.4Hz, 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).

[0487] Example 40: Synthesis of N-(5-(4-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0488]

[0489] 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 eq.) 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 in vacuo. The residue was purified by using 10%-70% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(5-(4-methyl-1H-pyrazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (10.5 mg, 19%) as a white solid. LCMS (ESI) m / z 323.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ12.64(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=4.4Hz,3H),2.05-1.97(m,1H),1.92(s,3H),0.83-0.74(m,4H).

[0490] 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

[0491]

[0492] To a stirred solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 eq.) in 1,4-dioxane / water (10:1, 1.1 mL) were added (2-cyanophenyl)boronic acid (68.6 mg; 0.467 mmol; 1.5 eq.), Pd(dppf)Cl2 (22.8 mg; 0.031 mmol; 0.10 eq.) and K 3 PO 4 (132.2mg; 0.622mmol; 2.00eq.). 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 / petroleum ether as eluent to give 2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4-yl)benzamide (50mg, crude) and N-(5-(2-cyanophenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15mg, crude). The residue was purified by flash chromatography on a silica gel column using 20-60% MeCN / water (10mmol / L NH 4 HCO 3 ) were purified by flash chromatography on a prepacked C18 column of 5-nitropropanediol to provide 2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4-yl)benzamide (28.8 mg, 26%) as a white solid and N-(5-(2-cyanophenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.3 mg, 4%) as a white solid. Analytical data of 2-(6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridin-4-yl)benzamide: LCMS (ESI) m / z 362.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.87(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=7.6,1.2Hz,1H),7.13(s,1H),3.00(d,J=4.4Hz,3H),2.05-1.96(m,1H),0.82-0.70(m,4H). Analytical data of N-(5-(2-cyanophenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: LCMS(ESI)m / z 344.1,[M+H] + . 1 HNMR (400 MHz, DMSO-d 6)δ11.00(s,1H),9.42(s,1H),8.25-8.15(m,1H),8.04-7.96(m,3H),7.88-7.79(m,1 H),7.68-7.54(m,2H),3.04(d,J=4.4Hz,3H),2.05-1.95(m,1H),0.81-0.70(m,4H).

[0493] Example 43: Synthesis of N-(5-benzyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0494]

[0495] To a stirred solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.) in THF / water (10:1, 2.2 mL) were added potassium benzyl trifluoroborate (61.8 mg; 0.312 mmol; 2.00 eq.), Pd(OAc) and 2 (3.5 mg; 0.016 mmol; 0.10 eq.), X-Phos (14.8 mg; 0.031 mmol; 0.20 eq.), and Cs 2 CO 3 (101.4 mg; 0.312 mmol; 2.00 eq.). The reaction mixture was stirred at 85 °C under nitrogen atmosphere for 12 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using 0-10% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to give N-(5-benzyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15 mg, crude). The product was prepared by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(5-benzyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (3.9 mg, 8%) as a white solid. LCMS (ESI) m / z 333.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.93(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=4.4Hz,3H),2.10-2.00(m,1H),0.90-0.75(m,4H).

[0496] Example 44: Synthesis of N-(5-(hydroxymethyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0497]

[0498] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 eq.) in 1,4-dioxane (10 mL) was added Pd(PPh 3 ) 4 (36.1 mg; 0.031 mmol; 0.10 eq.) and (tributylstannyl)methanol (300.9 mg; 0.937 mmol; 3.00 eq.). The reaction was stirred at 95 °C for 2.5 hours. The mixture was allowed to cool to room temperature. The desired product was observed by LCMS. The solvent was removed under reduced pressure. The reaction mixture was purified by using 20%-70% MeCN / water (10 mmol / L NH 4 HCO 3 The residue was purified by flash chromatography on a pre-packed C18 column with ) as eluent to provide N-(5-(hydroxymethyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg, 70%) as a white solid. LCMS (ESI) m / z 273.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.93(s,1H),9.32(s,1H),8.44(s,1H),7.92(s,1H),7.88-7.80(m,1H),4.87(t,J=5.0H z, 1H), 4.56 (d, J = 5.0Hz, 2H), 2.96 (d, J = 4.4Hz, 3H), 2.12-2.01 (m, 1H), 0.91-0.78 (m, 4H).

[0499] Example 45: Synthesis of N-(8-(methylamino)-5-(phenoxymethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0500]

[0501] To a solution of N-(5-(hydroxymethyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg; 0.110 mmol; 1.00 eq.) in THF (5 mL) was added phenol (104 mg; 1.10 mmol; 10.0 eq.), PPh 3 (55.7 mg; 0.212 mmol; 1.93 eq.). DIAD (43.3 mg; 0.214 mmol; 1.94 eq.) was added to the mixed reactants and stirred at room temperature for 1 hour. The desired product was detected by LCMS. The solvent was removed under reduced pressure. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with (2-10%) as eluent to provide N-(8-(methylamino)-5-(phenoxymethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (10 mg, crude). The product was purified by reverse phase preparative HPLC (XBridge Prep OBDC18 column, 30×150 mm, waters; gradient elution of 38%-48% MeCN / water over a 10 min period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 220 nm) to purify the crude product to provide N-(8-(methylamino)-5-(phenoxymethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (1.4 mg, 3%) as a white solid. LCMS (ESI) m / z 349.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.95(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=4.4Hz,3H),2.10-2.00(m,1H),0.86-0.75(m,4H).

[0502] Example 46: Synthesis of N-(8-(methylamino)-5-(4-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0503]

[0504] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg; 0.093 mmol; 1.00 eq.) in 1,4-dioxane / water (5:1, 1.8 mL) were added XPhos (4.4 mg; 0.009 mmol; 0.10 eq.), XPhos Pd G3 (CAS: 1445085-55-1) (8.1 mg; 0.010 mmol; 0.10 eq.), K 3 PO 4 (60 mg; 0.283 mmol; 2.00 eq.) and (4-(methylsulfonyl)phenyl)boronic acid (19 mg; 0.095 mmol; 1.00 eq.). The resulting solution was stirred at 90° C. for 2 hours under a nitrogen atmosphere. The reaction was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluted with methanol / dichloromethane (5-10%) as eluent to give 50 mg of crude product. The crude product was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(4-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30.0 mg, 81%) as a white solid. LCMS (ESI) m / z 397.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(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=4.4Hz,3H),2.06-1.98(m,1H),0.82-0.76(m,4H).

[0505] Example 47: Synthesis of N-(8-(methylamino)-5-(2-(methylthio)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0506]

[0507] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.) in DME / water (5:1, 1.2 mL) was added (2-(methylthio)phenyl)boronic acid (78.5 mg; 0.467 mmol; 3.00 eq.), Pd(PPh 3 ) 4 (18.0 mg; 0.016 mmol; 0.10 eq.) and Na 2 CO 3 (49.5 mg; 0.467 mmol; 3.00 eq.). The reaction was stirred at 100 °C for 3 h under nitrogen. The desired product was detected by LCMS. The resulting mixture was concentrated in vacuo. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(2-(methylthio)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (3.9 mg, 6%) as a white solid. LCMS (ESI) m / z 365.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(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=4.4Hz,3H),2.31(s,3H),2.02-1.93(m,1H),0.78-0.69(m,4H).

[0508] Example 48: Synthesis of N-(8-(methylamino)-5-(2-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0509]

[0510] At 0°C, N-(8-(methylamino)-5-(2-(methylthio)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (14 mg; 0.038 mmol; 1.00 eq.) was added to CH 2 Cl2 m-CPBA (13.3 mg; 0.077 mmol; 2.00 eq.) was added to a solution of 1 mL of 1% ethyl acetate. The reaction was stirred at room temperature for 1 hour under nitrogen. The resulting mixture was concentrated in vacuo and heated to room temperature using 2-10% MeOH / CH 2 Cl 2 Flash chromatography on a silica gel column as the eluent provided 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), respectively. The product was purified by using 20-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) were purified by flash chromatography on a prepacked C18 column of 4% paraformaldehyde to provide N-(8-(methylamino)-5-(2-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (3.7 mg, 24%) as a white solid and N-(8-(methylamino)-5-(2-(methylsulfinyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (0.8 mg, 5%) as a white solid. Analytical data of N-(8-(methylamino)-5-(2-(methylsulfonyl)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: LCMS (ESI) m / z 397.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(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=4.4Hz,3H),2.88(s,3H),2.00-1.93(m,1H),0.76-0.69(m,4H). Analytical data of 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-d 6)δ10.96(d,J=18.0Hz,1H),9.39(d,J=5.6Hz,1H),8.17-8.08(m,1H),7.99-7.61(m,5H),7.3 5-7.30(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).

[0511] 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

[0512]

[0513] Step 1: 3-Bromo-2-methoxybenzamide

[0514]

[0515] At 0°C, 3-bromo-2-methoxybenzoic acid (5.00 g; 21.6 mmol; 1.00 eq.) and DMF (0.321 g; 4.33 mmol; 0.20 eq.) were dissolved in CH 2 Cl 2 To a stirred solution of 50 mL was added dropwise oxalyl chloride (2 M) in CH 2 Cl 2 The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was then concentrated under reduced pressure. The crude product was added dropwise to NH 3 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 provide 3-bromo-2-methoxybenzamide (4.98 g, 73%) as a brown solid. LCMS (ESI) m / z 230.0, [M+H] + .

[0516] Step 2: 3-(3-Bromo-2-methoxyphenyl)-1H-1,2,4-triazole

[0517]

[0518] 3-Bromo-2-methoxybenzamide (4.98 g; 21.7 mmol; 1.00 eq.) was dissolved in DMF-DMA (25.9 g; 217 mmol; 10.0 eq.). The resulting mixture was stirred at 95 ° C for 0.5 hours under nitrogen. The resulting mixture was concentrated under reduced pressure to obtain a crude intermediate. The crude intermediate was dissolved in EtOH (10 mL) and then added dropwise to a pretreated cold solution (which contained a mixture of AcOH / EtOH (30 mL / 120 mL) and hydrazine hydrate (80%) (10.6 mL; 217 mmol; 10.0 eq.) at 0 ° C. The resulting reactant was stirred at room temperature for 4 hours. 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), the precipitated solid was collected by filtration, washed with water (3×15 mL) and dried under reduced pressure to provide 3-(3-bromo-2-methoxyphenyl)-1H-1,2,4-triazole (5.30 g, 96%) as a white solid. LCMS (ESI) m / z 254.0, [M+H] + .

[0519] Step 3: 3-(3-Bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole

[0520]

[0521] 3-(3-bromo-2-methoxyphenyl)-1H-1,2,4-triazole (5.30 g; 20.9 mmol; 1.00 eq.) and K 2 CO 3 A mixture of (8.65g; 62.6mmol; 3.00eq.) in DMF (50mL) was stirred under a nitrogen atmosphere for 30 minutes. MeI (3.26g; 22.9mmol; 1.10eq.) in DMF (10mL) was added dropwise to the stirred mixture at 0°C. The final reaction mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The desired product was observed by LCMS. The residue was purified by flash chromatography on a silica gel column using 20%-80% EtOAc / petroleum ether as eluent to provide 3-(3-bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole (1.06g, 19%) as a brown oil. LCMS (ESI) m / z 268.0, [M+H] + . 1 H NMR (400 MHz, methanol-d 4)δ8.46(s,1H),7.80(dd,J=10.4,2.4Hz,1H),7.66(dd,J=10.4,2.4Hz,1H),7.12(t,J=10.4Hz,1H),4.00(s,3H),3.76(s,3H).

[0522] 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

[0523]

[0524] 3-(3-Bromo-2-methoxyphenyl)-1-methyl-1H-1,2,4-triazole (300 mg; 1.12 mmol; 1.00 eq.), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (852 mg; 3.36 mmol; 3.00 eq.), Pd(dppf)Cl 2 .CH 2 Cl 2 (91.7mg; 0.113mmol; 0.10eq.) and KOAc (221mg; 2.25mmol; 2.01eq.) in 1,4-dioxane (5mL) were 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. A mixed solvent of petroleum ether / EtOAc (10: 1, 33mL) was added and a solid was formed. The mixture was stirred at room temperature for 2 hours. The precipitated solid was filtered with filter paper, and the solid was dried under reduced pressure to provide 3- (2-methoxy-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -1-methyl -1H-1,2,4-triazole (528mg, crude) as a brown solid. LCMS (ESI) m / z 316.2, [M+H] + .

[0525] 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

[0526]

[0527] Will Na 2 CO 3(49.7 mg; 0.469 mmol; 3.00 eq.), 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 eq.), N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.), and Pd(PPh 3 ) 4 A mixture of (18.1 mg; 0.016 mmol; 0.10 eq.) in DME / water (5:1, 1.2 mL) was stirred at 100° C. under nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The product was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20%-50% MeCN / water (0.05% formic acid) as eluent to afford N-(5-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg, crude) as a yellow solid. The crude product was purified by flash chromatography on a pre-packed C18 column using 20%-50% MeCN / water (0.05% formic acid) as eluent to afford N-(5-(2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide formate (35.5 mg, 53%) as a white solid. LCMS (ESI) m / z 430.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.87(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=4.4Hz,3H),2.04-1.93(m,1H)),0.78-0.71(m,4H).

[0528] Example 50: Synthesis of N-(8-(methylamino)-5-(pyrimidin-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0529]

[0530] CuI (3.6 mg; 0.019 mmol; 0.15 eq.), N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.) and Pd(PPh 3 ) 2 Cl 2 A mixture of (18.4 mg; 0.026 mmol; 0.21 eq.) 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 eq.). The reactants were stirred at 120 ° C for 5 hours under nitrogen. Additional 4-(tributylstannyl)pyrimidine (138.8 mg; 0.376 mmol; 3.00 eq.) was then added. The reactants were stirred at 120 ° C overnight. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The reaction was carried out by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using (1-5%) as eluent to afford the crude product (30 mg). The crude product was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with ) as the eluent to afford N-(8-(methylamino)-5-(pyrimidin-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15.1 mg, 37%) as a white solid. LCMS (ESI) m / z 321.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.98(s,1H),9.41(s,1H),9.23(s,1H),8.99(s,1H),8.83(d,J=5.2Hz,1H),8.42-8.32( m, 2H), 7.78 (d, J = 4.8Hz, 1H), 3.06 (d, J = 4.0Hz, 3H), 2.09-2.00 (m, 1H), 0.87-0.78 (m, 4H).

[0531] Example 51: Synthesis of N-(8-(methylamino)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0532]

[0533] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg; 0.093 mmol; 1.00 eq.), 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 eq.), Pd(PPh 3 ) 4 (10.8 mg; 0.009 mmol; 0.10 eq.) and Na 2 CO 3 A mixture of (53.5 mg; 0.505 mmol; 5.40 eq.) in DME / water (5:1, 3.0 mL) was stirred at 100° C. under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The product was purified by using 3-20% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to afford N-(8-(methylamino)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (26.9 mg, crude) as a brown solid. The product was prepared by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with ) as eluent to afford N-(8-(methylamino)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (10.6 mg, 28%) as a white solid. LCMS (ESI) m / z 393.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.95(s,1H),9.38(s,1H),8.19-8.14(m,1H),8.08(s,1H),7.99(s,1H) ,7.65(d,J=1.6Hz,1H),6.35(d,J=1.6Hz,1H),5.04-4.99(m,1H),3.88-3. 79(m,1H),3.29-3.25(m,1H),3.03(d,J=4.4Hz,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).

[0534] Example 52: Synthesis of N-(8-(methylamino)-5-(1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0535]

[0536] 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 eq.) 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 product was purified by using 20-40% MeCN / water (10 mmol / L NH 4 HCO 3 The residue was purified by flash chromatography on a pre-packed C18 column with 4% paraformaldehyde as eluent to afford N-(8-(methylamino)-5-(1H-pyrazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (26.2 mg, 62%) as a white solid. LCMS (ESI) m / z 309.1, [M+H] + 1H NMR (400MHz, DMSO-d 6 )δ12.92(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=4.4Hz,3H),2.08-2.00(m,1H),0.86-0.78(m,4H).

[0537] 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

[0538]

[0539] Step 1: 3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole and 5-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole

[0540]

[0541] To a stirred mixture of 3-(3-bromophenyl)-1H-1,2,4-triazole (1 g; 4.46 mmol; 1.00 eq.) in DMF (10 mL) was added K 2 CO3 (1.88 g; 13.63 mmol; 3.00 eq.), followed by dropwise addition of CH 3 A solution of I (697 mg; 4.91 mmol; 1.10 eq.) in DMF (1 mL). The reaction mixture was added to saturated NH 4 The resulting mixture was extracted with EtOAc (15 mL x 2). The combined organic layers were washed with saturated NaCl solution (5 mL x 2) and then dried over anhydrous Na 2 SO 4 The residue was purified by flash chromatography on a silica gel column using 30-70% EtOAc / petroleum ether as eluent to provide 3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole (732 mg, 68%) as a yellow oil and 5-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole (70 mg, 6%) as a yellow oil. LCMS (ESI) m / z 238.0, [M+H] + . HNMR of 3-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole: 1 H NMR (400 MHz, DMSO-d 6 )δ8.56(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). HNMR of 5-(3-bromophenyl)-1-methyl-1H-1,2,4-triazole: 1 H NMR (400 MHz, DMSO-d 6 )δ8.03(s,1H),7.98-7.95(m,1H),7.82-7.74(m,2H),7.56-7.51(m,1H),3.99(s,3H).

[0542] Step 2: 1-Methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole

[0543]

[0544] 3-(3-Bromophenyl)-1-methyl-1H-1,2,4-triazole (200 mg; 0.84 mmol; 1.00 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (640 mg; 2.52 mmol; 3.00 eq.), Pd(dppf)Cl2 (69 mg; 0.09 mmol; 0.10 eq.), KOAc (165 mg; 1.68 mmol; 2.00 eq.) in 1,4-dioxane (4 mL) was stirred at 100 ° C under a nitrogen atmosphere for 2 hours. The solvent was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of petroleum ether / EtOAc (10: 1, 30 mL). The resulting mixture was filtered and the filter cake was washed with a mixed solvent of petroleum ether / EtOAc (10: 1, 20 mL). The filtrate was concentrated under reduced pressure to provide 1-methyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole (350 mg, crude) as a brown solid. LCMS (ESI) m / z 286.2, [M+H] + .

[0545] Step 3: N-(5-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0546]

[0547] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.12 mmol; 0.10 eq.), 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 eq.), Pd(PPh 3 ) 4 (14mg; 0.01mmol; 0.10eq.), Na 2 CO 3 A mixture of (40 mg; 0.37 mmol; 3.00 eq.) in DME / water (5:1, 2.4 mL) was stirred at 100° C. under nitrogen atmosphere for 3 hours. After completion, the resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with (2-6%) as eluent to afford 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 product was prepared by using 20-60% MeCN / water (10 mmol / L NH 4 HCO 3) to provide N-(5-(3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (8.3 mg, 2%) as a white solid. LCMS (ESI) m / z 400.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.00(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=4.4Hz,3H),2.04-1.95(m,1H),0.79-0.72(m,4H).

