Wnk1 inhibitors

Abstract

The present invention relates to novel compounds of formula (I), to pharmaceutical compositions comprising such compounds and to their use in the treatment, alleviation or prevention of a disease or disorder associated with WNK1 activity. (I)

Description

Technical Field

[0001] This invention relates to novel compounds, pharmaceutical compositions comprising such compounds, and their use for treating, alleviating, or preventing diseases and conditions associated with WNK1 activity. The invention also relates to methods for treating, alleviating, and / or preventing diseases and conditions associated with WNK1 activity. Background Technology

[0002] WNK1 (WNK lysine-deficient protein kinase 1) belongs to the atypical serine-threonine kinase subfamily, characterized by the lack of conserved catalytic lysine (WNK1-4) in kinase subdomain II.

[0003] WNK1 is known to play a crucial role in ion transport through WNK1-mediated phosphorylation and activation of OSR1 (oxidative stress response kinase 1) and STK39 / SPAK (STE20 / SPS1-associated proline-alanine-rich protein kinase) kinases. Following WNK1 activation, OSR1 and STK39 / SPAK catalyze the phosphorylation of ion cotransporters in the SLC12 cation-coupled chloride cotransporter family, thereby activating Na+. + / K + Coupled Cl - Introporters SLC12A1 (NKCC1), SLC12A2 (NKCC2), and SLC12A3 (NCC)11-17 simultaneously inhibit K + Coupled Cl - Outward transporters SLC12A4-SLC12A7 (KCC1-KCC4).

[0004] WNK1 is known to participate in a variety of physiological processes, including ion transport (as mentioned above), cell volume regulation, sodium reabsorption, potassium secretion, hyperosmolar stress response, autophagy, and blood pressure regulation. Furthermore, elevated WNK1 activity is associated with a variety of diseases and conditions, including hypertension and cancers such as breast cancer, colon cancer, and pancreatic ductal adenocarcinoma, as well as hematological malignancies including leukemia and multiple myeloma.

[0005] WNK1 and hypertension

[0006] Hypertension is a long-term medical condition characterized by persistently elevated arterial blood pressure. It is a risk factor for a variety of disabling and often fatal diseases, including stroke, myocardial infarction, arrhythmia, congestive heart failure, kidney failure, and retinopathy.

[0007] The role of WNK1 in hereditary hypertension has been well elucidated. Mutations leading to WNK1 overexpression are associated with multiple hypertension types, including familial hyperkalemic hypertension (FHHt) and pseudohypoaldosteronism type II (PHAII). FHHt is characterized by increased renal salt reabsorption and potassium... + and H + Hereditary hypertension characterized by impaired excretion. PHAII is an autosomal dominant disorder presenting with hypertension, hyperkalemia, and renal tubular acidosis.

[0008] WNK1 and Cancer

[0009] WNK1-4 kinases are known to be dysregulated in a variety of cancers, and this dysregulation has been shown to promote tumor growth, metastasis and angiogenesis through complex mechanisms, including phosphorylation of the kinase substrate SPS1-associated proline / alanine-rich kinase (STK39 / SPAK) and oxidative stress response kinase 1 (OSR1).

[0010] WNK1 is specifically associated with various cancers, including breast cancer, colon cancer, and blood cancers such as leukemia and multiple myeloma.

[0011] US2008 / 0286809A1 discloses that hyperosmolar stress can increase the autophosphorylation rate of endogenously expressed WNK1 by approximately 5-fold in renal epithelial cells and breast and colon cancer cell lines.

[0012] WO2021 / 028438A1 discloses that inhibiting WNK1 is toxic to cells derived from leukemia and myeloma, and also discloses that conditional knockdown of WNK1 can prolong the lifespan of mice with acute myeloid leukemia (AML).

[0013] WNK1 inhibition

[0014] Given the role of WNK1 in various diseases as described above, inhibition of WNK1 is a promising target for the treatment of such diseases and conditions.

[0015] Current focus on developing WNK1-4 kinase inhibitors has resulted in several WNK1 inhibitors (Ishigami-Yuasa et al., 2017; Yamada et al., 2017; Yamada et al., 2016a; Yamada et al., 2016b). However, novel and highly effective WNK1 inhibitors are still needed to achieve efficient regulation of WNK1. Invention Overview

[0017] This invention relates to a series of compounds that are WNK1 inhibitors.

[0018] These compounds constitute a new group of potential drugs that can be used to treat or improve diseases and conditions associated with WNK1 dysregulation, including hypertension and cancers such as breast cancer, pancreatic cancer, colon cancer, and blood cancers such as leukemia and multiple myeloma.

[0019] In one key aspect, the present invention relates to compounds of formula (I):

[0020] Formula (I)

[0021] in: Y is C(H) or N; W is C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A is selected from H and C. 1-3 Alkoxy groups, CF3 groups, and groups of formula (II):

[0022] Equation (II)

[0023] in: X is C(H) or N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from the following groups: optionally substituents R, either the same or different. 7 Replacement C 1-6 Alkyl, wherein the C 1-6One or more methylene groups of the alkyl group may optionally be independently substituted with -O- or C=O; or may optionally be substituted with one or more identical or different substituents R. 7 Replacement C 3-6 cycloalkyl groups; and tetrahydropyranyl groups; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; R 7 Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl group; N(CH3)2; N(H)2; ;and ; Or, when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-; or R 5 With R 6 Connect them to form a loop, and R 5 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) substitution; and R 6 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) Replace; Two of the R 8 They can be arbitrarily connected together to form a ring with the middle atoms; R 8 Independently selected from: C that is optionally replaced by OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or, when two R 8 When connected to form a loop, the two R's 8 Independently selected from: C groups optionally substituted with one or two substituents selected from F, OH and NH21-3 Alkyl, and the C 1-3 One or both methylene groups of the alkyl diene may be independently replaced by -O-, -N(H)-, or -N(CH3)-; and R 9 For H, C 1-3 Alkyl, oxetane, or , Or its pharmaceutically acceptable salt. The prerequisite is that the compound is not N-[(2,3,5-trimethyl-1H-indol-7-yl)methyl]-2-quinoxaline.

[0024] In a second aspect, the present invention relates to compositions comprising compounds as defined herein.

[0025] In a third aspect, the present invention relates to methods for treating, alleviating, or preventing diseases and conditions associated with WNK1 activity, including administering the compounds described herein to a subject in need. Invention Details

[0027] definition

[0028] The term 'WNK1' as used in this article refers to 'WNK lysine-deficient protein kinase 1'. Other names for WNK1 include 'lysine-free (K) kinase 1'.

[0029] As used herein, the term 'WNK1 inhibitor' refers to a chemical compound that binds to WNK1 kinase and also has the ability to reduce, slow down, stop, or inhibit WNK1 kinase activity. The binding interaction itself and the binding activity can be confirmed by any conventional binding affinity assay method known to those skilled in the art, such as those described in the working examples.

[0030] Term 'C 1-6 alkyl', 'C 1-4 Alkyl' and 'C' 1-3 Alkyl refers to straight-chain or branched alkyl groups having 1-3, 1-4, or 1-5 carbon atoms, including but not limited to methyl, ethyl, prop-1-yl, prop-2-yl, isopropyl, tert-butyl, but-1-yl, but-2-yl, pent-1-yl, pent-2-yl, pent-3-yl, 2-methylbut-1-yl, 3-methylbut-1-yl), hex-1-yl, or 2,3-dimethylbut-1-yl.

[0031] Term 'C 3-6 Cycloalkyl refers to a group having 3-6 carbon atoms, including monocyclic or bicyclic carbon rings, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0032] Term 'C 1-3'Alkyl group' refers to a straight-chain or branched carbon atom bonded to an oxygen atom. 1-3 Alkyl group. C 1-3 Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy.

[0033] The term 'two of which are R' x Optional connections together with the middle atom form a ring, referring to two R atoms. x Substituents, together with the atoms in between, form optional substituted 3-6 membered (hetero)rings.

[0034] The term 'intervening atom(s)' refers to two R... x The atoms between the substituents. The intermediate atoms can be carbon, nitrogen, or oxygen.

[0035] Term 'C 1-5 alkanediyl', 'C 1-3 alkyl dienes and 'C 1-2 An alkyldiyl group refers to a straight-chain or branched alkyldiyl group having 1-2, 1-3, or 1-5 carbon atoms. Alkyl groups are derived from a parent alkane by removing two hydrogen atoms from a single carbon atom. Typical alkyldiyl groups include, but are not limited to, methanyl, ethylenediyl, propanediyl, butanediyl, or pentanediyl.

[0036] The terms “C=O” and “C(O)” both refer to the carbonyl group.

[0037] The term "treatment" refers to combating a disease or condition. As used herein, "treatment" includes any desired effect on the symptoms or pathology of the disease or condition described herein, and may include even minor changes or improvements in one or more measurable markers of the treated disease or condition. "Treatment" does not necessarily mean the complete eradication or cure of the disease or condition and its associated symptoms. In some implementations, the term "treatment" encompasses both improvement and prevention.

[0038] The term "alleviating" refers to reducing the severity of symptoms of a disease or condition. Any action taken to improve a patient's condition, or to attempt to correct or at least make unbearable conditions related to the patient's condition more acceptable, is considered "alleviating" treatment.

[0039] The term "prevention" refers to taking preventive action, in particular, to eliminate, mitigate, avoid, prevent, stop, or hinder something from happening.

[0040] compound

[0041] The scope of this invention includes providing compounds for treating, alleviating, and / or preventing diseases and conditions characterized by WNK1 dysregulation. The compounds of this invention comprise compounds capable of inhibiting WNK1, thereby reducing WNK1 activity or normalizing WNK1 activity.

[0042] On the one hand, the present invention provides a compound of formula (I):

[0043] Formula (I)

[0044] in

[0045] Y is C(H) or N; W is either C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A is selected from H and C. 1-3 Alkoxy groups, CF3 groups, and groups of formula (II):

[0046] Equation (II)

[0047] in

[0048] X is C(H) or N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from the following groups: optionally substituents R, either the same or different. 7 Replacement C 1-6 Alkyl, wherein the C 1-6 One or more methylene groups of the alkyl group may optionally be independently substituted with -O- or C=O; or may optionally be substituted with one or more identical or different substituents R. 7 Replacement C 3-6 cycloalkyl groups; and tetrahydropyranyl groups; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; R 7 Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl group; N(CH3)2; N(H)2; ;and ; Or when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-; or R 5 With R 6 Connect them to form a loop and R 5 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) substitution; and R 6 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) Replace; Two of the R 8 They can be arbitrarily connected together to form a ring with the middle atoms; R 8 Each is independently selected from C that is arbitrarily replaced by OH. 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R's 8 Independently selected from: C groups optionally substituted with one or two substituents selected from F, OH and NH2 1-3 Alkyl, and the C 1-3 One or both methylene groups of the alkyl diene may be independently substituted by -O-, -N(H)-, or -N(CH3)-; and R 9For H, C 1-3 Alkyl, oxetane, or , Or its pharmaceutically acceptable salt.

[0049] In one embodiment, the compound of the present invention is of formula (Ia): .

[0050] Formula (Ia)

[0051] In one embodiment, the compound of the present invention is of formula (Ib): .

[0052] Formula (Ib)

[0053] In one embodiment, the compound of the present invention is of formula (Ic): .

[0054] Formula (Ic)

[0055] In one embodiment, the compound of the present invention is of formula (Id): .

[0056] Formula (Id)

[0057] In one implementation, Y is C(H). In another implementation, Y is N.

[0058] In one implementation, W is C(H)2. In another implementation, W is C(D)2.

[0059] In one implementation, R 1 For H.

[0060] In one implementation, R 1 C 1-3 Alkyl group. In one embodiment, R 1 It is methyl. In one embodiment, R 1 It is isopropyl. In one embodiment, R 1 It is cyclopropyl.

[0061] In one implementation, R 2 For H.

[0062] In one implementation, R 2 C 1-3 Alkyl group. In one embodiment, R 2 It is a methyl group.

[0063] In one implementation, R2 C replaced by OH 1-3 Alkyl group. In one embodiment, R 2 It is CH2OH.

[0064] In one implementation, R 2 C 3-5 Cycloalkyl. In one embodiment, R 2 It is cyclopropyl.

[0065] In one implementation, R 3 For H.

[0066] In one implementation, R 3 C 1-3 Alkyl group. In one embodiment, R 3 It is methyl. In one embodiment, R 3 C replaced by OH 1-3 Alkyl group. In one embodiment, R 3 It is CH2OH.

[0067] In one implementation, R 3 For OC 1-3 Alkyl group. In one embodiment, R 3 It is a methoxy group.

[0068] In one implementation, R 3 -OC replaced by one or more F 1-3 Alkyl group. In one embodiment, R 3 It is -OCHF2.

[0069] In one implementation, R 3 It is -C(O)NHCH3.

[0070] In one implementation, R 3 For -NH2. In one implementation, R 3 It is -N(H)(CH3). In one implementation, R 3 It is -N(CH3)2.

[0071] In one implementation, R 3 It is a halogen. In one embodiment, R 3 It is Cl.

[0072] In one implementation, R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H. In one implementation, R 1 It is CH3, and R 2 For H. In one implementation, R 1 For H, R2 Let H be the number of 'R', and R be the number of 'R'. 3 For H. In one implementation, R 1 For H, R 2 It is CH3, and R 3 For H. In one implementation, R 1 For H, R 2 It is cyclopropyl, and R 3 For H. In one implementation, R 1 For H, R 2 It is CH2OH, and R 3 For H. In one implementation, R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 For H.

[0073] In one implementation, R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 The compound is NH2. In one embodiment, the compound is of formula (Id), and R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is NH2.

[0074] In one implementation, R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 The compound is N(CH3)2. In one embodiment, the compound is of formula (Ic), and R... 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is N(CH3)2.

[0075] In one implementation, R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 For Cl. In one embodiment, the compound is a compound of formula (Ic), and R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is Cl.

[0076] In one implementation, R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 The form is CH2OH. In one embodiment, the compound is of formula (Ic), and R... 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is CH2OH.

[0077] In one implementation, R 1 It is isopropyl, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 The compound is OCH3. In one embodiment, the compound is of formula (Ic), and R... 1 It is isopropyl, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is OCH3.

[0078] In one implementation, R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 The compound is OCH3. In one embodiment, the compound is of formula (Ic), and R... 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is OCH3.

[0079] In one implementation, R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 The compound is OCH3. In one embodiment, the compound is of formula (Ic), and R... 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is OCH3.

[0080] In one implementation, R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 The compound is C(O)NHCH3. In one embodiment, the compound is of formula (Ic), and R... 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is C(O)NHCH3.

[0081] In one implementation, R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 The compound is CHF2. In one embodiment, the compound is of formula (Ic), and R... 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is CHF2.

[0082] In one implementation, R 4 For H.

[0083] In one implementation, R 4 C 1-4 Alkyl group. In one embodiment, R 4 It is methyl. In one embodiment, R4 C 3-5 Cycloalkyl.

[0084] In one implementation, A is Equation (II):

[0085] Equation (II)

[0086] in: X is N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from the following groups: optionally surrounded by one or more identical or different R groups 7 C substituent 1-6 Alkyl, wherein the C 1-6 One or more methylene groups of the alkyl group are optionally and independently replaced by -O- or C=O; optionally replaced by one or more identical or different R groups. 7 C substituent 3-6 cycloalkyl groups; and tetrahydropyranyl groups; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; and R 7 Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl group; N(CH3)2; N(H)2; ;as well as ; Or when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-.

[0087] In one implementation, R 6 For H.

[0088] In one implementation, R 6 C 1-4 Alkyl group. In one embodiment, R 6 It is CH3.

[0089] In one implementation, R 5 For being one or more identical or different R 7 C substituent 1-6Alkyl group. In one embodiment, R 5 For being one or more identical or different R 7 A C1 alkyl group substituted with a substituent. In one embodiment, R 5 For being one or more identical or different R 7 A C2-alkyl group substituted with a substituent. In one embodiment, R 5 For being one or more identical or different R 7 A C3 alkyl group substituted with a substituent. In yet another embodiment, R... 5 For being one or more identical or different R 7 Substituents: C5 alkyl groups, such as neopentanediol.

[0090] In one implementation, R 5 For optional use by one or more identical or different R 7 C substituent 3-6 Cycloalkyl. In one embodiment, R 5 For being one or more identical or different R 7 A C3 cycloalkyl group substituted with a substituent. In one embodiment, R 5 For being one or more identical or different R 7 Substituent-substituted C4 cycloalkyl group. In one embodiment, R 5 For being one or more identical or different R 7 Substituent-substituted C6 cycloalkyl group.

[0091] In one implementation, R 5 It is a C6 cycloalkyl group.

[0092] In one implementation, R 5 It is a tetrahydropyranyl group.

[0093] In one implementation, A is... .

[0094] In one implementation, R 7 For OH. In one embodiment, R 7 For N(H)2. In one implementation, R 7 It is N(CH3)2.

[0095] In one implementation, R 7 C 1-3 Alkyl group. In one embodiment, R 7 It is OCH3.

[0096] In one implementation, R 7 C replaced by one or more F1-3 Alkyl group. In one embodiment, R 7 It is OCHF2.

[0097] In one implementation, R 7 C 1-3 Alkyl group. In one embodiment, R 7 It is CH3.

[0098] In one implementation, R 7 C replaced by OH 1-3 Alkyl group. In one embodiment, R 7 It is CH2OH.

[0099] In one implementation, R 7 for In another implementation, R 7 for .

[0100] In one embodiment, A is selected from the following groups: , , , , , and .

[0101] In one embodiment, A is selected from the following groups: , , , , , , , , , , , and .

[0102] In one implementation scheme, two R 7 Connected to form a loop, and the two Rs 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-.

[0103] In one implementation scheme, two R 7 Connected to form a loop, and the two Rs 7Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl group.

[0104] In one implementation scheme, two R 7 Connected to form a loop, and the two Rs 7 Selected independently from C 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-.

[0105] In one embodiment, A is selected from the following groups: , as well as .

[0106] In some implementation schemes, R 5 and R 6 Connect them to form a loop, and

[0107] R 5 It is a bond or optionally a single or multiple identical or different substituents R 8 Replacement C 1-5 Alkyl, and the C 1-5 One of the methylene groups in the alkyl diene is optionally prefixed with -O- or N(R) 9 Substitution; and

[0108] R 6 It is a bond or optionally a single or multiple identical or different substituents R 8 Replacement C 1-5 Alkyl, and the C 1-5 One of the methylene groups in the alkyl diene is optionally prefixed with -O- or N(R) 9 ) Replace; Two of the R 8 They can be arbitrarily connected together to form a ring with the middle atoms; R 8 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R's 8 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)-, or -N(CH3)-; and R 9 For H, C1-3 Alkyl, oxetyl, or .

[0109] In some implementation schemes, R 8 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; -F; -N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R 8 Independently selected from C14 groups that are substituted by one or two substituents selected from F and OH. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0110] In some implementation schemes, R 8 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; -F; -N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl.

[0111] In some implementations, two R 8 Connected to form a loop, and the two Rs 8 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0112] In one aspect, the present invention relates to compounds of formula (I):

[0113] Formula (I)

[0114] in: Y is C(H) or N; W is either C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A is piperidinyl, pyrrolidinyl, azacyclic butyl, piperazinyl, or morpholinyl. The piperidinyl, pyrrolidinyl, or aziridine group is optionally selected by one or more independently chosen R groups. 18 Replacement, of which two R 18 They can be arbitrarily connected together to form a ring with the middle atoms; The piperazine group thereon is optionally R 14 replace; The morpholino group is optionally replaced by one or more identical or different substituents R. 19 replace; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl, Or when two R 18 When connected to form a loop, the two R 18 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-; R 14 C 1-3 Alkyl, oxetane, or ;and R 19 Selected independently from C 1-3 Alkyl groups and C groups substituted with OH 1-3 alkyl.

[0115] In one implementation, A is R, which is arbitrarily selected by one or more independent choices. 18 Substituted piperidinyl groups, where both R groups are R groups 18 They can be arbitrarily connected together to form a ring with the middle atoms; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 18 When connected to form a loop, the two R 18 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0116] In one embodiment, the piperidinyl group is linked to formula (I) at the 1-position of the piperidinyl group.

[0117] In one implementation, A is arbitrarily assigned to an R. 18 Substituted piperidinyl, R 18 Selected from: C arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl.

[0118] In one implementation, A is arbitrarily selected by two Rs. 18 Substituted piperidinyl, R 18 Selected from: C arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 Alkyl group. In one embodiment, A is optionally selected by one or more independent R groups. 18 Substituted pyrroleyl groups, wherein two Rs 18 They can be arbitrarily connected together to form a ring with the middle atoms; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 18 When connected to form a loop, the two R 18 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0119] In one embodiment, the pyrrolidinium is linked to formula (I) at the 1-position of the pyrrolidinium.

[0120] In one implementation, A is R, which is arbitrarily selected by one or more independent choices. 18 Substituted nitrogen-containing heterocyclic butyl groups, wherein two R groups are substituted. 18They can be arbitrarily connected together to form a ring with the middle atoms; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 18 When connected to form a loop, the two R 18 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be independently replaced by -O-, -N(H)- or -N(CH3)-.

[0121] In one embodiment, the aziridine is attached to formula (I) at the 1-position of the aziridine.

[0122] In one embodiment, A is a piperazine group, which is optionally R at the 4-position of the piperazine group. 14 Replace, where R 14 C 1-3 Alkyl, oxetane, or In one embodiment, the piperazine group is linked to formula (I) at the 1-position of the piperazine group.

[0123] In one embodiment, A is a morpholino group, which is optionally replaced by one or more identical or different substituents R. 19 Replace, where R 19 Independently selected from C 1-3 Alkyl groups and C groups substituted with OH 1-3 Alkyl group. In one embodiment, the morpholino group is attached to formula (I) at the 4-position of the morpholino group.

[0124] In one implementation, R 18 For R 8 .

[0125] In one implementation, R 8 C 1-3 Alkyl group. In one embodiment, R 8 It is -CH3.

[0126] In one implementation, R 8 C replaced by OH 1-3 Alkyl group. In one embodiment, R 8 For -CH2OH. In one embodiment, R 8 For -OH. In one embodiment, R 8 For N(H)2. In one implementation, R 8-OC replaced by one or more F 1-3 Alkyl group. In one embodiment, R 8 It is -OCHF2.

[0127] In one implementation, R 19 For R 9 In one implementation, R 9 For H. In one implementation, R 9 C 1-3 Alkyl group. In one embodiment, R 9 For -CH3. In one implementation, R 9 It is an oxetane-butane. In one embodiment, R... 9 for .

[0128] In one aspect, the present invention relates to compounds of formula (I):

[0129] Formula (I)

[0130] in: Y is C(H) or N; W is C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A has equation (III):

[0131] Equation (III)

[0132] in: X 1 It is N or C(H); X 2 For C(R) 10 (R) 11 (or does not exist;) R 10 For H or C 1-3 alkyl; R 11 For H or C 1-3 alkyl; X 3 For C(R) 12 (R) 13 ), O or N (R 14 ); R 12 The C can be H, OH, NH2, or optionally substituted with OH. 1-3 Alkyl; and R 13 H or C substituted with OH (optionally) 1-3 Alkyl; or R 12 With R 13 They connect together with the middle atoms to form a ring, and R 12 -R 13 C 3-5 Alkyl group, wherein one or both methylene groups of the alkyl group are optionally surrounded by O, C(H)(NH2) or N(R) 17 ) Replace; R 17 For H or C 1-3 alkyl; R 14 For H, C 1-3 Alkyl, oxetane, or ; X 4 For C(R) 15 (R) 16 (or does not exist;) R 15 H; OH; C arbitrarily substituted with OH 1-3 Alkyl; or OC optionally substituted with one or more F. 1-3 Alkyl; and R 16 For H.

[0133] In one implementation, A has equation (III):

[0134] Equation (III)

[0135] in: X 1 It is N or C(H); X 2 For C(R) 10 (R) 11 (or does not exist;) R10 For H or C 1-3 alkyl; R 11 For H or C 1-3 alkyl; X 3 For C(R) 12 (R) 13 ), O or N (R 14 ); R 12 The C can be H, OH, NH2, or optionally substituted with OH. 1-3 Alkyl; and R 13 H or C substituted with OH (optionally) 1-3 Alkyl; or R 12 With R 13 They connect together with the middle atoms to form a ring, and R 12 -R 13 C 3-5 Alkyl group, wherein one or both methylene groups of the alkyl group are optionally surrounded by O, C(H)(NH2) or N(R) 17 ) Replace; R 17 For H or C 1-3 alkyl; R 14 For H, C 1-3 Alkyl, oxetane, or ; X 4 For C(R) 15 (R) 16 (or does not exist;) R 15 H; OH; C arbitrarily substituted with OH 1-3 Alkyl; or OC optionally substituted with one or more F. 1-3 Alkyl; and R 16 For H.

[0136] In one implementation, X 1 Let N, X 2 For C(R) 10 (R) 11 ), X 3 For C(R) 12 (R) 13 ), and X 4 For C(R) 15 (R) 16 ).

[0137] In one implementation, X 1 Let N, X 2 Does not exist, X3 For C(R) 12 (R) 13 ), and X 4 For C(R) 15 (R) 16 ).

[0138] In one implementation, X 1 Let N, X 2 Does not exist, X 3 For C(R) 12 (R) 13 ), and X 4 It does not exist.

[0139] In one implementation, X 1 Let N, X 2 For C(R) 10 (R) 11 ), X 3 It is O, and X 4 For C(R) 15 (R) 16 ).

[0140] In one implementation, X 1 Let N, X 2 For C(R) 10 (R) 11 ), X 3 For N(R) 14 ), and X 4 For C(R) 15 (R) 16 ).

[0141] In one implementation, X 1 Let N be the number of elements in the array.

[0142] In one implementation, X 1 It is C(H).

[0143] In one implementation, X 2 It does not exist.

[0144] In one implementation, X 2 For C(R) 10 (R) 11 ).

[0145] In one implementation, R 10 For H.

[0146] In one implementation, R 10 C 1-3 Alkyl group. In one embodiment, R 10 It is CH3.

[0147] In one implementation, R 11 For H.

[0148] In one implementation, R 11 C 1-3 Alkyl group. In one embodiment, R 11 It is CH3.

[0149] In one implementation, X 2 For C(H)2. In one implementation, X 2 It is C(H)(CH3). In one implementation, X 2 It is C(CH3)2.

[0150] In one implementation, X 3 For O. In one implementation, X 3 For N(R) 14 ).

[0151] In one implementation, R 14 For H.

[0152] In one implementation, R 14 C 1-3 Alkyl. In another embodiment, R 14 It is CH3.

[0153] In one implementation, R 14 It is an oxetane-butane. In one embodiment, R... 14 for In one implementation, R 14 for .

[0154] In one implementation, X 3 For N(H). In one implementation, X 3 For N(CH3). In one implementation, X 3 For C(R) 12 (R) 13 ).

[0155] In one implementation, R 12 For H. In one implementation, R 12 For OH. In one embodiment, R 12 For NH2. In one implementation, R 12 C 1-3 Alkyl group. In one embodiment, R 12 C replaced by OH 1-3 Alkyl group. In one embodiment, R 12 It is CH2OH.

[0156] In one implementation, R 13 For H. In one implementation, R 13 C 1-3 Alkyl group. In one embodiment, R 13 C replaced by OH 1-3 Alkyl group. In one embodiment, R 13 It is CH2OH.

[0157] In one implementation, X 3 For C(H)2. In one implementation, X 3 For C(H)(OH). In one embodiment, X 3 For C(H)(CH2OH). In one embodiment, X 3 It is C(CH2OH)2.

[0158] In one implementation, X 4 It does not exist. In one implementation, X 4 For C(R) 15 (R) 16 ).

[0159] In one implementation, R 15 For H. In one implementation, R 15 For OH. In one embodiment, R 15 C 1-3 Alkyl group. In one embodiment, R 15 For CH3. In one implementation, R 15 C replaced by OH 1-3 Alkyl group. In one embodiment, R 15 For CH2OH. In one embodiment, R 15 OC replaced by one or more F 1-3 Alkyl group. In one embodiment, R 15 It is OCHF2.

[0160] In one implementation, R 16 For H.

[0161] In one implementation, X 4 For C(H)2. In one implementation, X 4 It is C(H)(CH3). In one implementation, X 4 For C(H)(OH). In one embodiment, X 4 For C(H)(CH2OH). In one embodiment, X 4 It is C(H)(OCHF2).

[0162] In one embodiment, A is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0163] In one implementation, X 3 For C(R) 12 (R) 13 ), and R 12 With R 13 They connect together with the middle atoms to form a ring, where R 12 -R 13 C 3-5 Alkyl group, wherein one or both methylene groups of the alkyl group are optionally surrounded by O, C(H)(NH2) or N(R) 17 (replace)

[0164] In one implementation, R 17 For H.

[0165] In one implementation, R 17 C 1-3 Alkyl group. In one embodiment, R 17 It is CH3.

[0166] In one implementation, R 12 -R 13 It is -CH2-N(CH3)-CH2-. In one implementation, R 12 -R 13It is -CH2-N(H)-CH2-. In one embodiment, R 12 -R 13 For -CH2-O-CH2-. In one implementation, R 12 -R 13 It is -CH2-C(H)(NH2)-CH2-. In one embodiment, R 12 -R 13 It is -(CH2)3-O-. In one implementation, R 12 -R 13 It is -(CH2)2-O-(CH2)2-. In one embodiment, R 12 -R 13 It is -(CH2)-O-(CH2)3-. In one embodiment, R 12 -R 13 It is -(CH2)2-N(H)-(CH2)2-. In one embodiment, R 12 -R 13 It is -O-(CH2)2-O-(CH2)-.

[0167] In one embodiment, A is selected from the following groups: , , , , , , , , , , , and .

[0168] In one implementation, A is H. In another implementation, A is C. 1-3 Alkyl group. In one embodiment, A is OCH3. In one embodiment, A is CF3. In one embodiment, A is C 1-3 Alkyl group. In one embodiment, A is CH3. In one embodiment, A is CH2CH3. In one embodiment, A is C. 1-4 Alkyl group. In one embodiment, A is tert-butyl. In one embodiment, A is C... 3-5 Cycloalkyl. In one embodiment, A is cyclopropyl.

