Imidazolyl-amino-pyrazine-carbonitriles as CHK-1 inhibitors

Abstract

The present invention relates to compounds of formula (I) that can function as inhibitors of checkpoint kinase 1 (Chk1). The invention also relates to pharmaceutical compositions containing those compounds and their use in the treatment of diseases and conditions susceptible to Chk1 inhibition, such as cancer.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to compounds of formula (I) that can function as inhibitors of checkpoint kinase 1 (Chk1). The invention also relates to pharmaceutical compositions containing those compounds and their use in the treatment of diseases and conditions susceptible to Chk1 inhibition, such as cancer. [Background technology]

[0002] background Chk1 is a serine / threonine kinase involved in cell cycle regulation and maintenance of DNA integrity. DNA damage can be endogenous or induced (e.g., by genotoxic agents or ionizing radiation) and results in single- or double-strand breaks in DNA or stalled replication forks. After DNA damage, cell proliferation is arrested at checkpoints to allow time for DNA repair or, if the damage is too severe, induce apoptosis. There are four major cell cycle checkpoints involved in regulating cell cycle progression: G1 / S, intra-S, G2 / M, and spindle assembly checkpoints. Chk1 activates the intra-S, S, and G2 / M checkpoints, forming part of a network of signaling pathways called the DNA damage response (DDR) pathway. Inhibition of Chk1 kinase can result in inhibition of DNA repair, which can lead to increased cell death (Dai, Y. et al. Clin Cancer Res. 2010, 16, 376).

[0003] Cancer is a disease caused by abnormal cell proliferation, and defects in DNA repair pathways are common in cancer cells. Such defects can make cancer cells more dependent on DNA repair pathways, including cell cycle checkpoint control, than normal cells. For example, many cancers have defects in the tumor suppressor p53, which leads to deregulation of the G1 / S checkpoint and increased dependence on the intra-S, S, and G2 / M checkpoints (Ozaki, T. Cancers 2011, 3, 994). These cancers tend to be highly sensitive to Chk1 inhibitors. Other mutations or expression changes in DNA repair pathways can increase sensitivity to Chk1 inhibitors. Examples include ataxia telangiectasia mutated (ATM) kinase deficiency, defects in the Fanconi anemia homologous repair pathway, and mutations that disrupt RAD50 signaling. Another factor that leads to high sensitivity to Chk1 inhibition is MYC overexpression. MYC overexpression combined with Chk1 inhibition can result in synthetic lethality (Chen, H. et al. Sig. Transduct. Target Ther. 2018, 3, 5). The MYC oncogene is a major driver of many cancers, including breast, liver, and colorectal cancers (Wang, C. et al. Sig. Transduct. Target Ther. 2021, 6, 117). Blosser reported that cyclin E dysregulation can lead to Chk1 inhibition (Blosser, W.D. et al. Oncotarget 2020, 11, 216), and that E2F / G2M / SAC gene expression profiles are associated with sensitivity to Chk1 inhibitors, whereas immune gene expression is associated with resistance.

[0004] For example, conventional chemotherapy agents, such as topoisomerase inhibitors and antimetabolites, and ionizing radiation induce DNA damage that is mitigated by DNA damage repair pathways, including Chk1. Activation of the repair pathway protects cancer cells from conventional chemotherapy or radiotherapy. Therefore, combined chemotherapy or radiotherapy with a Chk1 inhibitor may overcome resistance (Neizer-Ashun, F. et al. Cancer Lett. 2021, 497, 202).

[0005] A number of small molecule inhibitors of Chk1 have been described. Examples include prexasertib (Angius, G. et al Cancer Chemother. Pharmacol. 2020, 85, 9), MK-8776 (SCH900776) (Guzi, TJ et al Mol. Cancer Ther. 2011, 10, 591), CCT245737 (SRA737) (Walton, MI et al Oncotarget 2016, 7, 2329), GDC-0425 (Infante, JR et al Clin. Cancer. Res. 2017, 23, 2423), ravusertib (King, C. et al Invest. New Drugs 2014 32, 213), and CCT244747 (Lainchbury, M. et al J. Med. Chem. 2012, 55, 10229). Further examples of Chk1 inhibitors are reported in patents such as WO201520390, WO2021043208, WO2021104461 and WO202119236.