[0548] 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

[0549]

[0550] Step 1: 1-Methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole

[0551]

[0552] 5-(3-Bromophenyl)-1-methyl-1H-1,2,4-triazole (70 mg; 0.295 mmol; 1.00 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (225 mg; 0.885 mmol; 3.00 eq.), Pd(dppf)Cl 2(21.5 mg; 0.029 mmol; 0.10 eq.), KOAc (57.8 mg; 0.589 mmol; 2.00 eq.) in 1,4-dioxane (4 mL) was stirred at 100 ° C under a nitrogen atmosphere for 2 hours. After completion, the reactant was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of petroleum ether / EtOAc (10: 1, 20 mL). The resulting mixture was filtered and the filter cake was washed with a mixed solvent of petroleum ether / EtOAc (10: 1, 10 mL). The filtrate was concentrated under reduced pressure to provide 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%-60% EtOAc / petroleum ether as eluent to give 1-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-1,2,4-triazole (40 mg, 47%) as a brown solid. LCMS (ESI) m / z 286.2, [M+H] + .

[0553] Step 2: N-(5-(3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0554]

[0555] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.12 mmol; 0.10 eq.), 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 eq.), Pd(PPh 3 ) 4 (14mg; 0.01mmol; 0.10eq.), Na 2 CO 3 A mixture of (39.7 mg; 0.37 mmol; 3.00 eq.) in DME / water (5:1, 2.4 mL) was stirred at 100° C. under nitrogen atmosphere for 3 hours. After cooling, the resulting mixture was concentrated under reduced pressure. The product was purified by using MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column with (2-6%) as eluent to afford 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 product was prepared by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(5-(3-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (16.7 mg, 29%) as a white solid. LCMS (ESI) m / z 400.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(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=4.4Hz,3H),2.05-1.98(m,1H),0.80-0.74(m,4H).

[0556] Example 55: Synthesis of N-(8-(methylamino)-5-(pyrrolidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0557]

[0558] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.), Pd-PEPPSI-I HeptCl (CAS: 1814936-54-3) (12.2 mg; 0.013 mmol; 0.10 eq.), Cs 2 CO 3 A mixture of 1,4-dioxane (4 mL) and 1,4-dioxane (122.3 mg; 0.375 mmol; 3.00 eq.) was stirred at 100 °C under nitrogen for 16 hours. The mixture was cooled to room temperature. The desired product was observed by LCMS. The product was purified by using MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column with 2% to 10% (2-10%) as eluent to provide N-(8-(methylamino)-5-(pyrrolidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg, crude). The product was prepared by using 20% ​​to 50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with ) as eluent to afford N-(8-(methylamino)-5-(pyrrolidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (23.5 mg, 60%) as a yellow solid. LCMS (ESI) m / z 312.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.95(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=4.4Hz,3H),2.11-2.01(m,1H),1.98-1.85(m,4H),0.91-0.78(m,4H).

[0559] Example 56: Synthesis of N-(8-(methylamino)-5-(piperidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0560]

[0561] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.) in dioxane (2.00 mL) was added Pd-PEPPSI-I HeptCl (12.1 mg; 0.012 mmol; 0.10 eq.), Cs 2 CO 3 (121.7 mg; 0.374 mmol; 3.00 eq.) and piperidine (21.2 mg; 0.249 mmol; 2.00 eq.). The reaction was stirred at 100 °C under nitrogen for 16 hours. Upon completion, the resulting mixture was concentrated in vacuo. The reaction was carried out by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with 1% to 9% (1-9%) as eluent to afford N-(8-(methylamino)-5-(piperidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30 mg, crude). The product was prepared by using 10% to 70% MeCN / water (10 mmol / L NH 4 HCO3 ) to provide N-(8-(methylamino)-5-(piperidin-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (21.9 mg, 54%) as a white solid. LCMS (ESI) m / z 326.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.91(s,1H),9.28(s,1H),8.46(s,1H),7.68(s,1H),7.61-7.53(m,1H),2.92(d,J=4.4Hz,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).

[0562] Example 57: Synthesis of N-(8-(methylamino)-5-(1H-pyrazol-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0563]

[0564] To N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.), CuI (29.6 mg; 0.158 mmol; 1.00 eq.), K 2 CO 3 (43.1 mg; 0.312 mmol; 2.00 eq.) and (1R,2R)-N 1 ,N 2 1H-pyrazole (13.0 mg; 0.191 mmol; 1.23 eq.) was added to a mixture of -dimethylcyclohexane-1,2-diamine (40 mg; 0.281 mmol; 1.80 eq.) in DMF (5 mL, deoxygenated before use). The reactants were stirred at 120 ° C for 16 hours under nitrogen. The mixture was cooled 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 washed with Na 2 SO 4 Dry, filter and remove the solvent under reduced pressure. 2 Cl 2The residue was purified by flash chromatography on a silica gel column with 20%-50% MeCN / water (0.05% formic acid) as eluent to provide 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 / water (0.05% formic acid) as eluent to provide N-(8-(methylamino)-5-(1H-pyrazol-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (10.6 mg, 22%) as a white solid. LCMS (ESI) m / z 309.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.00(s,1H),9.40(s,1H),8.25-8.18(m,1H),8.05(s,1H),8.04(s,1H),7.97(d,J=2.4Hz,1H),7.7 6(d,J=1.8Hz,1H), 6.52(t,J=2.1Hz,1H), 3.03(d,J=4.3Hz,3H), 2.07-1.96(m,1H), 0.82-0.75(m,4H).

[0565] Example 58: Synthesis of N-(5-(1,1-dioxoisothiazolidin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0566]

[0567] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.), isothiazolidine 1,1-dioxide (15.1 mg; 0.124 mmol; 1.00 eq.), Pd-PEPPSI-IPentCl (10.9 mg; 0.012 mmol; 0.10 eq.) and Cs 2 CO 3 A mixture of (81.5 mg; 0.25 mmol; 2.00 eq.) in 1,4-dioxane (2 mL) was stirred at 120° C. under nitrogen atmosphere for 12 hours. The reaction was monitored by LCMS. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 2-10% (2-10%) as eluent to give N-(5-(1,1-dioxoisothiazolidin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (12 mg, crude). The product was prepared by using 20-50% MeCN / water (10 mmol / L NH4 HCO 3 ) to provide N-(5-(1,1-dioxoisothiazolidin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.5 mg, 10%) as a white solid. LCMS (ESI) m / z 362.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(s,1H),9.34(s,1H),8.38(s,1H),8.14(q,J=4.4Hz,1H),8.04(s,1H),3.65(t,J=6.6Hz,2H), 3.45(t,J=7.4Hz,2H), 2.99(d,J=4.4Hz,3H), 2.50-2.42(m,2H), 2.12-2.02(m,1H), 0.92-0.79(m,4H).

[0568] 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

[0569]

[0570] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.12 mmol; 1.00 eq.) and 2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (51 mg; 0.18 mmol; 1.50 eq.) in dioxane (6 mL) was added Cs 2 CO 3 (81.5 mg; 0.25 mmol; 2.00 eq.) and Ephos Pd G 4 (CAS: 2132978-44-8) (11.4 mg; 0.012 mmol; 0.10 eq.), Ephos (CAS: 2118959-55-8) (6.6 mg; 0.012 mmol; 0.10 eq.). Stir at 120°C under nitrogen atmosphere for 12 hours. Monitor the reaction by LCMS. 2 Cl 2The residue was purified by flash chromatography on a silica gel column with (2-6%) as the eluent to afford N-(8-(methylamino)-5-(1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg, crude) as a yellow solid. The product was prepared by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(1-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (43.9 mg, 91%) as a white solid. LCMS (ESI) m / z 375.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.02(s,1H),9.40(s,1H),9.03(s,1H),8.86(d,J=5.2Hz,1H),8.19-8.14(m,1H),8.12(s,1H),7.95( s,1H),7.79(d,J=5.2Hz,1H),4.91(s,2H),3.02(d,J=4.4Hz,3H),2.04-1.96(m,1H),0.79-0.71(m,4H).

[0571] Example 60: Synthesis of N-(8-(methylamino)-5-(4-oxopyridin-1(4H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0572]

[0573] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 eq.) and pyridin-4-ol (177.9 mg; 1.871 mmol; 6.00 eq.) in DMSO (5 mL) were added dimethylglycine (28.9 mg; 0.280 mmol; 0.90 eq.), Cs 2 CO 3 (203.9 mg; 0.626 mmol; 2.01 eq.) and CuI (29.6 mg; 0.155 mmol; 0.50 eq.). Stirred at 120°C under nitrogen atmosphere for 18 hours. The desired product was observed by LCMS. The reaction mixture was prepared by using 10-30% MeCN / water (10 mmol / L NH 4 HCO 3The resulting mixture was purified by flash chromatography on a pre-packed C18 column with ) as the eluent to provide N-(8-(methylamino)-5-(4-oxopyridin-1(4H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (13.1 mg, 12%) as a yellow solid. LCMS (ESI) m / z 336.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.11(s,1H),9.42(s,1H),8.36-8.25(m,1H),8.14(s,1H),7.95(s,1H),7.68(d,J=7.6H z, 2H), 6.21 (d, J = 7.6Hz, 2H), 2.99 (d, J = 4.4Hz, 3H), 2.09-2.00 (m, 1H), 0.90-0.70 (m, 4H).

[0574] 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

[0575]

[0576] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 eq.) and pyridin-2-ol (178 mg; 1.872 mmol; 6.00 eq.) in DMSO (3 mL) were added CuI (29.5 mg; 0.155 mmol; 0.50 eq.) and Cs 2 CO 3 (203.9 mg; 0.626 mmol; 2.01 eq.), dimethylglycine (29 mg; 0.281 mmol; 0.90 eq.). After stirring at 120°C under nitrogen atmosphere for 3 days, the reactants were two peaks with the desired product mass (17% and 21%). By using 10-30% MeCN / water (10 mmol / L NH 4 HCO 3The resulting mixture was purified by flash chromatography on a prepacked C18 column with ) as the eluent to provide 8 mg of the less polar peak and 20 mg of the more polar peak. The mixture was then purified by reverse phase preparative HPLC (Prep-C18, XBridge Prep Phenyl OBD column, 19×250 mm, waters; gradient elution of 18-20% MeCN / water over a 10 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 25 mL / min, detector UV wavelength: 254 nm) to purify the less polar peak to provide N-(8-(methylamino)-5-(2-oxopyridine-1(2H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (3.4 mg, 3%) as a white solid. Reverse phase preparative HPLC (Prep-C18, XBridge Shield RP18 OBD column, 30×150 mm, waters; gradient elution of 30-40% MeCN / water over an 8 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to purify the more polar peak to provide N-(8-(methylamino)-5-(pyridin-2-yloxy)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (6.5 mg, 6%) as a white solid. LCMS (ESI) m / z 336.1, [M+H] + . HNMR of N-(8-(methylamino)-5-(2-oxopyridine-1(2H)-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(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=9.2Hz,1H),6.34(t,J=6.6Hz,1H),3.02(d,J=4.4Hz,3H),2.09-1.98(m,1H),0.85-0.72(m,4H). HNMR of N-(8-(methylamino)-5-(pyridin-2-yloxy)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide: 1 H NMR (400 MHz, DMSO-d 6)δ10.97(s,1H),9.37(s,1H),8.08(s,1H),8.03(dd,J=4.8,1.2Hz,1H),7.91-7.80(m ,3H),7.15-7.06(m,2H),2.99(d,J=4.4Hz,3H),2.09-2.00(m,1H),0.85-0.74(m,4H).

[0577] Example 63: Synthesis of N-(8-(methylamino)-5-(thiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0578]

[0579] At room temperature in N 2 To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.) in dioxane (2 mL) was added Pd(PPh 3 ) 2 Cl 2 (21.9 mg; 0.031 mmol; 0.20 eq.), CuI (4.5 mg; 0.024 mmol; 0.15 eq.) and 2-(tributylstannyl)thiazole (116.5 mg; 0.311 mmol; 2.00 eq.). The reaction was stirred at 100 °C for 16 hours. The desired product was observed by LCMS. The reaction was carried out by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 15-70% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(thiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (17.7 mg, 34%) as a yellow solid. LCMS (ESI) m / z 326.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.00(s,1H),9.40(s,1H),9.29(s,1H),8.46(s,1H),8.38-8.33(m,1H),7.96(d,J=3.2H z, 1H), 7.73 (d, J = 3.2Hz, 1H), 3.04 (d, J = 4.4Hz, 3H), 2.11-2.02 (m, 1H), 0.88-0.78 (m, 4H).

[0580] Example 64: Synthesis of N-(8-(methylamino)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0581]

[0582] Step 1: 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole

[0583]

[0584] 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 eq.) in DMF (7 mL) was added NaH (60%) (256 mg; 6.40 mmol; 2.50 eq.) at 0°C and stirred at room temperature for 0.5 hours. To the resulting mixture was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (597 mg; 2.57 mmol; 1.00 eq.) and stirred at room temperature under nitrogen atmosphere for 2 hours. There were two peaks with the desired product mass. The reaction mixture was washed with saturated NH 4 Cl solution (0.2mL) quenched. The resulting mixture was diluted with EtOAc (100mL) and washed with saturated NaCl solution (3×10mL). The organic phase was concentrated under reduced pressure to provide 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole (507mg, crude) as a yellow solid. The crude product was used directly in the next step without further purification. LCMS (ESI) m / z 277.1, [M+H] + .

[0585] Step 2: N-(8-(Methylamino)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0586]

[0587] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.), 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 eq.), Pd(PPh 3 ) 4 (18mg; 0.015mmol; 0.01eq.), Na 2 CO 3 A mixture of (50 mg; 0.47 mmol; 3.00 eq.) in DME / water (5:1, 0.4 mL, deoxygenated before use) was stirred at 100 °C under nitrogen atmosphere for 3 hours. After completion, the resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with (2-6%) petroleum ether as eluent to afford N-(8-(methylamino)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg, crude). The product was prepared by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (30.6 mg, 50%) as a white solid. LCMS (ESI) m / z 391.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.90(s,1H),9.37(s,1H),8.83(s,1H),8.20(s,1H),8.06-8.00(m,1H),7.96(d,J=2.0Hz,1H),6.6 2(d,J=2.0Hz,1H),5.17(q,J=9.2Hz,2H),3.01(d,J=4.4Hz,3H),2.08-2.00(m,1H),0.86-0.78(m,4H).

[0588] Example 65: Synthesis of N-(8-(methylamino)-5-(thiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0589]

[0590] 4-(tributylstannyl)thiazole (175 mg; 0.468 mmol; 3.00 eq.), N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.), Pd(PPh 3 ) 2 Cl 2 A mixture of 1,2-dioxane (13.5 mg; 0.019 mmol; 0.12 eq.) and CuI (2.7 mg; 0.014 mmol; 0.09 eq.) in dioxane (2 mL, deoxygenated before use) was stirred at 100 ° C. under a nitrogen atmosphere for 8 hours. The desired product was detected by LCMS. The reaction was concentrated under reduced pressure and purified by using MeOH / CH 2 Cl 2 The crude product was purified by flash chromatography on a silica gel column using 10-37% MeCN / water (10 mmol / L NH 4 HCO 3 ) to give N-(8-(methylamino)-5-(thiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (8.3 mg, 16%) as a light yellow solid. LCMS (ESI) m / z 326.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.93(s,1H),9.38(s,1H),9.26(d,J=2.0Hz,1H),8.72(s,1H),8.25(s,1H),8.10-8.04( m, 1H), 7.78 (d, J = 2.0Hz, 1H), 3.02 (d, J = 4.4Hz, 3H), 2.07-2.00 (m, 1H), 0.85-0.78 (m, 4H).

[0591] Example 66: Synthesis of N-(8-(methylamino)-5-(5-methylthiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0592]

[0593] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40.0 mg; 0.125 mmol; 1.00 eq.) and 5-methyl-2-(tributylstannyl)thiazole (241 mg; 0.625 mmol; 5.00 eq.), CuI (4.7 mg; 0.025 mmol; 0.20 eq.), Pd(PPh3 ) 2 Cl 2 A mixture of (34.9 mg; 0.050 mmol; 0.40 eq.) in dioxane (2 mL, deoxygenated before use) was stirred at 100° C. under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with ) as eluent to afford N-(8-(methylamino)-5-(5-methylthiazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (23.9 mg, 56%) as a yellow solid. LCMS (ESI) m / z 340.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.98(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=4.4Hz,3H),2.50(s,3H),2.09-2.01(m,1H),0.87-0.78(m,4H).

[0594] Example 67: Synthesis of N-(5-(3,6-dihydro-2H-pyran-4-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0595]

[0596] To a mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.) 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 eq.) in DME / water (5:1, 1.2 mL, deoxygenated before use) was added Pd(PPh 3 ) 4 (18.1 mg; 0.015 mmol / L; 0.10 eq.) and Na 2 CO 3(33 mg; 0.311 mmol / L; 2.00 eq.) and stirred at 100°C under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The solvent was concentrated in vacuo. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with ) as eluent to afford N-(5-(3,6-dihydro-2H-pyran-4-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (35 mg, 69%) as a white solid. LCMS (ESI) m / z 325.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.95(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=2.4Hz, 2H), 3.85 (t, J = 5.2Hz, 2H), 2.97 (d, J = 4.4Hz, 3H), 2.40-2.31 (m, 2H), 2.11-2.00 (m, 1H), 0.91-0.77 (m, 4H).

[0597] Example 68: Synthesis of N-(8-(methylamino)-5-(tetrahydro-2H-pyran-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0598]

[0599] 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 eq.) 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 using 2-9% MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column as eluent to provide N-(8-(methylamino)-5-(tetrahydro-2H-pyran-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15 mg, crude). The product was prepared by using 15-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(tetrahydro-2H-pyran-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.1 mg, 13%) as a white solid. LCMS (ESI) m / z 327.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.97(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=4.4Hz,3H),2.10-2.02(m,1H),1.81-1.68(m,4H),0.91-0.78(m,4H).

[0600] Example 69: Synthesis of N-(5-(cyclohex-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0601]

[0602] To a mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.) in a DME / water mixed solvent (5:1, 2.4 mL) was added Pd(PPh 3 ) 4 (18.0mg; 0.016mmol; 0.10eq.), Na 2 CO 3 (49.5 mg; 0.467 mmol; 3.00 eq.) and 2-(cyclohex-1-ene-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (97.5 mg; 0.469 mmol; 3.00 eq.). The reactants were stirred at 100 °C under nitrogen atmosphere for 3 hours. The desired product was observed by LCMS. The resulting mixture was concentrated in vacuo. The reaction mixture was purified by using MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column with 1% to 10% (1-10%) as eluent to afford N-(5-(cyclohex-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (65 mg, crude). The product was prepared by using 15% to 60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(5-(cyclohex-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (6.1 mg, 12%) as a white solid. LCMS (ESI) m / z 323.2, [M+H] + . 1 H NMR (400 MHz, methanol-d 4 )δ9.16(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).

[0603] Example 70: Synthesis of N-(5-cyclohexyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0604]

[0605] To a mixture of N-(5-(cyclohex-1-ene-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 69) (60 mg; 0.186 mmol; 1.00 eq.) 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 hours. The reactant was filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with 1% to 9% (1-9%) as eluent to afford N-(5-cyclohexyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude). The product was prepared by using 15% to 70% MeCN / water (10 mmol / L NH 4 HCO 3) to provide N-(5-cyclohexyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.8 mg, 8%) as a white solid. LCMS (ESI) m / z 325.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.93(s,1H),9.30(s,1H),8.44(s,1H),7.87(s,1H),7.68-7.63(m,1H),2.93(d,J=4.4Hz,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).