[0169] In one implementation, Y is N; W is C(H)2; R 1 It is H, CH3 or isopropyl; R 2 For H, CH3, cyclopropyl or CH2OH; R3 For H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is H, CF3 or formula (II):

[0170] Equation (II).

[0171] In one implementation, Y is N; W is C(H)2; R 1 It is H, CH3 or isopropyl; R 2 For H, CH3, cyclopropyl or CH2OH; R 3 For H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is H, CF3, , , , , , , , , , , , , , , , , , , , , , or .

[0172] In one embodiment, A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

[0173] In one embodiment, A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is formed by two or more R groups. 18 Replacement, of which two R 18The atoms connected together form a ring with the middle atom, and the two connected atoms forming the ring are R. 18 Independently selected from C 1-3 An alkyl diene, optionally substituted with one or two substituents selected from F, OH, and NH2, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0174] In one embodiment, A is a morpholino group, wherein the morpholino group is optionally replaced by one or more identical or different R groups. 19 Replace, where R 19 It is -CH3 or -CH2OH.

[0175] In one implementation, Y is N; W is C(H)2; R 1 It is H, CH3 or isopropyl; R 2 For H, CH3, cyclopropyl or CH2OH; R 3 For H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 The R is H or CH3; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

[0176] In one implementation, Y is N; W is C(H)2; R 1 It is H, CH3 or isopropyl; R 2 For H, CH3, cyclopropyl or CH2OH; R 3 For H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 The atom is H or CH3; and A is piperidinyl, pyrrolidinyl, azacyclic butyl, or piperazine, wherein the piperidinyl, pyrrolidinyl, azacyclic butyl, or piperazine is surrounded by two or more R atoms. 18 Replacement, of which two R 18 The atoms connected together form a ring with the middle atom, and the two connected atoms forming the ring are R. 18 Independently selected from C 1-3 An alkyl diene, optionally substituted with one or two substituents selected from F, OH, and NH2, and the C 1-3One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0177] In one implementation, Y is N; W is C(H)2; R 1 It is H, CH3 or isopropyl; R 2 For H, CH3, cyclopropyl or CH2OH; R 3 For H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is morpholino, wherein the morpholino group is optionally surrounded by one or more identical or different R groups. 19 Replace, where R 19 It is -CH3 or -CH2OH.

[0178] In one implementation, Y is N; W is C(H)2; R 1 It is H, CH3 or isopropyl; R 2 For H, CH3, cyclopropyl or CH2OH; R 3 For H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 The R is H or CH3; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

[0179] In one implementation, Y is N; W is C(H)2; R 1 It is H, CH3 or isopropyl; R 2 For H, CH3, cyclopropyl or CH2OH; R 3 For H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 The atom is H or CH3; and A is piperidinyl, pyrrolidinyl, azacyclic butyl, or piperazine, wherein the piperidinyl, pyrrolidinyl, azacyclic butyl, or piperazine is surrounded by two or more R atoms. 18 Replacement, of which two R 18 They connect together with the middle atoms to form a ring, and the two Rs that connect to form the ring... 18 Independently selected from C 1-3An alkyl diene, optionally substituted with one or two substituents selected from F, OH, and NH2, wherein the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0180] In one implementation, Y is N; W is C(H)2; R 1 It is H, CH3 or isopropyl; R 2 For H, CH3, cyclopropyl or CH2OH; R 3 For H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is morpholino, wherein the morpholino group is optionally surrounded by one or more identical or different R groups. 19 Replace, where R 19 It is -CH3 or -CH2OH.

[0181] In one implementation, Y is N; W is C(H)2; R 1 CH3; R 2 For H; R 3 For H, CH3, OCHF2, or OCH3; R 4 H is present; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

[0182] In one implementation, Y is N; W is C(H)2; R 1 CH3; R 2 For H; R 3 For H, CH3, OCHF2, or OCH3; R 4 H is present; and A is piperidinyl, pyrrolidinyl, azacyclic butyl, or piperazine, wherein the piperidinyl, pyrrolidinyl, azacyclic butyl, or piperazine is surrounded by two or more R groups. 18 Replacement, of which two R 18 They connect together with the middle atoms to form a ring, and the two Rs that connect to form the ring... 18 Independently selected from C 1-3 An alkyl diene, optionally substituted with one or two substituents selected from F, OH, and NH2, wherein the C 1-3One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0183] In one implementation, Y is N; W is C(H)2; R 1 CH3; R 2 For H; R 3 For H, CH3, OCHF2, or OCH3; R 4 H is present; and A is a morpholino group, wherein the morpholino group is optionally replaced by one or more identical or different substituents R. 19 Replace, where R 19 It is -CH3 or -CH2OH.

[0184] In one embodiment, the compound is of formula (Ia); Y is N; W is C(H)2; R 1 CH3; R 2 For H; R 3 It is H, CH3, OCHF2 or OCH3; and R 4 For H.

[0185] In one embodiment, the compound is of formula (Ib); Y is N; W is C(H)2; R 1 CH3; R 2 For H; R 3 It is H, CH3, OCHF2 or OCH3; and R 4 For H.

[0186] In one embodiment, the compound is of formula (Ic); Y is N; W is C(H)2; R 1 CH3; R 2 For H; R 3 It is H, CH3, OCHF2 or OCH3; and R 4 For H.

[0187] In one embodiment, the compound is of formula (Id); Y is N; W is C(H)2; R 1 CH3; R 2 For H; R 3 It is H, CH3, OCHF2 or OCH3; and R 4 For H.

[0188] In one embodiment, the compounds of the present invention are selected from: 7-Cyclopropyl-N-(1H-indol-6-ylmethyl)quinoxaline-2-amine, N-[(7-methyl-1H-indol-5-yl)methyl]quinoxaline-2-amine, N-(1H-indol-6-ylmethyl)-7-(piperidin-1-yl)quinoxaline-2-amine N-(1H-indol-5-ylmethyl)quinoxaline-2-amine 1-(3-{[(6-amino-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N-(1H-indol-4-ylmethyl)-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine, 1-[3-({[7-(hydroxymethyl)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 1-(3-{[1H-indol-4-yl(²H2)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N-(1H-indol-6-ylmethyl)-6-(piperidin-4-yl)pyrido[2,3-b]pyrazin-3-amine [6-({[6-(piperidin-1-yl)pyridino[2,3-b]pyrazin-3-yl]amino}methyl)-1H-indol-2-yl]methanol, N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]-6-(pyrrolidone-1-yl)pyrido[2,3-b]pyrazin-3-amine 6-N-cyclohexyl-3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazine-3,6-diamine, 1-[3-({[7-(dimethylamino)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-[(3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, N,3-Dimethyl-4-{[(6-{methyl[(1s,3s)-3-hydroxycyclobutyl]amino}pyrido[2,3-b]pyrazin-3-yl)amino]methyl}-1H-indole-7-carboxamide 1-[3-({[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(7-chloro-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, [(3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-yl]methanol, (3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, cis-(1s,3s)-3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyridino[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, N-[(1H-indol-6-yl)methyl]-6-{2-oxa-6-azaspiro[3.3]heptane-6-yl}pyrido[2,3-b]pyrazin-3-amine, 6-{2,6-diazaspiro[3.3]heptane-2-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 3-(hydroxymethyl)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, [(3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-yl]methanol, N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine cis-(1R,3R)-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclobutane-1-ol, [4-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-yl]methanol, 3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-N-[trans-4-aminocyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine, 7-tert-butyl-N-(1H-indol-6-ylmethyl)quinoxaline-2-amine N-[(1H-indol-6-yl)methyl]-6-(piperidin-1-yl)pyrido[2,3-b]pyrazin-3-amine [4-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-yl]methanol, N-(1H-indol-6-ylmethyl)-6-[4-(oxetane-3-yl)piperazin-1-yl]pyrido[2,3-b]pyrazin-3-amine 7-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}-7-azaspiro[3.5]nonane-2-amine, 1-{3-[({1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, 3-N-(1H-indol-6-ylmethyl)-6-N-(oxacyclohexane-4-yl)pyrido[2,3-b]pyrazine-3,6-diamine, [(2R)-4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, N-[(1H-indol-6-yl)methyl]-6-(pyrrolidone-1-yl)pyrido[2,3-b]pyrazin-3-amine 7-Ethyl-N-[(1H-indol-6-yl)methyl]quinoxaline-2-amine, N-(1H-indol-6-ylmethyl)-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine, 1-(3-{[(3-hydroxy-4-methoxyphenyl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 6-{2,7-diazaspiro[3.5]nonane-7-yl}-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, N-[(1H-indol-6-yl)methyl]-7-methylquinoxaloline-2-amine, 3-N-(1H-indol-6-ylmethyl)-6-N-{2-oxaspiro[3.3]heptane-6-yl}pyrido[2,3-b]pyrazine-3,6-diamine, N-[(2-methyl-1H-indol-5-yl)methyl]quinoxaline-2-amine, 6-{2,6-diazaspiro[3,4]octane-6-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N3-[(1H-indol-6-yl)methyl]-N6-[trans-4-(difluoromethoxy)cyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine N-(1H-indol-6-ylmethyl)-6-(morpholin-4-yl)pyrido[2,3-b]pyrazin-3-amine, (3R)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-3-ol, N-[(1H-indol-6-yl)methyl]-6-{2-oxa-6-azaspiro[3.4]octane-6-yl}pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-{1-oxa-9-azaspiro[5.5]undecane-9-yl}pyrido[2,3-b]pyrazin-3-amine, [(2R)-4-[3-({[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]morpholin-2-yl]methanol, 6-N-cyclohexyl-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, 1-(3-{[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3R,4R)-3-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, [(2R)-4-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}morpholin-2-yl]methanol, N-(1H-indol-6-ylmethyl)-6-{3-oxa-9-azaspiro[5.5]undecane-9-yl}pyrido[2,3-b]pyrazin-3-amine, trans-4-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclohexane-1-ol, 1-(3-{[(2-cyclopropyl-1H-indol-5-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N6-[2-(dimethylamino)ethyl]-N3-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazine-3,6-diamine, 6-{2,7-diazaspiro[3.5]nonane-7-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propane-1,2-diol, [(3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-yl]methanol, 1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-yl)methanol, trans-4-[methyl(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclohexane-1-ol, N-[(1H-indol-6-yl)methyl]quinoxaline-2-amine, 1-(3-{[(7-methoxy-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-ol, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N3-[(1H-indol-6-yl)methyl]-N6-(3-methoxypropyl)pyrido[2,3-b]pyrazine-3,6-diamine trans-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}(methyl)amino)cyclobutane-1-ol, N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-(piperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, cis-3-[(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, (3S,4S)-3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(2-methyl-1H-indol-5-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N3-[(1H-indol-6-yl)methyl]-N6-[trans-4-aminocyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]-2,2-dimethylpropane-1-ol, 6-N-{6,6-difluorospiro[3.3]heptane-2-yl}-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, 6-{4-[(1-aminocyclopropyl)carbonyl]piperazin-1-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 6-[cis-2,6-dimethylmorpholin-4-yl]-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, [(3S)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}pyrrolidine-3-yl]methanol, [4-(hydroxymethyl)-1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-yl]methanol, cis-3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)(methyl)amino]cyclobutane-1-ol, 4-[({6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyrido[2,3-b]pyrazin-3-yl}amino)methyl]-N,3-dimethyl-1H-indole-7-carboxamide, N-[(1H-indol-6-yl)methyl]-6-methylquinoxaloline-2-amine, 1-{3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propyl}azacycloheptane-2-one, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-ol, [4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, N-(1H-indol-6-ylmethyl)-6-(4-methylpiperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, trans-3-[methyl(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, (3S,4S)-3-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, 6-(azacyclobutan-1-yl)-N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, 1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3R,4R)-3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 6-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]spiro[3,3]heptane-2-ol, 3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-N-[trans-4-(dimethylamino)cyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine, (3S)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, trans-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclobutane-1-ol, (3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, [4-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, (3S)-1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)azacyclobutane-3-ol, 4-({[6-(4-hydroxypiperidin-1-yl)pyrido[2,3-b]pyrazin-3-yl]amino}methyl)-N,3-dimethyl-1H-indole-7-carboxamide, 6-{1,4-dioxa-9-azaspiro[5.5]undecane-9-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-{1-oxa-8-azaspiro[4.5]decane-8-yl}pyrido[2,3-b]pyrazin-3-amine, 6-[cis-2,6-dimethylmorpholin-4-yl]-N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, 6-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]spiro[3,3]heptane-2-ol, (3S,4S)-4-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-3-ol, N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-(4-methylpiperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine N-[(1H-indol-6-yl)methyl]-7-methoxyquinoxaline-2-amine, trans-4-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)(methyl)amino]cyclohexane-1-ol, 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propane-1-ol, 6-N-[4-(dimethylamino)cyclohexyl]-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, [1-(hydroxymethyl)-4-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclohexyl]methanol, 1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}azacyclobutane-3-amine, [(2R)-4-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, [4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)-6,6-dimethylmorpholin-2-yl]methanol, N3-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-N6-({2-oxabicyclo[2.2.2]octane-3-yl}methyl)pyrido[2,3-b]pyrazine-3,6-diamine, N-[(1H-indol-6-yl)methyl]-7-(trifluoromethyl)quinoxaline-2-amine, 6-{2,7-diazaspiro[3.5]nonane-2-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-5-ylmethyl)-6-(morpholin-4-yl)pyrido[2,3-b]pyrazin-3-amine, and 6-{3,9-diazaspiro[5.5]undecane-3-yl}-N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine.

[0189] In one aspect, the present invention relates to compounds selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,as well as .

[0190] In one embodiment, the compound is not N-[(2,3,5-trimethyl-1H-indol-7-yl)methyl]-2-quinoxaline.

[0191] In one implementation, the compound is not .

[0192] The compounds of this invention also include tautomeric forms. Tautomeric forms arise from the exchange of single bonds with adjacent double bonds and the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are isomeric protonated states having the same empirical formula and total charge. Exemplary proton transfer tautomers include keto-enol pairs, amide-imine pairs, lactam-lactamimide pairs, enamine-imide pairs, and cyclic forms, wherein a proton can occupy two or more positions in a heterocyclic system, such as 1H-imidazolium and 3H-imidazolium, 1H-1,2,4-triazole, 2H-1,2,4-triazole and 4H-1,2,4-triazole, 1H-isoindole and 2H-isoindole, and 1H-pyrazole and 2H-pyrazole. Tautomeric forms can be in equilibrium or spatially locked into one form by appropriate substitution. Tautomers can also include methyl transfer tautomers, which result from the exchange of single bonds with adjacent double bonds and the accompanying migration of methyl groups.

[0193] All compounds described herein and their pharmaceutically acceptable salts may exist with other substances such as water or solvents (e.g., in the form of hydrates and solvates).

[0194] In one aspect, the present invention relates to an intermediate compound or a pharmaceutically acceptable salt thereof, which can be used to synthesize the compounds of the present invention. For example, in some embodiments, the intermediate compound is one of the intermediate compounds disclosed in Example 1 herein or a pharmaceutically acceptable salt thereof. In some embodiments, the compounds of the present invention are selected from any intermediate compound disclosed in Example 1 herein or a pharmaceutically acceptable salt thereof.

[0195] The compounds of this invention may contain, for example, one or more asymmetric carbon atoms, and therefore may exist in stereoisomer, enantiomer, and diastereomer forms. Therefore, unless specifically indicated by stereochemistry, the scope of this invention should be understood to cover all possible stereoisomers of the compounds shown, including the pure stereoisomeric forms and mixtures of stereoisomers of any chemical structure disclosed herein. If the stereochemistry of a structure or part thereof is not indicated by, for example, a thick or dashed line, then that structure or part thereof should be interpreted as covering all its stereoisomers. If the stereochemistry of a structure or part thereof is indicated by, for example, a thick or dashed line, then that structure or part thereof should be interpreted as covering only the indicated stereoisomer.

[0196] As used herein, the term "stereoisomer" or "stereoisopure" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of the compound. For example, a stereoisopure compound having one chiral center will be substantially free of its mirror-image enantiomers, while a stereoisopure compound having two chiral centers will be substantially free of its other enantiomers and diastereomers. Typical stereoisopure compounds include more than about 80% by weight of one stereoisomer of the compound and equal to or less than about 20% by weight of other stereoisomers of the compound; more than about 90% by weight of one stereoisomer of the compound and equal to or less than about 10% by weight of other stereoisomers of the compound; more than about 95% by weight of one stereoisomer of the compound and equal to or less than about 5% by weight of other stereoisomers of the compound; or more than about 97% by weight of one stereoisomer of the compound and equal to or less than about 3% by weight of other stereoisomers of the compound.

[0197] In some implementations, the compound defined herein is in its stereoisomeric pure form.

[0198] The mixture of stereoisomers can be separated using standard techniques, such as using chiral columns or chiral resolving agents, as outlined in the Examples section.

[0199] Preparation of compounds

[0200] The compounds described in this invention can be prepared according to any conventional chemical synthesis method known to those skilled in the art, such as the method described in the working examples. The starting materials for the processes described in this application are known compounds, or can be readily obtained by those skilled in the art from commercially available chemicals using conventional methods.

[0201] The reaction end products described in this article can be separated using conventional techniques, such as extraction, crystallization, distillation, and chromatography.

[0202] The compounds of this invention can exist in a non-solventized form or as a solvate formed with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Generally, for the purposes of this invention, the solvated and non-solventized forms are considered equivalent.

[0203] Pharmaceutically acceptable salts

[0204] The chemical compounds of the present invention can be provided in any form suitable for intended administration, including pharmaceutically (i.e., physiologically) acceptable salts. Examples of pharmaceutically acceptable addition salts include, but are not limited to, non-toxic inorganic and organic acid addition salts such as hydrochlorides, hydrobromic acids, nitrates, perchlorates, phosphates, sulfates, formates, acetates, aconitates, ascorbic acid salts, benzenesulfonates, benzoates, cinnamates, citrates, embonates, heptanoates, fumarates, glutamates, glycolates, lactates, maleates, malonates, mandelates, methanesulfonates, naphthalene-2-sulfonates, phthalates, salicylates, sorbates, stearates, succinates, tartrates, p-toluenesulfonates, etc. Such salts can be prepared by methods known and described in the art. Other acids, such as oxalic acid, may not be considered pharmaceutically acceptable acids but can be used to prepare salts that can serve as intermediates in obtaining the chemical compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0205] Examples of pharmaceutically acceptable cationic salts of compounds of formula (I) of the present invention include, but are not limited to, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, choline, lysine, and ammonium salts of compounds of formula (I) of the present invention containing anionic groups. Such cationic salts can be formed by methods known and described in the art. In the context of the present invention, containing… N The "onium salt" of the compound is also considered a pharmaceutically acceptable salt. Preferred "onium salts" include alkylonium salts, cycloalkylonium salts, and cycloalkylalkylonium salts.

[0206] Labeled compounds

[0207] The compounds of this invention can be used in their labeled or unlabeled form. In the context of this invention, a labeled compound refers to a compound in which one or more atoms are replaced by atoms whose atomic mass or mass number differs from that of atoms normally found in nature. This labeling facilitates the quantitative detection of the compound.

[0208] The labeled compounds of this invention can be used as diagnostic tools, radiotracers, or monitors in various diagnostic methods and can be used for in vivo receptor imaging. The labeled isomers of this invention preferably contain at least one radionuclide as a label. Positron-emitting radionuclides are all suitable candidates. In the context of this invention, the radionuclide is preferably selected from… 2 H (deuterium) 3 H (tritium) 13 C 14 C 131 I, 125 I, 123 I and 18 F.

[0209] The physical methods for detecting the labeled isomers of the present invention may be selected from positron emission tomography (PET), single-photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI), and computed axial X-ray tomography (CAT), or combinations thereof.

[0210] Pharmaceutical Composition

[0211] The present invention also relates to a pharmaceutical composition comprising, for example, a pharmaceutically effective amount of a compound of formula (I) as defined above as an active ingredient. In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, excipient, or diluent.

[0212] Although the compound of formula (I) of the present invention for therapeutic use can be administered directly in the form of the original chemical compound, it is preferred to introduce the active ingredient (optionally in the form of a physiologically acceptable salt) into the pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents and / or other conventional pharmaceutical excipients.

[0213] In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a chemical compound of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, and optionally other therapeutic and / or preventative ingredients known and used in the art. The carrier shall be "acceptable" in the sense that it is compatible with other components in the formulation and harmless to its recipient.

[0214] Therapeutic effective dose refers to the amount of active ingredient that improves symptoms or condition. Therapeutic efficacy and toxicity, such as in erectile dysfunction (ED). 50 The therapeutic effect can be determined in cell cultures or laboratory animals using standard pharmacological procedures. The dose ratio between therapeutic and toxic effects is the therapeutic index, which can be expressed as the ratio between the plasma level producing a therapeutic effect and the plasma ratio producing a toxic effect. Pharmaceutical compositions exhibiting a large therapeutic index are preferred.

[0215] The dosage can be adjusted based on the individual's age, weight and condition, as well as the route of administration, dosage form and regimen, and the desired outcome, and the precise dosage can be determined by a licensed physician.

[0216] The actual dosage depends on the nature and severity of the disease being treated and is determined at the physician's discretion. It may be modified by dose titration according to the specific circumstances of the invention to produce the desired therapeutic effect. Currently, pharmaceutical compositions containing approximately 0.1 to approximately 10,000 mg of the active ingredient per single dose are considered suitable for therapeutic treatment. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof administered to the subject ranges from 0.001 to 100 mg / kg.

[0217] In one embodiment, the compound of formula (I) is administered in combination with one or more other therapeutically active ingredients. In one embodiment, the other therapeutically active ingredients are known for treating hypertension or cancer.

[0218] WNK1 inhibition

[0219] A series of compounds of formula (I) bind to WNK1. Based on this binding interaction, these compounds are able to modulate WNK1.

[0220] WNK463 (N-(tert-butyl-1-(1-(5-(5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl)pyridin-2-yl)piperidin-4-yl)-1H-imidazol-5-carboxamide) is known as an inhibitor of WNK1 catalytic activity (Yamada et al., 2016). As shown in Example 2, the compounds of the present invention compete with WNK463 for the same site of WNK1 kinase. Therefore, the compounds of the present invention are inhibitors of WNK1 catalytic activity.

[0221] In one embodiment, the compound of formula (I) is a WNK lysine-deficient protein kinase 1 (WNK1) inhibitor.

[0222] To further test whether the compound is a WNK1 inhibitor, its ability to inhibit the in vitro phosphorylation of myelin basic protein (MBP) by purified recombinant human WNK1 can be tested, as described by Yamada et al. (2016a). Additionally, as described in Yamada et al. (2016a), its ability to inhibit the in vitro phosphorylation of the natural substrate OSR1 by the purified recombinant WNK1 kinase domain, and its ability to inhibit the phosphorylation of endogenously and exogenously expressed OSR1 in HEK293 cells after sorbitol-induced osmotic stress can also be tested.

[0223] In one aspect, the present invention relates to a method for inhibiting WNK1, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0224] WNK1-4 suppression

[0225] A series of compounds of formula (I) (including compounds of formula (Ia) or (Ib)) bind to WNK1-4. Based on this binding interaction, these compounds are able to modulate WNK1-4.

[0226] In one embodiment, the compound of formula (I) is a WNK lysine-deficient protein kinase 1-4 (WNK1-4) inhibitor.

[0227] In one aspect, the present invention relates to a method for inhibiting WNK1-4, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0228] In one implementation, the compound of formula (I) is a WNK lysine-deficient protein kinase 2 (WNK2) inhibitor.

[0229] In one aspect, the present invention relates to a method for inhibiting WNK2, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0230] In one embodiment, the compound of formula (I) is a WNK lysine-deficient protein kinase 3 (WNK3) inhibitor.

[0231] In one aspect, the present invention relates to a method for inhibiting WNK3, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0232] In one embodiment, the compound of formula (I) is a WNK lysine-deficient protein kinase 4 (WNK4) inhibitor.

[0233] In one aspect, the present invention relates to a method for inhibiting WNK4, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0234] treat

[0235] As ligands of WNK1, compounds of formula (I) can be used to treat, prevent, and / or alleviate symptoms in organisms, including humans. The term "treatment" as used herein also includes the prevention and / or alleviation of diseases and symptoms. In one aspect, compounds of formula (I) described herein are used in medicine.

[0236] In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, for use as a medicine.

[0237] In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment, relief or prevention of diseases and conditions associated with WNK1 activity.

[0238] In one aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment, relief or prevention of diseases and conditions associated with WNK1-4 (such as WNK1, WNK2, WNK3 and / or WNK4) activity.

[0239] In one aspect, the present invention relates to a method for treating, alleviating, or preventing diseases and conditions associated with WNK1 activity, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need.

[0240] In another aspect, the present invention relates to a method for treating, alleviating or preventing diseases and conditions associated with WNK1-4 (such as WNK1, WNK2, WNK3 and / or WNK4) activity, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need.

[0241] In one aspect, the present invention relates to the use of compounds of formula (I), pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating, alleviating, or preventing diseases and conditions associated with WNK1 activity.

[0242] In one aspect, the present invention relates to the use of compounds of formula (I), pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof in the preparation of medicaments for treating, alleviating, or preventing diseases and conditions associated with WNK1-4 (such as WNK1, WNK2, WNK3, and / or WNK4) activity.

[0243] Treatment of hypertension

[0244] WNK1 inhibitors have been shown to be effective in treating or preventing a variety of diseases and conditions associated with increased WNK1 activity, including hypertension. As ligands of WNK1, compounds of formula (I) can be used to treat, prevent, and / or alleviate different types of hypertension in organisms, including humans, including familial hyperkalemic hypertension (FHHt) and pseudohypoaldosteronism type II (PHAII).

[0245] In one aspect, the present invention relates to the use of compounds of formula (I) described herein for the treatment, relief and / or prevention of hypertension.

[0246] In one aspect, the present invention relates to the use of compounds of formula (I) described herein for the treatment, relief and / or prevention of hereditary hypertension.

[0247] In one aspect, the present invention relates to a method for treating and / or preventing hypertension, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0248] Preferably, the subject is a mammal, such as a human. In some embodiments, the subject suffers from hypertension.

[0249] In some implementations, the subjects have, are suspected of having, or are at risk of developing hypertension. In some implementations, the subjects are human subjects who have, are suspected of having, or are at risk of developing hypertension.

[0250] In one aspect, the present invention relates to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the treatment of hypertension.

[0251] In one aspect, the present invention relates to a method for treating hypertension, comprising administering to a subject in need a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0252] In one aspect, the present invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating hypertension.

[0253] Cancer treatment

[0254] WNK1 inhibitors have been shown to be effective in treating or preventing a variety of diseases and conditions associated with increased WNK1 activity, including cancer. As ligands for WNK1, compounds of formula (I) can be used to treat, prevent, and / or alleviate different types of cancer, including breast cancer, colon cancer, pancreatic cancer (such as pancreatic ductal adenocarcinoma), and blood cancers such as leukemia (including acute myeloid leukemia), lymphoma, and myeloma (including multiple myeloma).

[0255] In one aspect, the present invention relates to the use of compounds of formula (I) described herein for the treatment, relief, and / or prevention of cancer.

[0256] In one aspect, the present invention relates to a method for treating and / or preventing cancer, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need.

[0257] Preferably, the subject is a mammal, such as a human. In some embodiments, the subject has cancer.

[0258] In one aspect, the present invention relates to compounds of formula (I), pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, for the treatment of cancer.

[0259] In one aspect, the present invention relates to a method of treating cancer, comprising administering to a subject in need a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0260] In one aspect, the present invention relates to the use of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer.

[0261] In one implementation, the cancer is selected from: adenoid cystic carcinoma, anal cancer, appendix cancer and PMP, cholangiocarcinoma, bladder cancer, hematologic malignancies, primary bone cancer, secondary bone cancer, colorectal cancer, brain tumors, breast cancer, uterine cancer, cancer of unknown primary, cervical cancer, connective tissue cancer, endocrine cancer, gallbladder (bile duct) cancer, head, neck and laryngeal cancer, Kaposi's sarcoma, kidney cancer, leukemia, primary liver cancer, secondary liver cancer, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, neuroendocrine tumors (NETs), uveal melanoma, ovarian cancer, pancreatic cancer, penile cancer, peritoneal cancer, prostate cancer, skin cancer, small intestine cancer, soft tissue sarcoma, stomach and esophageal cancer. Oesophageal cancers, testicular cancer, thymic cancer, thyroid cancer, upper tract urothelial cancer, vaginal cancer, and vulvar cancer.

[0262] In one embodiment, the cancer is selected from: acute myeloid leukemia (LAML), adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), brain lower grade glioma (LGG), breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), chronic myeloid leukemia (LCML), colon adenocarcinoma (COAD), esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), and head and neck squamous cell carcinoma. Renal carcinoma (HNSC), Kidney Chromophobe (KICH), Kidney renal clear cell carcinoma (KIRC), Kidney renal papillary cell carcinoma (KIRP), Liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), Lung squamous cell carcinoma (LUSC), Lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), Mesothelioma (MESO), Ovarianserous cystadenocarcinoma (OV), Pancreatic adenocarcinoma (PAAD), Pheochromocytoma and Paraganglioma;PCPG, prostate adenocarcinoma (PRAD), rectal adenocarcinoma (READ), sarcoma (SARC), skin cutaneous melanoma (SKCM), gastric adenocarcinoma (STAD), testicular germ cell tumor (TGCT), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), uterine corpus endometrial carcinoma (UCEC), and uveal melanoma (UVM).

[0263] In one embodiment, the cancer is selected from: leukemia (including acute myeloid leukemia), lymphoma, and myeloma (including multiple myeloma).

[0264] project

[0265] 1. Compound of formula (I):

[0266] Formula (I)

[0267] in: Y is C(H) or N; W is either C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A is selected from: H, C 1-3alkoxy groups, CF3 groups, and groups of formula (II):

[0268] Equation (II)

[0269] in: X is C(H) or N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from: optionally substituents R (one or more identical or different substituents) 7 Replacement C 1-6 Alkyl, wherein the C 1-6 One or more methylene groups of the alkyl group are optionally and independently substituted with -O- or C=O; optionally substituted with one or more identical or different substituents R. 7 Replacement C 3-6 cycloalkyl groups; and tetrahydropyranyl groups; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; R 7 Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl group; N(CH3)2; N(H)2; ;and ; Or when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-; or R 5 With R 6 Connect them to form a loop, and R 5 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) substitution; and R 6 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 (replace) Two of the R 8 They can be arbitrarily connected together to form a ring with the middle atoms; R 8 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R 8 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)-, or -N(CH3)-; and R 9 For H, C 1-3 Alkyl, oxetane, or , Or its pharmaceutically acceptable salt.