[0006] One area of ​​kinase drug development that continues to be challenging is the identification of central nervous system (CNS)-penetrating kinase inhibitors (Heffron, TP Neuro. Oncol 2018, 20, 307). Chk1 inhibitors that cross the blood-brain barrier may have additional utility in the treatment of CNS cancers such as glioma and medulloblastoma or brain metastases. For adenosine triphosphate (ATP)-competitive kinase inhibitors, hydrogen-bonding interactions with the kinase hinge region are typically essential for potent inhibitory activity (Xing, L. et al Bioorg. Med. Chem. Lett. 2015, 23, 6520). However, for improved CNS penetration, a reduced number of hydrogen bonds is preferred. In particular, a low number of hydrogen bond donor groups is advantageous for CNS penetration (Wager, TT et al. ACS Chem. Neurosci. 2016, 7, 767; Shi, Y. et al. Bioorg. Med. Chem. Lett. 2018, 28, 1981). Reducing the number of hydrogen bonds, especially the number of hydrogen bond donors, while maintaining good activity through hinge bond interactions remains a challenge in identifying kinase inhibitors, which may have potential for use in central nervous system disorders. Similarly, while a reduced topological polar surface area (tPSA) is advantageous for CNS penetration, the hydrogen bond groups of kinase inhibitors often form the primary binding interactions. Thus, maintaining good biological activity of kinase inhibitors with low PSA remains a challenge (Wager, TT et al. ACS Chem. Neurosci. 2016, 7, 767).

[0007] Many Chk1 inhibitors containing a pyrazole-NH-pyrazine moiety have been reported, such as prexasertib (Angius, G. et al. Cancer Chemother. Pharmacol. 2020, 85, 9; WO20110144126) and examples such as WO2022114189, WO2021119236, CN112457306, WO2017132928, and WO2015120390. Based on docking studies, the pyrazole functionality in these examples provides two hydrogen-bonding interactions (donor and acceptor) to Cys87 in the kinase hinge region (Xi, J. et al. 2021 Based on Computational Study, 10.21203 / rs.3.rs-509168 / v1). Given the importance of the hinge bond interaction, removal or attenuation of this key interaction would be expected to be detrimental to biological activity. In the present invention, the imidazole-NH-pyrazine motif has been associated with favorable Chk1 activity. The reduced hydrogen bond donor capacity of this motif confers great utility in the treatment of cancer, particularly CNS cancers.

[0008] Another challenge in the field of kinase drug discovery is kinase selectivity. Most small molecule kinase inhibitors interact with multiple members of the protein kinase family (Davis, M. et al. Nat. Biotechnol. 2011, 29, 1046). Such "off-target" activity can affect biological efficacy and promote undesirable effects (Yang, X. et al. J. Biomed. Inform. 2010, 43, 376), making selective agents potentially therapeutically ineffective. Several Chk1 inhibitors have been reported to also inhibit Chk2 (see, for example, WO2010077758; Zabludoff, SD et al. Mol. Cancer Ther. 2008, 7, 2955). However, selectivity for Chk2 favors the most potent S-phase checkpoint (Reader, JC et al J. Med. Chem. 2011, 54, 8328). Depletion of Chk2 in addition to Chk1 was shown to be inferior to Chk1 depletion alone in RNAi studies (Guzi, TJ et al Mol. Cancer Ther. 2011, 10, 591).

[0009] Another family of kinase proteins relevant to the field of Chk1 inhibitors is the ribosomal S6 kinase family (RSK). RSK phosphorylates Chk1 at the inhibitory site, Ser280 (Ray-David, H. et al. Oncogene 2013, 32, 4480). RSK inhibitors, such as SL0101, enhance Chk1 kinase activity by increasing the phosphorylation of Chk1 Ser345. Therefore, Chk1 inhibitors with reduced RSK activity may have biological advantages. Several Chk1 inhibitors have also been reported to inhibit RSK1 and / or RSK2 (Ditano, JP ACS Pharmacol. Transl. Sci. 2021, 4, 730; Walton, MI et al. Oncotarget 2016, 7, 2329).

[0010] Therefore, there remains a need for compounds that can act as Chk1 inhibitors with improved properties (which may include improved brain / CNS penetration and / or improved kinase selectivity, particularly with respect to Chk2 and RSK).