[0606] Example 71: Synthesis of N-(8-(methylamino)-5-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0607]

[0608] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.) in a mixed solvent of dioxane / water (5:1, 2.4 mL) was added Pd(DtBPF)Cl at room temperature. 2 (10.2mg; 0.016mmol; 0.10eq.), K 3 PO 4 (66.1 mg; 0.311 mmol; 2.00 eq.) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (72 mg; 0.467 mmol; 3.00 eq.). The reactants were stirred at 90 °C under nitrogen. 2 Stir under atmosphere for 2 hours. After completion, the resulting mixture was concentrated in vacuo. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 1% to 9% (1-9%) as the eluent to afford N-(8-(methylamino)-5-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg, crude). The product was prepared by using 10% to 70% MeCN / water (10 mmol / L NH 4 HCO 3) to provide N-(8-(methylamino)-5-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (5.2 mg, 12%) as a yellow solid. LCMS (ESI) m / z 269.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(s,1H),9.33(s,1H),8.48(s,1H),8.19(s,1H),8.02-7.95(m,1H),6.92(dd,J=17.6,11.2Hz,1H),5.66(d d,J=17.6,1.2Hz,1H),5.25(dd,J=11.2,1.2Hz,1H),2.98(d,J=4.4Hz,3H),2.09-2.03(m,1H),0.89-0.80(m,4H).

[0609] Example 72: Synthesis of N-(5-ethyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0610]

[0611] To a solution of N-(8-(methylamino)-5-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 71) (43 mg; 0.160 mmol; 1.00 eq.) 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 hours. The reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. The resulting mixture was concentrated in vacuo. The residue was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 1% to 9% MeCN as eluent to afford N-(5-ethyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (35 mg, crude). 4 HCO 3 ) to provide N-(5-ethyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20.8 mg, 48%) as a white solid. LCMS (ESI) m / z 271.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.97(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. 4Hz, 3H), 2.70-2.63 (m, 2H), 2.10-2.02 (m, 1H), 1.19 (t, J = 7.6Hz, 3H), 0.90-0.80 (m, 4H).

[0612] Example 73: Synthesis of N-(8-(methylamino)-5-(prop-1-en-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0613]

[0614] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (70 mg; 0.218 mmol; 1.00 eq.) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (36 mg; 0.214 mmol; 1.00 eq.) in a mixed solvent of 1,4-dioxane / water (7:1, 2.4 mL) was added Pd(DtBPF)Cl 2 (14 mg; 0.021 mmol; 0.10 eq.) and K 3 PO 4 (91 mg; 0.429 mmol; 2.00 eq.). The mixture was stirred at 90 °C under nitrogen atmosphere for 2 hours. The mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel using methanol / dichloromethane (5-10%) as eluent to give the desired crude product. The crude product was purified by using 20-50% MeCN / water (10 mmol / LNH 4 HCO 3 ) pre-packed C18 column flash chromatography further purified the crude product to provide N-(8-(methylamino)-5-(prop-1-en-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (5.0 mg) as a white solid for delivery. LCMS (ESI) m / z 283.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.94(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=4.4Hz,3H),2.08(s,3H),2.06-2.00(m,1H),0.88-0.78(m,4H)

[0615] Example 74: Synthesis of N-(5-isopropyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0616]

[0617] To a stirred mixture of N-(8-(methylamino)-5-(prop-1-ene-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (Example 73) (60 mg; 0.213 mmol; 1.00 eq.) in MeOH (10 mL) was added 10% Pd / C (60 mg; 100% w / w). The reactants were stirred at 40° C. under a hydrogen atmosphere (2 atm) for 12 hours. The desired product was observed by LCMS. The reactants were concentrated under reduced pressure and purified by using MeOH / CH 2 Cl 2 The crude product was purified by flash chromatography on a silica gel column (2-8%) to obtain the desired crude product. The product was purified by reverse phase preparative HPLC (Prep-C18, 5 μM OBD column, 19×250 mm, waters; gradient elution of 35-48% MeCN / water over 8 minutes, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to further purify the crude product to obtain N-(5-isopropyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (11.4 mg, 18%) as a white solid. LCMS (ESI) m / z 285.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.97(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=4.4Hz,3H),2.10-2.02(m,1H),1.27(d,J=6.8Hz,6H),0.89-0.80(m,4H).

[0618] Example 75: Synthesis of N-(5-(2,5-dihydrofuran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0619]

[0620] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.18 mmol; 1.00 eq.) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (44 mg; 0.22 mmol; 1.20 eq.), Pd(DtBPF)Cl 2 (12mg; 0.01mmol; 0.10eq.), K 3 PO 4 A mixture of (79 mg; 0.37 mmol; 2.00 eq.) in dioxane / water (5:1, 7.2 mL) was stirred at 90° C. under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using 2-6% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to afford N-(5-(2,5-dihydrofuran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg, crude). The product was then purified by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(5-(2,5-dihydrofuran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (3.1 mg, 5%) as a yellow solid. LCMS (ESI) m / z 311.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.06(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=4.4Hz,3H),2.11-2.03(m,1H),0.90-0.79(m,4H).

[0621] Example 76: Synthesis of N-(8-(methylamino)-5-(tetrahydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0622]

[0623] 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 eq.) 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 hours. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(tetrahydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (24.9 mg, 36%) as a yellow solid. LCMS (ESI) m / z 313.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.00(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=4.4Hz,3H),2.35-2.24(m,1H),2.10-1.99(m,2H),0.91-0.80(m,4H).

[0624] Example 77: Synthesis of N-(5-(5,6-dihydro-2H-pyran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0625]

[0626] A mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.) was added to 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 eq.), Pd(DtBPF)Cl 2 (8.12 mg; 0.012 mmol; 0.10 eq.) and K3 PO 4 (52.9 mg; 0.249 mmol; 2.00 eq.) and stirred at 90°C under nitrogen for 2 hours. The desired product was observed by LCMS. The reaction mixture was concentrated in vacuo. The residue was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with 2-7% (2-7%) to give 65 mg of the desired crude product. The crude product was purified by using 10-40% MeCN / water (10 mmol / L NH 4 HCO 3 ) to give N-(5-(5,6-dihydro-2H-pyran-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (3.5 mg, 8%) as a white solid. LCMS (ESI) m / z 325.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.93(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 = 4.4Hz, 3H), 2.31-2.22 (m, 2H), 2.09-2.01 (m, 1H), 0.89-0.79 (m, 4H).

[0627] Example 78: Synthesis of N-(8-(methylamino)-5-(tetrahydro-2H-pyran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0628]

[0629] 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 eq.) in MeOH (50 mL) was added 10% Pd / C (50 mg; 100% w / w) under a nitrogen atmosphere. The reactants were stirred at 40° C. overnight under a hydrogen atmosphere (2 atm). The desired product was observed by LCMS. The reactants were concentrated under reduced pressure and purified by using MeOH / CH 2 Cl 2The crude product was purified by flash chromatography on a silica gel column (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, waters; gradient elution of 37% MeCN / water over an 8-minute period, wherein 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 (6.1 mg, 12%) as a white solid. LCMS (ESI) m / z 327.2, [M+H] + . 1 HNMR (400 MHz, methanol-d 4 )δ9.28(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).

[0630] Example 79: Synthesis of (E)-N-(5-((dihydrofuran-3(2H)-ylidene)methyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0631]

[0632] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.187 mmol; 1.00 eq.), (E)-2-((dihydrofuran-3(2H)-ylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (47.3 mg; 0.225 mmol; 1.21 eq.), Pd(DtBPF)Cl 2 (12.2 mg; 0.019 mmol; 0.10 eq.) and K 3 PO 4 A mixture of (79.7 mg; 0.375 mmol; 2.01 eq.) in 1,4-dioxane / water (5:1, 2.4 mL) was stirred at 90° C. under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The product was purified by using MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column using (2-10%) as the eluent to provide the desired crude product. The product was purified by reverse phase preparative HPLC (XBridge Shield RP18 OBD column, 30×150 mm, waters; gradient elution of 30-40% MeCN / water over an 8 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to further purify the crude product to provide (E)-N-(5-((dihydrofuran-3(2H)-ylidene)methyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg, 82%) as a yellow solid. LCMS (ESI) m / z 325.2, [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ11.01(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=4.4Hz,3H),2.79-2.63(m,2H),2.10-2.02(m,1H),0.88-0.80(m,4H).

[0633] Example 80: Synthesis of N-(8-(methylamino)-5-((tetrahydrofuran-3-yl)methyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0634]

[0635] 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 eq.) 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 provide N-(8-(methylamino)-5-((tetrahydrofuran-3-yl)methyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg, crude) as a white solid. The product was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3The crude product was purified by flash chromatography on a pre-packed C18 column with ) as eluent to afford N-(8-(methylamino)-5-((tetrahydrofuran-3-yl)methyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (15.6 mg, 38%) as a white solid. LCMS (ESI) m / z 327.2, [M+H] + 1H NMR (400MHz, DMSO-d 6 )δ10.98(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=4.4Hz,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).

[0636] Example 81: Synthesis of N-(8-(methylamino)-5-(2-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0637]

[0638] Step 1: N-(8-(Methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0639]

[0640] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (500 mg; 1.557 mmol; 1.00 eq.) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) (3.96 g; 15.59 mmol; 10.00 eq.), Pd(dppf)Cl 2(128 mg; 0.175 mmol; 0.10 eq.), KOAc (306 mg; 3.118 mmol; 2.00 eq.) in 1,4-dioxane (24 mL) was stirred at 100 ° C under a nitrogen atmosphere for 3 hours. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of petroleum ether / EtOAc (10: 1, 200 mL) and a precipitate was formed. The solid was collected by filtration and washed with a mixed solvent 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 (916 mg, crude) as a brown solid. LCMS (ESI) m / z 369.2, [M+H] + .

[0641] Step 2: N-(8-(Methylamino)-5-(2-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0642]

[0643] 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 eq.), 4-bromo-2-methylthiazole (48.3 mg; 0.272 mmol; 1.00 eq.), Pd(DtBPF)Cl 2 (CAS: 95408-45-0) (17.7 mg; 0.027 mmol; 0.10 eq.) and K 3 PO 4 A mixture of (115 mg; 0.544 mmol; 2.00 eq.) in dioxane / water (6:1, 2.9 mL) was stirred at 90° C. under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The product was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was further purified by flash chromatography on a pre-packed C18 column with ) as the eluent to provide N-(8-(methylamino)-5-(2-methylthiazol-4-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20.7 mg, 21%) as a white solid. LCMS (ESI) m / z 340.1, [M+H]+ . 1 H NMR (400 MHz, DMSO-d 6 )δ10.93(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).

[0644] Example 82: Synthesis of N-(5-(isothiazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0645]

[0646] 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 eq.), 3-bromoisothiazole (44.5 mg; 0.272 mmol; 1.00 eq.), Pd(dppf)Cl 2 .CH 2 Cl 2 (22.1 mg; 0.027 mmol; 0.10 eq.) and K 3 PO 4 A mixture of (115 mg; 0.544 mmol; 2.00 eq.) in 1,4-dioxane / water (5:1, 3.0 mL) was stirred at 40° C. under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The product was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was further purified by flash chromatography on a pre-packed C18 column with ) as the eluent to provide N-(5-(isothiazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (8.6 mg, 10%) as a white solid. LCMS (ESI) m / z 326.1, [M+H] +. 1H NMR(400MHz,DMSO-d6)δ10.95(s,1H),9.39(s,1H),9.17(d,J=4.4Hz,1H),9.14(s,1H),8.42(s,1H),8 .23-8.17(m,1H),7.72(d,J=4.4Hz,1H),3.03(d,J=4.4Hz,3H),2.08-2.01(m,1H),0.86-0.78(m,4H).

[0647] Examples 83 and 84: Each compound in Table 3 below was prepared using a similar procedure used to prepare 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 halogenated aromatic hydrocarbon to prepare each compound in Table 3 below:

[0648] Table 3

[0649]

[0650] Example 85: Synthesis of N-(8-(methylamino)-5-(2-oxo-2,5-dihydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0651]

[0652] 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 solution (Example 81, Step 1) (71 mg; 0.193 mmol; 1.00 eq.) in dioxane / water (5:1, 4.8 mL, deoxygenated before use) was added Pd(DtBPF)Cl at room temperature 2 (12.6mg; 0.019mmol; 0.10eq.), K 3 PO 4 (81.8 mg; 0.385 mmol; 2.00 eq.) and 3-bromofuran-2(5H)-one (94.3 mg; 0.579 mmol; 3.00 eq.). The reaction was stirred at 90°C under nitrogen for 2 hours. The desired product was observed by LCMS. The resulting mixture was concentrated in vacuo. The reaction was carried out by using MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column with (2-8%) as the eluent to afford N-(8-(methylamino)-5-(2-oxo-2,5-dihydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude) as a yellow solid. The product was prepared by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to afford N-(8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.5 mg, 9%) as a white solid. The crude product was purified by flash chromatography on a pre-packed C18 column of 5% ethanol (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(2-oxo-2,5-dihydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (2.1 mg, 3%) as a white solid. LCMS (ESI) m / z 325.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.01(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=4.4Hz,3H),2.09-2.00(m,1H),0.89-0.78(m,4H).

[0653] Example 86: Synthesis of N-(8-(methylamino)-5-(2-oxotetrahydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0654]

[0655] 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 eq.) 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 product was purified by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3) to provide N-(8-(methylamino)-5-(2-oxotetrahydrofuran-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (1.8 mg, 4%) as a white solid. LCMS (ESI) m / z 327.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.00(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. 0Hz, 1H), 2.96 (d, J = 4.4Hz, 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).

[0656] Example 87: Synthesis of N-(5-(1-(cyanomethyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0657]

[0658] Step 1: 2-(3-Bromo-1H-pyrazol-1-yl)acetonitrile.

[0659]

[0660] 3-Bromo-1H-pyrazole (150 mg; 1.02 mmol; 1.00 eq.), 2-bromoacetonitrile (159.1 mg; 1.327 mmol; 1.5 eq.) and Cs 2 CO 3 A mixture of (665 mg; 2.04 mmol; 2.00 eq.) in DMF (5 mL) was stirred at room temperature for 6 hours. The reaction was monitored by LCMS. The reaction was diluted with EtOAc (80 mL) and washed with brine (2×10 mL) and washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. 4 HCO 3 The residue was purified by flash chromatography on a pre-packed C18 column of ) to provide 2-(3-bromo-1H-pyrazol-1-yl)acetonitrile (140 mg, 74%) as a brown solid. LCMS (ESI) m / z 186.0, [M+H] + .

[0661] Step 2: N-(5-(1-(cyanomethyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0662]

[0663] 2-(3-Bromo-1H-pyrazol-1-yl)acetonitrile (100 mg; 0.540 mmol; 2.00 eq.), 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 eq.), Pd(DtBPF)Cl 2 (17.7 mg; 0.027 mmol; 0.10 eq.) and K 3 PO 4 A mixture of (115.3 mg; 0.544 mmol; 2.00 eq.) in 1,4-dioxane / water (10:1, 2.2 mL) was stirred at 90° C. under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction was performed by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(5-(1-(cyanomethyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (2.7 mg, 3%) as a white solid. LCMS (ESI) m / z 348.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.93(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=4.4Hz,3H),2.15-1.98(m,1H),0.97-0.70(m,4H).

[0664] Example 88: Synthesis of N-(8-(methylamino)-5-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0665]

[0666] 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 eq.), 1,1,1-trifluoro-2-iodoethane (256.7 mg; 1.22 mmol; 3.00 eq.), XPhos Pd G 3 (34.5 mg; 0.040 mmol; 0.10 eq.), XPhos (19.4 mg; 0.040 mmol; 0.10 eq.), and K 3 PO 4 A mixture of (259.2 mg; 1.22 mmol; 3.00 eq.) in 1,4-dioxane / water (10:1, 2.2 mL, deoxygenated before use) was stirred at 90 °C under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was carried out by using 2-10% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to give N-(8-(methylamino)-5-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude). The product was prepared by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (10.1 mg, 4%) as a white solid. LCMS (ESI) m / z 325.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.02(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=4.4Hz,3H),2.12-2.01(m,1H),0.95-0.80(m,4H).

[0667] Example 89: Synthesis of N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide

[0668]

[0669] Step 1: N-(8-Hydroxy-2,7-naphthyridin-3-yl)acetamide

[0670]

[0671] Pd 2 (dba) 3 (250 mg; 0.273 mmol; 0.10 eq.) and XantPhos (325 mg; 0.562 mmol; 0.20 eq.), 6-chloro-2,7-naphthyridin-1-ol (500 mg; 2.77 mmol; 1.00 eq.), acetamide (650 mg; 11.0 mmol; 4.00 eq.) and Cs 2 CO 3 A mixture of (1.8 g; 5.53 mmol; 2.00 eq.) in dioxane (12 mL) was stirred at 110° C. under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The reaction was concentrated in vacuo and purified by using 30-100% EtOAc / petroleum ether and 2-20% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to give a crude product. 2 Cl 2 The crude product was diluted with 20 mL and then filtered. The filter cake was washed with a large amount of CH 2 Cl 2 Washed and dried to give N-(8-hydroxy-2,7-naphthyridin-3-yl)acetamide (560 mg, 99%) as a yellow solid. LCMS (ESI) m / z 204.1, [M+H] + .

[0672] Step 2: N-(8-chloro-2,7-naphthyridin-3-yl)acetamide

[0673]

[0674] N-(8-Hydroxy-2,7-naphthyridin-3-yl)acetamide (250 mg; 1.23 mmol; 1.00 eq.) was dissolved in POCl 3 (6 mL). The reaction was stirred at 100 °C for 30 minutes. The desired product was monitored by LCMS. The reaction was cooled to room temperature and concentrated in vacuo. The resulting mixture was washed with 100 mL of CH 2Cl 2 Dilute and add saturated NaHCO 3 The solution was neutralized to pH 7. The organic phase was concentrated in vacuo. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column to give N-(8-chloro-2,7-naphthyridin-3-yl)acetamide (80 mg, 29%) as a light yellow solid. LCMS (ESI) m / z 222.0, [M+H] + .

[0675] Step 3: N-(8-(Methylamino)-2,7-naphthyridin-3-yl)acetamide

[0676]

[0677] N-(8-Chloro-2,7-naphthyridin-3-yl)acetamide (80 mg; 0.361 mmol; 1.00 eq.) was added to a solution of methylamine in THF (2M, 4 mL). The reaction was stirred at 60 ° C overnight. The progress of the reaction was monitored by LCMS. To the mixture was added a solution of additional methylamine in THF (2M, 4 mL). The reaction was stirred at 60 ° C overnight. After completion, the resulting mixture was concentrated in vacuo. The reaction was carried out by using 2-14% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column to give N-(8-(methylamino)-2,7-naphthyridin-3-yl)acetamide (75 mg, 96%) as an off-white solid. LCMS (ESI) m / z 217.1, [M+H] + .