[0270] 2. Compound of formula (I):

[0271] Formula (I)

[0272] in: Y is C(H) or N; W is C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A is selected from H and C. 1-3 Alkoxy groups, CF3 groups, and groups of formula (II):

[0273] Equation (II)

[0274] in: X is C(H) or N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from the following groups: optionally substituents R, either the same or different. 7 Replacement C 1-6 Alkyl, wherein the C 1-6 One or more methylene groups of the alkyl group are optionally and independently substituted with -O- or C=O; optionally substituted with one or more identical or different substituents R. 7 Replacement C 3-6 cycloalkyl groups; and tetrahydropyranyl groups; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; R 7 Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl group; N(CH3)2; N(H)2; ;and ; Or when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-; or R 5 With R 6 Connect them to form a loop, and R 5 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) substitution; and R 6 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) Replace; Two of the R 8 They can be arbitrarily connected together to form a ring with the middle atoms; R 8 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R's 8 Independently selected C groups are substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)-, or -N(CH3)-; and R 9 For H, C 1-3 Alkyl, oxetane, or , Or its pharmaceutically acceptable salt. The premise is that the compound is not N-[(2,3,5-trimethyl-1H-indol-7-yl)methyl]-2-quinoxaline.

[0275] 3. Compound of formula (I):

[0276] Formula (I)

[0277] in: Y is C(H) or N; W is C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A is piperidinyl, pyrrolidinyl, aziridine, piperazinyl, or morpholinyl, wherein the piperidinyl, pyrrolidinyl, or aziridine is optionally selected by one or more independently chosen R. 18 Replacement, of which two R 18 Optionally linked together with the intermediate atom to form a ring; wherein the piperazine group is optionally R 14 Substitution; and wherein the morpholino group is optionally replaced by one or more identical or different substituents R. 19 replace; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl, Or when two R 18 When connected to form a loop, the two R's 18 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-; R 14 C 1-3 Alkyl, oxetane, or ;and R 19 Selected independently from C 1-3 Alkyl groups and C groups substituted with OH 1-3 alkyl.

[0278] 4. Compound of formula (I):

[0279] Formula (I)

[0280] in: Y is C(H) or N; W is C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A represents equation (III):

[0281] Equation (III)

[0282] in: X 1 It is N or C(H); X 2 For C(R) 10 (R) 11 (or does not exist;) R 10 For H or C 1-3 alkyl; R 11 For H or C 1-3 alkyl; X 3 For C(R) 12 (R) 13 ), O or N (R 14 ); R 12 The C can be H, OH, NH2, or optionally substituted with OH. 1-3 Alkyl; and R 13 H or C substituted with OH (optionally) 1-3 Alkyl; or R 12 With R 13 They connect together with the middle atoms to form a ring, and R 12 -R 13 C 3-5 Alkyl group, wherein one or both methylene groups of the alkyl group are optionally surrounded by O, C(H)(NH2) or N(R) 17 (replace) R 17 For H or C 1-3 alkyl; R 14 For H, C 1-3 Alkyl, oxetane, or ; X 4 For C(R) 15 (R) 16 (or does not exist;) R 15 H; OH; C arbitrarily substituted with OH 1-3Alkyl; or OC optionally substituted with one or more F. 1-3 Alkyl; and R 16 For H.

[0283] 5. The compounds according to items 1 to 4, wherein the compound is of formula (Ia): .

[0284] Formula (Ia)

[0285] 6. The compounds according to items 1 to 4, wherein the compound is of formula (Ib): .

[0286] Formula (Ib)

[0287] 7. The compounds according to items 1 to 4, wherein the compound is of formula (Ic): .

[0288] Formula (Ic)

[0289] 8. The compounds according to items 1 to 4, wherein the compound is of formula (Id): .

[0290] Formula (Id)

[0291] 9. A compound according to any of the preceding items, wherein Y is C(H).

[0292] 10. A compound according to any of the preceding items, wherein Y is N.

[0293] 11. A compound according to any of the preceding items, wherein W is C(H)2.

[0294] 12. A compound according to any of the preceding items, wherein W is C(D)2.

[0295] 13. A compound according to any of the preceding claims, wherein R 1 For H.

[0296] 14. A compound according to any of the preceding claims, wherein R 1 C 1-3 alkyl.

[0297] 15. A compound according to any of the preceding claims, wherein R 1 It is a methyl group.

[0298] 16. A compound according to any of the preceding claims, wherein R 1 It is isopropyl.

[0299] 17. A compound according to any of the preceding claims, wherein R 1 It is cyclopropyl.

[0300] 18. A compound according to any of the preceding claims, wherein R 2 For H.

[0301] 19. A compound according to any of the preceding claims, wherein R 2 C 1-3 alkyl.

[0302] 20. A compound according to any of the preceding claims, wherein R 2 It is a methyl group.

[0303] 21. A compound according to any of the preceding claims, wherein R 2 C replaced by OH 1-3 alkyl.

[0304] 22. The compound according to any one of the preceding claims, wherein R 2 It is CH2OH.

[0305] 23. The compound according to any one of the preceding claims, wherein R 2 C 3-5 Cycloalkyl.

[0306] 24. A compound according to any of the preceding claims, wherein R 2 It is cyclopropyl.

[0307] 25. A compound according to any of the preceding claims, wherein R 3 For H.

[0308] 26. A compound according to any of the preceding claims, wherein R 3 C 1-3 alkyl.

[0309] 27. A compound according to any of the preceding claims, wherein R 3 It is a methyl group.

[0310] 28. A compound according to any of the preceding claims, wherein R 3 C replaced by OH 1-3 alkyl.

[0311] 29. The compound according to any one of the preceding claims, wherein R 3 It is -CH2OH.

[0312] 30. The compound according to any one of the preceding claims, wherein R 3 -OC 1-3 alkyl.

[0313] 31. The compound according to any one of the preceding claims, wherein R 3 It is a methoxy group.

[0314] 32. The compound according to any one of the preceding claims, wherein R 3 -OC replaced by one or more F 1-3 alkyl.

[0315] 33. The compound according to any one of the preceding claims, wherein R 3 It is -OCHF2.

[0316] 34. The compound according to any one of the preceding claims, wherein R 3 It is -C(O)NHCH3.

[0317] 35. The compound according to any one of the preceding claims, wherein R 3 It is -NH2.

[0318] 36. The compound according to any one of the preceding claims, wherein R 3 It is -N(H)(CH3).

[0319] 37. The compound according to any one of the preceding claims, wherein R 3 It is -N(CH3)2.

[0320] 38. The compound according to any one of the preceding claims, wherein R 3 It is a halogen.

[0321] 39. The compound according to any one of the preceding claims, wherein R 3 It is Cl.

[0322] 40. The compound according to any one of the preceding claims, wherein R 1 Let H be the number of 'R', and R be the number of 'R'. 2 For H.

[0323] 41. The compound according to any one of the preceding claims, wherein R 1 It is CH3, and R 2 For H.

[0324] 42. The compound according to any one of the preceding claims, wherein R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 For H.

[0325] 43. The compound according to any one of the preceding claims, wherein R 1 For H, R 2 It is CH3, and R 3 For H.

[0326] 44. The compound according to any one of the preceding claims, wherein R 1 For H, R 2 It is cyclopropyl, and R 3 For H.

[0327] 45. The compound according to any one of the preceding claims, wherein R 1 For H, R 2 It is CH2OH, and R 3 For H.

[0328] 46. ​​The compound according to any one of the preceding claims, wherein R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 For H.

[0329] 47. The compound according to any one of the preceding claims, wherein R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is NH2.

[0330] 48. The compound according to any one of the preceding claims, wherein the compound is of formula (Id), and R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is NH2.

[0331] 49. The compound according to any one of the preceding claims, wherein R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is N(CH3)2.

[0332] 50. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is N(CH3)2.

[0333] 51. The compound according to any one of the preceding claims, wherein R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is Cl.

[0334] 52. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is Cl.

[0335] 53. The compound according to any one of the preceding claims, wherein R 1 CH3, R 2Let H be the number of 'R', and R be the number of 'R'. 3 It is CH2OH.

[0336] 54. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is CH2OH.

[0337] 55. The compound according to any one of the preceding claims, wherein R 1 It is isopropyl, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is OCH3.

[0338] 56. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and R 1 It is isopropyl, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is OCH3.

[0339] 57. The compound according to any one of the preceding claims, wherein R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is OCH3.

[0340] 58. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and R 1 CH3, R 2 For H, R 3 It is OCH3.

[0341] 59. The compound according to any one of the preceding claims, wherein R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is OCH3.

[0342] 60. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and R 1 For H, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is OCH3.

[0343] 61. The compound according to any one of the preceding claims, wherein R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is C(O)NHCH3.

[0344] 62. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'.3 It is C(O)NHCH3.

[0345] 63. The compound according to any one of the preceding claims, wherein R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is CHF2.

[0346] 64. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and R 1 CH3, R 2 Let H be the number of 'R', and R be the number of 'R'. 3 It is CHF2.

[0347] 65. A compound according to any of the preceding claims, wherein R 4 For H.

[0348] 66. A compound according to any of the preceding claims, wherein R 4 C 1-4 alkyl.

[0349] 67. A compound according to any of the preceding claims, wherein R 4 It is a methyl group.

[0350] 68. The compound according to any one of the preceding claims, wherein R 4 C 3-5 Cycloalkyl.

[0351] 69. A compound according to any one of the preceding claims, wherein A is of formula (II):

[0352] Equation (II)

[0353] in: X is N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from the following groups: C 1-6 Alkyl groups, optionally substituted with one or more identical or different substituents R 7 Instead, the C 1-6 One or more methylene groups of the alkyl group are optionally and independently replaced by -O- or C=O; C 3-6 cycloalkyl groups, optionally substituted with one or more identical or different substituents R 7 Substitution; and tetrahydropyranyl; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; and R 7Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl group; N(CH3)2; N(H)2; ;as well as ; Or when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-.

[0354] 70. The compound according to any one of the preceding claims, wherein R 6 For H.

[0355] 71. The compound according to any one of the preceding claims, wherein R 6 C 1-4 alkyl.

[0356] 72. The compound according to any one of the preceding claims, wherein R 6 It is CH3.

[0357] 73. The compound according to any one of the preceding claims, wherein R 5 For being substituents R by one or more identical or different substituents 7 Replacement C 1-6 alkyl.

[0358] 74. The compound according to any one of the preceding claims, wherein R 5 For being substituents R by one or more identical or different substituents 7 Substituted C1 alkyl groups.

[0359] 75. The compound according to any one of the preceding claims, wherein R 5 For being substituents R by one or more identical or different substituents 7 Substituted C2 alkyl group.

[0360] 76. The compound according to any one of the preceding claims, wherein R 5 For being substituents R by one or more identical or different substituents 7 Substituted C3 alkyl group.

[0361] 77. The compound according to any one of the preceding claims, wherein R 5 For being substituents R by one or more identical or different substituents 7 Substituted C5 alkyl groups, such as neopentanediol.

[0362] 78. The compound according to any one of the preceding claims, wherein R 5 For optional addition of one or more identical or different substituents R 7 Replacement C 3-6 Cycloalkyl.

[0363] 79. The compound according to any one of the preceding claims, wherein R 5 For being substituents R by one or more identical or different substituents 7 Substituted C4 cycloalkyl groups.

[0364] 80. The compound according to any one of the preceding claims, wherein R 5 For being substituents R by one or more identical or different substituents 7 Substituted C6 cycloalkyl groups.

[0365] 81. The compound according to any one of the preceding claims, wherein R 5 It is a C6 cycloalkyl group.

[0366] 82. The compound according to any one of the preceding claims, wherein R 5 It is a tetrahydropyranyl group.

[0367] 83. The compound according to any one of the preceding claims, wherein A is .

[0368] 84. The compound according to any one of the preceding claims, wherein R 7 It is OH.

[0369] 85. The compound according to any one of the preceding claims, wherein R 7 It is N(H)2.

[0370] 86. The compound according to any one of the preceding claims, wherein R 7 It is N(CH3)2.

[0371] 87. The compound according to any one of the preceding claims, wherein R 7 C 1-3 Alkyl group.

[0372] 88. The compound according to any one of the preceding claims, wherein R 7 It is OCH3.

[0373] 89. The compound according to any one of the preceding claims, wherein R 7 C replaced by one or more F 1-3 Alkyl group.

[0374] 90. The compound according to any one of the preceding claims, wherein R 7 It is OCHF2.

[0375] 91. The compound according to any one of the preceding claims, wherein R 7 C 1-3 alkyl.

[0376] 92. The compound according to any one of the preceding claims, wherein R 7 It is CH3.

[0377] 93. The compound according to any one of the preceding claims, wherein R 7 C replaced by OH 1-3 alkyl.

[0378] 94. The compound according to any one of the preceding claims, wherein R 7 It is CH2OH.

[0379] 95. The compound according to any one of the preceding claims, wherein R 7 for .

[0380] 96. The compound according to any one of the preceding claims, wherein R 7 for .

[0381] 97. The compound according to any one of the preceding claims, wherein A is selected from the following groups: , , , , , and .

[0382] 98. The compound according to any one of the preceding claims, wherein A is selected from the following groups: , , , , , , , , , , , and .

[0383] 99. The compound according to any one of the preceding claims, wherein two R... 7 Connected to form a loop, and the two Rs 7 Independently selected C groups are substituted by one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2One of the methylene groups in the alkyl diene may be optionally replaced by -O-.

[0384] 100. The compound according to any one of the preceding claims, wherein the two Rs 7 Connected to form a loop, and the two Rs 7 Independently selected C groups are substituted by one or two substituents selected from F and OH. 1-2 Alkyl group.

[0385] 101. The compound according to any one of the preceding claims, wherein the two Rs 7 Connected to form a loop, and the two Rs 7 Independently selected from C 1-2 Alkyl, and the C 1-2 One of the methylene groups in the alkyl diene may be optionally replaced by -O-.

[0386] 102. The compound according to any one of the preceding claims, wherein A is selected from the following groups: , and .

[0387] 103. The compound according to any one of the preceding claims, wherein R 5 and R 6 Connect them to form a loop, and

[0388] R 5 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) substitution; and

[0389] R 6 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) Replace; Two of the R 8 They can be arbitrarily connected together to form a ring with the middle atoms; R 8 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R 8Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)-, or -N(CH3)-; and R 9 For H, C 1-3 Alkyl, oxetane, or .

[0390] 104. The compound according to any one of the preceding claims, wherein A is R, which is optionally selected by one or more independent choices. 18 Substituted piperidinyl groups, where both R groups are R groups 18 They can be arbitrarily connected together to form a ring with the middle atoms; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 18 When connected to form a loop, the two R 18 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0391] 105. The compound according to any one of the preceding claims, wherein A is optionally coupled to an R. 18 Substituted piperidinyl, the R 18 Selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl.

[0392] 106. The compound according to any one of the preceding claims, wherein A is optionally coupled to two R. 18 Substituted piperidinyl, the R 18 Selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl.

[0393] 107. The compound according to any one of the preceding claims, wherein the piperidinyl group is connected to formula (I) at the 1-position of the piperidinyl group.

[0394] 108. The compound according to any one of the preceding claims, wherein A is R, which is optionally selected by one or more independent choices. 18 Substituted pyrroleyl groups, wherein two Rs 18 They can be arbitrarily connected together to form a ring with the middle atoms; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 18 When connected to form a loop, the two R 18 Independently selected C groups are substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0395] 109. The compound according to any of the preceding claims, wherein the pyrrolidinium is connected to formula (I) at the 1-position of the pyridinyl alkyl group.

[0396] 110. The compound according to any one of the preceding claims, wherein A is R, which is optionally selected by one or more independent choices. 18 Substituted nitrogen-containing heterocyclic butyl groups, wherein two R groups are substituted. 18 They can be arbitrarily connected together to form a ring with the middle atoms; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 18 When connected to form a loop, the two R 18 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0397] 111. The compound according to any of the preceding claims, wherein the aziridine is attached to formula (I) at the 1-position of the aziridine.

[0398] 112. The compound according to any one of the preceding claims, wherein A is optionally R at the 4-position of the piperazine group. 14 Substituted piperazine group, wherein R 14 C 1-3Alkyl, oxetane, or .

[0399] 113. The compound according to any of the preceding claims, wherein the piperazine group is connected to formula (I) at the 1-position of the piperazine group.

[0400] 114. The compound according to any one of the preceding claims, wherein A is optionally replaced by one or more identical or different substituents R. 19 Substituted morpholino group, wherein R 19 Independently selected from C 1-3 Alkyl groups and C groups substituted with OH 1-3 alkyl.

[0401] 115. The compound according to any of the preceding claims, wherein the morpholino group is connected to formula (I) at the 4 position of the morpholino group.

[0402] 116. The compound according to any one of the preceding claims, wherein R 18 For R 8 .

[0403] 117. The compound according to any one of the preceding claims, wherein R 8 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; -F; -N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R 8 Independently selected from C14 groups that are substituted by one or two substituents selected from F and OH. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0404] 118. The compound according to any one of the preceding claims, wherein R 8 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; -F; -N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl.

[0405] 119. The compound according to any one of the preceding claims, wherein two R... 8 Connected to form a loop, and the two Rs 8 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0406] 120. The compound according to any one of the preceding claims, wherein R 8 C 1-3 alkyl.

[0407] 121. The compound according to any one of the preceding claims, wherein R 8 It is -CH3.

[0408] 122. The compound according to any one of the preceding claims, wherein R 8 C replaced by OH 1-3 alkyl.

[0409] 123. The compound according to any one of the preceding claims, wherein R 8 It is -CH2OH.

[0410] 124. The compound according to any one of the preceding claims, wherein R 8 It is -OH.

[0411] 125. The compound according to any one of the preceding claims, wherein R 8 It is N(H)2.

[0412] 126. The compound according to any one of the preceding claims, wherein R 8 -OC replaced by one or more F 1-3 alkyl.

[0413] 127. The compound according to any one of the preceding claims, wherein R 8 It is -OCHF2.

[0414] 128. The compound according to any one of the preceding claims, wherein R 19 For R 9 .

[0415] 129. The compound according to any one of the preceding claims, wherein R 9 C 1-3 alkyl.

[0416] 130. The compound according to any one of the preceding claims, wherein R 9 It is -CH3.

[0417] 131. The compound according to any one of the preceding claims, wherein R 9 It is an oxocyclic butyl group.

[0418] 132. The compound according to any one of the preceding claims, wherein R 9 for .

[0419] 133. The compound according to any one of the preceding claims, wherein A is of formula (III):

[0420] Equation (III)

[0421] in: X 1 It is N or C(H); X 2 For C(R) 10 (R) 11 (or does not exist;) R 10 For H or C 1-3 alkyl; R 11 For H or C 1-3 alkyl; X 3 For C(R) 12 (R) 13 ), O or N (R 14 ); R 12 The C can be H, OH, NH2, or optionally substituted with OH. 1-3 Alkyl; and R 13 H or C substituted with OH (optionally) 1-3 Alkyl; or R 12 With R 13 They connect together with the middle atoms to form a ring, and R 12 -R 13 C 3-5 Alkyl group, wherein one or both methylene groups of the alkyl group are optionally surrounded by O, C(H)(NH2) or N(R) 17 ) Replace; R 17 For H or C 1-3 alkyl; R 14 For H, C 1-3 Alkyl, oxetane, or ; X 4 For C(R) 15 (R) 16 (or does not exist;) R 15 H; OH; C arbitrarily substituted with OH 1-3 Alkyl; or OC optionally substituted with one or more F. 1-3 Alkyl; and R 16 For H.

[0422] 134. The compound according to any one of the preceding claims, wherein X 1 Let N, X 2 For C(R) 10 (R) 11 ), X 3 For C(R) 12 (R) 13 ), and X 4 For C(R) 15 (R) 16 ).

[0423] 135. The compound according to any one of the preceding claims, wherein X 1 Let N, X 2 Does not exist, X 3 For C(R) 12 (R) 13 ), and X 4 For C(R) 15 (R) 16 ).

[0424] 136. The compound according to any one of the preceding claims, wherein X 1 Let N, X 2 Does not exist, X 3 For C(R) 12 (R) 13 ), and X 4 It does not exist.

[0425] 137. The compound according to any one of the preceding claims, wherein X 1 Let N, X 2 For C(R) 10 (R) 11 ), X 3 It is O, and X 4 For C(R) 15 (R) 16 ).

[0426] 138. The compound according to any one of the preceding claims, wherein X 1 Let N, X 2 For C(R) 10 (R) 11 ), X 3 For N(R) 14 ), and X 4 For C(R) 15 (R) 16 ).

[0427] 139. The compound according to any one of the preceding claims, wherein X 1 Let N be the number of elements in the array.

[0428] 140. The compound according to any one of the preceding claims, wherein X 1 It is C(H).

[0429] 141. The compound according to any one of the preceding claims, wherein X 2 It does not exist.

[0430] 142. The compound according to any one of the preceding claims, wherein X 2 For C(R) 10 (R) 11 ).

[0431] 143. The compound according to any one of the preceding claims, wherein R 10 For H.

[0432] 144. The compound according to any one of the preceding claims, wherein R 10 C 1-3 alkyl.

[0433] 145. The compound according to any one of the preceding claims, wherein R 10 It is CH3.

[0434] 146. The compound according to any one of the preceding claims, wherein R 11 For H.

[0435] 147. The compound according to any one of the preceding claims, wherein R 11 C 1-3 alkyl.

[0436] 148. The compound according to any one of the preceding claims, wherein R 11 It is CH3.

[0437] 149. The compound according to any one of the preceding claims, wherein X 2 It is C(H)2.

[0438] 150. The compound according to any one of the preceding claims, wherein X 2 It is C(H)(CH3).

[0439] 151. The compound according to any one of the preceding claims, wherein X 2 It is C(CH3)2.

[0440] 152. The compound according to any one of the preceding claims, wherein X 3 It is O.

[0441] 153. The compound according to any one of the preceding claims, wherein X 3 For N(R) 14 ).

[0442] 154. The compound according to any one of the preceding claims, wherein R 14 For H.

[0443] 155. The compound according to any one of the preceding claims, wherein R 14 C 1-3 alkyl.

[0444] 156. The compound according to any one of the preceding claims, wherein R 14 It is CH3.

[0445] 157. The compound according to any one of the preceding claims, wherein R 14 It is an oxocyclic butyl group.

[0446] 158. The compound according to any one of the preceding claims, wherein R 14 for .

[0447] 159. The compound according to any one of the preceding claims, wherein R 14 for .

[0448] 160. The compound according to any one of the preceding claims, wherein X 3 It is N(H).

[0449] 161. The compound according to any one of the preceding claims, wherein X 3 It is N(CH3).

[0450] 162. The compound according to any one of the preceding claims, wherein X 3 For C(R) 12 (R) 13 ).

[0451] 163. The compound according to any one of the preceding claims, wherein R 12 For H.

[0452] 164. The compound according to any one of the preceding claims, wherein R 12 It is OH.

[0453] 165. The compound according to any one of the preceding claims, wherein R 12 It is NH2.

[0454] 166. A compound according to any of the preceding claims, wherein R 12 C 1-3 alkyl.

[0455] 167. A compound according to any of the preceding claims, wherein R 12 C replaced by OH 1-3 alkyl.

[0456] 168. The compound according to any one of the preceding claims, wherein R 12 It is CH2OH.

[0457] 169. The compound according to any one of the preceding claims, wherein R 13 For H.

[0458] 170. A compound according to any of the preceding claims, wherein R 13 C 1-3 alkyl.

[0459] 171. A compound according to any of the preceding claims, wherein R 13 C replaced by OH 1-3 alkyl.

[0460] 172. The compound according to any one of the preceding claims, wherein R 13 It is CH2OH.

[0461] 173. The compound according to any one of the preceding claims, wherein X 3 It is C(H)2.

[0462] 174. The compound according to any one of the preceding claims, wherein X 3 It is C(H)(OH).

[0463] 175. The compound according to any one of the preceding claims, wherein X 3 It is C(H)(CH2OH).

[0464] 176. The compound according to any one of the preceding claims, wherein X 3 It is C(CH2OH)2.

[0465] 177. The compound according to any one of the preceding claims, wherein X 4 It does not exist.

[0466] 178. The compound according to any one of the preceding claims, wherein X 4 For C(R) 15 (R) 16 ).

[0467] 179. The compound according to any one of the preceding claims, wherein R 15 For H.

[0468] 180. The compound according to any one of the preceding claims, wherein R 15 It is OH.

[0469] 181. The compound according to any one of the preceding claims, wherein R 15 C1-3 alkyl.

[0470] 182. The compound according to any one of the preceding claims, wherein R 15 It is CH3.

[0471] 183. The compound according to any one of the preceding claims, wherein R 15 C replaced by OH 1-3 alkyl.

[0472] 184. The compound according to any one of the preceding claims, wherein R 15 It is CH2OH.

[0473] 185. The compound according to any one of the preceding claims, wherein R 15 OC replaced by one or more F 1-3 alkyl.

[0474] 186. The compound according to any one of the preceding claims, wherein R 15 It is OCHF2.

[0475] 187. The compound according to any one of the preceding claims, wherein R 16 For H.

[0476] 188. The compound according to any one of the preceding claims, wherein X 4 It is C(H)2.

[0477] 189. The compound according to any one of the preceding claims, wherein X 4 It is C(H)(CH3).

[0478] 190. The compound according to any one of the preceding claims, wherein X 4 It is C(H)(OH).

[0479] 191. The compound according to any one of the preceding claims, wherein X 4 It is C(H)(CH2OH).

[0480] 192. The compound according to any one of the preceding claims, wherein X 4 It is C(H)(OCHF2).

[0481] 193. The compound according to any one of the preceding claims, wherein A is selected from the following groups: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

[0482] 194. The compound according to any one of the preceding claims, wherein X 3 For C(R) 12 (R) 13 ), and R 12 With R 13 They connect together with the middle atoms to form a ring, where R 12 -R 13 C 3-5 Alkyl group, wherein one or both methylene groups of the alkyl group are optionally surrounded by O, C(H)(NH2) or N(R) 17 (replace)

[0483] 195. The compound according to any one of the preceding claims, wherein R 17 For H.

[0484] 196. The compound according to any one of the preceding claims, wherein R 17 C 1-3 alkyl.

[0485] 197. The compound according to any one of the preceding claims, wherein R 17 It is CH3.

[0486] 198. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -CH2-N(CH3)-CH2-.

[0487] 199. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -CH2-N(H)-CH2-.

[0488] 200. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -CH2-O-CH2-.

[0489] 201. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -CH2-C(H)(NH2)-CH2-.

[0490] 202. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -(CH2)3-O-.

[0491] 203. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -(CH2)2-O-(CH2)2-.

[0492] 204. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -(CH2)-O-(CH2)3-.

[0493] 205. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -(CH2)2-N(H)-(CH2)2-.

[0494] 206. The compound according to any one of the preceding claims, wherein R 12 -R 13 It is -O-(CH2)2-O-(CH2)-.

[0495] 207. The compound according to any one of the preceding claims, wherein A is selected from the following groups: , , , , , , , , , , , and .

[0496] 208. The compound according to any one of the preceding claims, wherein A is H.

[0497] 209. The compound according to any one of the preceding claims, wherein A is C. 1-3 Alkyl group.

[0498] 210. The compound according to any one of the preceding claims, wherein A is OCH3.

[0499] 211. The compound according to any one of the preceding claims, wherein A is CF3.

[0500] 212. The compound according to any one of the preceding claims, wherein A is C. 1-3 alkyl.

[0501] 213. The compound according to any one of the preceding claims, wherein A is CH3.

[0502] 214. The compound according to any one of the preceding claims, wherein A is CH2CH3.

[0503] 215. The compound according to any one of the preceding claims, wherein A is C. 3-5 Cycloalkyl.

[0504] 216. The compound according to any one of the preceding claims, wherein A is cyclopropyl.

[0505] 217. The compound according to any one of the preceding claims, wherein A is tert-butyl.

[0506] 218. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It can be H, CH3, or isopropyl; R 2 It can be H, CH3, cyclopropyl or CH2OH; R 3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is H, CF3, or formula (II):

[0507] Equation (II).

[0508] 219. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It can be H, CH3, or isopropyl; R 2 It can be H, CH3, cyclopropyl or CH2OH; R3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A represents H, CF3 , , , , , , , , , , , , , , , , , , , , , or .

[0509] 220. The compound according to any one of the preceding claims, wherein A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

[0510] 221. The compound according to any one of the preceding claims, wherein A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is formed by two or more R groups. 18 Replacement, of which two R 18 They connect together with the intermediate atoms to form a ring, and the two Rs that connect to form the ring... 18 Independently selected C groups are substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and wherein the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0511] 222. The compound according to any one of the preceding claims, wherein A is a morpholino group, wherein the morpholino group is optionally replaced by one or more identical or different substituents R. 19 Replace, where R 19 It is -CH3 or -CH2OH.

[0512] 223. The compound according to any one of the preceding claims, wherein...

[0513] Y is N; W is C(H)2; R 1 It can be H, CH3, or isopropyl; R 2 It can be H, CH3, cyclopropyl or CH2OH; R 3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

[0514] 224. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It can be H, CH3, or isopropyl; R 2 It can be H, CH3, cyclopropyl or CH2OH; R 3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2), Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is formed by two or more R groups. 18 Replacement, of which two R 18 They connect together with the intermediate atoms to form a ring, and the two Rs that connect to form the ring... 18 Independently selected C groups are substituted by one or two substituents selected from F, OH, and NH2.1-3 Alkyl, and wherein the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0515] 225. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It can be H, CH3, or isopropyl; R 2 It can be H, CH3, cyclopropyl or CH2OH; R 3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2), Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is a morpholino group, wherein the morpholino group is optionally replaced by one or more identical or different substituents R. 19 Replace, where R 19 It is -CH3 or -CH2OH.