[0678] Step 4: N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide

[0679]

[0680] To a stirred mixture of N-(8-(methylamino)-2,7-naphthyridin-3-yl)acetamide (141 mg; 0.652 mmol; 1.00 eq.) in DMF (4 mL) was added NBS (116 mg; 0.652 mmol; 1.00 eq.) at 0 ° C under a nitrogen atmosphere. The reactant was then stirred at room temperature for 1 hour. After completion, the mixture was diluted with EtOAc (80 mL) and washed with brine (20 mL×5). The organic layer was dried, concentrated in vacuo and purified by using 2-6% MeOH / CH 2 Cl 2The product was purified by flash chromatography on a silica gel column to give N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide (166 mg, 86%) as an off-white solid. LCMS (ESI) m / z 295.0, [M+H] + .

[0681] Step 5: N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide

[0682]

[0683] LiCl (16.7 mg; 0.394 mmol; 2.50 eq.), CuI (6.1 mg; 0.032 mmol; 0.20 eq.) and Pd(PPh 3 ) 4 (37mg; 0.032mmol; 0.20eq.) in dioxane (2.5mL, deoxygenated before use) was added to N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide (47mg; 0.159mmol; 1.00eq.) and 3-methoxy-2-(tributylstannyl)pyridine (319mg; 0.341mmol; 5.00eq.). 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 mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with 2-20% (2-20%) to give the desired crude product. The crude product was purified by using 10-30% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was further purified by flash chromatography on a pre-packed C18 column of ) to give N-(5-(3-methoxypyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)acetamide (31.5 mg, 61%) as a white solid. LCMS (ESI) m / z 324.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.54(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=4.4Hz,3H),2.05(s,3H).

[0684] Example 90: Synthesis of N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)acetamide

[0685]

[0686] 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 eq.) in dioxane / water (10:1, 2.2 mL) was added phenylboronic acid (33 mg, 0.272 mmol; 2.00 eq.), Pd(DtBPF)Cl under nitrogen atmosphere. 2 (8.8 mg; 0.014 mmol; 0.10 eq.) and K 3 PO 4 (57.5 mg, 0.272 mmol; 0.20 eq.). The reactant 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 reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 10-43% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was further purified by flash chromatography on a pre-packed C18 column using 4-(4-(6-nitro-2-yl)-1-nitro-2-ol as eluent to afford N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)acetamide (12.0 mg, 30%) as an off-white solid. LCMS (ESI) m / z 293.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.63(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=4.4Hz,3H),2.07(s,3H).

[0687] Example 91: 4-(3-methoxypyridin-2-yl)-N 1 -Methyl-N 6 Synthesis of -(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine

[0688]

[0689] Step 1: 6-Chloro-4-iodo-2,7-naphthyridin-1-ol

[0690]

[0691] A mixture of 6-chloro-2,7-naphthyridine-1-ol (1 g; 5.53 mmol; 1.00 eq.) and 1-iodopyrrolidine-2,5-dione (1.87 g; 8.30 mmol; 1.50 eq.) in DMF (10 mL) was stirred at room temperature under a nitrogen atmosphere for 5 hours. The resulting mixture was quenched by dropping water (50 mL) and stirred at room temperature for 30 minutes, and a large amount of precipitation was formed. The mixture was filtered and the solid was washed with water (10 mL). The solid was dried under reduced pressure to provide 6-chloro-4-iodo-2,7-naphthyridine-1-ol (1.05 g, 61%) as a yellow solid. LCMS (ESI) m / z 306.9, [M+H] + .

[0692] Step 2: 6-Chloro-4-(3-methoxypyridin-2-yl)-2,7-naphthyridin-1(2H)-one

[0693]

[0694] 6-Chloro-4-iodo-2,7-naphthyridin-1-ol (600 mg; 1.96 mmol; 1.00 eq.), 3-methoxy-2-(tributylstannyl)pyridine (2.34 g; 5.874 mmol; 3.00 eq.), Pd(PPh 3 ) 2 Cl 2 A mixture of 1,4-dioxane (5 mL) and 1,4-dioxane (137 mg; 0.196 mmol; 0.10 eq.) was stirred at 60 °C under nitrogen atmosphere for 18 hours. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by using MeOH / CH 2 Cl 2 The resulting residue was purified by flash chromatography on a silica gel column with (2-10%) as the eluent to provide 6-chloro-4-(3-methoxypyridin-2-yl)-2,7-naphthyridin-1(2H)-one (240 mg, 42%) as a yellow solid. LCMS (ESI) m / z 288.0, [M+H] + .

[0695] Step 3: 4-(3-methoxypyridin-2-yl)-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one

[0696]

[0697] 6-Chloro-4-(3-methoxypyridin-2-yl)-2,7-naphthyridin-1(2H)-one (330 mg; 1.14 mmol; 1.00 eq.), pyridin-2-amine (216 mg; 2.29 mmol; 2.00 eq.), Pd 2 (dba) 3 (105 mg; 0.115 mmol; 0.10 eq.), XantPhos (132 mg; 0.229 mmol; 0.20 eq.), and Cs 2 CO 3 A mixture of (934 mg; 2.87 mmol; 2.50 eq.) in dioxane (5 mL) was stirred at 110 °C under nitrogen atmosphere overnight. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature, concentrated under reduced pressure and eluted using MeOH / CH 2 Cl 2 Flash chromatography on a silica gel column with (5-20%) as the eluent afforded 4-(3-methoxypyridin-2-yl)-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one (350 mg, 88%) as a white solid. LCMS (ESI) m / z 346.1, [M+H] + .

[0698] Step 4: 8-Chloro-5-(3-methoxypyridin-2-yl)-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine

[0699]

[0700] Combine 4-(3-methoxypyridin-2-yl)-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one (200 mg; 0.579 mmol; 1.00 eq.) and POCl in a reaction flask. 3 (5 mL). 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 (200 mg; 95%) as a brown solid. LCMS (ESI) m / z 364.1, [M+H] + .

[0701] Step 5: 4-(3-methoxypyridin-2-yl)-N 1 -Methyl-N 6 -(Pyridin-2-yl)-2,7-naphthyridine-1,6-diamine

[0702]

[0703] 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 eq.), methylamine hydrochloride (184 mg; 2.73 mmol; 5.00 eq.) and DIPEA (706 mg; 5.47 mmol; 2.00 eq.) in NMP (5 mL) was stirred at 100 ° C for 16 hours. The reaction was monitored by LCMS. The mixture was cooled and concentrated. The reaction mixture was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The resulting residue was purified by flash chromatography on a prepacked C18 column using 4-(3-methoxypyridin-2-yl)-N-(4-(4-methoxypyridin-2-yl)-4-nitropropene as a yellow solid. 1 -Methyl-N 6 -(Pyridin-2-yl)-2,7-naphthyridine-1,6-diamine (60 mg, crude). The product was purified by reverse phase preparative HPLC (Prep-C18, XBridge Prep OBDC18 column, 30×150 mm, waters; gradient elution of 35-45% MeCN / water over a 10-min period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 220 nm) to purify the crude product to provide 4-(3-methoxypyridin-2-yl)-N-(3-methoxypyridin-2-yl)- 1 -Methyl-N 6 -(Pyridin-2-yl)-2,7-naphthyridine-1,6-diamine (35.2 mg, 17%). LCMS (ESI) m / z 359.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.78(s,1H),9.29(s,1H),8.28(d,J=4.4Hz,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=4.4Hz,3H).

[0704] Example 92: N 1 -methyl-4-phenyl-N 6 Synthesis of -(pyridin-2-yl)-2,7-naphthyridine-1,6-diamine

[0705]

[0706] Step 1: 6-Chloro-4-phenyl-2,7-naphthyridin-1(2H)-one

[0707]

[0708] 6-Chloro-4-iodo-2,7-naphthyridin-1-ol (Example 91, Step 1) (400 mg; 1.305 mmol; 1.00 eq.), phenylboronic acid (477 mg; 3.91 mmol; 3.00 eq.), Pd(PPh 3 ) 4 (151 mg; 0.131 mmol; 0.10 eq.) and Na 2 CO 3 A mixture of 1,4-dihydro-1,4-dihydro-2-nitropropene (748 mg; 7.06 mmol; 5.41 eq.) in a mixed solvent of DME / water (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 mixture was concentrated under reduced pressure. The product was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column (2-10%) as eluent to afford 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one (228 mg, 68%) as a yellow solid. LCMS (ESI) m / z 257.0, [M+H] + .

[0709] Step 2: 4-phenyl-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one

[0710]

[0711] 6-Chloro-4-phenyl-2,7-naphthyridin-1(2H)-one (200 mg; 0.779 mmol; 1.00 eq.), pyridin-2-amine (220 mg; 2.33 mmol; 3.00 eq.), Pd 2 (dba) 3 (71.4 mg; 0.078 mmol; 0.10 eq.), XantPhos (90.2 mg; 0.156 mmol; 0.20 eq.), and Cs 2 CO 3 A mixture of (507.8 mg; 1.55 mmol; 2.00 eq.) in 1,4-dioxane (10 mL) was stirred at 100° C. under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The reaction mixture was concentrated under reduced pressure. The product was purified by using 2-10% MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column as eluent to provide 4-phenyl-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one (98 mg, 40%). LCMS (ESI) m / z 315.1, [M+H] + .

[0712] Step 3: 8-Chloro-5-phenyl-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine

[0713]

[0714] 4-phenyl-6-(pyridin-2-ylamino)-2,7-naphthyridin-1(2H)-one (98 mg; 0.312 mmol; 1.00 eq.) was mixed with POCl 3 (4 mL) was mixed and the mixture was stirred at 100 °C under nitrogen atmosphere for 1 hour. After completion, the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 (50 mL). Use saturated NaHCO 3 The mixture was basified to pH ≈ 7 by using CH 2 Cl 2 The combined organic layers were washed with saturated NaCl solution (1×5 mL) and then purified by anhydrous Na 2 SO 4 The residue was purified by flash chromatography on a silica gel column using 20-80% EtOAc / petroleum ether as eluent to provide 8-chloro-5-phenyl-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine (43.2 mg, 41%) as a pale yellow solid. LCMS (ESI) m / z 333.1, [M+H] + .

[0715] Step 4: N 1 -methyl-4-phenyl-N 6 -(Pyridin-2-yl)-2,7-naphthyridine-1,6-diamine

[0716]

[0717] A mixture of 8-chloro-5-phenyl-N-(pyridin-2-yl)-2,7-naphthyridin-3-amine (43.2 mg; 0.130 mmol; 1.00 eq.), methylamine hydrochloride (18 mg; 0.267 mmol; 2.05 eq.) and DIPEA (83.9 mg; 0.649 mmol; 5.00 eq.) in NMP (2 mL) was stirred at 100 ° C. under nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature. The reaction mixture was heated to 40 ℃ and then dried over medium temperature by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The resulting mixture was purified by flash chromatography on a pre-packed C18 column using 4-(4-(2-nitropropene)-6-nitropropene) as eluent to afford N 1 -methyl-4-phenyl-N 6 -(Pyridin-2-yl)-2,7-naphthyridine-1,6-diamine (20.0 mg, 47%). LCMS (ESI) m / z 328.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.90(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=4.4Hz,3H).

[0718] Example 93: N 6 -(Cyclopropylmethyl)-N 1 Synthesis of methyl-4-phenyl-2,7-naphthyridine-1,6-diamine

[0719]

[0720] Step 1: 6-((Cyclopropylmethyl)amino)-4-phenyl-2,7-naphthyridin-1(2H)-one

[0721]

[0722] A mixture of 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one (Example 92, Step 1) (261 mg; 1.02 mmol; 1.00 eq.), cyclopropylmethylamine (725 mg; 10.1 mmol; 10.0 eq.) and DIPEA (329 mg; 2.55 mmol; 2.50 eq.) in NMP (5 mL) was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature. The reaction mixture was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The resulting mixture was purified by flash chromatography on a pre-packed C18 column with ) as the eluent to provide 6-((cyclopropylmethyl)amino)-4-phenyl-2,7-naphthyridin-1(2H)-one (145 mg, 48%) as a light yellow solid. LCMS (ESI) m / z 292.1, [M+H] + .

[0723] Step 2: 8-Chloro-N-(cyclopropylmethyl)-5-phenyl-2,7-naphthyridin-3-amine

[0724]

[0725] 6-((Cyclopropylmethyl)amino)-4-phenyl-2,7-naphthyridin-1(2H)-one (145 mg; 0.498 mmol; 1.00 eq.) was dissolved in POCl 3 (4 mL) and stirred at 100 °C under nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 (55 mL). Use saturated NaHCO 3 The mixture was basified to pH ≈ 7 by using CH 2 Cl 2 The combined organic layers were washed with saturated NaCl solution (1×5 mL) and then purified by anhydrous Na 2 SO 4 The residue was purified by flash chromatography on a silica gel column using EtOAc / petroleum ether (10-80%) as eluent to afford 8-chloro-N-(cyclopropylmethyl)-5-phenyl-2,7-naphthyridin-3-amine (84.7 mg, 54%) as a yellow solid. LCMS (ESI) m / z 310.1, [M+H] + .

[0726] Step 3: N 6 -(Cyclopropylmethyl)-N 1-Methyl-4-phenyl-2,7-naphthyridine-1,6-diamine

[0727]

[0728] A mixture of 8-chloro-N-(cyclopropylmethyl)-5-phenyl-2,7-naphthyridin-3-amine (74.7 mg; 0.241 mmol; 1.00 eq.), methylamine hydrochloride (48.6 mg; 0.72 mmol; 2.99 eq.) and DIPEA (155 mg; 1.20 mmol; 4.99 eq.) in NMP (3 mL) was stirred at 120° C. under nitrogen atmosphere for 12 hours. The reaction mixture was cooled to room temperature and heated to room temperature by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The resulting mixture was purified by flash chromatography on a pre-packed C18 column using 4-(4-(2-nitropropene)-6-nitropropene) as eluent to afford N 6 -(Cyclopropylmethyl)-N 1 -methyl-4-phenyl-2,7-naphthyridine-1,6-diamine (33.5 mg, 45%). LCMS (ESI) m / z 305.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.10(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),6.4 1(s,1H),3.13-3.08(m,2H),2.96(d,J=4.4Hz,3H),1.04-0.93(m,1H),0.44-0.38(m,2H),0.19-0.14(m,2H).

[0729] Example 94: N 1 -methyl-4-phenyl-N 6 Synthesis of -(2,2,2-trifluoroethyl)-2,7-naphthyridine-1,6-diamine

[0730]

[0731] Step 1: 4-phenyl-6-((2,2,2-trifluoroethyl)amino)-2,7-naphthyridin-1(2H)-one

[0732]

[0733] A mixture of 6-chloro-4-phenyl-2,7-naphthyridin-1(2H)-one (Example 92, Step 1) (100 mg; 0.390 mmol; 1.00 eq.), 2,2,2-trifluoroethane-1-amine (77.2 mg; 0.779 mmol; 2.00 eq.), Pd-PEPPSI-I HeptCl (37.9 mg; 0.039 mmol; 0.10 eq.) and t-BuOK (87.4 mg; 0.779 mmol; 2.00 eq.) 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 reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column (2-10%) as eluent to provide 4-phenyl-6-((2,2,2-trifluoroethyl)amino)-2,7-naphthyridin-1(2H)-one (80.6 mg, 64%) as an off-white solid. LCMS (ESI) m / z 320.1, [M+H] + .

[0734] Step 2: 8-Chloro-5-phenyl-N-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-amine

[0735]

[0736] 4-Phenyl-6-((2,2,2-trifluoroethyl)amino)-2,7-naphthyridin-1(2H)-one (80.6 mg; 0.252 mmol; 1.00 eq.) was dissolved in POCl 3 (3 mL). The reaction mixture was stirred at 100 °C under nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 (50 mL). Saturated NaHCO 3 The mixture was basified to pH ≈ 7 by using CH 2 Cl 2 The combined organic layers were washed with saturated NaCl solution (1×5 mL) and then purified by anhydrous Na 2 SO 4 The residue was purified by flash chromatography on a silica gel column using 20-80% EtOAc / petroleum ether as eluent to provide 8-chloro-5-phenyl-N-(2,2,2-trifluoroethyl)-2,7-naphthyridin-3-amine (76.6 mg, 89%) as a yellow solid. LCMS (ESI) m / z 338.1, [M+H] + .

[0737] Step 3: N 1 -methyl-4-phenyl-N 6 -(2,2,2-trifluoroethyl)-2,7-naphthyridine-1,6-diamine

[0738]

[0739] 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 eq.), methylamine hydrochloride (39.9 mg; 0.591 mmol; 3.00 eq.) and DIPEA (127 mg; 0.984 mmol; 4.99 eq.) in NMP (3 mL) was stirred at 120° C. under nitrogen atmosphere for 12 hours. The reaction was cooled to room temperature. The reaction mixture was stirred for 12 hours using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The resulting mixture was purified by flash chromatography on a pre-packed C18 column using 4-(4-(2-nitropropene)-6-nitropropene) as eluent to afford N 1 -methyl-4-phenyl-N 6 -(2,2,2-trifluoroethyl)-2,7-naphthyridine-1,6-diamine (41.3 mg, 63%). LCMS (ESI) m / z 333.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.17(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=4.4Hz,3H).

[0740] Example 95: Synthesis of N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0741]

[0742] Step 1: N-(8-Hydroxy-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0743]

[0744] 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 eq.) in dioxane (30 mL) under nitrogen atmosphere were added cyclopropanecarboxamide (1.46 g; 17.1 mmol; 4.00 eq.), Pd 2 (dba) 3 (394.4 mg; 0.429 mmol; 0.10 eq.), XantPhos (495 mg; 0.859 mmol; 0.20 eq.), and Cs 2 CO 3 (2.8 g; 8.58 mmol; 2.00 eq.). The reaction was stirred at 130 °C overnight under nitrogen. After completion, the reaction was concentrated under reduced pressure and purified by using MeOH / CH 2 Cl 2 The mixture was purified by flash chromatography on a silica gel column with 4% 4-nitropropanediol (3-15%) to give N-(8-hydroxy-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (560 mg, crude) as a light yellow solid. The crude product was diluted with water (20 mL) and then filtered, and the filter cake was washed with water and dried to give N-(8-hydroxy-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (180 mg, 13%) as a yellow solid. LCMS (ESI) m / z 306.1, [M+H] + .

[0745] Step 2: N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0746]

[0747] N-(8-Hydroxy-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (116 mg; 0.380 mmol; 1.00 eq.) was dissolved in phosphorus oxychloride (3 mL). The reaction was stirred at 100 °C for 1 hour under nitrogen. After completion, the reaction was concentrated under reduced pressure. 2 Cl 2 (50 mL) to dilute the resulting mixture. 3 The resulting mixture was washed with Na 2 SO 4The residue was purified by flash chromatography on a silica gel column using 20-50% EtOAc / petroleum ether to give a crude product. The product was purified by reverse phase preparative HPLC (Prep-C18, 5 μM OBD column, 19×250 mm, waters; gradient elution of 46-56% MeCN / water over an 8 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to further purify the crude product to obtain N-(8-chloro-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (1.9 mg, 1%) as a white solid. LCMS (ESI) m / z 324.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.35(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).