[0516] 226. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It can be H, CH3, or isopropyl; R 2 It can be H, CH3, cyclopropyl or CH2OH; R 3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

[0517] 227. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1It can be H, CH3, or isopropyl; R 2 It can be H, CH3, cyclopropyl or CH2OH; R 3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is formed by two or more R groups. 18 Replacement, of which two R 18 They connect together with the intermediate atoms to form a ring, and the two Rs that connect to form the ring... 18 Independently selected C groups are substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and wherein the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0518] 228. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It can be H, CH3, or isopropyl; R 2 It can be H, CH3, cyclopropyl or CH2OH; R 3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2), Cl, C(O)NHCH3, OCHF2, or OCH3; R 4 It is H or CH3; and A is a morpholino group, wherein the morpholino group is optionally replaced by one or more identical or different substituents R. 19 Replace, where R 19 It is -CH3 or -CH2OH.

[0519] 229. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It is CH3; R 2 For H; R 3 It can be H, CH3, OCHF2 or OCH3; R4 For H; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

[0520] 230. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It is CH3; R 2 For H; R 3 It can be H, CH3, OCHF2 or OCH3; R 4 For H; and A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is formed by two or more R groups. 18 Replacement, of which two R 18 They connect together with the intermediate atoms to form a ring, and the two Rs that connect to form the ring... 18 Independently selected C groups are substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and wherein the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

[0521] 231. The compound according to any one of the preceding claims, wherein: Y is N; W is C(H)2; R 1 It is CH3; R 2 For H; R 3 It can be H, CH3, OCHF2 or OCH3; R 4 For H; and A is a morpholino group, which is optionally replaced by one or more identical or different substituents R. 19 Replace, where R 19 It is -CH3 or -CH2OH.

[0522] 232. The compound according to any one of the preceding claims, wherein the compound is of formula (Ia); Y is N; W is C(H)2; R 1 It is CH3; R 2 For H; R 3 It is H, CH3, OCHF2, or OCH3; and R 4 For H.

[0523] 233. The compound according to any one of the preceding claims, wherein the compound is of formula (Ib); Y is N; W is C(H)2; R 1 It is CH3; R 2 For H; R 3 It is H, CH3, OCHF2, or OCH3; and R 4 For H.

[0524] 234. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic); Y is N; W is C(H)2; R 1 It is CH3; R 2 For H; R 3 It is H, CH3, OCHF2, or OCH3; and R 4 For H.

[0525] 227. The compound according to any one of the preceding claims, wherein the compound is of formula (Id); Y is N; W is C(H)2; R 1 It is CH3; R 2 For H; R 3 It is H, CH3, OCHF2, or OCH3; and R 4 For H.

[0526] 236. The compound according to any one of the preceding claims, wherein the compound is selected from: 7-Cyclopropyl-N-(1H-indol-6-ylmethyl)quinoxaline-2-amine, N-[(7-methyl-1H-indol-5-yl)methyl]quinoxaline-2-amine, N-(1H-indol-6-ylmethyl)-7-(piperidin-1-yl)quinoxalin-2-amine N-(1H-indol-5-ylmethyl)quinoxaline-2-amine 1-(3-{[(6-amino-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N-(1H-indol-4-ylmethyl)-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine 1-[3-({[7-(hydroxymethyl)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 1-(3-{[1H-indol-4-yl(²H2)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N-(1H-indol-6-ylmethyl)-6-(piperidin-4-yl)pyrido[2,3-b]pyrazin-3-amine [6-({[6-(piperidin-1-yl)pyridino[2,3-b]pyrazin-3-yl]amino}methyl)-1H-indol-2-yl]methanol, N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]-6-(pyrrolidone-1-yl)pyrido[2,3-b]pyrazin-3-amine 6-N-cyclohexyl-3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3,6-diamine, 1-[3-({[7-(dimethylamino)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-[(3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, N,3-Dimethyl-4-{[(6-{methyl[(1s,3s)-3-hydroxycyclobutyl]amino}pyrido[2,3-b]pyrazin-3-yl)amino]methyl}-1H-indole-7-carboxamide 1-[3-({[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(7-chloro-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, [(3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-yl]methanol, (3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, cis-(1s,3s)-3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyridino[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, N-[(1H-indol-6-yl)methyl]-6-{2-oxa-6-azaspiro[3.3]heptane-6-yl}pyrido[2,3-b]pyrazin-3-amine, 6-{2,6-diazaspiro[3.3]heptane-2-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 3-(hydroxymethyl)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, [(3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-yl]methanol, N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine cis-(1R,3R)-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclobutane-1-ol, [4-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-yl]methanol, 3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-N-[trans-4-aminocyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine, 7-tert-butyl-N-(1H-indol-6-ylmethyl)quinoxaline-2-amine N-[(1H-indol-6-yl)methyl]-6-(piperidin-1-yl)pyrido[2,3-b]pyrazin-3-amine [4-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-yl]methanol, N-(1H-indol-6-ylmethyl)-6-[4-(oxetane-3-yl)piperazin-1-yl]pyrido[2,3-b]pyrazin-3-amine 7-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}-7-azaspiro[3.5]nonane-2-amine, 1-{3-[({1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, 3-N-(1H-indol-6-ylmethyl)-6-N-(oxacyclohexane-4-yl)pyrido[2,3-b]pyrazine-3,6-diamine, [(2R)-4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, N-[(1H-indol-6-yl)methyl]-6-(pyrrolidone-1-yl)pyrido[2,3-b]pyrazin-3-amine 7-Ethyl-N-[(1H-indol-6-yl)methyl]quinoxaline-2-amine, N-(1H-indol-6-ylmethyl)-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine, 1-(3-{[(3-hydroxy-4-methoxyphenyl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 6-{2,7-diazaspiro[3.5]nonane-7-yl}-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, N-[(1H-indol-6-yl)methyl]-7-methylquinoxaloline-2-amine, 3-N-(1H-indol-6-ylmethyl)-6-N-{2-oxaspiro[3.3]heptane-6-yl}pyrido[2,3-b]pyrazine-3,6-diamine, N-[(2-methyl-1H-indol-5-yl)methyl]quinoxaline-2-amine, 6-{2,6-diazaspiro[3,4]octane-6-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N3-[(1H-indol-6-yl)methyl]-N6-[trans-4-(difluoromethoxy)cyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine N-(1H-indol-6-ylmethyl)-6-(morpholin-4-yl)pyrido[2,3-b]pyrazin-3-amine, (3R)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-3-ol, N-[(1H-indol-6-yl)methyl]-6-{2-oxa-6-azaspiro[3.4]octane-6-yl}pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-{1-oxa-9-azaspiro[5.5]undecane-9-yl}pyrido[2,3-b]pyrazin-3-amine, [(2R)-4-[3-({[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]morpholin-2-yl]methanol, 6-N-cyclohexyl-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, 1-(3-{[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3R,4R)-3-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, [(2R)-4-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}morpholin-2-yl]methanol, N-(1H-indol-6-ylmethyl)-6-{3-oxa-9-azaspiro[5.5]undecane-9-yl}pyrido[2,3-b]pyrazin-3-amine, trans-4-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclohexane-1-ol, 1-(3-{[(2-cyclopropyl-1H-indol-5-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N6-[2-(dimethylamino)ethyl]-N3-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazine-3,6-diamine, 6-{2,7-diazaspiro[3.5]nonane-7-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propane-1,2-diol, [(3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-yl]methanol, 1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-yl)methanol, trans-4-[methyl(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclohexane-1-ol, N-[(1H-indol-6-yl)methyl]quinoxaline-2-amine, 1-(3-{[(7-methoxy-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-ol, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N3-[(1H-indol-6-yl)methyl]-N6-(3-methoxypropyl)pyrido[2,3-b]pyrazine-3,6-diamine trans-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}(methyl)amino)cyclobutane-1-ol, N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-(piperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, cis-3-[(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, (3S,4S)-3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(2-methyl-1H-indol-5-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N3-[(1H-indol-6-yl)methyl]-N6-[trans-4-aminocyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]-2,2-dimethylpropane-1-ol, 6-N-{6,6-difluorospiro[3.3]heptane-2-yl}-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, 6-{4-[(1-aminocyclopropyl)carbonyl]piperazin-1-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 6-[cis-2,6-dimethylmorpholin-4-yl]-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, [(3S)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}pyrrolidine-3-yl]methanol, [4-(hydroxymethyl)-1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-yl]methanol, cis-3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)(methyl)amino]cyclobutane-1-ol, 4-[({6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyrido[2,3-b]pyrazin-3-yl}amino)methyl]-N,3-dimethyl-1H-indole-7-carboxamide, N-[(1H-indol-6-yl)methyl]-6-methylquinoxaloline-2-amine, 1-{3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propyl}azacycloheptan-2-one, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-ol, [4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, N-(1H-indol-6-ylmethyl)-6-(4-methylpiperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, trans-3-[methyl(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, (3S,4S)-3-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, 6-(azacyclobutan-1-yl)-N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, 1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3R,4R)-3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 6-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]spiro[3,3]heptane-2-ol, 3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-N-[trans-4-(dimethylamino)cyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine, (3S)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, trans-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclobutane-1-ol, (3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, [4-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, (3S)-1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)azacyclobutane-3-ol, 4-({[6-(4-hydroxypiperidin-1-yl)pyrido[2,3-b]pyrazin-3-yl]amino}methyl)-N,3-dimethyl-1H-indole-7-carboxamide, 6-{1,4-dioxa-9-azaspiro[5.5]undecane-9-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-{1-oxa-8-azaspiro[4.5]decane-8-yl}pyrido[2,3-b]pyrazin-3-amine, 6-[cis-2,6-dimethylmorpholin-4-yl]-N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, 6-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]spiro[3,3]heptane-2-ol, (3S,4S)-4-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-3-ol, N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-(4-methylpiperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine N-[(1H-indol-6-yl)methyl]-7-methoxyquinoxaline-2-amine, trans-4-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)(methyl)amino]cyclohexane-1-ol, 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propane-1-ol, 6-N-[4-(dimethylamino)cyclohexyl]-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, [1-(hydroxymethyl)-4-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclohexyl]methanol, 1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}azacyclobutane-3-amine, [(2R)-4-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, [4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)-6,6-dimethylmorpholin-2-yl]methanol, N3-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-N6-({2-oxabicyclo[2.2.2]octane-3-yl}methyl)pyrido[2,3-b]pyrazine-3,6-diamine, N-[(1H-indol-6-yl)methyl]-7-(trifluoromethyl)quinoxaline-2-amine, 6-{2,7-diazaspiro[3.5]nonane-2-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-5-ylmethyl)-6-(morpholin-4-yl)pyrido[2,3-b]pyrazin-3-amine, and 6-{3,9-diazaspiro[5.5]undecane-3-yl}-N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine.

[0527] 236. Selected from the following compounds: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,and .

[0528] 237. The compound according to any one of the preceding claims, wherein the compound is an inhibitor of WNK lysine deficiency protein kinase 1 (WNK1).

[0529] 238. The compound according to any one of the preceding claims, wherein the compound is a WNK lysine deficiency protein kinase 2 (WNK2) inhibitor.

[0530] 239. The compound according to any one of the preceding claims, wherein the compound is an inhibitor of WNK lysine deficiency protein kinase 3 (WNK3).

[0531] 240. The compound according to any one of the preceding claims, wherein the compound is an inhibitor of WNK lysine deficiency protein kinase 4 (WNK4).

[0532] 241. A pharmaceutical composition comprising a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

[0533] 242. The compound according to any one of claims 1 to 240, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 241, used as a medicine.

[0534] 243. The compound of any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 241, for the treatment, relief or prevention of diseases and conditions associated with WNK1 activity.

[0535] 244. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 240, or a pharmaceutical composition according to claim 241, for the treatment, relief or prevention of diseases and conditions associated with WNK1-4 (such as WNK1, WNK2, WNK3 and / or WNK4) activity.

[0536] 245. A method for treating, alleviating, or preventing diseases and conditions associated with WNK1 activity, the method comprising administering to a subject in need a compound of any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 241.

[0537] 246. A method for treating, alleviating, or preventing diseases and conditions associated with WNK1-4 activity, the method comprising administering to a subject in need a compound of any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 241.

[0538] 247. Use of any compound of any one of claims 1 to 240, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 241, in the preparation of a medicament for treating, alleviating, or preventing diseases and conditions associated with WNK1 activity.

[0539] 248. Use of any compound of any one of claims 1 to 240, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 241, in the preparation of a medicament for treating, alleviating, or preventing diseases and conditions associated with WNK1 activity.

[0540] 249. The compound of any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 241, for the treatment of hypertension.

[0541] 250. A method of treating hypertension, comprising administering to a subject in need a compound as described in any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 241.

[0542] 251. Use of any compound of any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 241 in the preparation of a medicament for treating hypertension.

[0543] 252. The compound of any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 241, for the treatment of cancer.

[0544] 253. A method of treating cancer, comprising administering to a subject in need a compound as described in any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described in claim 241.

[0545] 254. Use of any compound of any one of claims 1 to 240 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 241 in the preparation of a medicament for treating cancer.

[0546] 255. The compound or pharmaceutical composition used as described in claim 247, the method described in claim 250, or the use described in claim 254, wherein the cancer is selected from: adenoid cystic carcinoma, anal cancer, appendiceal cancer and PMP, cholangiocarcinoma (cholangiocarcinoma), bladder cancer, hematologic malignancies, primary bone cancer, secondary bone cancer, intestinal cancer, brain tumors, breast cancer, uterine cancer, cancer of unknown primary origin, cervical cancer, connective tissue cancer, endocrine cancer, gallbladder (bile duct) cancer, head and neck laryngeal cancer, Kaposi's sarcoma, kidney cancer, leukemia, primary liver cancer, secondary liver cancer, lung cancer, lymphoma, melanoma, mesothelioma, myeloma, neuroendocrine tumors (NETs), uveal melanoma, ovarian cancer, pancreatic cancer, penile cancer, peritoneal cancer, prostate cancer, skin cancer, small intestine cancer, soft tissue sarcoma, gastroesophageal cancer, testicular cancer, thymic cancer, thyroid cancer, upper urinary tract urothelial carcinoma, vaginal cancer, and vulvar cancer.

[0547] 256. A compound or pharmaceutical composition for the use described in claim 247, the method described in claim 250, or the use described in claim 254, wherein the cancer is selected from: acute myeloid leukemia (LAML), adrenocortical carcinoma (ACC), bladder urothelial carcinoma (BLCA), low-grade glioma (LGG), invasive breast carcinoma (BRCA), cervical squamous cell carcinoma and cervical adenocarcinoma (CESC), cholangiocarcinoma (CHOL), chronic myeloid leukemia (LCML), colonic adenocarcinoma (COAD), esophageal cancer (ESCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), chromophobe renal carcinoma (KICH), clear cell renal carcinoma (KIRC), and papillary renal carcinoma. (KIRP), hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), lymphoid tumor diffuse large B-cell lymphoma (DLBC), mesothelioma (MESO), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), pheochromocytoma and paraganglioma (PCPG), prostate adenocarcinoma (PRAD), rectal adenocarcinoma (READ), sarcoma (SARC), cutaneous melanoma (SKCM), gastric adenocarcinoma (STAD), testicular germ cell tumor (TGCT), thymoma (THYM), thyroid cancer (THCA), uterine carcinosarcoma (UCS), uterine endometrial cancer (UCEC), and uveal melanoma (UVM).

[0548] 257. A compound or pharmaceutical composition for use according to claim 247, or a method according to claim 250, or a use according to claim 254, wherein the cancer is selected from leukemia, including acute myeloid leukemia; lymphoma and myeloma include multiple myeloma.

[0549] Example

[0550] Example 1: Synthesis Scheme

[0551] General synthesis instructions: abbreviation Acetyl group aq (aqueous solution) BBBPY 4,4′-Di-tert-butyl-2,2′-Bipyridine Boc2O (boc acid anhydride) BTMG 2-tert-butyl-1,1,3,3-tetramethylguanidine cat-catalyzed [Cp IrCl2]2 pentamethylcyclopentadienyliridium(III) chloride dimer CV column volume dba dibenzylidene acetone DCM dichloromethane DIPEA N,N- Diisopropylethylamine DMAP 4-Dimethylaminopyridine DMF N , N -Dimethylformamide dppf 1,1'-bis(diphenylphosphine)ferrocene eq equivalent Et Ethyl EtOH (ethanol) HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium HFP hexafluorophosphate i Pr isopropyl KO t Potassium tert-butoxide LiAlH4 lithium aluminum hydride Me methyl MeCN Acetonitrile MeOH (methanol) N2 nitrogen gas (g) NH3 ammonia NMP 1-Methyl-2-pyrrolidone Palladium on Pd / C activated carbon Pd(dppf)Cl2 1,1'-bis(diphenylphosphine)ferrocene palladium dichloride Pd2(dba)3 tris(dibenzylacetone)dipalladium(0) Ph phenyl RBF round-bottom flask rt room temperature RT Retention Time RuPhos 2-Dicyclohexylphosphine-2′,6′-Diisopropoxybiphenyl SCX-2 ISOLUTE® SCX-2 Capture-Release Solid Phase Extraction Column (Sulfonic Acid Type) SPhos 2-Bicyclohexylphosphine-2',6'-Dimethoxybiphenyl TBAF Tetrabutylammonium Fluoride t Bu tert-butyl TBDMS tert-butyldimethylsilyl TBDMS-Cl tert-butyldimethylchlorosilane TEA Triethylamine TFA (trifluoroacetic acid) THF Tetrahydrofuran ZnCN Zinc Cyanide All reagents obtained from commercial sources were used directly without further purification. Anhydrous solvents were purchased from commercial sources and used without additional drying.

[0552] The reaction process was monitored by LCMS and / or TLC.

[0553] Thin-layer chromatography analysis was performed using Merck Type 60 F coated with... 254 The reaction was carried out on 5 cm × 10 cm silica gel plates. Microwave heating was performed using an Anton Parr MonoWave or CEM Discover® instrument. The photochemical reaction was performed in a Hepatochem Lucent 360™ advanced photoreactor. The hydrogenation reduction reaction was carried out under a hydrogen atmosphere at atmospheric pressure, using a setup including burettes with hydrogen replaced by water and sealed Rodavis® glass connectors, which were supported and oscillated on a Heidolph oscillator under a hydrogen atmosphere. Hydrogen was generated by electrolysis of water using a Domnick Hunter® NITROX™ UHP hydrogen generator.

[0554] Evaporation and drying of the compounds were performed using a Buchi rotary evaporator and / or a Biotage® V-10 Touch evaporation system. Lyophilization of the aqueous mixtures obtained by preparative reversed-phase chromatography was performed using a LABCONCO FreeZone 4.5L -84C freeze dryer.

[0555] purification

[0556] The compound is purified by rapid chromatography, reversed-phase preparative chromatography, or a combination of both techniques.

[0557] Rapid chromatography in ISCO CombiFlash Rf 200, Rf 200i, Rf 300+ and Rf+ Lumen TM Completed on the system, using pre-installed silicone columns (RediSep) ® Rf normal-phase silica rapid column (35-70µm, 60 Å), RediSep Rf Gold ® High-efficiency normal-phase silica gel columns (20-40µm, 60 Å), RediSep ® Rf reversed-phase C18 column (40-63µm, 60 Å) or RediSep RfGold ® High-efficiency reversed-phase C18 columns (20-40µm, 100 Å).

[0558] The reversed-phase preparative chromatography method is performed using the following approach: The AccQPrep HP125 (Teledyne ISCO) system was equipped with a Phenomenex Gemini® NX 5 µm C18(2) column (150 mm × 21.2 mm inner diameter) at a flow rate of 20 mL / min. -1 ; or a Gemini® NX 5 µm C18(2) column (250 mm × 30 mm inner diameter) from Phenomenex, at a flow rate of 40 mL / min. -1 Equipped with UV (214 and 254 nm) and ELS detectors. pH 4 eluent: Solvent A: Water + 0.08% (v / v) formic acid; Solvent B: Acetonitrile + 0.08% (v / v) formic acid. pH 9 eluent: Solvent A: Water + 0.08% (v / v) concentrated ammonia solution; Solvent B: Acetonitrile + 0.08% (v / v) concentrated ammonia solution. Neutral eluent: Solvent A: Water; Solvent B: Acetonitrile.

[0559] Analytical methods

[0560] Analytical LC-MS: The compounds of this invention were characterized by high performance liquid chromatography-mass spectrometry (HPLC-MS). The instruments and methods used are as follows: LCMS (Method A): An Agilent 1260 liquid chromatograph coupled with an Agilent InfinityLab LC / MSD XT single quadrupole mass spectrometer was used, operating in both positive and negative ion electrospray ionization modes. The molecular weight scan range was 100 to 1350 m / z. Parallel UV detection wavelengths were 210 nm, 254 nm, and 270 nm. Samples were provided as 1 mM acetonitrile solution or a THF / water (1:1) mixture, injected via 5 µL loop injection. The column specifications were ZORBAX Eclipse XDB-C18, 1.8 µm, 50 mm × 4.6 mm inner diameter. The operating temperature was 40°C, the flow rate was 1 mL / min, and gradient elution was used with 0.02% v / v formic acid aqueous solution (solvent A) and 0.02% v / v formic acid acetonitrile solution (solvent B), starting at 100% solvent A and ending at 100% solvent B over various durations.

[0561] LCMS (Method B): An Agilent 1290 Infinity II UHPLC system connected to a TOF 6230 mass spectrometer, equipped with an ES ionization source (positive or negative mode ionization). LCMS used a buffered mobile phase: polar phase: water / 10 mM ammonium formate / 0.08% (v / v) formic acid pH=3.3; nonpolar phase: acetonitrile / 5.3% (v / v) ammonium formate / 0.08% (v / v) formic acid. The mobile phase was passed through a Phenomenex Kinetex C18 column (2.6 μm, 50 × 2 mm), temperature 55°C, flow rate 1.3 mL / min. 1 μL of sample was injected, eluted with a 5% to 95% gradient for 1.18 min, for a total run time of 1.95 min.

[0562] 1 H-NMR measurements were performed using a Bruker Avance NEO 400 MHz NMR spectrometer with DMSO-d6 or CDCl3 as the solvent. 1 H-NMR data are expressed as δ values ​​in parts per million (ppm), with solvent residue peaks (2.50 ppm for DMSO-d6 and 7.26 ppm for CDCl3) used as internal standards. Splitting modes are labeled as: s (singleton), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplex), app s (apparent singleton), br s (broad singleton), br d (broad doublet), br t (broad triplet), br m (broad multiplex), dd (double doublet), td (triple doublet), dt (double triplet), qd (quadruple doublet), ddd (double double doublet), dm (double multiplex). Specific implementation examples:

[0564] Intermediate 1a: Methyl 2-[(4-cyclopropyl-2-nitrophenyl)amino]acetate

[0565] A mixture of 4-cyclopropyl-1-fluoro-2-nitrobenzene (200 mg, 1.1 mmol, 1 eq), methyl glycine (98 mg, 1.1 mmol, 1 eq), potassium carbonate (168 mg, 1.21 mmol, 1.1 eq), ethanol (1 mL), and water (0.2 mL) was heated to 90°C and reacted for 18 hours. After cooling, the mixture was diluted with DMF (1 mL), treated with iodomethane (206.27 µL, 2.28 g / mL, 3.31 mmol, 3 eq), and stirred for 16 hours. The crude reaction mixture was partitioned between water and dichloromethane. The aqueous layer was extracted twice more with dichloromethane. The combined organic phases were washed with brine, passed through a phase separator, and concentrated to give an orange gel-like residue. The crude product was loaded onto an ISOLUTE HM-N and purified by automated rapid chromatography (Combiflash Rf, RediSep silica gel, 24 g column) using a gradient elution from heptane to heptane containing 75% ethyl acetate. After vacuum concentration, the title compound 1a (86 mg, 0.34 mmol, 31%) was obtained as a red solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.26(t, J = 5.9 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.28 (dd, J = 8.9, 2.3 Hz,1H), 6.85 (d, J = 8.9 Hz, 1H), 4.27 (d, J = 5.9 Hz, 2H), 3.70 (s, 3H), 2.02 –1.87 (m, 1H), 0.95 – 0.82 (m, 2H), 0.67 – 0.58 (m, 2H).

[0566]

[0567] Intermediate 1b: 7-Cyclopropyl-3,4-Dihydro-1H-Quinoxolin-2-one

[0568] To a solution of (1a) methyl 2-[(4-cyclopropyl-2-nitrophenyl)amino]acetate (86 mg, 0.34 mmol) in methanol (2 mL) and acetic acid (0.85 mL), reduced iron (192 mg, 3.43 mmol, 10 eq) was added. The reaction mixture was heated to 70°C for 2.5 h. The reaction mixture was slowly poured into a mixture of ice and a saturated solution of NaHCO3 and extracted three times with ethyl acetate. The combined organic phases were washed with brine and dried over anhydrous MgSO4. The entire mixture was then filtered through a phase separator and concentrated under reduced pressure. The crude mixture was dry-loaded onto an ISOLUTE HM-N solid-phase extraction column and purified by automated rapid chromatography (Combiflash Rf, RediSep silica gel, 12 g column) using a gradient elution from heptane to heptane containing 100% ethyl acetate. The column was then washed with ethyl acetate and 10% methanol to give title compound 1b (25.7 mg, 0.14 mmol, 40%) as a beige solid. LCMS (Method A); RT 0.90 min, m / z [M+H] + 189.2. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 6.73 (d, J = 8.3 Hz, 1H), 6.62 (dd, J = 8.2, 2.1 Hz, 1H), 6.59 – 6.44 (m, 2H), 5.76 (s, 1H), 3.72 – 3.63 (m, 2H), 1.83 – 1.69 (m, 1H), 0.89 – 0.78 (m, 2H), 0.54 – 0.45 (m, 2H).

[0569]

[0570] Intermediate 1c: 7-Cyclopropyl-1H-Quinoxolin-2-one

[0571] To a THF (0.5 mL) solution of (1b) 7-cyclopropyl-3,4-dihydro-1H-quinoxalin-2-one (35 mg, 0.19 mmol), manganese dioxide (62 mg, 0.71 mmol, 3.8 eq) was added fractionally at 0°C, followed by reaction at room temperature for 16 hours. The crude reaction mixture was filtered through diatomaceous earth, washed with dichloromethane and then with ethyl acetate. The combined organic phases were concentrated under vacuum to give title compound 1c (18.2 mg, 0.1 mmol, 52%) as a beige solid. The product was used directly in the next reaction without purification. LCMS (Method A); RT 0.89 min, m / z [M+H] + 187.2.1 H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (s, 1H), 8.04 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 6.99 (d, J = 8.9 Hz, 2H), 2.03 (dd, J = 13.1, 8.3, 4.7 Hz, 1H), 1.09 – 1.01 (m,2H), 0.74 (t, J = 6.7, 4.4 Hz, 2H).

[0572]

[0573] Intermediate 1d: 2-chloro-7-cyclopropylquinoxaline

[0574] (1c) 7-cyclopropyl-1H-quinoxalin-2-one (43 mg, 0.23 mmol) was mixed with phosphorus oxychloride (370 µL, 1.65 g / mL, 3.93 mmol, 17 eq) and heated to 110°C for 1 hour. The mixture was added dropwise to ice and stirred until the reagent was quenched. The aqueous layer was neutralized with 1M NaOH aqueous solution under stirring in an ice bath, and extracted three times with ethyl acetate. The combined organic phases were dried over anhydrous MgSO4, filtered, and concentrated to give a brown oily crude product. The product was transferred to ethyl acetate (3 mL) and dried over a Biotage V10 evaporator to give the title compound 1d (27.7 mg, 0.14 mmol, 59%) as a brown gel. LCMS (Method A); retention time 1.25 min, m / z [M+H] + 205.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.89(s, 1H), 8.03 (d, J = 8.7 Hz, 1H), 7.74 (d, J = 2.0 Hz, 1H), 7.63 (dd, J =8.7, 2.0 Hz, 1H), 2.23 (m, 1H), 1.17 – 1.10 (m, 2H), 1.00 – 0.82 (m, 2H).

[0575]

[0576] Specific Example 1: 7-Cyclopropyl-N-(1H-indol-6-ylmethyl)quinoxalin-2-amine

[0577] A mixture of (1d)-2-chloro-7-cyclopropylquinoxaline (27 mg, 0.13 mmol), (1H-indol-6-yl)methylamine (21 mg, 0.15 mmol, 1.1 eq), and 1,4-dioxane (1 mL) was heated to 90°C and reacted for 19 hours. The reaction mixture was partitioned between ethyl acetate and water, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The crude product was dissolved in DMSO (2.5 mL) and purified by reverse-phase (AccQPrep HP125 preparative HPLC) at pH 9 to give title compound 1 (4.3 mg, 0.01 mmol, 10%) as a deep yellow solid. LC-HRMS (Method B); retention time 1.18 min; target mass 314.1531; measured mass ion [M+H] + 315.1608; the empirical formula is C20 H18 N4. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (app s,1H), 8.27 (s, 1H), 7.97 (t, J = 5.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.49(d, J = 8.1 Hz, 1H), 7.42 – 7.38 (m, 1H), 7.31 – 7.27 (m, 1H), 7.22 (d, J =2.0 Hz, 1H), 7.07 – 7.01 (m, 2H), 6.40 – 6.36 (m, 1H), 4.68 (d, J = 5.7 Hz, 2H), 2.09 – 1.99 (m, 1H), 1.05 – 0.97 (m, 2H), 0.82 – 0.74 (m, 2H).

[0578]

[0579] Specific Example 2: N-[(7-methyl-1H-indol-5-yl)methyl]quinoxalin-2-amine

[0580] A mixture of 2-chloroquinoxaline (100 mg, 0.61 mmol), (7-methyl-1H-indol-5-yl)methylamine (117 mg, 0.73 mmol, 1.2 eq), and potassium carbonate (235 mg, 1.7 mmol, 2.8 eq) in 1,4-dioxane (3 mL) was heated to 90°C and reacted for 24 hours. The reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was dry-loaded onto an ISOLUTE HM-N and purified by automated rapid chromatography (Combiflash Rf 300+, Gold RediSep, 24 g silica gel column) with a gradient elution of heptane to 100% ethyl acetate in heptane to give 85 mg of a yellow solid. The substance was dissolved in DMSO and methanol, and further purified by preparative HPLC (pH 9) to give title compound 2 (40.2 mg, 0.14 mmol, 23%) as a yellow solid. LC-HRMS (Method B); retention time 1.04 min; target mass 288.1375; measured m / z [M+H] + 289.1455; empirical formula C18 H16 N4. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.01 (apps, 1H), 8.37 (s, 1H), 7.96 (t, J = 5.5 Hz, 1H), 7.78 – 7.73 (m, 1H), 7.60 –7.50 (m, 2H), 7.42 – 7.38 (m, 1H), 7.34 – 7.28 (m, 2H), 6.97 – 6.93 (m, 1H), 6.41 – 6.36 (m, 1H), 4.63 (d, J = 5.5 Hz, 2H), 2.46 (s, 3H).