[0748] Example 96: Synthesis of N-(8-ethyl-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0749]

[0750] Step 1: N-(5-phenyl-8-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0751]

[0752] 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 eq.) in dioxane / water (5:1, 6 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (76 mg; 0.493 mmol; 2.00 eq.), Pd(DtBPF)Cl 2 (16 mg; 0.025 mmol; 0.10 eq.) and K 3 PO 4 (105 mg; 0.493 mmol; 2.00 eq.). The reaction was stirred at 90 °C for 2 h under nitrogen. After completion, the reaction was concentrated under reduced pressure. The reaction was evaporated to room temperature using EtOAc / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column with 4% (10-30%) to give N-(5-phenyl-8-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg, 77%) as a light yellow solid. LCMS (ESI) m / z 316.1, [M+H] + .

[0753] Step 2: N-(8-ethyl-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0754]

[0755] To a stirred mixture of N-(5-phenyl-8-vinyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.159 mmol; 1.00 eq.) 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 hours. The resulting mixture was filtered and washed with CH 2 Cl 2 The filter cake was washed with a mixed solvent of 1:1 / MeOH (50 mL). The filtrate was concentrated under reduced pressure. The reaction mixture was purified by using 10-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to give N-(8-ethyl-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (12.5 mg, 24%) as an off-white solid. LCMS (ESI) m / z 318.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.13(s,1H),9.58(s,1H),8.50(s,1H),8.41(s,1H),7.59-7.47(m,5H),3.4 1(q,J=7.2Hz,2H),2.09-2.01(m,1H),1.41(t,J=7.2Hz,3H),0.82-0.78(m,4H).

[0756] Example 97: N 1 -Methyl-N 6 Synthesis of -(3-oxetane-1,6-diamine)-4-phenyl-2,7-naphthyridine

[0757]

[0758] Step 1: 6-Chloro-N-methyl-2,7-naphthyridin-1-amine

[0759]

[0760] To a stirred mixture of 6-chloro-2,7-naphthyridin-1(2H)-one (Example 2, Step 3) (1 g; 5.53 mmol; 1.00 eq.) and PyBOP (5.7 g; 10.95 mmol; 2.00 eq.) in DMA (15 mL) was added methylamine hydrochloride (1.11 g; 16.44 mmol; 3.00 eq.), DIEA (3.6 g; 27.85 mmol; 5.00 eq.). After stirring at 80 °C under a nitrogen atmosphere for 16 hours, the reactants were 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). EtOAc was concentrated in vacuo. The residue was purified by using 10-40% EtOAc / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to afford 1.5 g of crude product. The product was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with 4% paraformaldehyde (5% paraformaldehyde) as the eluent to afford 6-chloro-N-methyl-2,7-naphthyridin-1-amine (676 mg, 63%) as an off-white solid. LCMS (ESI) m / z 194.0, [M+H] + .

[0761] Step 2: 6-Chloro-4-iodo-N-methyl-2,7-naphthyridin-1-amine

[0762]

[0763] To a solution of 6-chloro-N-methyl-2,7-naphthyridin-1-amine (612 mg; 3.16 mmol; 1.00 eq.) in DMF (12 mL) was slowly added NIS (1.07 g; 4.75 mmol; 1.50 eq.) at 0°C. The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with EtOAc (150 mL) and then washed with saturated NaCl solution (5×10 mL). The resulting solution (EtOAc) was washed with Na 2 SO 4 Dry and concentrate in vacuo. 2 Cl 2 The residue was diluted with 4% paraformaldehyde (15 mL) to precipitate a solid. The solid was collected by filtration and purified by CH 2 Cl 2 Washing gave 6-chloro-4-iodo-N-methyl-2,7-naphthyridin-1-amine (983 mg, 97%) as a yellow solid. LCMS (ESI) m / z 319.9, [M+H]+ .

[0764] Step 3: 6-Chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine

[0765]

[0766] To a mixture of 6-chloro-4-iodo-N-methyl-2,7-naphthyridin-1-amine (950 mg; 2.97 mmol; 1.00 eq.) and phenylboronic acid (363 mg; 2.97 mmol; 1.00 eq.) in dioxane / water (10:1, 13.2 mL) was added K 3 PO 4 (1.26 g; 5.93 mmol; 2.00 eq.) and Pd(dppf)Cl 2 .CH 2 Cl 2 (242 mg; 0.297 mmol; 0.10 eq.). After stirring at 60 °C under 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 / petroleum ether as eluent to provide 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine (620 mg, 77%) as a yellow solid. LCMS (ESI) m / z 270.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.45(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=4.4Hz,3H).

[0767] Step 4: N 1 -Methyl-N 6 -(Oxetane-3-yl)-4-phenyl-2,7-naphthyridine-1,6-diamine

[0768]

[0769] A mixture of 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine (40 mg; 0.148 mmol; 1.00 eq.), Pd-PEPPSI-I HeptCl (CAS: 1814936-54-3) (14.4 mg; 0.015 mmol; 0.10 eq.), t-BuOK (33.3 mg; 0.297 mmol; 2.00 eq.) and oxetane-3-amine (10.8 mg; 0.148 mmol; 1.00 eq.) in dioxane (2 mL) was stirred at 90 ° C for 2 hours. After completion, the resulting mixture was concentrated in vacuo. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with (1-9%) as eluent to provide N 1 -Methyl-N 6 -(Oxetane-3-yl)-4-phenyl-2,7-naphthyridine-1,6-diamine (20 mg, crude). The product was prepared by using 10%-70% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column of 5-(4-(4-nitropropene)-4-nitropropene) to afford N 1 -Methyl-N 6 -(Oxetane-3-yl)-4-phenyl-2,7-naphthyridine-1,6-diamine (6.3 mg, 13%). LCMS (ESI) m / z 307.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.11(s,1H),7.71(s,1H),7.69-7.64(m,1H),7.53-7.45(m,3H),7.42-7.35(m,3H),6.4 1(s,1H),4.95-4.85(m,1H),4.79-4.73(m,2H),4.45-4.40(m,2H),2.96(d,J=4.4Hz,3H).

[0770] Examples 98-100: Using similar experimental procedures used to prepare Example 97, each compound in Table 4 was prepared using 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine as a common intermediate and the appropriate amine.

[0771] Table 4

[0772]

[0773]

[0774] Example 101: Synthesis of 1-methyl-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide

[0775]

[0776] 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 eq.) was added 1-methylcyclopropane-1-carboxamide (21.9 mg; 0.221 mmol; 2.00 eq.), Pd 2 (dba) 3 (10.2 mg; 0.011 mmol; 0.10 eq.), XantPhos (12.9 mg; 0.022 mmol; 0.20 eq.), and Cs 2 CO 3 (72.1 mg; 0.221 mmol; 1.99 eq.). 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 using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with 20-55% MeCN / water (10 mmol / LNH 4 HCO 3 ) to give 1-methyl-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (24.4 mg, 66%) as an off-white solid. LCMS (ESI) m / z 333.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ9.59(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=4.4Hz,3H),1.41(s,3H),1.11-1.07(m,2H),0.65-0.61(m,2H)

[0777] Example 102 was prepared using similar experimental procedures used to prepare Example 97.

[0778]

[0779] 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)

[0780]

[0781] Step 1: 2-Fluorocyclopropane-1-carboxamide

[0782]

[0783] At 0°C, 2-fluorocyclopropane-1-carboxylic acid (200 mg; 1.92 mmol; 1.00 eq.) and DMF (28 mg; 0.383 mmol; 0.20 eq.) were dissolved in CH 2 Cl 2 To a stirred solution of 2 mL of oxalyl chloride (2 M) in CH 2 Cl 2 The resulting mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. After completion, the resulting mixture was concentrated under reduced pressure. The crude product was added dropwise to NH 3 (g) was added to a stirred solution of MeOH (7M, 3 mL). 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 using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column (1%-9%) as eluent to afford 2-fluorocyclopropane-1-carboxamide (40 mg, 20%) as an off-white solid. LCMS (ESI) m / z 104.0, [M+H] + .

[0784] Step 2: 2-Fluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (cis-isomer and trans-isomer)

[0785]

[0786] 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 eq.) in dioxane (2 mL) was added Pd 2 (dba) 3 (13.6mg; 0.015mmol; 0.10eq.), XantPhos (17.2mg; 0.030mmol; 0.20eq.), Cs2 CO 3 (96.6 mg; 0.296 mmol; 2.00 eq.) and 2-fluorocyclopropane-1-carboxamide (23 mg; 0.223 mmol; 1.50 eq.). The reaction was stirred at 110°C for 3 hours. The desired product was detected by LCMS. The resulting mixture was concentrated in vacuo. The reaction was carried out by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using (1-9%) as eluent to provide two separate peaks with the desired product mass. The less polar peak was a minor component (~10 mg) compared to the more polar peak (30 mg). The product was purified by using 10%-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) were further purified by flash chromatography on a pre-packed C18 column of 5-nitropropane-2-yl)-1-carboxamide (trans isomer) (3.8 mg, 7%) as a white solid and 2-fluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (cis isomer) (21.5 mg, 43%) as a white solid. LCMS (ESI) m / z 337.1, [M+H] + . HNMR of the trans isomer: 1 HNMR (400 MHz, DMSO-d 6 )δ11.09(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=4.4Hz,3H),2.60-2.54(m,1H),1.54-1.42(m,1H),1.26-1.16(m,1H). HNMR of cis isomer: 1 H NMR (400 MHz, DMSO-d 6 )δ10.97(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=4.4Hz,3H),2.25-2.16(m,1H),1.66-1.53(m,1H),1.18-1.08(m,1H).

[0787] Example 105: Synthesis of 2,2-difluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide

[0788]

[0789] Step 1: N-(2,4-dimethoxybenzyl-2,2-difluorocyclopropane-1-carboxamide

[0790]

[0791] A mixture of 2,2-difluorocyclopropane-1-carboxylic acid (200 mg; 1.63 mmol; 1.00 eq.) and HATU (741 mg; 1.94 mmol; 1.19 eq.) in DMF (2 mL) was stirred at room temperature under a nitrogen atmosphere for 20 minutes. DIPEA (629 mg; 4.86 mmol; 3.00 eq.) and (2,4-dimethoxyphenyl)methylamine (543 mg; 3.24 mmol; 1.98 eq.) were added to the reaction mixture. The resulting mixture was stirred for an additional 2 hours at room temperature. The reaction was monitored by LCMS. The reaction mixture was purified by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to afford N-(2,4-dimethoxybenzyl-2,2-difluorocyclopropane-1-carboxamide (393 mg, 88%) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =272.1.

[0792] Step 2: 2,2-Difluorocyclopropane-1-carboxamide

[0793]

[0794] A mixture of N-(2,4-dimethoxybenzyl-2,2-difluorocyclopropane-1-carboxamide (393 mg; 1.44 mmol; 1.00 eq.) in trifluoroacetaldehyde (3 mL) was stirred at 70° C. under nitrogen atmosphere for 1 hour. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction was performed by using 2-6% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide 2,2-difluorocyclopropane-1-carboxamide (170 mg, 97%) as a white solid. LCMS (ESI) m / z 122.0, [M+H] + .

[0795] Step 3: 2,2-difluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide

[0796]

[0797] To 6-chloro-N-methyl-4-phenyl-2,7-naphthyridin-1-amine (Example 97, Step 3) (50 mg; 0.185 mmol; 1.00 eq.) and 2,2-difluorocyclopropane-1-carboxamide (27 mg; 0.223 mmol; 1.20 eq.) in dioxane (4 mL) and Cs 2 CO 3 Pd (121.6 mg; 0.373 mmol; 2.00 eq.) was added to the solution 2 (dba) 3 (14 mg; 0.015 mmol; 0.10 eq.) and XantPhos (17 mg; 0.02 mmol; 0.20 eq.). Stir at 110°C under nitrogen atmosphere for 3 hours. Monitor the reaction by LCMS. After completion, the resulting mixture was concentrated under reduced pressure. The reaction was carried out by using 2-6% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to afford 2,2-difluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (50 mg, crude) as a yellow solid. The product was prepared by using 20%-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide 2,2-difluoro-N-(8-(methylamino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropane-1-carboxamide (24.5 mg, 46%) as a white solid. LCMS (ESI) m / z 355.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.15(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=4.4Hz,3H),3.00-2.94(m,1H),2.05-1.91(m,2H).

[0798] Example 106: Synthesis of N-(8-(methylamino)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0799]

[0800] K 3 PO 4 A mixture of 1,4-dioxane / water (5:1, 2.4 mL) and 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (53 mg; 0.250 mmol; 2.00 eq.), N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.), 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 eq.) was stirred at 90 °C under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature and the solvent was concentrated under reduced pressure. The reaction mixture was stirred at 90 °C for 2 hours using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 1-10% MeCN as eluent to afford the crude product. 4 HCO 3 The crude product was further purified by flash chromatography on a pre-packed C18 column with ) as the eluent to provide N-(8-(methylamino)-5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (23.5 mg, 52%) as a white solid. LCMS (ESI) m / z 359.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.88(s,1H),10.92(s,1H),9.41(s,1H),8.36(s,1H),8.28(dd,J=4.8,1.2Hz,1H),8.10-7.96(m,2H),7.75(dd,J=4.8,1 .2Hz,1H),7.58(d,J=2.4Hz,1H),7.06(dd,J=8.0,4.8Hz,1H),3.04(d,J=4.4Hz,3H),2.05-1.94(m,1H),0.81-0.68(m,4H).

[0801] Examples 107-119: Using similar experimental procedures used to prepare Example 106, each compound in Table 5 was prepared using N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide as a common intermediate and the appropriate boronic ester or boronic acid.

[0802] Table 5

[0803]

[0804]

[0805]

[0806]

[0807] Example 120: Synthesis of 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid

[0808]

[0809] Step 1: Methyl 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylate

[0810]

[0811] To a solution of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (200 mg; 0.623 mmol; 1.00 eq.) in a mixed solvent of DMSO / methanol (2:1, 9 mL) was added Pd(dppf)Cl in a pressure box. 2 .CH 2 Cl 2 (51 mg; 0.063 mmol; 0.10 eq.) and Et 3 N (189 mg; 1.868 mmol; 3.00 eq.) was added. The mixture was pressurized to 20 atm with carbon monoxide and stirred at 130°C overnight. The reaction mixture was cooled to room temperature. After completion, the reaction solution was diluted with EtOAc (100 mL), washed with brine (3×20 mL), and washed with Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide methyl 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylate (170 mg, 90%) as a yellow solid. LCMS (ESI) m / z 301.1, [M+H] + .

[0812] Step 2: 6-(Cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid

[0813]

[0814] A mixture of 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid methyl ester (150 mg; 0.499 mmol; 1.00 eq.) and lithium hydroxide monohydrate (42 mg; 1.00 mmol; 2.00 eq.) in THF / water (3: 1, 12 mL) was stirred overnight at room temperature under a nitrogen atmosphere. After completion, the reaction mixture was concentrated in vacuo. The residue was dissolved in water (2 mL). The mixture was acidified to pH ≈ 6 with 1M HCl. The precipitated solid was collected by filtration and washed with water (2 mL). The solid was dried in vacuo to obtain 6-cyclopropanecarboxamido-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (140 mg, 97%) as a white solid. 10 mg of the crude product was then further purified by flash chromatography on a pre-packed C18 column using 10-60% MeCN / water (0.05% formic acid) to afford 6-cyclopropanecarboxamido-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (2.9 mg) as a white solid. LCMS (ESI) m / z 287.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.39(s,1H),9.34(s,1H),8.73(s,1H),8.55-8.48(m,1H),3.04(d,J=4.4Hz,3H),2.09-2.00(m,1H),0.88-0.77(m,4H).

[0815] Example 121: Synthesis of N-(8-(methylamino)-5-(4-phenoxypiperidine-1-carbonyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0816]

[0817] A mixture of 6-cyclopropanecarboxamido-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (50 mg; 0.175 mmol; 1.00 eq.), 4-phenoxypiperidine (37.2 mg; 0.210 mmol; 1.20 eq.), HATU (100 mg; 0.263 mmol; 1.51 eq.) and DIPEA (67.6 mg; 0.523 mmol; 2.99 eq.) in DMF (3 mL) was stirred at room temperature for 2 h. After completion, the mixture was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3The reaction mixture was purified by flash chromatography on a pre-packed C18 column of ) to provide N-(8-(methylamino)-5-(4-phenoxypiperidine-1-carbonyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (59.1 mg, 75%) as a white solid. LCMS (ESI) m / z 446.2, [M+H] + . 1 H NMR (400 MHz, methanol-d 4 )δ9.23(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).

[0818] Example 122: Synthesis of N-(8-(methylamino)-5-(piperidine-1-carbonyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0819]

[0820] A mixture of 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (50 mg; 0.175 mmol; 1.00 eq.), piperidine (17.9 mg; 0.210 mmol; 1.20 eq.), HATU (100 mg; 0.263 mmol; 1.50 eq.) and DIPEA (67.6 mg; 0.523 mmol; 3.00 eq.) in DMF (3 mL) was stirred at room temperature for 1 hour. The desired product was observed by LCMS. The product was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The reaction mixture was purified by flash chromatography on a pre-packed C18 column of ) to provide N-(8-(methylamino)-5-(piperidine-1-carbonyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (42.6 mg, 69%) as a white solid. LCMS (ESI) m / z 354.2, [M+H] + . 1 H NMR (400 MHz, methanol-d 4)δ9.23(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).

[0821] Example 123: Synthesis of 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxamide

[0822]

[0823] 6-(Cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (21.3 mg; 0.074 mmol; 1 eq.), NH 4 A mixture of Cl (19.7 mg; 0.371 mmol; 5.00 eq.), HATU (42.4 mg; 0.112 mmol; 1.50 eq.) and DIPEA (28.8 mg; 0.223 mmol; 3.00 eq.) in DMF (1.5 mL) was stirred at room temperature for 1 hour. After completion, the reaction mixture was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The reaction mixture was purified by flash chromatography on a pre-packed C18 column of ) to provide 6-(cyclopropanecarboxamido)-1-(methylamino)-2,7-naphthyridine-4-carboxamide (8.6 mg, 40%) as a white solid. LCMS (ESI) m / z 286.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.86(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=4.4Hz,3H),2.09-2.01(m,1H),0.90-0.78(m,4H).

[0824] Example 124: Synthesis of 6-(cyclopropanecarboxamido)-N-methyl-1-(methylamino)-2,7-naphthyridine-4-carboxamide

[0825]

[0826] To a stirred mixture of 6-cyclopropanecarboxamido-1-(methylamino)-2,7-naphthyridine-4-carboxylic acid (26 mg; 0.09 mmol; 1.00 eq.) in DMF (1 mL) was added HATU (51.8 mg; 0.136 mmol; 1.50 eq.). The reaction was stirred at room temperature for 20 minutes. To the reaction mixture was added DIPEA (35.1 mg; 0.272 mmol; 3.00 eq.) and MeNH 2 HCl (7.2 mg; 0.108 mmol; 1.2 eq.). The reaction was stirred at room temperature for 1 hour. After completion, the mixture was heated to 40 ℃ with 20-80% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide 6-cyclopropanecarboxamido-N-methyl-1-(methylamino)-2,7-naphthyridine-4-carboxamide (1.4 mg, 9%) as a white solid. LCMS (ESI) m / z 300.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.89(s,1H),9.32(s,1H),8.85(s,1H),8.21(s,1H),8.20-8.13(m,2H),3.0 0(d,J=4.4Hz,3H),2.76(d,J=4.4Hz,3H),2.07-1.99(m,1H),0.86-0.77(m,4H).

[0827] Example 125: Synthesis of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0828]

[0829] Step 1: N-(8-(Methylamino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0830]

[0831] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (500 mg; 1.557 mmol; 1.00 eq.) in DMF (7 mL, deoxygenated before use) at room temperature were added CuI (9 mg; 0.047 mmol; 0.03 eq.), Pd(PPh 3 ) 2 Cl 2(21.9mg; 0.031mmol; 0.02eq.), PPh 3 (8.2 mg; 0.031 mmol; 0.02 eq.), piperidine (205 mg; 2.411 mmol; 1.55 eq.) and ethynyltrimethylsilane (504.6 mg; 5.137 mmol; 3.30 eq.). 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). 2 SO 4 The organic phase was dried, filtered and the solvent removed under reduced pressure. 4 HCO 3 ) to provide N-(8-(methylamino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (397 mg, 75%) as a yellow solid. LCMS (ESI) m / z 339.2, [M+H] + .

[0832] Step 2: N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0833]

[0834] To a stirred mixture of N-(8-(methylamino)-5-((trimethylsilyl)ethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (397 mg; 1.17 mmol; 1.00 eq.) in MeOH (10 mL) was added K 2 CO 3 (431 mg; 3.16 mmol; 2.70 eq.). The reaction was stirred at room temperature for 2 hours. Upon completion, the reaction was diluted with EtOAc (100 mL) and the organic phase was washed with saturated NaCl solution (2×10 mL). 2 SO 4 The organic phase was dried, filtered and the solvent removed under reduced pressure. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to afford N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (300 mg, 96%) as a yellow solid. The product was then purified by using 20-60% MeCN / water (10 mmol / L NH 4 HCO 3) to provide N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (2.9 mg) as a white solid. LCMS (ESI) m / z 267.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.06(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=4.4Hz,3H),2.11-2.03(m,1H),0.91-0.80(m,4H).

[0835] Example 126: Synthesis of N-(5-(3-bromoisoxazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0836]

[0837] To a stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (80 mg; 0.300 mmol; 1.00 eq.) in EtOAc / water (5:1, 3.6 mL) was added KHCO 3 (90.3 mg; 0.902 mmol; 3.00 eq.) and 1,1-dibromoformaldehyde oxime (140.1 mg; 0.691 mmol; 2.30 eq.). The reaction was stirred at room temperature for 1 hour. Another portion of KHCO 3 (90.3 mg; 0.902 mmol; 3.00 eq.) and 1,1-dibromoformaldehyde oxime (140.1 mg; 0.691 mmol; 2.30 eq.). 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). 2 SO 4 The organic phase was dried, filtered and the solvent removed under reduced pressure. 2 Cl 2The residue was purified by flash chromatography on a silica gel column as eluent to provide N-(5-(3-bromoisoxazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (70 mg, crude). The product was then purified by reverse phase preparative HPLC (Prep-C18, 5 μM OBD column, 30×150 mm, waters; gradient elution of 40-48% MeCN / water over an 8 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 20 mg of the purified crude product was purified by HPLC (flow rate: 60 mL / min, detector UV wavelength: 254 nm) to provide N-(5-(3-bromoisoxazol-5-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.7 mg) as a yellow solid. LCMS (ESI) m / z 388.0, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.12(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=4.4Hz,3H),2.12-2.02(m,1H),0.90-0.82(m,4H).

[0838] Example 127: Synthesis of N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0839]

[0840] Step 1: 1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one

[0841]

[0842] CuI (38.9 mg; 0.204 mmol; 0.04 eq.) and Pd(PPh 3 ) 2 Cl 2 To a stirred mixture of cyclopropanecarbonyl chloride (530.6 mg; 5.076 mmol; 1.00 eq.), Et 3N (519.9 mg; 5.138 mmol; 1.01 eq.) and ethynyltrimethylsilane (500 mg; 5.091 mmol; 1.00 eq.). The reactants were stirred at room temperature under N 2 Stir for 1 hour under atmosphere. The desired product was observed by LCMS. 4 The mixture was quenched with Cl solution (20 mL) and then extracted with EtOAc (3×20 mL). The combined organic phases were washed with saturated NaCl solution (1×5 mL). 2 SO 4 Dry, filter and remove the solvent under reduced pressure. The residue was purified by flash chromatography on a silica gel column using 1-10% EtOAc / petroleum ether as eluent to provide 1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one (520 mg, 61%) as a yellow oil. LCMS (ESI) m / z 167.1, [M+H] + .

[0843] Step 2: N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0844]

[0845] To Pd(PPh 3 ) 2 Cl 2 (45.6mg; 0.062mmol; 0.10eq.), PPh 3 To a mixture of EtOH (32.7 mg; 0.124 mmol; 0.20 eq.), CuI (59.3 mg; 0.312 mmol; 0.50 eq.) and N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (200 mg; 0.625 mmol; 1.00 eq.) in DMF (10 mL, deoxygenated before use) was added Et 3 N (145.1 mg; 1.43 mmol; 2.30 eq.) and 1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-one (155.6 mg; 0.937 mmol; 1.50 eq.). To this mixture was added a solution of TBAF in THF (1 M) (0.93 mL; 0.93 mmol; 1.50 eq.). The reaction mixture was stirred at 90° C. for 3 hours. The resulting mixture was diluted with EtOAc (100 mL) and the organic phase was washed with saturated NaCl solution (3×10 mL). The mixture was stirred for 3 hours at 90° C. The mixture was stirred for 3 hours at 90° C. The mixture was stirred for 3 hours at 90° C. The mixture was stirred for 3 hours at 90° C. The organic phase was washed with NaCl solution (3×10 mL). The mixture was stirred for 3 hours at 90° C. ... 2 SO 4 The organic phase was dried, filtered and the solvent removed under reduced pressure.2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to afford the crude product. The product was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with ) as the eluent to provide N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg, 48%) as a white solid. Then 2.1 mg of the desired product was delivered. LCMS (ESI) m / z 335.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.12(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 .4Hz,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).

[0846] Example 128: Synthesis of N-(8-(methylamino)-5-propionyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0847]

[0848] Step 1: (Z)-N-(5-(1-ethoxyprop-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0849]

[0850] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.) in ethylene glycol (2 mL, deoxygenated before use) was added Pd(OAc) 2 (0.7 mg; 0.003 mmol; 0.02 eq.), DPPP (2.6 mg; 0.006 mmol; 0.04 eq.), and Et 3N (31.6 mg; 0.312 mmol; 2.00 eq.). The reaction was stirred at 80 ° C for 2 minutes, and then (E)-1-ethoxyprop-1-ene (26.9 mg; 0.312 mmol; 2.00 eq.) 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 washed with Na 2 SO 4 Dry, filter and remove the solvent under reduced pressure. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide (Z)-N-(5-(1-ethoxyprop-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (17 mg, 33%) as a yellow solid. LCMS (ESI) m / z 327.2, [M+H] + .

[0851] Step 2: N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0852]

[0853] To a stirred mixture of (Z)-N-(5-(1-ethoxyprop-1-en-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide solution (17 mg; 0.026 mmol; 1.00 eq.) in DMF (2 mL) was added 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 reaction mixture was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The product mixture was purified by flash chromatography on a pre-packed C18 column with ) as the eluent to provide N-(5-(3-cyclopropyl-3-oxoprop-1-yn-1-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (1.9 mg, 24%) as a yellow solid. LCMS (ESI) m / z 299.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.91(s,1H),9.49(s,1H),9.35(s,1H),8.84(s,1H),8.65-8.60(m,1H),3.06(d,J=4.4H z, 3H), 2.96 (q, J = 7.2Hz, 2H), 2.08-2.02 (m, 1H), 1.09 (t, J = 7.2Hz, 3H), 0.90-0.80 (m, 4H).

[0854] Example 129: Synthesis of (E)-N-(8-(methylamino)-5-(prop-1-en-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0855]

[0856] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.), Pd(OAc) 2 A mixture of ethylene glycol (2 mL, deoxygenated before use) and DPPP (0.7 mg; 0.003 mmol; 0.02 eq.) in ethylene glycol (2 mL, deoxygenated before use). To the reaction mixture was added Et 3 N (31.6 mg; 0.312 mmol; 2.00 eq.). The reaction was stirred at 80°C for 2 minutes; then (E)-1-ethoxyprop-1-ene (26.9 mg; 0.312 mmol; 2.00 eq.) 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 washed with Na 2 SO 4 Dry, filter and remove the solvent under reduced pressure. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide a crude product. The product was then eluted by reverse phase preparative HPLC (Prep-C18, 5 μM OBD column, 19×150 mm, waters; gradient elution of 22-32% MeCN / water over an 8 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to purify the crude product to provide (E)-N-(8-(methylamino)-5-(prop-1-en-1-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (2.6 mg, 35%) as a yellow solid. LCMS (ESI) m / z 283.1, [M+H] + .1 H NMR (400 MHz, DMSO-d 6 )δ11.00(s,1H),9.32(s,1H),8.43(s,1H),8.08(s,1H),7.92-7.85(m,1H),6.57(d,J=14.8Hz,1H),6.13 -6.03(m,1H),2.96(d,J=4.4Hz,3H),2.10-2.02(m,1H),1.89(dd,J=6.4,1.2Hz,3H),0.90-0.79(m,4H).

[0857] Example 130: Synthesis of N-(8-(methylamino)-5-(2-methyloxazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0858]

[0859] To a stirred mixture of N-(5-ethynyl-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.188 mmol; 1.00 eq.) in MeCN (2.5 mL) was added (triphenyl((1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methyl)sulfonamido)-λ 5 -phosphine)gold (13.9 mg; 0.019 mmol; 0.10 eq.), 8-methylquinoline 1-oxide (38.9 mg; 0.244 mmol; 1.30 eq.) and methanesulfonic acid (20.0 mg; 0.208 mmol; 1.11 eq.). The reactants were stirred at 60 ° C for 16 hours. The desired product can be detected by LCMS. The resulting mixture was concentrated in vacuo. The reaction was carried out by using 1-9% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide N-(8-(methylamino)-5-(2-methyloxazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20 mg, crude). The product was then purified by reverse phase preparative HPLC (Prep-C18, 5 μM YMC-Actus Triart column, 30×150 mm, waters; gradient elution of 19-29% MeCN / water over a 10 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3, flow rate: 60 mL / min, detector UV wavelength: 254 nm) to purify the crude product to provide N-(8-(methylamino)-5-(2-methyloxazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (2.1 mg, 3%) as a yellow solid. LCMS (ESI) m / z 324.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.07(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=4.4Hz,3H),2.48(s,3H),2.10-2.02(m,1H),0.89-0.79(m,4H).

[0860] Example 131: Synthesis of N-(5-(1-benzyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0861]

[0862] Step 1: (1-Benzyl-1H-pyrazol-3-yl)boronic acid

[0863]

[0864] 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 eq.) in DMF (5 mL) was added NaH (206.1 mg; 5.154 mmol; 2.00 eq., 60%) at 0 ° C and stirred at room temperature under a nitrogen atmosphere for 30 minutes. To the reaction mixture was added (bromomethyl)benzene (528.8 mg; 3.092 mmol; 1.20 eq.) 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 washed with saturated NH 4 The mixture was quenched with 10-40% MeCN / water (10 mmol / L NH 4 HCO 3 The resulting mixture was purified by flash chromatography on a pre-packed C18 column with ) as the eluent to provide (1-benzyl-1H-pyrazol-3-yl)boronic acid (180 mg, 24%) as an off-white oil. LCMS (ESI) m / z 203.1, [M+H] + .

[0865] Step 2: N-(5-(1-benzyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0866]

[0867] To a stirred mixture of (1-benzyl-1H-pyrazol-3-yl)boronic acid (31.4 mg; 0.156 mmol; 1.00 eq.) in a mixed solvent of 1,4-dioxane / water (5:1, 1.2 mL) was added XPhos Pd G 3 (13.2mg; 0.016mmol; 0.1eq.), XPhos (7.4mg; 0.016mmol; 0.10eq.), K 3 PO 4 (99.1 mg; 0.468 mmol; 3.00 eq.) and N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50 mg; 0.156 mmol; 1.00 eq.). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 2 hours. After completion, the mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using 1-8% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide 25 mg of crude product. The product was purified by using 10-40% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with ) as the eluent to afford N-(5-(1-benzyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (21.0 mg, 33%) as an off-white solid. LCMS (ESI) m / z 399.2, [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.88(s,1H),9.35(s,1H),9.00(s,1H),8.21(s,1H),7.96-7.92(m,1H),7.90(d,J=2.0Hz,1H),7.45-7. 28(m,5H),6.53(d,J=2.0Hz,1H),5.37(s,2H),3.00(d,J=4.4Hz,3H),2.08-2.02(m,1H),0.90-0.80(m,4H).

[0868] Example 132: Synthesis of N-(8-(methylamino)-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0869]

[0870] Step 1: 1-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine

[0871]

[0872] 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 eq.) in THF (2 mL) was added PPh 3 (238.3 mg; 0.908 mmol; 2.00 eq.), 1-methylpiperidin-4-ol (104.6 mg; 0.908 mmol; 2.00 eq.) and DIAD (183.7 mg; 0.908 mmol; 2.00 eq.). The reaction mixture was stirred at room temperature under nitrogen atmosphere overnight. The reaction was monitored by LCMS. After completion, the resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine (48 mg; 34%) as a white solid. LCMS (ESI) m / z 318.2 [M+H] + .

[0873] Step 2: N-(8-(Methylamino)-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0874]

[0875] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (36 mg; 0.112 mmol; 1.00 eq.), 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)piperidine (36 mg; 0.112 mmol; 1.00 eq.), Pd(DtBPF)Cl 2 (8 mg; 0.011 mmol; 0.10 eq.) and K3 PO 4 A mixture of (48 mg; 0.224 mmol; 2.00 eq.) in 1,4-dioxane / water (5:1, 1.2 mL) was stirred at 90° C. under nitrogen atmosphere for 2 hours. The reaction was monitored by LCMS. The reaction mixture was concentrated under reduced pressure. The reaction mixture was purified by using 2-10% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to give a crude product. The crude product was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (12.4 mg, 26%) as a yellow solid. LCMS (ESI) m / z 432.2, [M+H] + . 1 H NMR (400 MHz, methanol-d 4 )δ9.25(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)

[0876] Example 133: Synthesis of N-(8-(methylamino)-5-(5-methyloxazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0877]

[0878] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (60 mg; 0.187 mmol; 1.00 eq.), 5-methyl-2-(tributylstannyl)oxazole (104.3 mg; 0.280 mmol; 1.50 eq.), Pd(PPh 3 ) 4A mixture of 1,4-dioxane (3 mL) (43.3 mg; 0.037 mmol; 0.20 eq.), CuI (7.12 mg; 0.037 mmol; 0.2 eq.) and LiCl (15.8 mg; 0.373 mmol; 2.00 eq.) was stirred at 100 °C for 3 hours. After completion, the resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with 2% (0-20%) as eluent to afford N-(8-(methylamino)-5-(5-methyloxazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (36.4 mg, crude) as a yellow solid. The product was prepared by using 20-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(5-methyloxazol-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (5.7 mg, 9%) as a yellow solid. LCMS (ESI) m / z 324.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.96(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=4.4Hz,3H),2.38(s,3H),2.09-2.04(m,1H),0.90-0.81(m,4H).

[0879] Example 134: Synthesis of N-(8-(methylamino)-5-(phenylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0880]

[0881] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40 mg; 0.125 mmol; 1.00 eq.), aniline (11.6 mg; 0.125 mmol; 1.00 eq.), EPhos Pd G 4 (11.5 mg; 0.013 mmol; 0.10 eq.), EPhos (7 mg; 0.013 mmol; 0.10 eq.), and Cs 2 CO 3A mixture of (81.2 mg; 0.250 mmol; 2.00 eq.) in 1,4-dioxane (1.5 mL) was stirred at 100° C. under nitrogen atmosphere for 12 hours. The reaction was monitored by LCMS. The reaction was concentrated and purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(phenylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (28.4 mg, 69%) as a yellow solid. LCMS (ESI) m / z 334.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.90(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=4.4Hz,3H),2.09-1.99(m,1H),0.82-0.71(m,4H).

[0882] Example 135 and Example 136: Synthesis of (E)-N-(5-(4-methoxyphenylvinyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide and (Z)-N-(5-(4-methoxyphenylvinyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0883]

[0884] To a stirred mixture of N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (50.0 mg; 0.156 mmol; 1.00 eq.) in DMF (2 mL) was added Pd(PPh 3 ) 2 Cl 2 (10.9mg; 0.016mmol; 0.10eq.), Na 2 CO 3(33.0 mg; 0.312 mmol; 2.00 eq.) and 1-methoxy-4-vinylbenzene (20.8 mg; 0.156 mmol; 1.00 eq.). The resulting mixture was stirred at 100 °C under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The mixture was cooled to room temperature. The resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using 1-6% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide a mixture of 15 mg crude products. The product was purified by reverse phase preparative HPLC (Prep-C18, XBridge Shield RP18 OBD column, 30×150 mm, waters; gradient elution of 35-45% MeCN / water over a 10 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to purify the mixture of crude products to provide (E)-N-(5-(4-methoxyphenylvinyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (8.9 mg, 15%) as a yellow solid. LCMS (ESI) m / z 375.2, [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ11.02(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=16.4Hz,1H),7.04-6.95(m,3H),3.79(s,3H),3.01(d,J=4.4Hz,3H),2.13-2.02(m,1H),0.92-0.79(m,4H); and (Z)-N-(5-(4-methoxyphenylvinyl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (2.7 mg, 4%) as a white solid. LCMS(ESI)m / z375.2,[M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.81(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=1.2Hz,1H),5.16(d,J=1.2Hz,1H),3.73(s,3H),3.00(d,J=4.4Hz,3H),2.00-1.91(m,1H),0.79-0.72(m,4H).

[0885] Example 137: Synthesis of N-(8-(methylamino)-5-(phenylethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0886]

[0887] N-(5-bromo-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (100 mg; 0.311 mmol; 1.00 eq.), CuI (1.8 mg; 0.009 mmol; 0.02 eq.), Pd(PPh 3 ) 2 Cl 2 (4.4 mg; 0.006 mmol; 0.02 eq.), piperidine (26.5 mg; 0.311 mmol; 1.00 eq.), and PPh 3 A mixture of (1.6 mg; 0.006 mmol; 0.02 eq.) in DMF (3 mL) was stirred at 90 °C under nitrogen atmosphere for 12 h. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The product was purified by using 2-10% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to give the desired crude product. The crude product was purified by using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The product was then purified by flash chromatography on a pre-packed C18 column of ) to provide N-(8-(methylamino)-5-(phenylethynyl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (20.7 mg, 19.4%) as a white solid. LCMS (ESI) m / z 343.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.06(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=4.4Hz,3H),2.11-2.02(m,1H),0.95-0.80(m,4H).