[0581]

[0582] Intermediate 3a: 7-bromo-N-(1H-indole-6-ylmethyl)quinoxaline-2-amine

[0583] 7-Bromo-2-chloroquinoxaline (200 mg, 0.82 mmol) was dissolved in 1,4-dioxane (8 mL), and (1H-indol-6-yl)methylamine (120 mg, 0.82 mmol, 1 eq) and potassium carbonate (230 mg, 1.64 mmol, 2 eq) were added. The mixture was heated to 90°C under nitrogen protection. After the reaction mixture was cooled to room temperature, it was partitioned with ethyl acetate / water. The organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and loaded onto an ISOLUTE HM-N column. It was purified by automated rapid chromatography (Combiflash Rf 300+, RediSep 12 g silica column) with a gradient elution of 50% ethyl acetate from heptane to heptane to give title compound 3a (238 mg, 0.67 mmol, 82%) as a colorless gel. LCMS (Method A); Retention time 1.23 minutes; m / z [M+H] + 353.2. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.02 (s, 1H), 8.38 (s, 1H), 8.29 (t, J = 5.6 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.50(dt, J = 8.0, 0.8 Hz, 1H), 7.46 – 7.38 (m, 2H), 7.30 (dd, J = 3.1, 2.4 Hz,1H), 7.04 (dd, J = 8.1, 1.5 Hz, 1H), 6.39 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H),4.68 (d, J = 5.6 Hz, 2H).

[0584]

[0585] Intermediate 3b: 6-{[(7-bromoquinoxalo-2-yl)(tert-butyloxycarbonyl)amino]methyl}indole-1-carboxylic acid tert-butyl ester

[0586] 7-Bromo-N-(1H-indol-6-ylmethyl)quinoxalin-2-amine 3a (152 mg, 0.43 mmol, 1 eq) was dissolved in dichloromethane (6 mL), treated with DMAP (16 mg, 0.13 mmol, 0.3 eq) and DIPEA (157 µL, 0.78 g / mL, 0.95 mmol, 2.2 eq), followed by treatment with Boc anhydride (275 mg, 1.29 mmol, 3 eq). The mixture was stirred at room temperature under nitrogen protection for 2 hours, and then partitioned with dichloromethane and a saturated aqueous sodium bicarbonate solution. The organic phase was evaporated to dryness using a phase separator, loaded onto an ISOLUTE HM-N column, and purified by automated rapid chromatography (Combiflash 300+, RediSep 12g silica column) with a heptane to 15% ethyl acetate / heptane gradient elution to give title compound 3b (182 mg, 0.33 mmol, 76%) as a clear gel. LCMS (Method A); retention time 1.59 min; m / z [M-tBu+H] + 497.

[0587]

[0588] Intermediate 3c: 6-{[(tert-butyloxycarbonyl)[7-(piperidin-1-yl)quinoxalin-2-yl]amino]methyl}indole-1-carboxylic acid tert-butyl ester

[0589] A solution of 6-{[(7-bromoquinoxalo-2-yl)(tert-butyloxycarbonyl)amino]methyl}indole-1-carboxylic acid tert-butyl ester 3b (90 mg, 0.16 mmol, 1 eq) in toluene (3 mL) was treated with piperidine (48.3 µL, 0.49 mmol, 3 eq) and sodium tert-butoxide (18.75 mg, 0.2 mmol, 1.2 eq). After bubbling the mixture with nitrogen, 3-(methylamino)-2-phenylphenyl-1-yldicyclohexyl[2-(2,6-diisopropoxyphenyl)phenyl]phosphine palladium(II) methanesulfonic acid (7 mg, 8.13 µmol, 0.05 eq) and RuPhos (3.8 mg, 8.13 µmol, 0.05 eq) were added. The container was sealed and heated to 120°C for 16 hours behind an explosion-proof shield. After cooling the reaction mixture to room temperature, it was partitioned with ethyl acetate / saturated sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness before being loaded onto an ISOLUTE HM-N column. Purification was then performed by automated rapid chromatography (Combiflash Rf 300+, 12g RediSep column with silica), eluting with a gradient from heptane to 20% ethyl acetate / heptane, to give the title compound 3c (51 mg, 0.09 mmol, 56%) as a green gel. LCMS (Method B); retention time 1.56 min; m / z [M+H] + 558.3.

[0590]

[0591] Specific Example 3: N-(1H-indol-6-ylmethyl)-7-(piperidin-1-yl)quinoxalin-2-amine

[0592] A mixture of 6-{[(tert-butyloxycarbonyl)[7-(piperidin-1-yl)quinoxalin-2-yl]amino]methyl}indole-1-carboxylic acid tert-butyl ester 3c (51 mg, 0.09 mmol) in hexafluoro-2-propanol (2 mL) was heated to 100°C for 2 hours. The reaction mixture was cooled to room temperature and evaporated, then redissolved in dichloromethane and dry-loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica column), eluting with heptane to 100% ethyl acetate, to give title compound 3 (19 mg, 0.05 mmol, 58% yield) as a yellow solid. LC-HRMS (Method B); retention time 1.13 min; target mass 357.1965; measured m / z [M+H] + 358.2041; Actual empirical formula C22 H23 N5. 1HNMR (400 MHz, DMSO-d6) δ ppm 10.99 (app s, 1H), 8.07 (s, 1H), 7.79 (t, J =5.7 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.40 – 7.37(m, 1H), 7.30 – 7.27 (m, 1H), 7.08 (dd, J = 9.1, 2.8 Hz, 1H), 7.03 (dd, J =8.1, 1.5 Hz, 1H), 6.78 (d, J = 2.8 Hz, 1H), 6.40 – 6.36 (m, 1H), 4.67 (d, J =5.7 Hz, 2H), 3.31 – 3.24 (m, 4H), 1.67 – 1.52 (m, 6H).

[0593]

[0594] Specific Example 4: N-(1H-indol-5-ylmethyl)quinoxalin-2-amine

[0595] Potassium carbonate (235 mg, 1.7 mmol, 2.8 eq) was added to a mixture of 2-chloroquinoxaline (100 mg, 0.61 mmol) and (1H-indol-5-yl)methylamine (106.58 mg, 0.73 mmol, 1.2 eq) in 1,4-dioxane (3 mL), and the mixture was heated to 90°C for 4 days. The reaction mixture was cooled to room temperature, diluted with water, and extracted three times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude mother liquor was dry-loaded onto an ISOLUTE HM-N filter and purified by automated rapid chromatography (Combiflash Rf 300+, Gold RediSep, 12 g silica column) with a gradient elution from heptane to 100% ethyl acetate, followed by washing with 10% methanol / dichloromethane. The product was dissolved in DMSO and then purified again by preparative HPLC (ISCO AccQPrep HP125) at pH 4. Lyophilization yielded title compound 4 (68 mg, 0.25 mmol, 41%) as a yellow solid. LC-HRMS (Method B); retention time 0.97 min; target mass 274.1221; measured m / z [M+H] + 275.1294; empirical formula C17 H14 N4. 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.03 (app s, 1H), 8.36 (s, 1H), 8.00 (t, J = 5.5 Hz, 1H), 7.78 –7.73 (m, 1H), 7.59 – 7.50 (m, 3H), 7.38 – 7.34 (m, 1H), 7.34 – 7.29 (m, 2H), 7.15 (dd, J = 8.3, 1.7 Hz, 1H), 6.40 – 6.36 (m, 1H), 4.66 (d, J = 5.5 Hz, 2H).

[0596]

[0597] Intermediate 5a: N-(4-cyano-1H-indole-6-yl)tert-butyl carbamate

[0598] 6-Amino-1H-indole-4-carboxynitrile [Advanced ChemBlocks Inc., catalog number Q55346] (250 mg, 1.59 mmol) and DMAP (39 mg, 0.32 mmol, 0.2 eq) were added to THF (2 mL) and stirred under nitrogen protection. A solution of (Boc)₂O (695 mg, 3.2 mmol, 2 eq) in THF (2 mL) was added to the mixture, followed by TEA (0.46 mL, 3.34 mmol, 2.1 eq), and the mixture was stirred at room temperature for 1.5 h. The mixture was partitioned with ethyl acetate and saturated sodium bicarbonate aqueous solution. The organic layer was washed with brine, filtered through a phase separator, and concentrated. The crude product was dry-loaded onto ISOLUTE HM-N and purified by automated rapid chromatography (Combiflash Rf 300+, Gold RediSep, 24 g silica column) with a 0-100% gradient elution of heptane / ethyl acetate. The column was washed with 10-20% methanol / ethyl acetate to give intermediate 5a (299.7 mg, 0.84 mmol, 53%), which was used directly in the next reaction without further purification.

[0599]

[0600] Intermediate 5b: 4-(aminomethyl)-6-[(tert-butyloxycarbonyl)amino]indole-1-carboxylic acid tert-butyl ester

[0601] A mixture of 5a-6-[(tert-butyloxycarbonyl)amino]-4-cyanoindole-1-carboxylic acid tert-butyl ester (300 mg, 0.84 mmol, 1 eq) in THF (6 mL) and MeOH (6 mL) was cooled to 0°C, and cobalt(II) chloride (217.75 mg, 1.68 mmol, 2 eq) was added, and the reaction was stirred for 1 min. Sodium borohydride (317.24 mg, 8.39 mmol, 10 eq) was added in portions over 10 min, followed by heating to room temperature for 1 h. The reaction mixture was diluted with ethyl acetate, filtered through a diatomaceous earth mat, and washed with ethyl acetate and 1 / 10 NH3OH / water. After partitioning the organic and aqueous layers, the organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was dissolved in methanol / dichloromethane and loaded onto an SCX-2 rapid column. It was washed with 3 column volumes of methanol / dichloromethane, then extracted with 3 column volumes of (1% NH3 / methanol) / dichloromethane. After concentration, 5b (218 mg, 0.6 mmol) was obtained as a yellow solid crude product. This material was used directly in subsequent steps without further purification.

[0602]

[0603] Intermediate 5c: 6-[(tert-Butoxycarbonyl)amino]-4-[({6-chloropyridino[2,3-b]pyrazin-3-yl}amino)methyl]indole-1-carboxylic acid tert-butyl ester

[0604] Triethylamine (139 µL, 1 mmol, 2 eq) was added to a mixture of 3,6-dichloropyrido[2,3-b]pyrazine [Combi-Blocks JP-8070] (100 mg, 0.5 mmol, 1 eq) and 4-(aminomethyl)-6-[(tert-butyloxycarbonyl)amino]indole-1-carboxylic acid tert-butyl ester 5b (216 mg, 0.6 mmol, 1.2 eq) in dichloromethane (5 mL). The reaction mixture was stirred at 0°C for 1 hour, then heated to room temperature and reacted for 24 hours. The reaction mixture was quenched with water, the dichloromethane layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and then dry-loaded onto an ISOLUTE HM-N column. The purified solution was purified by automated rapid chromatography (Combiflash Rf300+, Gold RediSep, 12 g silica column) with a 0-100% ethyl acetate / heptane gradient elution. The compound was isolated by vacuum evaporation using a Biotage V10 to give the title compound 5c (57.5 mg, 0.11 mmol, 21.91%) as a yellow solid, which could be used directly in the next reaction without further purification. LCMS (Method A); retention time 1.31 min; m / z [M+H] + 1.31.

[0605]

[0606] Intermediate 5e: 6-[(tert-butyloxycarbonyl)amino]-4-({[6-(4-hydroxypiperidin-1-yl)pyridino[2,3-b]pyrazin-3-yl]amino}methyl)indole-1-carboxylic acid tert-butyl ester

[0607] (5f)-6-[(tert-butyloxycarbonyl)amino]-4-[({6-chloropyridino[2,3-b]pyrazin-3-yl}amino)methyl]indole-1-carboxylic acid tert-butyl ester (57 mg, 0.11 mmol, 1 eq) was treated in 1-propanol (1.1 mL) with 4-hydroxypiperidine (12.08 mg, 0.12 mmol, 1.1 eq) and triethylamine (30 µL, 0.22 mmol, 2 eq). The reaction mixture was heated to 100°C for 16 hours. The reaction mixture was partitioned into water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate. The combined organic phases were washed with brine, passed through a phase separator, and concentrated under vacuum. The crude product was dissolved in DMSO and methanol, filtered, and purified by preparative HPLC (AccQPrep P125, Prep HPLC). Lyophilization gave the title compound 5e (16.8 mg, 0.03 mmol, 26%) as a yellow solid. LCMS (Method A); retention time 1.14 min; m / z [M+H] + 590.4

[0608] Specific Example 5: 1-(3-{[(6-amino-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol

[0609] A mixture of (5e)N-[4-({[6-(4-hydroxypiperidin-1-yl)pyrido[2,3-b]pyrazin-3-yl]amino}methyl)-1H-indol-6-yl]aminocarboxylic acid tert-butyl ester (5.2 mg, 0.01 mmol, 1 eq) in HFP (300 µL) was reacted in a sealed microwave reaction tube at 100°C (within a blast-proof enclosure) for 16 h. The reaction mixture was concentrated under reduced pressure and dissolved in DMSO / methanol / a small amount of water, then purified automatically by reverse-phase chromatography (AccQPrep HP125, Prep HPLC), and lyophilized to give title compound 5 (2.04 mg, 0.01 mmol, 49%) as a yellow solid. LC-HRMS (Method B); retention time 1.18 min; target mass 314.1531; determined mass ion [M+H] +315.1608; Actual measured empirical formula C20 H18 N4. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 10.55 – 10.48 (m, 1H), 8.02 (s, 1H), 7.87 (t, J = 5.5 Hz, 1H), 7.77 (d, J = 9.1 Hz, 1H), 6.99 – 6.92 (m, 2H), 6.49 – 6.46 (m, 1H), 6.39 (d,J = 1.9 Hz, 1H), 6.31 – 6.27 (m, 1H), 4.71 (d, J = 5.5 Hz, 2H), 4.22 – 4.10(m, 2H), 3.79 – 3.68 (m 1H), 3.29 – 3.18 (m, 2H), 1.86 – 1.74 (m, 2H), 1.43 – 1.29 (m, 2H). No NH2 or OH signals were observed.

[0610]

[0611] Intermediate 6a: 6-chloro-N-(1H-indol-4-ylmethyl)pyrido[2,3-b]pyrazin-3-amine

[0612] A mixture of 3,6-dichloropyrido[2,3-b]pyrazine (100 mg, 0.5 mmol) and 4-aminomethylindole (80 mg, 0.55 mmol, 1.1 eq) in dichloromethane (5 mL) was added to triethylamine (140 µL, 1 mmol, 2 eq). The reaction was stirred at 0°C for 1.5 hours, then slowly heated to room temperature for 6 hours. After adding water, the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated onto an ISOLUTE HM-N support. Purification was achieved by automated rapid chromatography (Combiflash Rf 300+, Gold RediSep, 12 g silica column) with a gradient elution of 0-100% ethyl acetate in heptane. The column was then washed with 10-20% methanol / ethyl acetate, and the eluents were combined. The resulting solid residue was dissolved in DMSO and methanol after evaporation, and then purified by preparative automated chromatography (AccQPrep HP125, Prep HPLC). The purified residue was lyophilized to give the title compound 6a (41 mg, 0.13 mmol, 26%). LCMS (Method A); RT 1.05 min; m / z [M+H] + 310.2 (chlorine isotope). 1H-NMR (400 MHz, DMSO-d6) δ ppm 11.11 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 8.38 (s, 1H), 8.12(d, J = 8.3 Hz, 1H), 7.34 – 7.24 (m, 3H), 7.04 – 6.91 (m, 2H), 6.53 – 6.45 (m, 1H), 4.82 (d, J = 5.5 Hz, 2H).

[0613]

[0614] Specific Example 6: N-(1H-indol-4-ylmethyl)-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine

[0615] 6-Chloro-N-(1H-indol-4-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 6a (87 mg, 0.28 mmol), was dissolved in 1-propanol (4 mL), and 2-methyl-2,7-diazaspiro[3.5]nonane dihydrochloride (89.8 mg, 0.42 mmol, 1.5 eq) and DIPEA (233 µL, 1.4 mmol, 5 eq) were added. The mixture was heated to 120°C for 16 hours in a sealed tube behind an explosion-proof shield. After cooling, the reaction mixture was partitioned with dichloromethane / salt water. The organic phase was separated by a phase separator and evaporated to dryness. The residue was redissolved in DMSO, purified by preparative automated chromatography (AccQPrep HP150, Prep HPLC), and lyophilized on a freeze dryer to give title compound 6 (23 mg, 0.05 mmol, 19%) as a yellow solid. LC-HRMS (Method B); Retention time 0.57 min; Target mass 413.2328; Measured mass ion [M+H] + 413.2332, empirical formula C24 H27 N7. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (app s, 1H), 8.00 (s, 1H), 7.90 (t, J = 5.5 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.37 – 7.29 (m, 2H), 7.04(t, J = 7.6 Hz, 1H), 7.01 – 6.95 (m, 1H), 6.58 (d, J = 8.8 Hz, 1H), 6.55 –6.50 (m, 1H), 4.86 (d, J = 5.5 Hz, 2H), 3.65 – 3.35 (br m, 4H), 2.61 – 2.37(m, 4H), 2.24 (s, 3H), 2.05 – 1.85 (m, 2H), 1.85 – 1.70 (m, 2H).

[0616]

[0617] Intermediate 7a: (4-bromo-1H-indol-7-yl)methanol

[0618] Methyl 4-bromo-1H-indole-7-carboxylate (500 mg, 1.97 mmol) was dissolved in THF (20 mL) and cooled to 0°C. Lithium aluminum hydride (2.95 mL (1 M), 2.95 mmol, 1.5 eq) was slowly added dropwise, and the mixture was heated to room temperature and reacted for 16 hours. After recooling to 0°C, the reaction was quenched by adding water (100 µL) and then by adding 100 µL of 15% sodium hydroxide aqueous solution. The mixture was diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to give a clear, oily title compound 7a (470 mg, 2.08 mmol, quantitative). LCMS (Method A); retention time 1.46 min; m / z [M+H] + 340. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.33 (s, 1H), 7.42 (t, J = 2.8 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 7.01 (dd, J = 7.6, 1.0 Hz, 1H), 6.40 (dd, J = 3.2, 1.8 Hz, 1H), 5.23 (t,J = 5.7 Hz, 1H), 4.75 (dd,J = 5.6, 0.9 Hz, 2H).

[0619]

[0620] Intermediate 7b: 4-Bromo-7-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indole

[0621] A mixture of (7a) (4-bromo-1H-indol-7-yl)-methanol (470 mg, 2 mmol), TBDMS-Cl (376 mg, 2.5 mmol, 1.2 eq), and imidazole (350 mg, 5.2 mmol, 2.5 eq) in THF (15 mL) was stirred at room temperature for 16 hours under nitrogen protection. The reaction mixture was extracted with ethyl acetate / water, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. Purification was achieved by automated rapid chromatography (Combiflash Rf 300+, RediSep 24 g silica column) with a gradient elution from heptane to 10% ethyl acetate / heptane to give title compound 7b (514 mg, 1.51 mmol, 73%) as a beige solid. LCMS (Method A); retention time 1.46 min; m / z [M+H] + 341.

[0622]

[0623] Intermediate 7c: (4-bromo-3-methyl-1H-indol-7-yl)methanol

[0624] 4-Bromo-7-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indole 7b (514 mg, 1.5 mmol), KO t Bu (170 mg, 1.51 mmol, 1 eq) and [Cp] A mixture of IrCl₂[12 mg, 0.02 mmol, 0.01 eq] in methanol (10 mL) was placed in a sealed tube and heated to 120°C for 48 hours under explosion-proof protection. After cooling, the reaction mixture was partitioned with ethyl acetate / saline, and the organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated to dryness, and loaded onto ISOLUTEH M-N. The mixture was purified by automated rapid chromatography (Combiflash Rf, 12 g RediSep silica gel column) with a gradient elution from heptane to 100% ethyl acetate / heptane to give the title compound 7c (70 mg, 0.29 mmol, 19%) as a beige solid. LCMS (Method A); retention time 1.02 min; m / z [M+H] + 238. 1H NMR (400 MHz, DMSO-d6) δ ppm10.94 –10.83 (m, 1H), 7.17 (dq, J = 2.0, 1.0 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 6.94(d, J = 7.6, 0.9 Hz, 1H), 5.18 (t, J = 5.7 Hz, 1H), 4.70 (dd, J = 5.7, 0.9Hz, 2H), 2.46 (d, J = 1.1 Hz, 3H).

[0625]

[0626] Intermediate 7d: 4-bromo-7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indole

[0627] (4-Bromo-3-methyl-1H-indol-7-yl)methanol 7c (70 mg, 0.29 mmol) was dissolved in THF (4 mL), and TBDMS-Cl (53 mg, 0.35 mmol, 1.2 eq) and imidazole (50 mg, 0.73 mmol, 2.5 eq) were added. The mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction mixture was partitioned with ethyl acetate / water. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and loaded onto an ISOLUTE HM-N filter. Purification was performed by automated rapid chromatography (Combiflash Rf, RediSep 4g silica gel column) with a 0-10% ethyl acetate / heptane gradient to give the title compound 7d (71 mg, 0.2 mmol, 69%) as a clear oil. LCMS (Method A); retention time 1.50 min; m / z [M+H] + 356.2 (bromine isotope). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.85 (s, 1H), 7.12 (dd, J = 2.5, 1.2 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 4.84 (d, J = 1.0 Hz, 2H), 0.82 (s, 9H), 0.00 (s, 6H).

[0628]

[0629] Intermediate 7e: 7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indole-4-carboxynitrile

[0630] 4-Bromo-7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indole 7d (71 mg, 0.2 mmol) was dissolved in NMP (1.5 mL), and zinc powder (2.6 mg, 0.04 mmol, 0.2 eq), zinc cyanide (25 mg, 0.2 mmol, 1 eq), Pd2(dba)3 (28 mg, 0.03 mmol, 0.15 eq), and Pd(dppf)Cl2 (33 mg, 0.06 mmol, 0.3 eq) were added sequentially, followed by degassing with nitrogen. The mixture was heated to 140°C and reacted for 24 hours. After cooling to room temperature, it was diluted with ethyl acetate, filtered through a diatomaceous earth filter, and washed with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep 12g silica gel column) with a 0-40% ethyl acetate / heptane gradient elution. After concentration and drying under reduced pressure, 7e (21 mg, 0.07 mmol, 35%) 3651-SB-033-001 was given as a colorless solid. LCMS (Method A); retention time 1.42 min; m / z [M+H] + 300.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.30 (s, 1H), 7.49 (d, J =7.5 Hz, 1H), 7.38 (dd, J = 2.5, 1.1 Hz, 1H), 7.23 (dd, J = 7.5, 1.0 Hz, 1H), 5.04 (d, J = 1.0 Hz, 2H), 2.45 (d, J = 1.1 Hz, 3H), 0.92 (s, 9H), 0.10 (s, 6H).

[0631]

[0632] Intermediate 7f: (7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indol-4-yl)methylamine

[0633] 7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indole-4-carboxynitrile 7e (21 mg, 0.07 mmol) was dissolved in methanol (1.5 mL) and tetrahydrofuran (1.5 mL) and cooled to 0°C. Cobalt(II) chloride (18 mg, 0.14 mmol, 2 eq) was then added to the solution, followed by sodium borohydride (26 mg, 0.7 mmol, 10 eq) after 1 minute. The reaction was stirred at room temperature under a nitrogen atmosphere. The reaction was attempted to be quenched after 15 minutes. The reaction solution was diluted with ethyl acetate, filtered through diatomaceous earth, and washed with 3% ammonia solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and loaded onto an ISOLUTE HM-N column. Purification was performed using automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica gel column) with a 0-12% methanol gradient in dichloromethane / methanol (methanol solution containing 1% 1NNH3). Concentration under reduced pressure and drying under vacuum gave the title compound 7f (7 mg, 0.02 mmol, 33%) as a colorless solid. LCMS (Method A); retention time 1.03 min; m / z [MH] - 303.2. 1 H NMR (400MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 7.02 (dd, J = 2.5, 1.2 Hz, 1H), 6.99 (d, J= 7.3 Hz, 1H), 6.90 (d, J = 7.3 Hz, 1H), 4.92 (d, J = 0.9 Hz, 2H), 4.07 (s,2H), 2.43 (d, J = 1.1 Hz, 3H), 0.90 (s, 9H), 0.07 (s, 6H).

[0634]

[0635] Intermediate 7g: N-[(7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indol-4-yl)methyl]-6-chloropyrido[2,3-b]pyrazin-3-amine

[0636] (7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indol-4-yl)methylamine 7f (7 mg, 0.02 mmol) and 3,6-dichloropyrido[2,3-b]pyrazine (6 mg, 0.03 mmol, 1.2 eq) were dissolved in DMF (1 mL), and DIPEA (8 µL, 0.05 mmol, 2 eq) was added. The mixture was stirred at room temperature for 6 hours under a nitrogen atmosphere. The reaction mixture was partitioned with ethyl acetate and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated onto ISOLUTE HM-N. It was then purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica gel column) with 0-10% ethyl acetate in dichloromethane as eluent. After evaporation, the mixture was dried under vacuum to give 7 g (11 mg, 0.02 mmol, quantified) of the title compound as a white solid. LCMS (Method A); Retention time 1.44 minutes; m / z [M+H] + 468.2. 1 H NMR (400 MHz, DMSO-d6)δ ppm 10.60 (d, J = 2.5 Hz, 1H), 8.49 (t, J = 4.8 Hz, 1H), 8.39 (s, 1H), 8.11(d, J = 8.3 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.04 (dd, J = 2.5, 1.2 Hz,1H), 6.96 (d, 1H), 6.89 (d, J = 7.4 Hz, 1H), 4.88 (s, 2H), 4.84 (d, J = 4.8Hz, 2H), 2.30 (d, J = 1.0 Hz, 3H), 0.82 (s, 9H), -0.00 (s, 6H).

[0637]

[0638] Intermediate 7h: 1-(3-{[(7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol

[0639] A mixture of 7 g (11 mg, 0.02 mmol, 1 eq) of N-[(7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indol-4-yl)methyl]-6-chloropyrido[2,3-b]pyrazin-3-amine, 4-hydroxypiperidine (7 mg, 0.07 mmol, 3 eq), and DIPEA (20 µL, 0.78 g / mL, 0.12 mmol, 5 eq) in 1-propanol (1.5 mL) was added to a sealed tube and heated to 120°C for 16 h after an explosion-proof shield. After cooling the reaction mixture to room temperature, it was partitioned with dichloromethane / salt water. The organic phase was separated by a phase separator and evaporated onto an ISOLUTE HM-N support, followed by purification by automated rapid chromatography (Combiflash Rf 300+, RediSep 4 g silica gel column) with a 0–100% ethyl acetate / heptane gradient elution. Evaporation and vacuum drying yielded the title compound (10 mg, 0.02 mmol, 80%) as a yellow solid after 7 h. LCMS (Method A); retention time 1.26 min; m / z [M+H] + 533.4 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.65 (d, J =2.5 Hz, 1H), 8.04 (s, 1H), 7.83 (t, J = 4.8 Hz, 1H), 7.78 (d, J = 9.0 Hz,1H), 7.10 (dd, J = 2.4, 1.2 Hz, 1H), 7.02 (d, J = 7.3 Hz, 1H), 6.99 – 6.86 (m, 2H), 4.95 (s, 2H), 4.88 (d, J = 4.8 Hz, 2H), 4.71 (d, J = 4.3 Hz, 1H), 4.27 – 4.11 (m, 1H), 3.74 (td, J = 8.6, 4.3 Hz, 1H), 3.24 (td, J = 10.1, 4.9Hz, 2H), 2.39 (d, J = 1.0 Hz, 3H), 1.87 – 1.74 (m, 2H), 1.41 – 1.29 (m, 2H), 0.91 (s, 9H), 0.09 (s, 6H).

[0640]

[0641] Specific Example 7: 1-[3-({[7-(hydroxymethyl)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol

[0642] 1-(3-{[(7-{[(tert-butyldimethylsilyl)oxy]methyl}-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol 7h (10 mg, 0.02 mmol) was dissolved in THF (1 mL), and TBAF (1M THF solution) (56 µL, 0.06 mmol, 3 eq) was added. After 2.5 hours, the mixture was partitioned between ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated onto ISOLUTE HM-N, and purified by automated rapid chromatography (Combiflash Rf 300+, RediSep 4 g silica gel column) with a 2-10% methanol / dichloromethane gradient to give title compound 7 (3 mg, 0.01 mmol, 38%) as a yellow solid. LC-HRMS (Method B); retention time 0.64 min; target mass 418.2117; measured mass ion [M+H] + 419.2198; Empirical formula: C23H26N6O2. 1 H-NMR(400 MHz, DMSO-d6) δ ppm 10.65 (d, J = 2.5 Hz, 1H), 8.05 (s, 1H), 7.83 (t, J= 4.9 Hz, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.08 (dd, J = 2.4, 1.2 Hz, 1H), 7.02– 6.93 (m, 2H), 6.90 (d, J = 7.3 Hz, 1H), 5.09 (t, J = 5.6 Hz, 1H), 4.88 (d,J = 4.7 Hz, 2H), 4.73 (dd, J = 9.9, 4.9 Hz, 3H), 4.17 (dt, J = 13.3, 4.6 Hz, 2H), 3.74 (tq, J = 8.6, 4.1 Hz, 1H), 3.32 – 3.18 (m, 2H), 2.39 (d, J = 1.1Hz, 3H), 1.84 – 1.76 (m, 2H), 1.43 – 1.30 (m, 2H).

[0643]

[0644] Intermediate 8a: 4-{[(tert-butyloxycarbonyl)amino](²H₂)methyl}indole-1-carboxylic acid tert-butyl ester

[0645] To a dry DMF (15 mL) solution of 1-boc-4-bromoindole (500 mg, 1.7 mmol), add sequentially nickel(II) glycol dimethyl ether complex (20 mg, 0.08 mmol, 0.05 eq); boc-Gly-OH-2,2-d2 (0.45 mL, 1 g / mL, 2.53 mmol, 1.5 eq); BTMG (0.5 mL, 2.5 mmol, 1.5 eq); (4,4'-di-tert-butyl-2,2'-bipyridine)bis[3,5-difluoro-2-[5-trifluoromethyl-2-pyridyl-kN)phenyl-kC]iridium(III) hexafluorophosphate (99%) [CAS:870987-63-6] (20 mg, 17 µmol, 0.01 eq) and BBBPY (23 mg, 0.08 mmol, 0.05 eq). The reaction mixture was irradiated with a nitrogen stream for 5 minutes. The reaction system was then irradiated with a blue LED (450 nm, 50 W, 75% intensity) for 16 hours at 25°C (cooled by an auxiliary circulating cooler) in a Lucent 360 reactor. After the reaction was complete, the mixture was quenched with water, and the product was extracted with ethyl acetate (3 times). The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered, and dry-loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 12 g silica gel column) using a 0-100% ethyl acetate / heptane gradient. Evaporation and drying yielded the title compound 8a (240 mg, 0.69 mmol, 40%) as a colorless oil. LCMS (Method A); retention time 1.36 min; m / z [MH] - 347.2. 1 H-NMR (400 MHz, DMSO-d6) δ7.96 (dt, J = 8.3, 0.9 Hz, 1H), 7.69 (d, J = 3.8 Hz, 1H), 7.42 (s, 1H), 7.27(dd, J = 8.3, 7.3 Hz, 1H), 7.10 (dd, J = 7.4, 0.9 Hz, 1H), 6.89 – 6.83 (m,1H), 1.63 (s, 9H), 1.40 (s, 9H).

[0646]

[0647] Intermediate 8b: 1H-indol-4-yl(²H₂)methylamine

[0648] 4-{[(tert-Butoxycarbonyl)amino](²H₂)methyl}indole-1-carboxylic acid tert-butyl ester 8a (100 mg, 0.29 mmol, 1 eq) was dissolved in HPF (3 mL, 28 mmol, 100 eq) and heated at 110°C for 16 hours behind an explosion-proof shield. The reaction mixture was cooled and concentrated. The crude product was dissolved in dichloromethane / methanol, loaded onto an SCX column, and eluted with dichloromethane / methanol. The product was eluted with a dichloromethane / 7N NH₃ methanol solution, and evaporation gave the title compound 8b (45 mg, 0.3 mmol, 105.8%) as a brown gel. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.35 (s, 1H), 7.49 – 7.39 (m,2H), 7.40 – 7.20 (m, 2H), 7.18 – 7.09 (m, 2H), 6.67 (ddd, J = 3.0, 1.9, 0.9Hz, 1H).

[0649]

[0650] Specific Example 8: 1-(3-{[1H-indol-4-yl(²H2)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol

[0651] DIPEA (0.11 mL, 0.61 mmol, 1.2 eq) was added to a 3 mL NMP solution containing 3,6-dichloropyrido[2,3-b]pyrazine (121.47 mg, 0.61 mmol, 1.2 eq) and 1H-indol-4-yl(²H₂)methylamine (75 mg, 0.51 mmol, 1 eq), and the mixture was stirred for 1 hour. Subsequently, 4-hydroxypiperidine (155 mg, 1.52 mmol, 3 eq) and additional DIPEA (0.26 mL, 1.52 mmol, 3 eq) were added, the reaction mixture was sealed, and heated in a microwave at 150°C for 2 hours. The cooled reaction mixture was quenched with water and extracted with ethyl acetate (x3). The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was redissolved in DMSO (1.5 mL) and purified using a preparative high-performance liquid chromatography (HPLC) automated purification system (ISCOAccQPrep HP125, Prep HPLC). The solvent was removed by freeze-drying for 16 hours, finally yielding title compound 8 (7 mg, 0.02 mmol, 4%) as a yellow solid. LC-HRMS (Method B); retention time 0.67 min; target mass 376.1981; measured m / z [M+H] + 377.2058; Empirical formula: C21 H20 D2 N6 O. 1 H NMR (400 MHz, DMSO-d6) δppm 11.15 (app s, 1H), 8.02 (s, 1H), 7.91 (s, 1H), 7.78 (d, J = 9.0 Hz, 1H), 7.36 – 7.30 (m, 2H), 7.04 (dd, J = 8.0, 7.1 Hz, 1H), 7.00 – 6.93 (m, 2H), 6.55 – 6.51 (m, 1H), 4.71 (d, J = 4.2 Hz, 1H), 4.21 – 4.11 (m, 2H), 3.78 –3.68 (m, 1H), 3.29 – 3.19 (m, 2H), 1.86 – 1.74 (m, 2H), 1.42 – 1.30 (m, 2H).

[0652]

[0653] Intermediate 9a: 6-chloro-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine

[0654] Triethylamine (1.81 mL, 13 mmol, 2 eq) was added to a mixture of 3,6-dichloropyrido[2,3-b]pyrazine (1.3 g, 6.5 mmol, 1 eq) and 1H-indole-6-methylamine (855 mg, 5.85 mmol, 0.9 eq) in dichloromethane (60 mL). The reaction was stirred at 0°C for 1 hour, then heated to room temperature and continued for 3 hours. The reaction was quenched with water, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, then evaporated to dryness and adsorbed onto an ISOLUTE HM-N column. The purified column was then purified by automated rapid chromatography (Combiflash Rf 300+, Silica 40 g Gold RediSep 40 g silica column) with a 0-100% (3:1 ethyl acetate / ethanol) / n-heptane gradient elution. Evaporation via Biotage V10 yielded the title compound 9a (1.37 g, 4.42 mmol, 76%) as a yellow solid. LCMS (Method A); retention time 0.938 min; m / z [M+H]+ 310.1 (chlorine isotope). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.05 (s, 1H), 8.76 – 8.66 (m, 1H), 8.44 (s,1H), 8.19 (d, J = 8.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 1H), 7.47 – 7.41 (m, 1H),7.38 (d, J = 8.3 Hz, 1H), 7.35 – 7.27 (m, 1H), 7.06 (dd, J = 8.1, 1.5 Hz,1H), 6.43 – 6.37 (m, 1H), 4.73 (d, J = 5.7 Hz, 2H).

[0655]

[0656] Intermediate 9b: 4-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidine-1-carboxylic acid tert-butyl ester

[0657] In a round-bottom flask, 6-chloro-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine 9a (100 mg, 0.32 mmol), Pd(dppf)Cl2:DCM complex (2.6 mg, 0.01 eq), potassium carbonate (133.85 mg, 0.97 mmol, 3 eq), and N-Boc-1,2,3,6-tetrahydropyridine-4-boronic acid pinacol ester (110 mg, 0.36 mmol, 1.1 eq) were dissolved in tetrahydrofuran (5 mL) and water (1 mL). After purging with nitrogen for 5 minutes, the reaction mixture was stirred at 70°C for 16 hours under a nitrogen atmosphere. After cooling the reaction solution to room temperature, a 10% Pd / C catalyst (30 mg) solution in isopropanol (1 mL) was added and diluted with methanol (5 mL). The flask was evacuated and backfilled with nitrogen three times, and finally evacuated and backfilled with hydrogen. The reaction mixture was shaken for 16 hours at room temperature and under a hydrogen atmosphere of 1 atm, and the amount of hydrogen absorbed was measured by volume. The reaction mixture was filtered through diatomaceous earth under nitrogen protection and washed with dichloromethane. The combined organic phases were washed with saturated sodium bicarbonate aqueous solution and dried over anhydrous magnesium sulfate. The entire solution was re-filtered and concentrated onto an ISOLUTE HM-N plate, and eluted with an automated rapid chromatography method (Combiflash Rf 300+, GoldRediSep, 12 g silica gel column) using a 0-100% ethyl acetate / heptane gradient to give the title compound 9b (123 mg, 0.27 mmol, 83%) as a yellow solid. LCMS (Method A); retention time 1.12 min; m / z [M-tBu+H] + 459.4. 1 H NMR(400 MHz, DMSO-d6) δ ppm 11.05 – 10.98 (m, 1H), 8.38 (s, 1H), 8.07 (d, J =8.2 Hz, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.41 (s, 1H), 7.30 (t, 1H), 7.28 (d, J= 8.2 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.39 (dd, J = 3.0, 1.9, 0.9Hz, 1H), 4.73 (d, J = 5.5 Hz, 2H), 4.09 (d, J = 11.9 Hz, 2H), 3.04 – 2.92 (m,1H), 1.91 – 1.81 (m, 2H), 1.65 (qd, J = 12.5, 4.3 Hz, 2H), 1.42 (s, 9H).

[0658]

[0659] Specific Example 9: N-(1H-indol-6-ylmethyl)-6-(piperidin-4-yl)pyrido[2,3-b]pyrazin-3-amine

[0660] 4-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidine-1-carboxylic acid tert-butyl ester (3614-CAM-015-002, 123 mg, 0.27 mmol, 1 eq) was dissolved in hexafluoroisopropanol (3 mL) and placed in a sealed tube behind an explosion-proof screen. The mixture was heated at 110°C for 16 hours. The reaction mixture was concentrated under vacuum and redissolved in DMSO / methanol / trace water. The mixture was separated by preparative HPLC (ISCO AccQPrep HP125, Prep HPLC) and freeze-dried to give N-(1H-indol-6-ylmethyl)-6-(piperidine-4-yl)pyrido[2,3-b]pyrazin-3-amine (6.8 mg, 0.02 mmol, yield 7%) as a milky white solid. LC-HRMS (Method B); retention time 0.66 min, target mass 358.1906, measured m / z 359.1982, measured molecular formula C21H22N6. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.04 (apps, 1H), 8.42 – 8.34 (m, 2H), 8.09 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 8.1 Hz,1H), 7.42 – 7.39 (m, 1H), 7.32 – 7.29 (m, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.05 (dd, J = 8.1, 1.5 Hz, 1H), 6.42 – 6.36 (m, 1H), 4.73 (d, J = 5.5 Hz, 2H), 3.26 – 3.16 (m, 2H), 3.04 – 2.93 (m, 1H), 2.87 – 2.75 (m, 2H), 1.96 – 1.76 (m, 4H). No piperidine NH signal was observed.

[0661]

[0662] Intermediate 10a: 2-(hydroxymethyl)-1H-indole-6-carboxynitrile

[0663] Methyl 6-cyano-1H-indole-2-carboxylate (525 mg, 2.62 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0°C. Lithium aluminum hydride (2.62 mL, 1 M THF solution, 2.62 mmol, 1 eq) was slowly added dropwise, and the mixture was allowed to warm naturally to room temperature. After 15 minutes, the system was recooled to 0°C, and the reaction was quenched by adding 0.1 mL of water, followed by 0.3 mL of 15% sodium hydroxide aqueous solution and an additional 0.3 mL of water. The mixture was diluted with ethyl acetate and dried over anhydrous magnesium sulfate. The mixture was filtered and evaporated, then loaded onto an ISOLUTE HM-N column and purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 12 g silica gel column) with a 0-80% ethyl acetate / heptane gradient to give title compound 10a (293 mg, 1.7 mmol, 65% yield) as a yellow solid. LCMS (Method A); Retention time 0.84 minutes; m / z [MH] - 172.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.60 (s, 1H), 7.77 (dt, J = 1.6, 0.8Hz, 1H), 7.70 – 7.48 (m, 1H), 7.28 (dd, J = 8.2, 1.5 Hz, 1H), 6.43 (dd, J =2.1, 1.0 Hz, 1H), 5.43 (t, J = 5.6 Hz, 1H), 4.66 (dd, J = 5.5, 0.8 Hz, 2H).

[0664]

[0665] Intermediate 10b: 2-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indole-6-carboxynitrile

[0666] 2-(hydroxymethyl)-1H-indol-6-carboxynitrile 10a (330 mg, 1.92 mmol) was dissolved in DMF (12 mL), cooled to 0°C, and then TBDMS-Cl (477 mg, 3.2 mmol, 1.7 eq) and imidazole (390 mg, 3.84 mmol, 5.8 eq) were added sequentially. The mixture was stirred at room temperature for 5 hours under a nitrogen atmosphere. The reaction solution was extracted with ethyl acetate / saturated ammonium chloride aqueous solution, the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated onto an ISOLUTE HM-N support. The solution was then subjected to automated rapid chromatography (Combiflash Rf 300+, RediSep, 12 g silica gel column) with a 0-70% ethyl acetate / heptane gradient elution to give a colorless solid, title compound 10b (400 mg, 1.41 mmol, 73%). LCMS (Method A): Retention time 1.42 min; m / z [M+H] + 287.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.64 – 11.51 (m, 1H),7.80 (dt, J = 1.6, 0.8 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.29 (dd, J = 8.2,1.5 Hz, 1H), 6.47 (dd, J = 2.1, 0.9 Hz, 1H), 4.85 (d, J = 0.9 Hz, 2H), 0.89 (s, 9H), 0.09 (s, 6H).

[0667]

[0668] Intermediate 10c: (2-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indol-6-yl)methylamine

[0669] 2-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indol-6-carboxynitrile 10b (100 mg, 0.35 mmol) was dissolved in methanol (2.5 mL) and tetrahydrofuran (2.5 mL). After cooling to 0°C, cobalt(II) chloride (90 mg, 0.7 mmol, 2 eq) and sodium borohydride (132 mg, 3.49 mmol, 10 eq) were added sequentially. The mixture was stirred at room temperature under a nitrogen atmosphere. After 15 minutes, the reaction solution was extracted with ethyl acetate / water (with 2 mL of ammonium hydroxide aqueous solution added beforehand). The organic phase was filtered through diatomaceous earth and dried over anhydrous magnesium sulfate. After filtering the entire solution again, the solution was evaporated and loaded onto an ISOLUTE HM-N column. Automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica gel column) was used, eluting with a gradient of 0-20% methanol (methanol solution containing 1% 1N NH3) / dichloromethane to give the off-white solid title compound 10c (53 mg, 0.18 mmol, 52%). LCMS (Method A): retention time 1.07 min; m / z [MH] - 289.2. 1 H NMR (400MHz, DMSO-d6) δ ppm 10.90 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.29 (s, 1H), 6.92 (dd, J = 8.1, 1.5 Hz, 1H), 6.30 – 6.22 (m, 1H), 4.76 (s, 2H), 3.77 (s, 2H), 2.20 (s, width, 2H), 0.88 (s, 9H), 0.06 (s, 6H).

[0670]

[0671] Intermediate 10d: N-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indol-6-yl)methyl]-6-chloropyrido[2,3-b]pyrazin-3-amine

[0672] (2-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indol-6-yl)methylamine 10c (130.7 mg, 0.45 mmol) was dissolved in dichloromethane (5 mL), cooled to 0°C, and triethylamine (125 µL, 0.9 mmol, 2 eq) was added, followed by 3,6-dichloropyridino[2,3-b]pyrazine (90 mg, 0.45 mmol, 1 eq). The mixture was stirred at 0°C for 1 hour. The reaction solution was partitioned using dichloromethane and brine. After separation by a phase separator, the organic phase was evaporated onto an ISOLUTE HM-N column and purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 12 g silica gel column) with a 0-100% ethyl acetate / heptane gradient to give the title compound 10d (116 mg, 0.26 mmol, 57%) as an off-white solid. LCMS (Method A); retention time 1.42 min; m / z 454.4 (chlorine isotope) [M+H] + 454.4 (chlorine isotope). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.98 (d, J = 1.9 Hz, 1H), 8.71 (t,J = 5.8 Hz, 1H), 8.43 (s, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.45 (d, J = 8.1 Hz,1H), 7.40 – 7.33 (m, 2H), 7.02 (dd, J = 8.1, 1.5 Hz, 1H), 6.28 (dd, J = 2.1,0.9 Hz, 1H), 4.76 (d, J = 0.7 Hz, 2H), 4.70 (d, J = 5.6 Hz, 2H), 0.87 (s,9H), 0.05 (s, 6H).

[0673]

[0674] Intermediate 10e: N-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indol-6-yl)methyl]-6-(piperidin-1-yl)pyrido[2,3-b]pyrazin-3-amine

[0675] N-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indol-6-yl)methyl]-6-chloropyrido[2,3-b]pyrazin-3-amine 10d (116 mg, 0.26 mmol) was dissolved in 1-propanol (5 mL), and piperidine (30 µL, 0.31 mmol, 1.2 eq) and triethylamine (70 µL, 0.51 mmol, 2 eq) were added. The mixture was heated to 100°C under nitrogen protection. The reaction mixture was partitioned with dichloromethane and brine, and the organic phase was separated using a phase separator. The organic phase was evaporated and loaded onto an ISOLUTEH M-N ​​column, and purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica gel column) with a 0-60% ethyl acetate / heptane gradient elution to give a yellow solid 10e (39 mg, 0.08 mmol, 30%). LCMS (Method A); retention time 1.42 min; m / z [M+H] + 503.4. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.94 (d, J =2.1 Hz, 1H), 8.01 (s, 1H), 7.94 (t, J = 5.7 Hz, 1H), 7.77 (d, J = 9.0 Hz,1H), 7.43 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 6.99 (dd, J = 8.1, 1.5 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.27 (dd, J = 2.1, 0.9 Hz, 1H), 4.76 (s, 2H), 4.68(d, J = 5.6 Hz, 2H), 3.68 (t, J = 5.4 Hz, 4H), 1.64 (q, J = 5.1, 4.2 Hz, 2H), 1.59 – 1.49 (m, 4H), 0.87 (s, 9H), 0.05 (s, 6H).

[0676]

[0677] Specific Example 10: [6-({[6-(piperidin-1-yl)pyridino[2,3-b]pyrazin-3-yl]amino}methyl)-1H-indol-2-yl]methanol

[0678] N-[(2-{[(tert-butyldimethylsilyl)oxy]methyl}-1H-indol-6-yl)methyl]-6-(piperidin-1-yl)pyrido[2,3-b]pyrazin-3-amine 10e (39 mg, 0.08 mmol) was dissolved in THF (3 mL), and TBAF (1 M HF solution) (120 µL 0.12 mmol, 1.5 eq) was added. The mixture was stirred at room temperature under a nitrogen atmosphere. After 90 minutes, the reaction mixture was partitioned with ethyl acetate / water. The organic phase was dried over anhydrous magnesium sulfate, filtered, concentrated, and loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica gel column) with a 0-100% ethyl acetate / heptane gradient. The concentrated residue was ground with diethyl ether, and the solid was collected by filtration. The filter cake was dried under vacuum at 40°C to give the title compound 10 (22 mg, 0.06 mmol, 72%) as a yellow solid. LC-HRMS (Method B): retention time 0.84 min, theoretical mass 388.2012, measured m / z 389.2093, measured molecular formula C22H24N6O. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.93 (app s, 1H), 8.00 (s, 1H), 7.93 (t, J = 5.7 Hz, 1H), 7.77 (d,J = 9.1 Hz, 1H), 7.41 (d, J = 8.1 Hz, 1H), 7.33 – 7.29 (m, 1H), 6.98 (dd, J =8.1, 1.4 Hz, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.25 – 6.21 (m, 1H), 5.19 (t, J =5.6 Hz, 1H), 4.67 (d, J = 5.7 Hz, 2H), 4.57 (d, J = 5.6 Hz, 2H), 3.74 – 3.61 (m, 4H), 1.69 – 1.50 (m, 6H).

[0679]

[0680] Intermediate 11a: 3-Isopropyl-7-methoxy-1H-indole-4-carboxynitrile

[0681] In a sealed tube, 99% trifluoroacetic acid (0.39 mL, 5.23 mmol, 1.5 eq) and triethylsilane (1.67 mL, 10 mmol, 3 eq) were added to toluene (12 mL). 7-Methoxy-1H-indole-4-carboxynitrile (600 mg, 3.48 mmol) was added in portions, followed by acetone (2.56 mL, 35 mmol, 10 eq). The mixture was degassed with nitrogen for 5 minutes, sealed, and heated at 130°C for 24 hours under explosion-proof protection. The reaction solution was partitioned with dichloromethane / saturated sodium bicarbonate aqueous solution to separate the organic phase. The sample was evaporated and loaded onto an ISOLUTE HM-N column, and purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 24g silica gel column) with a gradient elution from heptane to 25% ethyl acetate / heptane to give title compound 11a (62 mg, 0.29 mmol, 8%) as a colorless solid. LCMS (Method A): Retention time 1.12 min; m / z [M+H] + 215.2. 1 H NMR(400 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.26 (dd, J= 2.6, 0.8 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 3.99 (s, 3H), 3.54 - 3.39 (m,1H), 1.30 (d, J = 6.8 Hz, 6H).

[0682]

[0683] Intermediate 11b: (3-isopropyl-7-methoxy-1H-indol-4-yl)methylamine

[0684] 3-Isopropyl-7-methoxy-1H-indole-4-carboxynitrile 11a (96 mg, 0.45 mmol) was dissolved in THF (3 mL) and methanol (3 mL) and cooled to 0°C. Cobalt(II) chloride (116 mg, 0.9 mmol, 2 eq) was added sequentially, followed by sodium borohydride (170 mg, 4.48 mmol, 10 eq) in portions. The reaction mixture was stirred at room temperature for 15 minutes under nitrogen protection. The mixture was filtered through diatomaceous earth and the diatomaceous earth pad was washed with 3% ammonia. The filtrates were combined and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated, and loaded onto an ISOLUTE HM-N column. The purified organic phase was purified by automated rapid chromatography (Combiflash 300+, Silica 4g RediSep column) and eluted with a 1-10% methanol (methanol solution containing 1% 1N NH3) in dichloromethane solution to give the title compound 11b (57 mg, 0.26 mmol, 58%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm10.82 (s, 1H), 7.00 (dd, J = 2.6, 0.7 Hz, 1H), 6.86 (d, J = 7.9 Hz, 1H), 6.55(d, J = 7.8 Hz, 1H), 4.02 (d, J = 0.8 Hz, 2H), 3.87 (s, 3H), 3.42 – 3.28 (m,1H), 1.99 (s, width, 2H), 1.26 (d, J = 6.8 Hz, 6H).

[0685]

[0686] Intermediate 11c: 6-chloro-N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine

[0687] (3-Isopropyl-7-methoxy-1H-indol-4-yl)methylamine 11b (57 mg, 0.26 mmol) was dissolved in DMF (2.5 mL), followed by the sequential addition of 3,6-dichloropyridino[2,3-b]pyrazine (57 mg, 0.29 mmol, 1.1 eq) and DIPEA (87 µL, 0.52 mmol, 2 eq). The mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction mixture was partitioned with dichloromethane / saline. The organic phase was separated by a phase separator, evaporated, and loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf300+, RediSep, 4 g silica gel column) with 0–40% ethyl acetate / heptane elution to give 11c (88 mg, 0.23 mmol, 88%) as a yellow solid. LCMS (Method A); retention time 1.19 min; m / z [M+H] + 382.2 (chlorine isotope). 1 HNMR (400 MHz, DMSO-d6) δ ppm 11.02 (s, 1H), 8.54 (t, J = 4.8 Hz, 1H), 8.47(s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.10 (d, J = 2.6Hz, 1H), 6.92 (d, J = 7.9 Hz, 1H), 6.61 (d, J = 7.9 Hz, 1H), 4.86 (d, J = 4.7Hz, 2H), 3.90 (s, 3H), 3.28 – 3.17 (m, 1H), 1.23 (d, J = 6.7 Hz, 6H).

[0688]

[0689] Specific Example 11: N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]-6-(pyrrolidone-1-yl)pyrido[2,3-b]pyrazin-3-amine

[0690] 6-Chloro-N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine 11c (44 mg, 0.12 mmol) was dissolved in 1-propanol (3.5 mL), and pyrrolidine (20 µL, 0.23 mmol, 2 eq) and DIPEA (57 µL, 0.35 mmol, 3 eq) were added. The mixture was heated to 120°C for 16 hours in a sealed tube behind an explosion-proof screen. The reaction solution was partitioned with dichloromethane and brine. After separation of the organic phase by a phase separator, it was evaporated onto an ISOLUTE HM-N column and purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica gel column) with a 0-60% ethyl acetate / heptane gradient to give title compound 11 (33 mg, 0.08 mmol, 70%) as a yellow solid. LC-HRMS (Method B): Retention time 0.89 minutes, target mass 416.2325, measured m / z 417.2422, measured molecular formula C24H28N6O. 1 H NMR(400 MHz, DMSO-d6) δ ppm 10.97 (d, J = 2.6 Hz, 1H), 7.99 (s, 1H), 7.77 (d, J= 8.9 Hz, 1H), 7.73 (t, J = 4.7 Hz, 1H), 7.08 (d, J = 2.6 Hz, 1H), 6.87 (d, J= 7.9 Hz, 1H), 6.62 – 6.56 (m, 2H), 4.80 (d, J = 4.7 Hz, 2H), 3.88 (s, 3H), 3.56 – 3.45 (m, 4H), 3.32 – 3.21 (m, 1H), 2.01 – 1.91 (m, 4H), 1.23 (d, J = 6.8 Hz, 6H).

[0691]

[0692] Intermediate 12a: 7-methoxy-3-methyl-1H-indole-4-carboxynitrile

[0693] 7-Methoxy-1H-indole-4-carboxynitrile (900 mg, 5.23 mmol) was dissolved in methanol (25 mL), and KOtBu (587 mg, 5.23 mmol, 1 eq) and [Cp] were added. IrCl₂]₂ (42 mg, 0.05 mmol, 0.01 eq) was degassed with nitrogen and sealed, then heated at 140°C for 16 hours behind an explosion-proof screen. The reaction solution was partitioned with ethyl acetate and brine. The organic phase was dried over anhydrous MgSO₄, filtered, evaporated, and loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, Silica 12 g RediSep, 12 g silica gel column) with a 0-40% ethyl acetate / heptane gradient to give the title compound 12a (139 mg, 0.74 mmol, 14%) as a colorless solid. LCMS (Method A); retention time 0.98 min; m / z [M+H] + 187.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 7.46 (d, J = 8.1 Hz,1H), 7.25 (dd, J = 2.5, 1.1 Hz, 1H), 6.80 (d, J = 8.1 Hz, 1H), 3.99 (s, 3H),2.42 (d, J = 1.0 Hz, 3H).

[0694]

[0695] Intermediate 12b: (7-methoxy-3-methyl-1H-indol-4-yl)methylamine

[0696] 7-Methoxy-3-methyl-1H-indole-4-carboxynitrile 12a (314 mg, 1.69 mmol) was dissolved in THF (11 mL) and methanol (11 mL) and stirred at 0°C under a nitrogen atmosphere. Cobalt(II) chloride (440 mg, 3.37 mmol, 2 eq) was added to the solution, followed by the addition of sodium borohydride (640 mg, 17 mmol, 10 eq) in portions, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth, the filter cake was washed with 3% ammonia, and the organic phase was separated and dried over anhydrous magnesium sulfate. All solutions were filtered again and evaporated onto ISOLUTE HM-N, and then purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 12 g silica column) with a gradient elution of 0-10% methanol (methanol solution containing 1% 1N NH3) / dichloromethane to give a colorless solid title compound 12b (176 mg, 0.93 mmol, 54.86%). 1H-NMR (400 MHz, DMSO-d6)δ ppm 10.74 (s, 1H), 6.95 (dd, J = 2.5, 1.1 Hz, 1H), 6.80 (d, J = 7.8 Hz,1H), 6.53 (d, J = 7.8 Hz, 1H), 4.02 (s, 2H), 3.87 (s, 3H), 2.41 (d, J = 1.0Hz, 3H).

[0697]

[0698] Intermediate 12c: 6-chloro-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine

[0699] (7-Methoxy-3-methyl-1H-indol-4-yl)methylamine 12b (114 mg, 0.6 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (170 µL, 1.2 mmol, 2 eq) was added. The solution was cooled to 0°C. Then, 3,6-dichloropyridine and [2,3-b]pyrazine (120 mg, 0.6 mmol, 1 eq) was added to the mixture, and the mixture was stirred at 0°C for 1 hour, followed by further reaction at room temperature under nitrogen protection for 16 hours. The reaction mixture was partitioned with dichloromethane / salt water, and the organic phase was separated by a phase separator and evaporated onto an ISOLUTE HM-N support. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 12 g silica gel column) with a 0-50% ethyl acetate / heptane gradient to give the title compound 12c (53 mg, 0.15 mmol, 25%) as a yellow solid. Liquid chromatography-mass spectrometry (Method A); retention time 1.06 min; m / z [M+H] + 354.2 (chlorine isotope). 1H NMR (400MHz, DMSO-d6) δ ppm 10.92 (d, J = 2.3 Hz, 1H), 8.52 (t, J = 4.8 Hz, 1H), 8.47(s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.03 (dd, J =2.5, 1.2 Hz, 1H), 6.91 (d, J = 7.8 Hz, 1H), 6.60 (d, J = 7.9 Hz, 1H), 5.76(s, 1H), 4.84 (d, J = 4.6 Hz, 2H), 3.90 (s, 3H), 2.34 (d, J = 1.1 Hz, 3H).

[0700]

[0701] Specific Example 12: 6-N-cyclohexyl-3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazine-3,6-diamine

[0702] 6-Chloro-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine 12c (53 mg, 0.15 mmol) was dissolved in 1-propanol (5 mL), and cyclohexylamine (150 µL, 1.65 mmol, 9 eq) and DIPEA (125 µL, 0.75 mmol, 5 eq) were added. The mixture was heated to 120°C N2. After 40 hours, the reaction mixture was cooled and partitioned with DCM / salt water. The organic phase was separated by a phase separator, evaporated onto an ISOLUTE HM-N, and purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica gel column) with a 0-70% ethyl acetate / heptane gradient. The purified solid was dried under vacuum at 40°C to give title compound 12 (14 mg, 0.03 mmol, 22%) as a beige solid. LC-HRMS (Method B): Retention time 0.93 min, target mass 416.2325, measured m / z 417.2332, measured molecular formula C24H28N6O. 1H-NMR(400 MHz, DMSO-d6) δ ppm 10.87 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.64 – 7.58(m, 2H), 7.04 – 6.97 (m, 2H), 6.84 (d, J = 7.8 Hz, 1H), 6.57 (d, J = 7.8Hz,1H), 6.53 (d, J = 8.9 Hz, 1H), 4.77 (d, J = 4.6 Hz, 2H), 4.03 – 3.89 (br m,1H), 3.88 (s, 3H), 2.35 (d, J = 1.0 Hz, 3H), 1.97 – 1.87 (m, 2H), 1.78 – 1.67 (m, 2H), 1.66 – 1.55 (m, 1H), 1.45 – 1.29 (m, 2H), 1.28 – 1.11 (m, 3H).