[0888] Example 138: Synthesis of N-(8-(methylamino)-5-(3-methylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0889]

[0890] 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 eq.), 5-bromo-3-methylisothiazole (24.1 mg; 0.135 mmol; 1.00 eq.), XPhos Pd G 3 (11.5 mg; 0.014 mmol; 0.10 eq.), XPhos (6.5 mg; 0.014 mmol; 0.10 eq.), and K 3 PO 4 A mixture of (86.4 mg; 0.407 mmol; 3.00 eq.) in a mixed solvent of 1,4-dioxane / water (7:1, 2.4 mL) was stirred at 90° C. under a nitrogen atmosphere for 1 hour. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The product was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 0-20% (0-20%) as eluent to afford a brown crude solid (30.1 mg). The product was purified by using 33-62% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by C18 column with ) as eluent to provide N-(8-(methylamino)-5-(3-methylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (14.9 mg, 32%) as a white solid. LCMS (ESI) m / z 340.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ11.07(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=4.4Hz,3H),2.48(s,3H),2.09-2.04(m,1H),0.90-0.78(m,4H).

[0891] Examples 139-145: Each of the compounds in Table 6 below was prepared following the same experimental procedure as previously described in Example 138.

[0892] Table 6

[0893]

[0894]

[0895]

[0896] Example 146: Synthesis of N-(8-(methylamino)-5-(3-phenylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0897]

[0898] Step 1: 5-Chloro-3-phenylisothiazole

[0899]

[0900] CuCl 2 (58 mg; 0.426 mmol; 1.50 eq.) and tert-butyl nitrite (44 mg; 0.426 mmol; 1.50 eq.) in MeCN (1 mL). The reaction mixture was stirred at 60 ° C for 2 minutes. To the mixture was added a solution of 3-phenylisothiazol-5-amine (50 mg; 0.284 mmol; 1.00 eq.) in MeCN (0.5 mL) and the reaction mixture was stirred at 60 ° C for 1 hour. The reaction was monitored by LCMS. The mixture was acidified to pH ≈ 3 with HCl solution (1 N). The reaction mixture was stirred at 60 ° C for 2 minutes with CH 2 Cl 2 The resulting mixture was extracted with 1% ethanol (2×20 mL). The combined organic layers were washed with brine (1×5 mL) and purified by anhydrous Na 2 SO 4 Dry. 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 / petroleum ether as eluent to give 5-chloro-3-phenylisothiazole (30 mg, 75%) as a white solid. LCMS (ESI) m / z 196.0, [M+H]+ .

[0901] Step 2: N-(8-(Methylamino)-5-(3-phenylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0902]

[0903] 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 eq.) in a 1,4-dioxane / water mixture (5:1, 1.2 mL) were added 5-chloro-3-phenylisothiazole (16 mg; 0.081 mmol; 1.00 eq.), XPhos Pd G 3 (6.9 mg; 0.008 mmol; 0.10 eq.), XPhos (3.9 mg; 0.008 mmol; 0.10 eq.), and K 3 PO 4 (34.6 mg; 0.162 mmol; 2.00 eq.). The resulting mixture was stirred at 90° C. under nitrogen atmosphere for 3 hours. The reaction was monitored by LCMS. The reaction mixture was purified by using (MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was re-purified by flash chromatography on a pre-packed C18 column of ) to provide N-(8-(methylamino)-5-(3-phenylisothiazol-5-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (8.6 mg, 27%) as a white solid. LCMS (ESI) m / z 402.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.10(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=4.4Hz,3H),2.10-2.02(m,1H),0.87-0.78(m,4H).

[0904] Example 147: Synthesis of N-(5-(1-ethyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0905]

[0906] Step 1: 3-Bromo-1-ethyl-1H-pyrazole and 5-Bromo-1-ethyl-1H-pyrazole

[0907]

[0908] 3-Bromo-1H-pyrazole (500.2 mg; 3.40 mmol; 1.00 eq.) and Cs 2 CO 3 (2.21g; 6.78mmol; 2.00eq.) was added to a stirred solution of iodoethane (796.6mg; 5.10mmol; 1.50eq.) in DMF (10mL). The resulting mixture was stirred at room temperature for 2 hours. The desired product (two peaks with the desired product mass) can be detected by LCMS. The resulting mixture was diluted with EtOAc (100mL). Then normal water treatment was performed with EtOAc. The combined organic layer was washed with brine (5mL×3). The resulting EtOAc was purified by Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column (0-2%) to provide 3-bromo-1-ethyl-1H-pyrazole (340.5 mg, 57%) as a yellow oil and 5-bromo-1-ethyl-1H-pyrazole (60 mg, 10%) as a yellow oil. LCMS (ESI) m / z 175.0, [M+H] + .

[0909] Step 2: N-(5-(1-ethyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0910]

[0911] To a stirred solution of 3-bromo-1-ethyl-1H-pyrazole (36.8 mg; 0.21 mmol; 1.30 eq.) 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 eq.) in a 1,4-dioxane / water mixture (10:1, 3.3 mL) was added XPhos PdG3 (13.7 mg; 0.016 mmol; 0.10 eq.), XPhos (7.7 mg; 0.016 mmol; 0.10 eq.), and K 3 PO 4 (90 mg; 0.42 mmol; 2.00 eq.). The resulting mixture was stirred at 90° C. under nitrogen atmosphere for 1 hour. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with 4-6% (4-6%) to afford the crude product (20 mg). The product was purified by using 50-70% MeCN / water (50-70% and 10 mmol / L NH 4 HCO 3 ) to provide N-(5-(1-ethyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (10.2 mg, 30%) as an off-white solid. LCMS (ESI) m / z 337.2, [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.87(s,1H),9.35(s,1H),9.01(s,1H),8.20(s,1H),7.96-7.91(m,1H),7.81(d,J=2.0Hz,1H),6.47(d,J=2.0H z, 1H), 4.19 (q, J = 7.2Hz, 2H), 3.00 (d, J = 4.4Hz, 3H), 2.09-2.01 (m, 1H), 1.46 (t, J = 7.2Hz, 3H), 0.88-0.78 (m, 4H).

[0912] Example 148: Synthesis of N-(5-(1-isopropyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0913]

[0914] Step 1: 3-Bromo-1-isopropyl-1H-pyrazole and 5-Bromo-1-isopropyl-1H-pyrazole

[0915]

[0916] 3-Bromo-1H-pyrazole (500.2 mg; 3.40 mmol; 1.00 eq.) and Cs 2 CO 32-Iodopropane (867.4 mg; 5.103 mmol; 1.50 eq.) was added to a stirred solution of (2.21 g; 6.804 mmol; 2.00 eq.) in DMF (10 mL). 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 reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with (1-2%) as eluent to provide 3-bromo-1-isopropylpyrazole (370 mg, 57%) as a yellow oil and 5-bromo-1-isopropyl-1H-pyrazole (120 mg, 18%) as a yellow oil. LCMS (ESI) m / z 189.0, [M+H] + .

[0917] Step 2: N-(5-(1-isopropyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0918]

[0919] To a stirred solution of 3-bromo-1-isopropylpyrazole (39.8 mg; 0.211 mmol; 1.30 eq.) 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 eq.) in a mixed solvent of 1,4-dioxane / water (10:1, 3.3 mL) was added XPhosPd G 3 (13.7 mg; 0.016 mmol; 0.10 eq.), XPhos (7.7 mg; 0.016 mmol; 0.10 eq.), and K 3 PO 4 (90 mg; 0.42 mmol; 2.00 eq.). The resulting mixture was stirred at 90° C. under nitrogen atmosphere for 1 hour. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using (0-5%) as eluent to afford the title compound (20 mg, crude). The product was prepared by using 20-60% MeCN / water (10 mmol / L NH 4 HCO 3) to provide N-(5-(1-isopropyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (7.1 mg, 20%) as an off-white solid. LCMS (ESI) m / z 351.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.87(s,1H),9.35(s,1H),9.09(s,1H),8.21(s,1H),7.98-7.92(m,1H),7.83(d,J=2.0Hz,1H),6.47(d,J=2. 0Hz,1H),4.60-4.48(m,1H),3.00(d,J=4.4Hz,3H),2.09-2.01(m,1H),1.50(d,J=6.8Hz,6H),0.90-0.78(m,4H).

[0920] Example 149: Synthesis of N-(5-(1-isobutyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0921]

[0922] Step 1: 3-Bromo-1-isobutyl-1H-pyrazole and 5-Bromo-1-isobutyl-1H-pyrazole

[0923]

[0924] 3-Bromo-1H-pyrazole (500.2 mg; 3.40 mmol; 1.00 eq.) and Cs 2 CO 3 1-iodo-2-methylpropane (945.2 mg; 5.10 mmol; 1.5 eq.) was added to a stirred solution of (2.21 g; 6.80 mmol; 2.00 eq.) in DMF (10 mL). 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 organic layer was concentrated under reduced pressure. The reaction mixture was purified by using CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with petroleum ether (0-60%) as eluent to provide 3-bromo-1-isobutyl-1H-pyrazole (150 mg, 21%) as a yellow oil and 5-bromo-1-isobutyl-1H-pyrazole (20 mg, 2%) as a yellow oil. LCMS (ESI) m / z 203.0, [M+H]+ .

[0925] Step 2: N-(5-(1-isobutyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0926]

[0927] To a stirred solution of 3-bromo-1-isobutyl-1H-pyrazole (42.8 mg; 0.211 mmol; 1.30 eq.) 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 eq.) in a mixed solvent of 1,4-dioxane / water (10:1, 3.3 mL) was added XPhosPd G 3 (13.7 mg; 0.016 mmol; 0.10 eq.), XPhos (7.7 mg; 0.016 mmol; 0.10 eq.), and K 3 PO 4 (90 mg; 0.42 mmol; 2.00 eq.). 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 reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by silica gel column using 10-37% MeCN / water (10 mmol / L NH 4 HCO 3 The crude product was purified by flash chromatography on a pre-packed C18 column with ) as the eluent to afford N-(5-(1-isobutyl-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (6.9 mg, 23%) as an off-white solid. LCMS (ESI) m / z 365.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.87(s,1H),9.35(s,1H),8.94(s,1H),8.18(s,1H),7.98-7.90(m,1H),7.79(d,J=2.0Hz,1H),6.46(d,J=2.0Hz,1H),3. 95(d,J=7.2Hz,2H),3.00(d,J=4.4Hz,3H),2.30-2.20(m,1H),2.08-2.00(m,1H),0.89(d,J=6.8Hz,6H),0.84-0.77(m,4H).

[0928] 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

[0929]

[0930] Step 1: 3-((3-Bromo-1H-pyrazol-1-yl)methyl)-1-methyl-1H-1,2,4-triazole

[0931]

[0932] 3-Bromo-1H-pyrazole (212.2 mg; 1.442 mmol; 1.20 eq.) and Cs 2 CO 3 3-(Chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (200.3 mg; 1.198 mmol; 1.00 eq.) was added to a stirred solution of (780.3 mg; 2.394 mmol; 2.00 eq.) in DMF (4 mL). The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The desired product can 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 washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide 3-((3-bromo-1H-pyrazol-1-yl)methyl)-1-methyl-1H-1,2,4-triazole (220 mg, 76%) as a yellow oil. LCMS (ESI) m / z 242.0, [M+H] + .

[0933] 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

[0934]

[0935] 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 eq.) 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 eq.) in a mixed solvent of 1,4-dioxane / water (5:1, 2.4 mL) was added XPhos Pd G 3 (23.4mg; 0.027mmol; 0.10eq.), XPhos (13.2mg; 0.027mmol; 0.10eq.), K 3 PO 4 (172.8 mg; 0.815 mmol; 3.00 eq.). The resulting mixture was stirred at 90° C. under nitrogen atmosphere for 1 hour. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using (5-20%) as the eluent to provide a 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 of 15-25% MeCN / water over a 10 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 10 mL / min, detector UV wavelength: 254 nm) to purify the crude product to provide 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 (2.4 mg, 2%) as a yellow solid. LCMS (ESI) m / z 404.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6)δ10.88(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=2.0Hz,1H) ,6.50(d,J=2.0Hz,1H),5.38(s,2H),3.85(s,3H),3.00(d,J=4.4Hz,3H),2.10-2.00(m,1H),0.90-0.78(m,4H).

[0936] Example 151: Synthesis of N-(8-(methylamino)-5-(1-(thiazol-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0937]

[0938] Step 1: 2-((3-Bromo-1H-pyrazol-1-yl)methyl)thiazole

[0939]

[0940] A mixture of 3-bromo-1H-pyrazole (395.2 mg; 2.689 mmol; 1.20 eq.) in DMF (5 mL) was treated with NaH (107.8 mg; 4.492 mmol; 2.00 eq.) at 0 ° C and stirred at room temperature under a nitrogen atmosphere for 0.5 hours. 2-(Chloromethyl)thiazole (300.0 mg; 2.246 mmol; 1.00 eq.) was added dropwise to the mixture at 0 ° C. The resulting mixture was stirred for another 2 hours at room temperature. The desired product can be detected by LCMS. The reactant was washed with saturated NH 4 The mixture was quenched with Cl solution (50 mL). The resulting mixture was extracted with EtOAc (50 mL×3). The organic layer was washed with brine (10 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. 2 Cl 2 The residue was purified by silica gel column with petroleum ether as eluent to provide 2-((3-bromo-1H-pyrazol-1-yl)methyl)thiazole (309.0 mg, 56%) as a yellow solid. LCMS (ESI) m / z 243.9, [M+H] + .

[0941] Step 2: N-(8-(Methylamino)-5-(1-(thiazol-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0942]

[0943] To a mixture of 2-((3-bromo-1H-pyrazol-1-yl)methyl)thiazole (66.2 mg; 0.271 mmol; 1.00 eq.) 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 eq.) in a mixed solvent of 1,4-dioxane / water (5:1, 2.4 mL) was added XPhos Pd G 3 (22.9 mg; 0.027 mmol; 0.10 eq.) and XPhos (12.9 mg; 0.027 mmol; 0.10 eq.) and K 3 PO 4 (172.9 mg; 0.815 mmol; 3.00 eq.). The resulting mixture was stirred at 90°C under nitrogen atmosphere for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using 2-10% MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to afford the crude product. The product was purified by using 20-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) to provide N-(8-(methylamino)-5-(1-(thiazol-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.5 mg, 4%) as a white solid. LCMS (ESI) m / z 406.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.90(s,1H),9.36(s,1H),8.85(s,1H),8.21(s,1H),8.02(d,J=2.0Hz,1H),8.01-7.97(m,1H),7.79(d,J=3.2Hz,1H) ,7.69(d,J=3.2Hz,1H),6.57(d,J=2.0Hz,1H),5.75(s,2H),3.00(d,J=4.4Hz,3H),2.09-2.01(m,1H),0.88-0.76(m,4H).

[0944] 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

[0945]

[0946] Step 1: 3-((3-Bromo-1H-pyrazol-1-yl)methyl)-5-methyl-1,2,4-oxadiazole

[0947]

[0948] To a mixture of 3-bromo-1H-pyrazole (399 mg; 2.72 mmol; 1.20 eq.) in DMF (5.0 mL) was added Cs 2 CO 3 (1.84 g; 5.66 mmol; 2.50 eq.), then 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (300 mg; 2.26 mmol; 1.00 eq.) was added in portions at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The desired product can be detected by LCMS. The mixture was allowed to cool to room temperature. The resulting mixture was concentrated under reduced pressure. The reaction mixture was evaporated to room temperature using 25-60% EtOAc / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide 3-((3-bromo-1H-pyrazol-1-yl)methyl)-5-methyl-1,2,4-oxadiazole (150 mg, 27%) as an off-white oil. LCMS (ESI) m / z 243.0, [M+H] + .

[0949] 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

[0950]

[0951] 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 eq.), 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 eq.) in a mixed solvent of 1,4-dioxane / water (5:1, 3 mL) was added Pd(DtBPF)Cl2 (17.8 mg; 0.027 mmol; 0.100 eq.) and K 3 PO 4 (115 mg; 0.542 mmol; 2.00 eq). The resulting mixture was stirred at 90 °C under nitrogen atmosphere for 2 hours. The desired product was observed by LCMS. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 25-60% MeCN / water (10 mmol / L NH 4 HCO 3 ) as eluent, the crude product was purified by C18 column to afford N-(5-(1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (14.6 mg, 13%) as a white solid. LCMS (ESI) m / z 405.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.96(s,1H),9.40(s,1H),8.85(s,1H),8.10(s,1H),7.99(d,J=2.0Hz,1H),6.58(d,J=2.0H z,1H),5.54(s,2H),3.03(d,J=4.4Hz,3H),2.57(s,3H),2.09-2.01(m,1H),0.90-0.79(m,4H).

[0952] 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

[0953]

[0954] Step 1: Methanesulfonic acid (tetrahydro-2H-thiopyran-4-yl)methyl ester

[0955]

[0956] At 0°C, (tetrahydro-2H-thiopyran-4-yl)methanol (300.2 mg; 2.269 mmol; 1.00 eq.) and DIPEA (703.8 mg; 5.446 mmol; 2.4 eq.) were added to CH 2 Cl 2Methanesulfonic anhydride (830.1 mg; 4.992 mmol; 2.20 eq.) was added portionwise to a stirred solution in 4 mL of 1% ethanol. The resulting mixture was stirred at room temperature for 1 hour. The residue was washed with CH 2 Cl 2 (80 mL) and washed with water (2×10 mL). The organic layer was washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide (tetrahydro-2H-thiopyran-4-yl)methyl methanesulfonate (450 mg, 94%) as a yellow solid. LCMS (ESI) m / z 211.0, [M+H] + .

[0957] Step 2: 3-Bromo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazole

[0958]

[0959] 3-Bromo-1H-pyrazole (365.3 mg; 2.483 mmol; 1.49 eq.) and Cs 2 CO 3 To a stirred solution of (1.08 g; 3.333 mmol; 2.00 eq.) in DMF (5 mL) was added (tetrahydro-2H-thiopyran-4-yl)methyl methanesulfonate (350.2 mg; 1.664 mmol; 1.00 eq.). The resulting mixture was stirred at 50 °C under nitrogen atmosphere overnight. The desired product could be detected by LCMS. The resulting mixture was purified by CH 2 Cl 2 (70 mL). The resulting mixture was washed with saturated NaCl solution (2×5 mL). The organic layer was washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. 4 HCO 3 ) to provide 3-bromo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazole (190.2 mg, 43%) as a white solid. LCMS (ESI) m / z 261.0, [M+H] + .