[0703]

[0704] Intermediate 13a: 4-bromo-N,N-dimethyl-2-nitroaniline

[0705] 4-Bromo-2-nitroaniline (8 g, 37 mmol) was dissolved in DMF (180 mL), cooled to 0°C under nitrogen protection, and sodium hydride (4.42 g, 60% suspension in mineral oil, 111 mmol, 3 eq) was added in portions, with stirring for 30 min. Iodomethane (6.9 mL, 111 mmol, 3 eq) was slowly added dropwise, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to half its original volume and partitioned with ethyl acetate / water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 220 g silica gel column) with a 0-20% ethyl acetate / heptane gradient elution. After evaporation and vacuum drying, the title compound 13a (8.7 g, 36 mmol, 97%) was obtained as an orange oil. LCMS (Method A); Retention time 1.18 minutes; m / z [M+H] + 245 & 247 (bromine isotopes). 1 H-NMR (400 MHz, DMSO-d6) δ ppm7.94 (d, J = 2.5 Hz, 1H), 7.63 (dd, J = 9.1, 2.5 Hz, 1H), 7.15 (d, J = 9.1Hz, 1H), 2.82 (s, 6H).

[0706]

[0707] Intermediate 13b: 4-bromo-N,N-dimethyl-1H-indole-7-amine

[0708] 4-Bromo-N,N-Dimethyl-2-nitroaniline 13a (4.52 g, 18.4 mmol) was dissolved in THF (130 mL), degassed under nitrogen, and cooled to -78°C (using an acetone / dry ice bath). Vinyl magnesium bromide (55 mL, 1 MTHF solution, 3 eq) was then added to the solution, and the mixture was stirred continuously at -78°C for 2 hours under nitrogen protection. The reaction mixture was transferred to an ice bath and slowly heated to 0°C, with stirring continued for 1 hour. The reaction solution was partitioned with ethyl acetate / saturated ammonium chloride aqueous solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated, and loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep 220 g silica gel column) using a 0-20% ethyl acetate / heptane gradient to give the title compound 13b (2.1 g, 8.8 mmol, 48%) as a beige solid. LCMS (Method A): Retention time 1.18 minutes; m / z [M+H] + 247 (bromine isotope).

[0709] Intermediate 13c: 4-bromo-N,N,3-trimethyl-1H-indole-7-amine

[0710] 4-Bromo-N,N-dimethyl-1H-indole-7-amine 13b (700 mg, 2.93 mmol) was dissolved in methanol (15 mL), and potassium tert-butoxide (330 mg, 2.93 mmol, 1 eq) and [Cp] were added. IrCl2]2 (23 mg, 0.03 mmol, 0.01 eq). The mixture was sealed and heated at 120°C for 16 hours under explosion-proof protection. The cooled reaction solution was partitioned with ethyl acetate / saline, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N. Automated rapid chromatography (Combiflash Rf 300+, Gold RediSep 40 g silica gel column) with a 0-15% ethyl acetate / heptane gradient elution yielded the title compound 13c (324 mg, 1.28 mmol, 44%) as a beige solid. LCMS (Method A): Retention time 1.22 min; m / z [M+H] + 253.2 (bromine isotope). 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 7.10 (dd, J = 2.5, 1.2 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.51 (d, J = 8.0 Hz, 1H), 2.75 (s, 6H), 2.44 (d, J = 1.0 Hz, 3H).

[0711]

[0712] Intermediate 13 d: 7-(dimethylamino)-3-methyl-1H-indole-4-carboxynitrile

[0713] 4-Bromo-N,N,3-trimethyl-1H-indole-7-amine 13c (324 mg, 1.28 mmol) was dissolved in NMP (3 mL), and zinc cyanide (150.3 mg, 1.28 mmol, 1 eq) and zinc powder (17 mg, 0.26 mmol, 0.2 eq) were added. After degassing the mixture with a nitrogen stream, Pd2(dba) (176 mg, 0.19 mmol, 0.15 eq) and Pd(dppf)Cl2 (212.87 mg, 0.38 mmol, 0.3 eq) were added. The mixture was then heated to 140°C for 16 hours under a nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate, filtered through a diatomaceous earth filter, and dried over anhydrous magnesium sulfate. After filtration and evaporation to dryness, the sample was loaded onto an ISOLUTE HM-N column and purified by automated rapid chromatography (Combiflash Rf 300+, RediSep 40 g silica column) with elution of 0-50% ethyl acetate / heptane to give the title compound 13d (223 mg, 1.12 mmol, 87%) as a beige solid. LCMS (Method A); retention time 1.05 min; m / z [M+H] + 200.2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.06 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 (dd, J = 2.5, 1.2 Hz, 1H), 6.60 (d, J = 8.1Hz, 1H), 2.94 (s, 6H), 2.42 (d, J = 1.0 Hz, 3H).

[0714]

[0715] Intermediate 13e: 4-(aminomethyl)-N,N,3-trimethyl-1H-indole-7-amine

[0716] 7-(dimethylamino)-3-methyl-1H-indole-4-carboxynitrile 13d (223 mg, 1.12 mmol) was dissolved in THF (5 mL) and methanol (5 mL) and cooled to 0°C in an ice bath. Cobalt(II) chloride (290 mg, 2.24 mmol, 2 eq) was added to the solution, followed by sodium borohydride (425 mg, 11.2 mmol, 10 eq) in portions after several minutes. The ice bath was removed, and the reaction mixture was heated to room temperature and held for 15 minutes. The reaction mixture was diluted with ethyl acetate, filtered through a diatomaceous earth mat, and washed with ethyl acetate and 3% ammonia / water. After separation of the organic and aqueous phases, the organic phase was dried over anhydrous magnesium sulfate. After filtration, the mixture was concentrated under reduced pressure, and the crude product was dissolved in a methanol / dichloromethane mixture and loaded onto an SCX-2 column. The column was washed successively with 3 column volumes of methanol / dichloromethane and 3 column volumes of (1N NH3 / methanol) / dichloromethane. After evaporating the solvent, the solution was dried over a Biotage V10 tube to give the title compound 13e (184 mg, 0.91 mmol, 81%) as a deep yellow solid. LCMS (Method A); retention time 0.39 min; m / z [M+H] + Massless ions. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 6.98 – 6.94 (m, 1H), 6.79 (dd, J = 7.6, 0.8 Hz, 1H), 6.55 (d, J = 7.6 Hz, 1H), 4.01 (d, J = 0.7 Hz,2H), 2.74 (s, 6H), 2.42 (d, J = 1.1 Hz, 3H).

[0717]

[0718] Intermediate 13f: 4-[({6-chloropyridino[2,3-b]pyrazin-3-yl}amino)methyl]-N,N,3-trimethyl-1H-indole-7-amine

[0719] 4-(aminomethyl)-N,N,3-trimethyl-1H-indole-7-amine 13e (183 mg, 0.9 mmol) was dissolved in DMF (5 mL), and DIPEA (0.39 mL, 2.25 mmol, 2.5 eq) was added. Then, 3,6-dichloropyridino[2,3-b]pyrazine (180 mg, 0.9 mmol, 1 eq) was added in portions, and the mixture was stirred at room temperature for 30 minutes to ensure a homogeneous solution. The reaction mixture was then heated to 40°C and reacted for 1 hour. After cooling to room temperature, the reaction mixture was quenched with saturated NH4Cl (aq) and extracted twice with EtOAc. The combined organic phases were washed with brine and dried over anhydrous MgSO4. The filtrate was evaporated after filtration, loaded onto an ISOLUTE HM-N column, and purified by automated rapid chromatography (Combiflash Rf 300+, Gold RediSep, 24 g silica gel column) with a 0-30% EtOAc / DCM gradient. After evaporation and drying on a Biotage V10, the title compound 13f (202 mg, 0.55 mmol, 61%) was obtained as a yellow solid. LCMS (Method A): Retention time 1.02 min; m / z [M+Na] + 389.2 (chlorine isotope). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.68 (d, J = 2.5 Hz, 1H), 8.53 (t, J = 4.6 Hz, 1H), 8.47 (s, 1H), 8.20 (d, J = 8.3 Hz, 1H), 7.39 (d, J = 8.3Hz, 1H), 7.05 (dd, J = 2.5, 1.2 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 6.60 (d, J= 7.7 Hz, 1H), 4.83 (d, J = 4.6 Hz, 2H), 2.77 (s, 6H), 2.34 (d, J = 1.1 Hz, 3H).

[0720]

[0721] Example 13: 1-[3-({[7-(dimethylamino)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol

[0722] 4-[({6-chloropyridino[2,3-b]pyrazin-3-yl}amino)methyl]-N,N,3-trimethyl-1H-indole-7-amine 13f (50 mg, 0.14 mmol) was dissolved in 1-propanol (1.4 mL), followed by the sequential addition of 4-hydroxypiperidine (15 mg, 0.15 mmol, 1.1 eq) and triethylamine (40 µL, 0.27 mmol, 2 eq). The mixture was heated to 100°C and reacted for 16 hours. After cooling to room temperature, the reaction mixture was extracted separately with water and ethyl acetate. The aqueous phase was extracted twice more with ethyl acetate, and the combined organic phases were washed with brine and concentrated under vacuum. The residue was dissolved in DMSO and methanol, purified by preparative high-performance liquid chromatography (AccQPrep HP125, Prep HPLC), and lyophilized to give title compound 13 (14.7 mg, 0.03 mmol, 25%) as a cream-colored solid. LC-HRMS (Method B): Retention time 0.66 minutes, target mass 431.2434, measured m / z 432.251, measured molecular formula C24H29N7O. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.64 (d, J = 2.5 Hz, 1H), 8.03 (s,1H), 7.81 – 7.74 (m, 2H), 7.05 – 7.00 (m, 1H), 6.95 (d, J = 9.1 Hz, 1H), 6.85(d, J = 7.7 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 4.77 (d, J = 4.6 Hz, 2H), 4.71(d, J = 4.3 Hz, 1H), 4.23 – 4.12 (m, 2H), 3.79 – 3.69 (m, 1H), 3.30 – 3.20(m, 2H), 2.76 (s, 6H), 2.34 (d, J = 1.1 Hz, 3H), 1.86 – 1.75 (m, 2H), 1.43 –1.31 (m, 2H).

[0723]

[0724] Intermediate 14a: 3-methyl-1H-indole-4-carboxynitrile

[0725] To a stirred NMP (10 mL) solution of 4-bromo-3-methyl-1H-indole (1 g, 4.76 mmol), zinc cyanide (560 mg, 4.76 mmol, 1 eq), zinc powder (62 mg, 0.95 mmol, 0.2 eq), Pd(dppf)Cl2 (396 mg, 0.71 mmol, 0.15 eq), and Pd2(dba)3 (327 mg, 0.36 mmol, 0.08 eq) were added sequentially. The mixture was heated to 140°C and reacted for 16 hours under nitrogen protection. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and a small amount of water, filtered through a diatomaceous earth column (10 g, pre-washed with ethyl acetate), and eluted with more ethyl acetate. The organic phases were combined, evaporated, and loaded onto an ISOLUTEH M-N ​​column. Purification was then performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 40 g silica gel column) with a 0-30% ethyl acetate / heptane gradient to give the title compound (616 mg, 3.94 mmol, 83%) as a beige solid. LCMS (Method A); retention time 0.98 min; m / z 157 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.40(s, 1H), 7.69 (dd, J = 8.2, 0.9 Hz, 1H), 7.47 (dd, J = 7.4, 1.0 Hz, 1H), 7.43– 7.37 (m, 1H), 7.20 (dd, J = 8.2, 7.4 Hz, 1H), 2.46 (d, J = 1.0 Hz, 3H).

[0726]

[0727] Intermediate 14b: (3-methyl-1H-indol-4-yl)methylamine

[0728] 3-Methyl-1H-indole-4-carboxynitrile 14a (616 mg, 3.94 mmol, 1 eq) was dissolved in THF (20 mL) / methanol (20 mL), cooled in an ice bath, and cobalt(II) chloride (1.02 g, 7.89 mmol, 2 eq) was added. After 2 minutes, sodium borohydride (1.49 g, 39 mmol, 10 eq) was added in portions, the ice bath was removed, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was diluted with ethyl acetate and filtered through diatomaceous earth (10 g, pre-washed with ethyl acetate), followed by elution with ethyl acetate and 3% ammonia. The aqueous phase was extracted again with ethyl acetate after separation, and the organic phases were combined, dried over anhydrous magnesium sulfate, and concentrated by evaporation. The residue was ground with diethyl ether, filtered, and the title compound 14b (391 mg, 2.44 mmol, 62%) was collected as a pink solid. LCMS (Method A); retention time 0.322 min; m / z: no mass ions detected. 1 ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.08 – 6.87 (m, 3H), 4.09 (s, 2H), 2.43 (s, 3H), 1.93 –1.80 (m, width, 2H).

[0729]

[0730] Intermediate 14c: 6-chloro-N-[(3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine

[0731] (3-Methyl-1H-indol-4-yl)methylamine 14b (391 mg, 2.44 mmol) was dissolved in DMF (22 mL), and 3,6-dichloropyrido[2,3-b]pyrazine (537 mg, 2.68 mmol, 1.1 eq) and DIPEA (810 µL, 4.88 mmol, 2 eq) were added. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was partitioned with ethyl acetate / saline, and the organic phase was dried over anhydrous magnesium sulfate. After filtration, the residue was concentrated and ground with dry methanol. The residue was collected by filtration and dried under vacuum to give the title compound 14c (664 mg, 2.05 mmol, 84%) as a beige solid. LCMS (Method A); retention time 1.09 min; m / z [M+H] + 324.2 (chlorine isotope). 1H NMR (400 MHz, DMSO-d6) δ ppm10.86 (s, 1H), 8.62 (t, J = 4.9 Hz, 1H), 8.49 (s, 1H), 8.20 (d, J = 8.3 Hz,1H), 7.39 (d, J = 8.3 Hz, 1H), 7.31 (dd, J = 8.0, 1.2 Hz, 1H), 7.13 (dd, J =2.4, 1.2 Hz, 1H), 7.03 (dd, J = 8.0, 7.2 Hz, 1H), 6.97 (dd, J = 7.1, 1.2 Hz,1H), 4.95 (d, J = 4.9 Hz, 2H), 2.40 (d, J = 1.1 Hz, 3H).

[0732]

[0733] Specific Example 14: 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-[(3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine

[0734] 6-Chloro-N-[(3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine 14c (50 mg, 0.15 mmol, 1 eq) was dissolved in 1-propanol (5 mL), and cis-2,6-dimethylmorpholine (40 µL, 0.31 mmol, 2 eq) and DIPEA (80 µL, 0.46 mmol, 3 eq) were added. The reaction mixture was sealed and placed in an explosion-proof enclosure, and heated to 120°C for 16 hours. After cooling to room temperature, the mixture was partitioned with dichloromethane / saline. The organic phase was separated by a phase separator, evaporated to dryness, and loaded onto an ISOLUTE HM-N column. The purified phase was then purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica gel column) with a 0-5% methanol / dichloromethane gradient elution. The residue was further purified by preparative high-performance liquid chromatography (AccQPrep HP150, Prep HPLC), and after lyophilization, the title compound 14 (23 mg, 0.06 mmol, 37%) was obtained as a yellow solid. LC-HRMS (Method B): retention time 0.94 min, target mass 402.2168, measured m / z 403.2257, measured molecular formula C23H26N6O. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.83 (app s, 1H), 8.10 (s, 1H), 7.93(t, J = 4.9 Hz, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 7.9 Hz, 1H), 7.13– 7.08 (m, 1H), 7.03 – 6.94 (m, 2H), 6.91 (d, J = 7.1 Hz, 1H), 4.90 (d, J =4.9 Hz, 2H), 4.43 – 4.30 (m, 2H), 3.66 – 3.53 (m, 2H), 2.56 – 2.44 (m, 2H),2.39 (s, 3H), 1.17 (d, J = 6.2 Hz, 6H).

[0735]

[0736] Intermediate 15a: 4-bromo-1H-indole-7-carboxylic acid

[0737] Methyl 4-bromo-1H-indole-7-carboxylate (300 mg, 1.18 mmol) was dissolved in 1,4-dioxane (8 mL), and lithium hydroxide monohydrate (247.74 mg, 5.9 mmol, 5 eq) and water (2 mL) were added. The mixture was heated in a microwave at 100°C for 1 hour. The cooled reaction solution was partitioned with an ethyl acetate / 0.5 N hydrochloric acid aqueous solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to give the title compound 15a (285 mg, 1.19 mmol, quantitative) as a colorless solid. LCMS (Method A): retention time 0.98 min, m / z [M+H] + 240 (bromine isotope). 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (s,1H), 11.42 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 2.9 Hz, 1H), 7.35(d, J = 8.0 Hz, 1H), 6.51 (dd, J = 3.2, 2.0 Hz, 1H).

[0738]

[0739] Intermediate 15b: 4-bromo-N-methyl-1H-indole-7-carboxamide

[0740] 4-Bromo-1H-indole-7-carboxylic acid (661 mg, 2.75 mmol) was dissolved in DMF (18 mL), and HBTU (1.25 g, 3.3 mmol, 1.2 eq), DIPEA (0.96 mL, 5.51 mmol, 2 eq), and methylamine (0.3 mL, 2M THF solution, 8.26 mmol, 3 eq) were added sequentially. The mixture was stirred at room temperature for 2.5 hours under a nitrogen atmosphere. The reaction solution was extracted with ethyl acetate, washed successively with sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N column. The sample was then purified by automated rapid chromatography (Combiflash Rf 300+, RediSep, 24 g silica gel column) with a 0-60% ethyl acetate / heptane gradient to give the title compound 15b (516 mg, 2.04 mmol, 74%) as a colorless solid. LCMS (Method A); Retention time 0.98 minutes; m / z [M+H] + 255 (bromine isotope). 1 H NMR (400 MHz, DMSO-d6) δppm 11.48 (s, 1H), 8.58 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.45(t, J = 2.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 6.45 (dd, J = 3.2, 2.1 Hz, 1H), 2.84 (d, J = 4.5 Hz, 3H).

[0741]

[0742] Intermediate 15c: 4-bromo-N,3-dimethyl-1H-indole-7-carboxamide

[0743] Methyl 4-bromo-1H-indole-7-carboxylic acid ester 15b (279 mg, 1.1 mmol) was dissolved in methanol (10 mL), and potassium tert-butoxide (125 mg, 1.1 mmol, 1 eq) and [Cp] were added. IrCl₂]₂ (9 mg, 0.01 mmol, 0.01 eq), sealed and heated at 120°C for 16 hours behind an explosion-proof screen. The cooled reaction solution was separated with ethyl acetate / saline solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 12 g silica gel column) with a 0-100% ethyl acetate / heptane gradient to give the title compound 15c (91 mg, 0.34 mmol, 31%) as an off-white solid. LCMS (Method A); retention time 1.07 min; m / z [M+H] + 267 (bromine isotope). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.11 (s, 1H), 8.53 (d, J = 4.6 Hz,1H), 7.45 (d, J = 8.1 Hz, 1H), 7.25 - 7.19 (m, 2H), 2.83 (d, J = 4.5 Hz, 3H),2.47 (d, J = 1.1 Hz, 3H).

[0744]

[0745] Intermediate 15d: 4-cyano-N,3-dimethyl-1H-indole-7-carboxamide

[0746] 4-Bromo-N,3-Dimethyl-1H-indole-7-carboxamide 15c (91 mg, 0.34 mmol) was dissolved in NMP (5 mL), and zinc powder (5 mg, 0.07 mmol, 0.2 eq), zinc cyanide (40 mg, 0.34 mmol, 1 eq), Pd2(dba)3 (50 mg, 0.05 mmol, 0.15 eq), and Pd(dppf)Cl2 (57 mg, 0.1 mmol, 0.3 eq) were added. The mixture was degassed with a nitrogen stream and then heated to 140°C for 24 hours. After cooling, the reaction solution was partitioned with ethyl acetate / saline. The aqueous phase was filtered through diatomaceous earth and then extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N plate. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep 24 g silica column) with a 0-80% ethyl acetate / heptane gradient elution to give the title compound 15d (56 mg, 0.26 mmol, 77%) as an off-white solid. LCMS (Method A); retention time 0.89 min; m / z [M+H] + 212.2.1 H NMR (400 MHz, DMSO-d6) δ ppm 11.38 (s,1H), 8.73 (d, J = 4.8 Hz, 1H), 7.64 (d, J = 7.7 Hz, 1H), 7.56 (d, J = 7.8 Hz,1H), 7.39 (dd, J = 2.5, 1.2 Hz, 1H), 2.86 (d, J = 4.6 Hz, 3H), 2.47 (d, J =1.0 Hz, 3H).

[0747]

[0748] Intermediate 15e: 4-(aminomethyl)-N,3-dimethyl-1H-indole-7-carboxamide

[0749] 15d of 4-cyano-N,3-dimethyl-1H-indole-7-carboxamide (115 mg, 0.54 mmol) was dissolved in methanol (4 mL) and tetrahydrofuran (4 mL). After cooling to 0°C, cobalt(II) chloride (140 mg, 1.08 mmol, 2 eq) was added. After 2 minutes, sodium borohydride (200 mg, 5.39 mmol, 10 eq) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was diluted with ethyl acetate and filtered through a diatomaceous earth filter. The diatomaceous earth was washed with 3% ammonia solution and then extracted with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N plate. The title compound 15e (75 mg, 0.35 mmol, 64%) was purified by automated rapid chromatography (Combiflash Rf 300+, RediSep 4 g silica column) with a gradient elution of 0-15% methanol (methanol solution containing 1% 1N NH3) / dichloromethane to obtain a colorless solid. 1 H NMR (400 MHz, DMSO-d6) δppm 10.77 (s, 1H), 8.39 (q, J = 4.6 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.07(dd, J = 2.4, 1.2 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 4.16 (s, 2H), 2.82 (d, J= 4.6 Hz, 3H), 2.44 (d, J = 1.1 Hz, 3H), 1.90 (s, width, 2H).

[0750]

[0751] Intermediate 15f: 4-[({6-chloropyridino[2,3-b]pyrazin-3-yl}amino)methyl]-N,3-dimethyl-1H-indole-7-carboxamide

[0752] 4-(aminomethyl)-N,3-dimethyl-1H-indole-7-carboxamide 15e (75 mg, 0.35 mmol) was dissolved in DMF (3 mL), and 3,6-dichloropyridino[2,3-b]pyrazine (76 mg, 0.38 mmol, 1.1 eq) and DIPEA (115 µL, 0.69 mmol, 2 eq) were added. The mixture was stirred at room temperature for 16 hours under nitrogen protection. The reaction solution was extracted with ethyl acetate / salt solution, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep 12g silica gel column) with a 0-100% ethyl acetate / dichloromethane gradient to give the title compound 15f (70 mg, 0.18 mmol, 53%) as an off-white solid. LCMS (Method A): Retention time 0.99 minutes; m / z [M+H] + 381.2 (chlorine isotope). 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.92(d, J = 2.3 Hz, 1H), 8.69 (t, J = 5.1 Hz, 1H), 8.51 (s, 1H), 8.45 (d, J = 4.7Hz, 1H), 8.22 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 7.7 Hz, 1H), 7.40 (d, J = 8.3Hz, 1H), 7.17 (dd, J = 2.4, 1.2 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 5.03 (d, J= 5.0 Hz, 2H), 2.83 (d, J = 4.5 Hz, 3H), 2.44 (d, J = 1.1 Hz, 3H).

[0753]

[0754] Specific Example 15: N,3-Dimethyl-4-{[(6-{methyl[(1s,3s)-3-hydroxycyclobutyl]amino}pyrido[2,3-b]pyrazin-3-yl)amino]methyl}-1H-indole-7-carboxamide

[0755] 4-[({6-chloropyridino[2,3-b]pyrazin-3-yl}amino)methyl]-N,3-dimethyl-1H-indole-7-carboxamide 15f (35 mg, 0.09 mmol) was dissolved in 1-propanol (5 mL), and cis-3-(methylamino)cyclobutane-1-ol hydrochloride (50 mg, 0.36 mmol, 4 eq) and DIPEA (100 µL, 0.55 mmol, 6 eq) were added. The mixture was sealed in a test tube and heated at 120°C under a blast-proof cover. After 3 days, the reaction solution was cooled and partitioned with ethyl acetate / saline. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was redissolved in DMSO, automatically purified by preparative high-performance liquid chromatography (AccQPrepHP150, Prep HPLC), and lyophilized to give title compound 15 (5 mg, 0.01 mmol, 13%) as a yellow solid. LC-HRMS (Method B): retention time 0.72 min, target mass 445.2226, measured m / z 446.2304, measured molecular formula C24H27N7O2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.89 (d, J = 2.4 Hz,1H), 8.43 (q, J = 4.6 Hz, 1H), 8.07 (s, 1H), 7.95 (t, J = 5.1 Hz, 1H), 7.80(d, J = 9.0 Hz, 1H), 7.53 (d, J = 7.7 Hz, 1H), 7.17 – 7.12 (m, 1H), 6.96 (d,J = 7.7 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 5.11 (br s, 1H), 4.98 (d, J = 5.1Hz, 2H), 4.62 – 4.49 (m, 1H), 3.93 – 3.81 (m, 1H), 3.05 (s, 3H), 2.82 (d, J =4.6 Hz, 3H), 2.57 – 2.48 (m, 2H), 2.44 (d, J = 1.0 Hz, 3H), 2.07 – 1.96 (m,2H).

[0756]

[0757] Intermediate 16a: 4-bromo-1-(difluoromethoxy)-2-nitrobenzene

[0758] 4-Bromo-2-nitrophenol (1 g, 4.59 mmol) was dissolved in acetonitrile (10 mL), and potassium hydroxide (10 mL, 6 M, 60 mmol, 13 eq) was added, followed by difluoromethyl trifluoromethanesulfonate (1.16 mL, 9.2 mmol, 2 eq). The mixture was stirred for 1 hour. The reaction mixture was partitioned with ethyl acetate / water, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, 40 g silica gel column), eluting with heptane to 7% ethyl acetate / heptane, to give title compound 16a (1.15 g, 4.29 mmol, 94%) as a yellow oil. LCMS (Method A): retention time 1.12 min; m / z: no mass ions detected. 1 H-NMR (400 MHz, DMSO-d6) δ ppm8.34 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 8.9, 2.5 Hz, 1H), 7.50 (d, J = 8.9Hz, 1H), 7.38 (t, J = 72.4 Hz, 1H). 19 F NMR (376 MHz, DMSO) δ ppm -83.20 (s,2F).

[0759]

[0760] Intermediate 16b: 4-Bromo-7-(difluoromethoxy)-1H-indole

[0761] 4-Bromo-1-(difluoromethoxy)-2-nitrobenzene 16a (1.15 g, 4.29 mmol) was dissolved in THF (22 mL) and cooled to -78°C under nitrogen protection. While stirring at -78°C, vinyl magnesium bromide (13 mL, 1M THF solution, 13 mmol, 3 eq) was added dropwise. After 2.5 hours, the reaction mixture was partitioned with ethyl acetate / saturated ammonium chloride aqueous solution. The organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 24 g silica gel column) with a 0–15% ethyl acetate / heptane gradient to give title compound 16b (231 mg, 0.88 mmol, 21%) as a yellow oil. LCMS (Method A); retention time 1.16 min; m / z [MH] - 260. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.88 (s, 1H), 7.55 – 7.46 (m,1H), 7.32 (t, J = 74 Hz, 1H) 7.22 (d, J = 8.2 Hz, 1H), 6.89 (dt, J = 8.3, 1.0Hz, 1H), 6.46 (dd, J = 3.1, 2.0 Hz, 1H).

[0762]

[0763] Intermediate 16c: 4-bromo-7-(difluoromethoxy)-3-methyl-1H-indole

[0764] 4-Bromo-7-(difluoromethoxy)-1H-indole 16b (231 mg, 0.88 mmol) was dissolved in methanol (5 mL), and KO was added. t Bu (100 mg, 0.88 mmol, 1 eq) and [Cp IrCl₂]₂ (7 mg, 0.01 mmol, 0.01 eq) was sealed in a test tube and heated at 120°C for 16 hours under explosion-proof protection. The cooled reaction mixture was partitioned with ethyl acetate / saline, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N column. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep 12 g silica gel column) with a 0-15% ethyl acetate / heptane gradient to give the title compound 16c (38 mg, 0.14 mmol, 16%) as a beige oil. LCMS (Method A); retention time 1.33 min; m / z [M+H] + 276. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 11.44 (s, 1H), 7.29 (t, J = 74.0 Hz, 1H), 7.24 (d, J = 1.2 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.85 – 6.76 (m, 1H), 2.46 (d, J = 1.1 Hz, 3H).

[0765]

[0766] Intermediate 16d: 7-(difluoromethoxy)-3-methyl-1H-indole-4-carboxynitrile

[0767] 4-Bromo-7-(difluoromethoxy)-3-methyl-1H-indole 16c (38 mg, 0.14 mmol) was dissolved in NMP (2 mL), followed by the addition of zinc powder (2 mg, 0.03 mmol, 0.2 eq), zinc cyanide (20 mg, 0.14 mmol, 1 eq), Pd₂(dba)₃ (20 mg, 0.02 mmol, 0.15 eq), and Pd(dppf)Cl₂ (23 mg, 0.04 mmol, 0.3 eq). The mixture was degassed with a stream of nitrogen and heated to 140°C under a nitrogen atmosphere. After reacting for 16 hours, the cooled reaction solution was partitioned with ethyl acetate / salt water. The aqueous phase was filtered through diatomaceous earth and washed with ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered, evaporated, and loaded onto an ISOLUTE HM-N plate. Purification was performed by automated rapid chromatography (Combiflash Rf 300+, RediSep, 12 g silica column) with a 0-60% ethyl acetate / heptane gradient elution to give the title compound 16d (7 mg, 0.03 mmol, 23%) as a colorless solid. LCMS (Method A); retention time 1.06 min; m / z [MH] - 221. 1 H-NMR (400 MHz, DMSO-d6) δ ppm11.82 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 73.3 Hz, 1H), 7.42 (dd,J = 2.5, 1.1 Hz, 1H), 7.04 (dt, J = 8.1, 1.0 Hz, 1H), 2.45 (d, J = 1.0 Hz, 3H).

[0768]

[0769] Intermediate 16e: [7-(difluoromethoxy)-3-methyl-1H-indole-4-yl]methylamine

[0770] 16d (39 mg, 0.18 mmol) of 7-(difluoromethoxy)-3-methyl-1H-indole-4-carboxynitrile (THF) and 1.5 mL of methanol were dissolved in 1.5 mL of THF and 1.5 mL of methanol. After cooling to 0°C, cobalt(II) chloride (45.58 mg, 0.35 mmol, 2 eq) was added sequentially. After 2 minutes, sodium borohydride (70 mg, 1.76 mmol, 10 eq) was added. The mixture was stirred at room temperature under a nitrogen atmosphere. After 15 minutes, ethyl acetate was added, followed by dropwise addition of 3% ammonia solution. After stirring, the mixture was filtered through diatomaceous earth and washed with ethyl acetate. The organic phase was separated, dried over anhydrous magnesium sulfate, filtered, evaporated, and loaded onto an ISOLUTE HM-N plate. The title compound 16e (27 mg, 0.12 mmol, 68%) was obtained by automated rapid chromatography (Combiflash Rf 300+, RediSep, 4 g silica column) with a gradient elution of 0–15% methanol (methanol solution containing 1% 1N NH3) / dichloromethane. LCMS (Method A); retention time 0.54 min; m / z [MH] - 225. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.00 (s, 1H),7.21 (t, J = 74.7 Hz, 1H), 7.07 (dd, J = 2.4, 1.2 Hz, 1H), 6.90 (d, J = 7.9Hz, 1H), 6.84 – 6.77 (m, 1H), 4.08 (s, 2H), 2.44 (d, J = 1.1 Hz, 3H), 1.87 (s, 2H).

[0771]

[0772] Intermediate 16f: 6-chloro-N-{[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}pyrido[2,3-b]pyrazin-3-amine

[0773] [7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methylamine 16e (27 mg, 0.12 mmol) was dissolved in DMF (1.2 mL), and 3,6-dichloropyridino[2,3-b]pyrazine (26 mg, 0.13 mmol, 1.1 eq) and DIPEA (40 µL, 0.24 mmol, 2 eq) were added. The mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was extracted with ethyl acetate / salt water, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated before being loaded onto an ISOLUTE HM-N. The sample was purified by automated rapid chromatography (Combiflash Rf 300+, RediSep 4 g silica gel column) with a gradient elution of 0-40% ethyl acetate / heptane to give the title compound 16f (34 mg, 0.09 mmol, 73%) as a yellow solid. LCMS (Method A); Retention time 1.13 minutes; m / z [M+H] + 390.2 (chlorine isotope). 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.20 (s, 1H), 8.63 (t, J = 4.9Hz, 1H), 8.48 (s, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.26 (t, J = 74.4 Hz, 1H), 7.17 (dd, J = 2.5, 1.2 Hz, 1H), 6.97 (d, J = 7.9Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 4.93 (d, J = 4.8 Hz, 2H), 4.09 (q, J = 5.3Hz, 1H), 2.39 (d, J = 1.1 Hz, 3H).

[0774]

[0775] Example 16: 1-[3-({[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol

[0776] 6-Chloro-N-{[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}pyrido[2,3-b]pyrazin-3-amine 16f (34 mg, 0.09 mmol) was dissolved in 1-propanol (5 mL), and 4-hydroxypiperidine (18 mg, 0.17 mmol, 2 eq) and DIPEA (45 µL, 0.26 mmol, 3 eq) were added. The mixture was sealed in a test tube, placed under a blast-proof cover, and heated to 120°C for 16 hours. The cooled reaction mixture was partitioned with dichloromethane / saline. The organic phase was separated by a phase separator and evaporated onto an ISOLUTE HM-N plate. The compound was purified by automated rapid chromatography (Combiflash Rf 300+, RediSep 4 g silica column) with a 0-100% ethyl acetate / heptane gradient elution to give title compound 16 (27.6 mg, 0.06 mmol, 70%) as a yellow solid. LC-HRMS (Method B): retention time 0.81 min, target mass 454.1929, measured m / z 455.2011, measured molecular formula C23H24F2N6O2. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.15 (d, J = 2.4 Hz,1H), 8.04 (s, 1H), 7.87 (t, J = 4.9 Hz, 1H), 7.78 (d, J = 9.1 Hz, 1H), 7.24(t, J HF = 74.4 Hz, 1H), 7.16 – 7.13 (m, 1H), 6.96 (d, J = 9.1 Hz, 1H), 6.91(d, J = 7.9 Hz, 1H), 6.87 – 6.82 (m, 1H), 4.87 (d, J = 4.9 Hz, 2H), 4.71 (d,J = 4.2 Hz, 1H), 4.22 – 4.11 (m, 2H), 3.79 – 3.69 (m, 1H), 3.29- 3.19 (m,2H), 2.39 (d, J = 1.1 Hz, 3H), 1.85 – 1.75 (m, 2H), 1.43 – 1.30 (m, 2H). 19 FNMR (376 MHz, DMSO) δ -80.76 (s, 2F).

[0777] Specific embodiments 17-125: The following example compounds in Table 1 were prepared using a similar method.

[0778] Table 1

[0779] Example 2: WNK1 TR-FRET binding assay

[0780] The binding activity of the compound was determined using an in vitro assay plate (corning #3574) with internally prepared terbium-labeled phosphorylated or dephosphorylated WNK1 protein Tb-8His-Halo-TEV-WNK1 (210-482) (UniProtKB® Master Registry No. Q9H4A3), the amino acid sequence of which is: MHHHHHHHHAEIGTGFPFDPHYVEVLGERMHYVDVGPRDGTPVLFLHGNPTSSYVWRNIIPHVAPTHRCIAPDLIGMGKSDKPDLGYFFDDHVRFMDAFIEALGLEEVVLVIHDWGSALGFHWAKRNPERVKGIAFMEFIRPIPTWD EWPEFARETFQAFRTTDVGRKLIIDQNVFIEGTLPMGVVRPLTEVEMDHYREPFLNPVDREPLWRFPNELPIAGEPANIVALVEEYMDWLHQSPVPKLLFWGTPGVLIPPAEAARLAKSLPNCKAVDIGPGLNLLQEDNPDLIGSEI ARWLSTLEISGGGSENLYFQCKAVGMSNDGRFLKFDIEIGRGSFKTVYKGLDTETTVEVAWCELQDRKLTKSERQRFKEEAEMLKGLQHPNIVRFYDSWESTVKGKKCIVLVTELMTSGTLKTYLKRFKVMKIKVLRSWCRQILKGL QFLHTRTPPIIHRDLKCDNIFITGPTGSVKIGDLGLATLKRASFAKSVIGTPEFMAPEMYEEKYDESVDVYAFGMCMLEMATSEYPYSECQNAAQIYRRVTSGVKPASFDKVAIPEVKEIIEGCIRQNKDERYSIKDLLNHAFFQEE (SEQ ID NO. 1).

[0781] Terbium-labeled WNK1 protein was conjugated to a fluorescein-labeled ATP-competitive probe, VER-00540269. VER-00540269 was designed based on the reported inhibitor WNK463 (Yamada et al., 2016a), replacing the tert-butylamide with a flexible linker arm to connect the fluorescein-labeled protein. WNK463 (MCE) was added... ® Product code: HY-100626. It competes with the inhibitor probe for the same binding site, and the TR-FRET signal is reduced due to probe displacement. WNK463 has been shown to inhibit OSR1 phosphorylation in a dose-dependent manner in HEK293 cells (Yamada et al., 2016).

[0782] Compounds were screened using serial dilutions of n=2, 11 points, and 3-fold. The assay system consisted of 1 nM terbium-labeled WNK1, 2 nM or 150 nM VER-00540269 probe, 50 mM HEPES (4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid) pH 7.5, 150 mM NaCl, 0.01% Tween-20, 1 mM dithiothreitol, and 5% DMSO. The assay system was incubated at 23°C for 2 hours.

[0783] TR-FRET assays were performed on a BioTek Synergy Neo2 microplate reader. TR-FRET was measured as follows: terbium donors were excited with 340 nm light, and after a 100 μs delay, the emission signals of terbium and luciferin were measured at 495 nm and 520 nm, respectively, within a 300 μs time window. This measurement was repeated 20 times for each emission light (495 nm and 520 nm), with a 300 μs time window between each repetition. The TR-FRET signal was calculated as the emission ratio at 520 nm to 495 nm.

[0784] The TR-FRET signals of the test compounds were normalized to baselines of 0% and 100% inhibition control wells, and the inhibition percentage of the test compounds was calculated. The potency (IC50) of the test compounds was estimated using an Xlfit 4 (IDBS, Guildford, Surrey, UK, Model 205) via a variable-slope sigmoid dose-response nonlinear regression model. 50 ).

[0785] y = (A+((BA) / (1+((C / x)^D))))

[0786] Where y is the normalized TR-TRET signal measurement at a given concentration of the test compound, x is the concentration of the test compound, A is the estimated efficacy (inhibition %) at infinite dilution, B is the maximum efficacy (inhibition %), and C is the IC50 value. 50 The value, D, is the Hill slope coefficient.

[0787] The Ki value is based on the methods described in Cer et al., Nucleic Acids Res, 2009, 37 (WebServer Special Issue): W441-W445, by IC. 50 The value is determined. The inhibition constant (Ki) is determined by the complete binding inhibition curve (cKi).

[0788] cK i The value is determined by the following formula from IC 50 Value determined:

[0789] in , , , and .

[0790] in This refers to the total protein content. This represents the total number of probes. To achieve 50% inhibition, (Probe K) d (This was determined through experiments.) IC 50 The concentration of free inhibitor at that time, IC 50 The concentration of the free probe at that time.

[0791] The compounds of this invention were screened using the above-described assays, and the cKi values ​​of each compound are listed in Table 2 below: where "A" represents cK i Less than 1 nM, "B" represents cK i Values ​​in the range of 1 nM to 100 nM, where "C" represents cK. i The value is in the range of greater than 100 nM to 1000 nM.

[0792] Table 2. cK i value

[0793] References

[0794] Ishigami-Yuasa M et al.: Development of WNK signaling inhibitors as a new class of antihypertensive drugs. Bioorg Med Chem. 2017, 25(14):3845-3852.

[0795] Yamada K et al.: Small-molecule WNK inhibition regulates cardiovascular and renal function. Nat Chem Biol. 2016,12:896-898. (Yamada etal., 2016a)

[0796] Yamada K, et al.: Discovery and Characterization of Allosteric WNKKinase Inhibitors. ACS Chem Biol. 2016, 11(12):3338-3346. (Yamada et al.,2016b)

[0797] Yamada K et al.: Optimization of Allosteric With-No-Lysine (WNK)Kinase Inhibitors and Efficacy in Rodent Hypertension Models. J Med Chem.2017 Aug 24;60(16):7099-7107.

[0798] Xiu, M., Li, L., Li, Y. et al. An update regarding the role of WNKkinases in cancer. Cell DeathDis 13, 795 (2022).

Claims

1. Compound of formula (I): Formula (I) in Y is C(H) or N; W is either C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A is selected from H and C. 1-3 Alkoxy groups, CF3 groups, and groups of formula (II): Equation (II) in X is C(H) or N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from the following groups: optionally substituents R, either the same or different. 7 Replacement C 1-6 Alkyl, wherein the C 1-6 One or more methylene groups of the alkyl group are optionally and independently substituted with -O- or C=O; optionally substituted with one or more identical or different substituents R. 7 Replacement C 3-6 cycloalkyl groups; and tetrahydropyranyl groups; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; R 7 Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl group; N(CH3)2; N(H)2; ;and ; Or when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-; or R 5 With R 6 Connect them to form a loop, and R 5 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) substitution; and R 6 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) Replace; Two of the R 8 They can be arbitrarily connected together to form a ring with the middle atoms; R 8 Independently selected from the following groups: C groups optionally substituted with OH 1-3 Alkyl; -OH; -F; -N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R's 8 Independently selected from: C groups optionally substituted with one or two substituents selected from F, OH and NH2 1-3 Alkyl, and the C 1-3 One or both methylene groups of the alkyl diene may be optionally and independently replaced by -O-, -N(H)-, or -N(CH3)-; and R 9 For H, C 1-3 Alkyl, oxetane, or , Or its pharmaceutically acceptable salt. The premise is that the compound is not N-[(2,3,5-trimethyl-1H-indol-7-yl)methyl]-2-quinoxaline.

2. The compound according to claim 1, wherein the compound is of formula (Ia), formula (Ib), formula (Ic), or formula (Id): Formula (Ia) Formula (Ib) Formula (Ic), Formula (Id).

3. The compound according to any one of the preceding claims, wherein R 1 It is H, CH3 or isopropyl; R 2 It is H, CH3, cyclopropyl or CH2OH; and R 3 The possible values ​​are H, CH3, CH2OH, NH2, N(CH3)2, Cl, C(O)NHCH3, OCHF2, or OCH3.

4. The compound according to any one of the preceding claims, wherein the compound is of formula (Ib), and wherein R 1 For H, R 2 For H, R 3 It can be H, CH3, or OCH3.

5. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and wherein R 1 CH3, R 2 For H, R 3 The possible values ​​are H, N(CH3)2, Cl, CH2OH, OCHF2, C(O)NHCH3 or OCH3.

6. The compound according to any one of the preceding claims, wherein the compound is of formula (Ib), and wherein R 1 For H, R 2 For CH3, cyclopropyl or CH2OH, R 3 For H.

7. The compound according to any one of the preceding claims, wherein the compound is of formula (Ic), and wherein R 1 It is isopropyl, R 2 For H, R 3 It is H or OCH3.

8. The compound according to any one of the preceding claims, wherein R 4 It can be H or CH3.

9. The compound according to any one of the preceding claims, wherein A is H, CF3, or formula (II): Equation (II) in X is N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from: C 1-6 Alkyl groups, optionally substituted with one or more identical or different substituents R 7 Instead, the C 1-6 One or more methylene groups of the alkyl group are optionally and independently replaced by -O- or C=O; C 3-6 cycloalkyl groups, optionally substituted with one or more identical or different substituents R 7 Substitution; and tetrahydropyranyl; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; and R 7 Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl group; N(CH3)2; N(H)2; ;as well as ; Or when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-.

10. The compound according to any one of the preceding claims, wherein R 6 It can be H or CH3.

11. The compound according to any one of the preceding claims, wherein R 5 For being substituents R by one or more identical or different substituents 7 Substituted C1 alkyl group, or substituted with one or more identical or different substituents R 7 Substituted C2 alkyl group, or substituted with one or more identical or different substituents R 7 Substituted C3 alkyl group, or with one or more identical or different substituents R 7 Substituted C4 alkyl group, or with one or more identical or different substituents R 7 Substituted C5 alkyl group, or with one or more identical or different substituents R 7 Substituted C6 alkyl group, which is formed by one or more identical or different substituents R. 7 The substituted C4 cycloalkyl group, or the C6 cycloalkyl group, or the group containing one or more identical or different substituents R 7 Substituted C6 cycloalkyl groups.

12. The compound according to any one of the preceding claims, wherein R 7 For OH, N(H)2, N(CH3)2, OCH3, OCHF2, CH3, CH2OH, or .

13. The compound according to any one of the preceding claims, wherein A is piperidinyl, pyrrolidinyl, aziridine, piperazine, or morpholinyl, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replacement, of which two R 18 Optionally linked together with the intermediate atom to form a ring; and wherein said morpholino group is optionally replaced by one or more identical or different substituents R. 19 Replace, where R 19 Independently selected from C 1-3 Alkyl groups and C groups substituted with OH 1-3 alkyl; R 18 Independently selected from C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 18 When connected to form a loop, the two R's 18 Independently selected from C14 groups that are optionally substituted by one or two substituents selected from F, OH, and NH2. 1-3 Alkyl, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

14. The compound according to any one of the preceding claims, wherein A is piperidinyl, pyrrolidinyl, aziridine, or piperazine, wherein the piperidinyl, pyrrolidinyl, aziridine, or piperazine is optionally selected by one or more independently chosen R. 18 Replace, where R 18 It is -CH3, -CH2OH, -OH, N(H)2, OCHF2, -F, oxetane or .

15. The compound according to any one of the preceding claims, wherein A is piperidinyl, pyrrolidinyl, azacyclobutyl, or piperazine, wherein the piperidinyl, pyrrolidinyl, azacyclobutyl, or piperazine is formed by two or more R... 18 Replacement, of which two R 18 They connect together with the middle atoms to form a ring, and the two Rs that connect to form the ring... 18 Independently selected C-type carbon atoms, which are optionally substituted by one or two substituents selected from F, OH, and -NH2. 1-3 Alkyl, and wherein the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)- or -N(CH3)-.

16. The compound according to any one of the preceding claims, wherein A is a morpholino group, wherein the morpholino group is optionally replaced by one or more identical or different substituents R. 19 Replace, where R 19 It is -CH3 or -CH2OH.

17. The compound according to any one of the preceding claims, wherein A is selected from: H, CF3, 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

18. The compound according to any one of the preceding claims, wherein the compound is selected from: 7-Cyclopropyl-N-(1H-indol-6-ylmethyl)quinoxaline-2-amine, N-[(7-methyl-1H-indol-5-yl)methyl]quinoxaline-2-amine, N-(1H-indol-6-ylmethyl)-7-(piperidin-1-yl)quinoxalin-2-amine N-(1H-indol-5-ylmethyl)quinoxaline-2-amine 1-(3-{[(6-amino-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N-(1H-indol-4-ylmethyl)-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine 1-[3-({[7-(hydroxymethyl)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 1-(3-{[1H-indol-4-yl(²H2)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N-(1H-indol-6-ylmethyl)-6-(piperidin-4-yl)pyrido[2,3-b]pyrazin-3-amine [6-({[6-(piperidin-1-yl)pyridino[2,3-b]pyrazin-3-yl]amino}methyl)-1H-indol-2-yl]methanol, N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]-6-(pyrrolidone-1-yl)pyrido[2,3-b]pyrazin-3-amine 6-N-cyclohexyl-3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazine-3,6-diamine, 1-[3-({[7-(dimethylamino)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-N-[(3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, N,3-Dimethyl-4-{[(6-{methyl[(1s,3s)-3-hydroxycyclobutyl]amino}pyrido[2,3-b]pyrazin-3-yl)amino]methyl}-1H-indole-7-carboxamide 1-[3-({[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]piperidin-4-ol, 3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(7-chloro-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, [(3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-yl]methanol, (3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, cis-(1s,3s)-3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyridino[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, N-[(1H-indol-6-yl)methyl]-6-{2-oxa-6-azaspiro[3.3]heptane-6-yl}pyrido[2,3-b]pyrazin-3-amine, 6-{2,6-diazaspiro[3.3]heptane-2-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 3-(hydroxymethyl)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, [(3R)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-yl]methanol, N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine cis-(1R,3R)-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclobutane-1-ol, [4-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-yl]methanol, 3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-N-[trans-4-aminocyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine, 7-tert-butyl-N-(1H-indol-6-ylmethyl)quinoxaline-2-amine N-[(1H-indol-6-yl)methyl]-6-(piperidin-1-yl)pyrido[2,3-b]pyrazin-3-amine [4-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-yl]methanol, N-(1H-indol-6-ylmethyl)-6-[4-(oxetane-3-yl)piperazin-1-yl]pyrido[2,3-b]pyrazin-3-amine 7-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}-7-azaspiro[3.5]nonane-2-amine, 1-{3-[({1H-pyrrolo[2,3-b]pyridin-5-yl}methyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, 3-N-(1H-indol-6-ylmethyl)-6-N-(oxacyclohexane-4-yl)pyrido[2,3-b]pyrazine-3,6-diamine, [(2R)-4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, N-[(1H-indol-6-yl)methyl]-6-(pyrrolidone-1-yl)pyrido[2,3-b]pyrazin-3-amine 7-Ethyl-N-[(1H-indol-6-yl)methyl]quinoxaline-2-amine, N-(1H-indol-6-ylmethyl)-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine, 1-(3-{[(3-hydroxy-4-methoxyphenyl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 6-{2,7-diazaspiro[3.5]nonane-7-yl}-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, N-[(1H-indol-6-yl)methyl]-7-methylquinoxaloline-2-amine, 3-N-(1H-indol-6-ylmethyl)-6-N-{2-oxaspiro[3.3]heptane-6-yl}pyrido[2,3-b]pyrazine-3,6-diamine, N-[(2-methyl-1H-indol-5-yl)methyl]quinoxaline-2-amine, 6-{2,6-diazaspiro[3,4]octane-6-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N3-[(1H-indol-6-yl)methyl]-N6-[trans-4-(difluoromethoxy)cyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine N-(1H-indol-6-ylmethyl)-6-(morpholin-4-yl)pyrido[2,3-b]pyrazin-3-amine, (3R)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-3-ol, N-[(1H-indol-6-yl)methyl]-6-{2-oxa-6-azaspiro[3.4]octane-6-yl}pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-{1-oxa-9-azaspiro[5.5]undecane-9-yl}pyrido[2,3-b]pyrazin-3-amine, [(2R)-4-[3-({[7-(difluoromethoxy)-3-methyl-1H-indol-4-yl]methyl}amino)pyrido[2,3-b]pyrazin-6-yl]morpholin-2-yl]methanol, 6-N-cyclohexyl-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, 1-(3-{[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3R,4R)-3-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, [(2R)-4-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}morpholin-2-yl]methanol, N-(1H-indol-6-ylmethyl)-6-{3-oxa-9-azaspiro[5.5]undecane-9-yl}pyrido[2,3-b]pyrazin-3-amine, trans-4-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclohexane-1-ol, 1-(3-{[(2-cyclopropyl-1H-indol-5-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N6-[2-(dimethylamino)ethyl]-N3-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazine-3,6-diamine, 6-{2,7-diazaspiro[3.5]nonane-7-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propane-1,2-diol, [(3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-yl]methanol, 1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-yl)methanol, trans-4-[methyl(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclohexane-1-ol, N-[(1H-indol-6-yl)methyl]quinoxaline-2-amine, 1-(3-{[(7-methoxy-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-ol, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N3-[(1H-indol-6-yl)methyl]-N6-(3-methoxypropyl)pyrido[2,3-b]pyrazine-3,6-diamine trans-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}(methyl)amino)cyclobutane-1-ol, N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-{2-methyl-2,7-diazaspiro[3.5]nonane-7-yl}pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-(piperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, cis-3-[(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, (3S,4S)-3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 1-(3-{[(2-methyl-1H-indol-5-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, N3-[(1H-indol-6-yl)methyl]-N6-[trans-4-aminocyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]-2,2-dimethylpropane-1-ol, 6-N-{6,6-difluorospiro[3.3]heptane-2-yl}-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, 6-{4-[(1-aminocyclopropyl)carbonyl]piperazin-1-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, 6-[cis-2,6-dimethylmorpholin-4-yl]-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, [(3S)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}pyrrolidine-3-yl]methanol, [4-(hydroxymethyl)-1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-yl]methanol, cis-3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)(methyl)amino]cyclobutane-1-ol, 4-[({6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]pyrido[2,3-b]pyrazin-3-yl}amino)methyl]-N,3-dimethyl-1H-indole-7-carboxamide, N-[(1H-indol-6-yl)methyl]-6-methylquinoxaloline-2-amine, 1-{3-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propyl}azacycloheptane-2-one, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-3-ol, [4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, N-(1H-indol-6-ylmethyl)-6-(4-methylpiperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine, trans-3-[methyl(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclobutane-1-ol, (3S,4S)-3-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-4-ol, 6-(azacyclobutan-1-yl)-N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, 1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, (3R,4R)-3-(hydroxymethyl)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)piperidin-4-ol, 6-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]spiro[3,3]heptane-2-ol, 3-N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-N-[trans-4-(dimethylamino)cyclohexyl]pyrido[2,3-b]pyrazine-3,6-diamine, (3S)-1-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, trans-3-({3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}amino)cyclobutane-1-ol, (3S)-1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, [4-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, (3S)-1-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)pyrrolidine-3-ol, 1-(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)azacyclobutane-3-ol, 4-({[6-(4-hydroxypiperidin-1-yl)pyrido[2,3-b]pyrazin-3-yl]amino}methyl)-N,3-dimethyl-1H-indole-7-carboxamide, 6-{1,4-dioxa-9-azaspiro[5.5]undecane-9-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-6-ylmethyl)-6-{1-oxa-8-azaspiro[4.5]decane-8-yl}pyrido[2,3-b]pyrazin-3-amine, 6-[cis-2,6-dimethylmorpholin-4-yl]-N-[(3-isopropyl-7-methoxy-1H-indol-4-yl)methyl]pyrido[2,3-b]pyrazin-3-amine, 6-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]spiro[3,3]heptane-2-ol, (3S,4S)-4-(hydroxymethyl)-1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}piperidin-3-ol, N-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-6-(4-methylpiperazin-1-yl)pyrido[2,3-b]pyrazin-3-amine N-[(1H-indol-6-yl)methyl]-7-methoxyquinoxaline-2-amine, trans-4-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)(methyl)amino]cyclohexane-1-ol, 3-[(3-{[(1H-indol-6-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]propane-1-ol, 6-N-[4-(dimethylamino)cyclohexyl]-3-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazine-3,6-diamine, [1-(hydroxymethyl)-4-[(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)amino]cyclohexyl]methanol, 1-{3-[(1H-indol-6-ylmethyl)amino]pyrido[2,3-b]pyrazin-6-yl}azacyclobutane-3-amine, [(2R)-4-(3-{[(3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)morpholin-2-yl]methanol, [4-(3-{[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]amino}pyrido[2,3-b]pyrazin-6-yl)-6,6-dimethylmorpholin-2-yl]methanol, N3-[(7-methoxy-3-methyl-1H-indol-4-yl)methyl]-N6-({2-oxabicyclo[2.2.2]octane-3-yl}methyl)pyrido[2,3-b]pyrazine-3,6-diamine, N-[(1H-indol-6-yl)methyl]-7-(trifluoromethyl)quinoxaline-2-amine, 6-{2,7-diazaspiro[3.5]nonane-2-yl}-N-(1H-indol-6-ylmethyl)pyrido[2,3-b]pyrazin-3-amine, N-(1H-indol-5-ylmethyl)-6-(morpholin-4-yl)pyrido[2,3-b]pyrazin-3-amine, and 6-{3,9-diazaspiro[5.5]undecane-3-yl}-N-[(1H-indol-6-yl)methyl]pyrido[2,3-b]pyrazin-3-amine.

19. The compound according to any one of the preceding claims, wherein the compound of formula (I) is a WNK lysine deficiency protein kinase 1 (WNK1) inhibitor.

20. A pharmaceutical composition comprising the compound of claims 1-19 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, excipients and / or diluents.

21. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, for use as a medicine.

22. Compound of formula (I): Formula (I) in Y is C(H) or N; W is C(H)2 or C(D)2; R 1 For H, C 1-3 Alkyl or cyclopropyl; R 2 H; C can be substituted with OH. 1-3 Alkyl; or C 3-5 cycloalkyl; R 3 H; C can be substituted with OH. 1-3 Alkyl; -OC optionally substituted with one or more F 1-3 Alkyl group; -C(O)NHCH3; -NH2; -N(H)(CH3); -N(CH3)2; or halogen; R 4 For H, C 1-4 Alkyl or C 3-5 cycloalkyl; A is selected from H and C. 1-3 Alkoxy groups, CF3 groups, and groups of formula (II): Equation (II) in X is C(H) or N; R 6 For H or C 1-4 Alkyl; and R 5 Selected from: optionally substituents R (one or more identical or different substituents) 7 Replacement C 1-6 Alkyl, wherein the C 1-6 One or more methylene groups of the alkyl group are optionally and independently substituted with -O- or C=O; optionally substituted with one or more identical or different substituents R. 7 Replacement C 3-6 cycloalkyl groups; and tetrahydropyranyl groups; Two of the R 7 They can be arbitrarily connected together to form a ring with the middle atoms; R 7 Independently selected from: C arbitrarily replaced by one or more Fs 1-3 Alkoxy; -OH; -O-benzyl; C optionally substituted with OH 1-3 Alkyl; N(CH3)2; N(H)2; ;and ; Or when two R 7 When connected to form a loop, the two R's 7 Independently selected from: C14 groups substituted with one or two substituents selected from F and OH. 1-2 Alkyl, and the C 1-2 One methylene group of the alkyl diene may optionally be replaced by -O-; or R 5 With R 6 Connect them to form a loop, and R 5 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) substitution; and R 6 For the bond or optionally by one or more identical or different substituents R 8 Replacement C 1-5 Alkyl, and C 1-5 One methylene group of the alkyl diene is optionally replaced by -O- or N(R) 9 ) Replace; Two of the R 8 They can be arbitrarily connected together to form a ring with the middle atoms; R 8 Independently selected from: C that is arbitrarily substituted with OH 1-3 Alkyl; -OH; F; N(H)2; and -OC optionally substituted with one or more F. 1-3 alkyl; Or when two R 8 When connected to form a loop, the two R's 8 Independently selected from C 1-3 An alkyl diene, optionally substituted with one or two substituents selected from F, OH, and NH2, and the C 1-3 One or both methylene groups in the alkyl diene may be optionally and independently replaced by -O-, -N(H)-, or -N(CH3)-; and R 9 For H, C 1-3 Alkyl, oxetane, or , Or its pharmaceutically acceptable salts, for the treatment, relief or prevention of diseases and conditions associated with WNK1 activity.

23. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 20, for the treatment, relief or prevention of diseases and conditions associated with WNK1 activity.

24. The compound used according to claim 21 or 22, wherein the disease or condition associated with WNK1 activity is hypertension.

25. The compound used according to claim 21 or 22, wherein the disease or condition associated with WNK1 activity is cancer.

26. The compound used according to claim 24, wherein the cancer is selected from leukemia, lymphoma, and myeloma.

27. Use of any compound of claims 1-19 or a pharmaceutically acceptable salt thereof or the pharmaceutical composition of claim 20 in the preparation of a medicament for treating, alleviating or preventing diseases and conditions associated with WNK1 activity.

28. A method for treating, alleviating, or preventing diseases and conditions associated with WNK1 activity, the method comprising administering to a subject in need a compound of any one of claims 1-19 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 20.

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