[0960] Step 3: N-(8-(Methylamino)-5-(1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0961]

[0962] To a stirred solution of 3-bromo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazole (46.2 mg; 0.176 mmol; 1.30 eq.) 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 eq.) in a mixed solvent of 1,4-dioxane / water (5:1, 2.4 mL) was added XPhos Pd G 3 (11.5 mg; 0.014 mmol; 0.10 eq.), XPhos (6.5 mg; 0.014 mmol; 0.10 eq.), and K 3 PO 4 (86.2 mg; 0.405 mmol; 2.98 eq.). 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 reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (0.05% formic acid) as eluent to provide a crude product. The crude product was further purified by flash chromatography on a pre-packed C18 column using 20-50% MeCN / water (0.05% formic acid) as eluent to provide 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] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.98(s,1H),9.40(s,1H),9.14(s,1H),8.10(s,1H),7.79(d,J=2.0Hz,1H),6.48(d,J=2.0Hz,1H),4.00(d,J=7.2Hz,2H),3.04(d,J=4.4H z,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).

[0963] Example 153B: Synthesis of N-(5-(1-((1,1-dioxanionyltetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0964]

[0965] Step 1: 4-((3-Bromo-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide

[0966]

[0967] A mixture of 3-bromo-1-((tetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazole (50.2 mg; 0.191 mmol; 1.00 eq.) and m-CPBA (100.2 mg; 0.581 mmol; 3.00 eq.) in dichloromethane (2 mL) was stirred at room temperature under air atmosphere for 1 hour. After the reaction was complete, the mixture was washed with CH 2 Cl 2 (80 mL) and washed with water (2×10 mL). The organic layer was washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. 2 Cl 2 The residue was purified by flash chromatography on a silica gel column as eluent to provide 4-((3-bromo-1H-pyrazol-1-yl)methyl)tetrahydro-2H-thiopyran 1,1-dioxide (50.3 mg, 89%) as a white solid. LCMS (ESI) m / z 293.0, [M+H] + .

[0968] Step 2: N-(5-(1-((1,1-dioxoanionyltetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0969]

[0970] 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 eq.) 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 eq.) in a mixed solvent of 1,4-dioxane / water (5:1, 2.4 mL) was added XPhos Pd G 3 (11.5 mg; 0.014 mmol; 0.10 eq.), XPhos (6.5 mg; 0.014 mmol; 0.10 eq.), and K 3 PO 4 (86.5 mg; 0.408 mmol; 2.97 eq.). The resulting mixture was stirred at 90° C. under a nitrogen atmosphere for 2 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using 20-50% MeCN / water (10 mmol / L NH 4 HCO 3 ) The crude product was further purified by flash chromatography on a pre-packed C18 column to give N-(5-(1-((1,1-dioxanionyltetrahydro-2H-thiopyran-4-yl)methyl)-1H-pyrazol-3-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (7.2 mg, 11%) as a white solid. LCMS (ESI) m / z 455.2, [M+H] + . 1 HNMR (400 MHz, DMSO-d 6 )δ10.93(s,1H),9.35(s,1H),9.17(s,1H),8.21(s,1H),7.98-7.95(m,1H),7.79(d,J=2.0Hz,1H),6.47(d,J=2.0Hz,1H),4.09(d,J=7.2Hz,2 H),3.21-3.02(m,4H),3.00(d,J=4.4Hz,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).

[0971] Example 154: Synthesis of N-(8-(methylamino)-5-(1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0972]

[0973] Step 1: 2-((3-Bromo-1H-pyrazol-1-yl)methyl)pyridine

[0974]

[0975] 3-Bromo-1H-pyrazole (500 mg; 3.40 mmol; 1.00 eq.), 2-(bromomethyl)pyridine hydrobromide (1.29 g; 5.10 mmol; 1.50 eq.) and Cs 2 CO 3 A mixture of (3.33 g; 10.2 mmol; 3.00 eq.) in DMF (10.0 mL) was stirred at room temperature under nitrogen atmosphere for 3 hours. 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 purified by anhydrous Na 2 SO 4 The residue was purified by flash chromatography on a silica gel column using 30-60% EtOAc / petroleum ether as eluent to provide 2-((3-bromo-1H-pyrazol-1-yl)methyl)pyridine (600 mg, 73%) as a yellow crude oil. LCMS (ESI) m / z 238.0, [M+H] + .

[0976] Step 2: N-(8-(Methylamino)-5-(1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0977]

[0978] To a stirred mixture of 2-((3-bromo-1H-pyrazol-1-yl)methyl)pyridine (25.9 mg; 0.109 mmol; 1.00 eq.), N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40.0 mg; 0.109 mmol; 1.00 eq.) in 1,4-dioxane / water (5:1, 3 mL) was added XPhos Pd G 3(9.19 mg; 0.011 mmol; 0.10 eq.), XPhos (5.18 mg; 0.011 mmol; 0.10 eq.), and K 3 PO 4 (69.2 mg; 0.327 mmol; 3.00 eq.). The mixture was stirred at 90°C for 1 hour. The desired product was observed by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column with (0-20%) as eluent to provide a yellow crude solid (20.0 mg). The product was purified by reverse phase preparative HPLC (Prep-C18, 5 μM Bridge Prep Phenyl OBD column, 19×150 mm, waters; gradient elution of MeCN / water (23-28%) over an 8 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to further purify the crude product to provide N-(8-(methylamino)-5-(1-(pyridin-2-ylmethyl)-1H-pyrazol-3-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (4.6 mg, 11%) as a white solid. LCMS (ESI) m / z 400.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.91(s,1H),9.35(s,1H),8.93(s,1H),8.56-8.54(m,1H),8.20(s,1H),7.99-7.97(m,1H),7.96(d,J=2.0Hz,1H),7.80-7.75(m,1H) ,7.34-7.30(m,1H),7.27-7.24(m,1H),6.56(d,J=2.0Hz,1H),5.49(s,2H),3.00(d,J=4.4Hz,3H),2.07-2.01(m,1H),0.87-0.78(m,4H).

[0979] Example 155: Synthesis of N-(8-((2-hydroxyethyl)amino)-5-phenyl-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0980]

[0981] Step 1: 2-Bromo-[1,2,4]triazolo[1,5-a]pyridine

[0982]

[0983] To a mixture of tert-butyl nitrite (340 mg; 3.297 mmol; 1.47 eq.) in MeCN (12 mL) was added CuBr (480 mg; 3.346 mmol; 1.50 eq.). The reaction mixture was stirred at 60 ° C for 10 minutes. To the mixture was added a solution of [1,2,4] triazolo[1,5-a]pyridine-2-amine (300 mg; 2.236 mmol; 1.00 eq.) in MeCN (5 mL) and stirred at 60 ° C for 1 hour. The desired product was observed by LCMS. The reactant was filtered and washed with MeCN (3x10 mL). The filtrate was collected and concentrated in vacuo to give 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (300 mg, crude) as a brown solid. The crude product was used in the next step without further purification. LCMS (ESI) m / z 198.0, [M+H] + .

[0984] Step 2: N-(5-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0985]

[0986] XPhos Pd G 3 (92mg; 0.109mmol; 0.20eq.), K 3 PO 4 To a mixture of 1,4-dioxane / water (350 mg; 1.649 mmol; 3.04 eq.) and XPhos (52 mg; 0.109 mmol; 0.20 eq.) was added N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (200 mg; 0.543 mmol; 1 eq.) and 2-bromo-[1,2,4]triazolo[1,5-a]pyridine (107 mg; 0.540 mmol; 0.99 eq.). The reaction was stirred at 60 °C for 2 hours. The desired product was observed by LCMS. The reaction was concentrated in vacuo. The reaction was carried out by using 5-10% MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column as eluent to give a crude product. The product was purified by reverse phase preparative HPLC (Prep-C18, 5 μM XBridge Prep Phenyl OBD column, 19×150 mm, waters; gradient elution of 20-25% MeCN / water over an 8 minute period, wherein both water and MeCN contained 10 mmol / L NH 4 HCO 3 , flow rate: 60 mL / min, detector UV wavelength: 254 nm) to purify the crude product to provide N-(5-([1,2,4]triazolo[1,5-a]pyridin-2-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (12.5 mg, 6.4%) as an off-white solid. LCMS (ESI) m / z 360.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.94(s,1H),9.51(s,1H),9.41(s,1H),8.97-8.93(m,1H),8.81(s,1H),8.32-8.27(m,1H),7.88-7.84( m,1H),7.71-7.66(m,1H),7.21-7.17(m,1H),3.06(d,J=4.4Hz,3H),2.12-2.04(m,1H),0.91-0.79(m,4H).

[0987] Example 156: Synthesis of N-(5-(2-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0988]

[0989] Step 1: 2,7-Dibromo-[1,2,4]triazolo[1,5-a]pyridine

[0990]

[0991] To a solution of CuBr (504 mg; 3.51 mmol; 1.50 eq.) in MeCN (8.0 mL) was added t-BuONO (364 mg; 3.53 mmol; 1.50 eq.) with stirring. The mixture was stirred at room temperature under a nitrogen atmosphere for 10 minutes. To the reaction mixture was added 7-bromo-[1,2,4]triazolo[1,5-a]pyridine-2-amine (500 mg; 2.35 mmol; 1.00 eq.) in MeCN (1 mL) in portions at room temperature. The reactants were stirred at 80 ° C for 4 hours. The desired product can be detected by LCMS. The resulting mixture was diluted with EtOAc (200 mL), washed with brine (3×10 mL), and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to provide 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (194 mg, crude) as a green solid. LCMS (ESI) m / z 275.9, [M+H] + .

[0992] Step 2: N-(5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0993]

[0994] To a mixture of N-(8-(methylamino)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (194 mg; 0.527 mmol; 1.00 eq.) in a mixed solvent of 1.4-dioxane / water (5:1, 6 mL) were added 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (146 mg; 0.527 mmol; 1.00 eq.), Pd(DtBPF)Cl 2 (34.3 mg; 0.053 mmol; 0.10 eq.) and K 3 PO 4 (223 mg; 1.05 mmol; 2.00 eq.). The reaction mixture was stirred at room temperature under nitrogen atmosphere for 1 hour. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The reaction mixture was purified by using MeOH / CH 2 Cl 2 The residue was purified by flash chromatography on a silica gel column using (0-20%) as eluent to afford a yellow solid (118 mg, 51%). The product was then purified by using 30-60% MeCN / water (10 mmol / L NH 4 HCO 3) as eluent to provide N-(5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (1.4 mg) as a white solid. LCMS (ESI) m / z 438.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ11.02(s,1H),9.42(s,1H),9.06-9.02(m,1H),8.39(s,1H),8.23-8.18(m,1H),8.12(s,1H),7. 86-7.84(m,1H),7.36-7.33(m,1H),3.04(d,J=4.4Hz,3H),2.06-1.98(m,1H),0.82-0.76(m,4H).

[0995] Step 3: N-(5-(2-(azetidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide

[0996]

[0997] To a mixture of N-(5-(2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (40.0 mg; 0.091 mmol; 1.00 eq.) in 1,4-dioxane (2.5 mL) were added Pd(DtBPF)Cl2 (6 mg; 0.009 mmol; 0.10 eq.), Cs 2 CO 3 (59.5 mg; 0.183 mmol; 2.00 eq.) and azetidine (21 mg, 0.36 mmol, 4 eq.). The reaction 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 reaction mixture was purified by using MeOH / CH 2 Cl 2The residue was purified by flash chromatography on a silica gel column with (0-20%) as eluent to give an off-white crude solid. The residue was dissolved in DMSO (3 mL). The precipitated solid was collected by filtration and washed with water (3 × 5 mL) to provide N-(5-(2-(azetidine-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-8-(methylamino)-2,7-naphthyridin-3-yl)cyclopropanecarboxamide (13.0 mg, 34%) as an off-white solid. LCMS (ESI) m / z 415.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 )δ10.99(s,1H),9.40(s,1H),8.74-8.70(m,1H),8.36(s,1H),8.14-8.09(m,1H),8.05(s,1H),7.46-7.44(m,1H),7. 01-6.98(m,1H),4.08-4.00(m,4H),3.02...

Claims

1. A compound of formula (I): and pharmaceutically acceptable salts thereof, in: X is CH or N; Y is CH2, S or NH; L is a single bond, double bond, 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 is alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, methyl, CD3 or H; R 2 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro, cyano, or a 5- or 6-membered substituted or unsubstituted aryl, or a monocyclic or bicyclic heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S and N, wherein the substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, 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, hydroxyl, -COOH (and esters), sulfonyl, alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3-6-membered cycloalkyl or heterocycloalkyl, 3-6-membered aryl or heteroaryl, any of which may have one or more substituents; R 3 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro, cyano, aminoalkyl, aminocycloalkyl, aminoheterocycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-phenyl, -NH2, -NH-CH-CF3, 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; R 4 Selected from the group consisting of H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, and alkylhydroxy.

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

3. The compound according to claim 1, wherein R1 is methyl or ethyl. The compound according to claim 1 , wherein L is a single bond.

5. The compound according to claim 1, wherein X is CH. The compound according to claim 1 , wherein X is N.

7. The compound according to claim 1, wherein R 3 yes: wherein R4 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro or cyano.

8. The compound according to claim 1, wherein R 3 yes:

9. The compound according to claim 1, wherein R 2 yes: Where L 2 is substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or a bond connecting said groups; A or B is independently a 5- or 6-membered substituted or unsubstituted aryl or heteroaryl ring, the heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S and N, wherein the substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro, cyano, -CH2-cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxyl, -COOH (and esters), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3-6-membered cycloalkyl or heterocycloalkyl, 3-6-membered aryl or heteroaryl, any of which may have one or more substituents.

10. The compound according to claim 1, wherein R 2 It is phenyl.

11. The compound according to claim 1, wherein R 2 yes: wherein each X is independently N or CH; R 5 is selected from the group consisting of: H, halogen, hydroxy, -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.

12. The compound according to claim 1, wherein R 2 yes: wherein Z is O or S, and each X is independently N or CH; R5 is selected from the group consisting of H, halogen, hydroxy, -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 bicyclic heteroalkyl, substituted or unsubstituted bridged bicyclic heteroalkyl, substituted or unsubstituted spirobicyclic heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; And n is 0, 1, 2 or 3.

13. The compound according to claim 1, wherein R 2 yes: wherein each X is independently N or CH; R5 is selected from the group consisting of H, halogen, hydroxy, -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 bicyclic heteroalkyl, substituted or unsubstituted bridged bicyclic heteroalkyl, substituted or unsubstituted spirobicyclic heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; And n is 0, 1, 2 or 3.

14. The compound according to claim 1, wherein LR 2 yes: wherein each X is independently N or CH; Z is independently O or NR 6 ; R 5 and R 5 ` is independently H, halogen, hydroxy, -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.

15. The compound according to claim 1, wherein LR 2 yes: Where Z is N or O, Each X is independently N or CH; R5 and R5' are independently H, halogen, hydroxy, -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 spiro bicycloheteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 0, 1, 2 or 3.

16. The compound according to claim 1, wherein LR 2 yes: wherein R5 is selected from the group consisting of H, halogen, hydroxy, -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.

17. The compound according to claim 1, wherein the compound is selected from the group consisting of:

18. The compound according to claim 1, wherein the compound is selected from the group consisting of:

19. A method of treating a patient suffering from a neurological disorder, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of formula (I): and pharmaceutically acceptable salts thereof, in: X is CH or N; Y is CH2, S or NH; L is a single bond, double bond, 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 is alkyl, cycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, methyl, CD3 or H; R 2 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro, cyano, or a 5- or 6-membered substituted or unsubstituted aryl, or a monocyclic or bicyclic heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S and N, wherein the substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, 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, hydroxyl, -COOH (and esters), sulfonyl, alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3-6-membered cycloalkyl or heterocycloalkyl, 3-6-membered aryl or heteroaryl, any of which may have one or more substituents; R 3 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro, cyano, aminoalkyl, aminocycloalkyl, aminoheterocycloalkyl, -NH-aryl, -NH-heteroaryl, -NH-phenyl, -NH2, -NH-CH-CF3, 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; R 4 Selected from the group consisting of H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, nitro, cyano, and alkylhydroxy.

20. The compound of claim 1, wherein Y is NH.

21. The method of claim 19, wherein Y is NH.

22. The method of claim 19, wherein R1 is methyl.

23. The method of claim 19, wherein L is a single bond.

24. The method of claim 19, wherein X is CH.

25. The method of claim 19, wherein X is N.

26. The method of claim 19, wherein R 3 yes: wherein R4 is H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, cycloalkyl, spirocycloalkyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro or cyano.

27. The method of claim 19, wherein R 3 yes:

28. The method of claim 19, wherein R 2 yes: Where L 2 is substituted or unsubstituted alkyl, heteroalkyl, alkoxy, heteroalkoxy, cycloalkyl, heterocycloalkyl, haloalkyl, halocycloalkyl, aryl, heteroaryl, or a bond connecting said groups; A or B is independently a 5- or 6-membered substituted or unsubstituted aryl or heteroaryl ring, the heteroaryl ring optionally containing one or more heteroatoms independently selected from O, S and N, wherein the substitution on the 5- or 6-membered aryl or heteroaryl ring is: H, halogen, alkyl, branched alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyloxy, haloalkoxy, nitro, cyano, -CH2-cycloalkyl, -CF2-cycloalkyl, -CH(CH3)-cycloalkyl, -CH2-aryl, -CF2-aryl, -CH(-CH3)-aryl, C(=O)-alkyl, -C(=O)cycloalkyl, -C(=O)-NH-alkyl, -C(=O)NH2, hydroxyl, -COOH (and esters), alkylsulfonyl, arylsulfonyl, sulfonamide, amino, 3-6-membered cycloalkyl or heterocycloalkyl, 3-6-membered aryl or heteroaryl, any of which may have one or more substituents.

29. The method of claim 19, wherein R 2 It is phenyl.

30. The method of claim 19, wherein R 2 yes: wherein each X is independently N or CH; R 5 is selected from the group consisting of: H, halogen, hydroxy, -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)nOR 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.

31. The method of claim 19, wherein R 2 yes: wherein Z is O or S, and each X is independently N or CH; R5 is selected from the group consisting of H, halogen, hydroxy, -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)nOR 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 bicyclic heteroalkyl, substituted or unsubstituted bridged bicyclic heteroalkyl, substituted or unsubstituted spirobicyclic heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; And n is 0, 1, 2 or 3.

32. The method of claim 19, wherein R 2 yes: wherein each X is independently N or CH; R5 is selected from the group consisting of H, halogen, hydroxy, -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)nOR 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 bicyclic heteroalkyl, substituted or unsubstituted bridged bicyclic heteroalkyl, substituted or unsubstituted spirobicyclic heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; And n is 0, 1, 2 or 3.

33. The method of claim 19, wherein LR 2 yes: wherein each X is independently N or CH; Z is independently O or NR 6 ; R 5 and R 5 ` is independently H, halogen, hydroxy, -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.

34. The method of claim 19, wherein LR 2 yes: Where Z is N or O, Each X is independently N or CH; R5 and R5' are independently H, halogen, hydroxy, -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 spiro bicycloheteroalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and n is 0, 1, 2 or 3.

35. The method of claim 19, wherein LR 2 yes: wherein R5 is selected from the group consisting of H, halogen, hydroxy, -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.

36. The method of claim 19, wherein the compound is any one of the compounds of any one of claims 17 or 18.

37. A pharmaceutical composition comprising a therapeutically effective compound according to claim 1.

38. The pharmaceutical composition of claim 37, wherein the composition further comprises at least one additional excipient.

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