[0011] In the present invention, compounds containing the imidazole-NH-pyrazine motif according to formula (I) have been associated with favorable selectivity for Chk2 and RSK proteins, and these compounds may have utility in cancer therapy. Summary of the Invention

[0012] It has been found that compounds of formula (I) can function as Chk1 inhibitors and, therefore, can treat diseases and conditions susceptible to Chk1 inhibition, such as cancer. Furthermore, they possess certain advantageous properties compared to known compounds, leading to increased potential for use as drugs. This may be due to their efficacy, solubility, selectivity profile, safety profile, and / or other notable pharmacokinetic properties. In particular, advantages may be found in the selectivity of the compounds, particularly related to kinase selectivity. For example, the compounds may be selective for Chk1 inhibition relative to ribosomal S6 kinase (RSK) inhibition, which may lead to improved cancer treatment capabilities and / or fewer side effects. Furthermore, another particular advantage of the compounds may be their improved brain / CNS penetration, which may be demonstrated by their reduced brain excretion compared to known compounds. This may lead to improved capabilities for treating brain- and CNS-related cancers.

[0013] As a result, the present invention provides a compound of formula (I): [ka] {In the formula, Each X is independently N or CR 2 and; Each Y is independently N or CR 3 and; 0, 1, or 2 of X or Y are N; R 1 , R 2 , and R 3 are independently the following: (a) H, halo, (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 3- C9) Cycloalkyl, -OR 4 , -NR 5 R 6 , -C(O)R 7 , where (C 1- C6) alkyl, (C 1- C6) haloalkyl, and (C 3- C9) Cycloalkyl can be one or more R 8 is optionally replaced by; (b) one or more R 9 a 4- to 7-membered non-aromatic heterocycle optionally substituted with (c) Each of them (C 1- C6) alkyl, (C 1- C6) haloalkyl, and a 7-10 membered spiro, bridged, or fused heterocyclic ring system optionally substituted with one or more of -NR2; Selected from; R 4 is (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 1- C6) alkylene-NR2, a 4- to 6-membered non-aromatic heterocycle, and a 6- to 9-membered heterocyclic spiro system, wherein the 4- to 6-membered non-aromatic heterocycle and the 6- to 9-membered heterocyclic spiro system are selected from halo and (C 1- C6) optionally substituted with one or more alkyl; R 5 is H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl; R 6 is H, (C 1- C6) alkyl, (C 1- C6) haloalkyl, and 4- to 7-membered non-aromatic heterocycle, wherein the heterocycle is selected from halo and (C 1-C6) optionally substituted with one or more alkyl; R 7 is H, (C 1- C6) alkyl, (C 1- C6) haloalkyl, —NR2, and a 4- to 7-membered non-aromatic heterocycle, wherein the heterocycle is selected from halo and (C 1- C6) optionally substituted with one or more alkyl; R 8 is -NR2, and (O) n -(4- to 7-membered non-aromatic heterocycle), wherein the 4- to 7-membered non-aromatic heterocycle is selected from halo and (C 1- C6) optionally substituted with one or more alkyl; R 9 is halo, (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 3- C6) cycloalkyl, (C 1- C6)alkoxy, -NR2, -N(R)(C 1- C6) hydroxyalkyl, (C 1- C6) alkylene-NR2, a 4- to 6-membered non-aromatic heterocycle, and a 5- to 8-membered heterocyclic spiro system, wherein the (C 3- C6) cycloalkyl, 4-6 membered non-aromatic heterocycles, 5-8 membered heterocyclic spiro systems are also included, including halo and (C 1- C6) optionally substituted with one or more alkyl; and Each R is independently H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl} or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, diastereoisomer, isotopic form, N-oxide, and / or prodrug thereof.

[0014] These compounds are compounds of the present invention. In the compounds of the present invention, each X is independently N or CR, so long as at most two of the four ring atoms of X and Y are N. 2 and each Y is independently N or CR 3This means that in the compounds of the present invention, 0, 1, or 2 of X and Y are N. When neither X nor Y is N, then each X is CR 2 and each Y is a CR 3 This means that the ring containing X and Y in formula (I) is a C6 aryl, i.e., an optionally substituted phenyl. In this case, the compound of the present invention has the following formula (II): [ka] is a compound of

[0015] The ring containing the X and Y atoms may be an optionally substituted pyridyl. This is the case when one of the four X and Y groups is N. For example, if one X is N and the other X is CR 3 and each Y is CR 2 Then, the compound of the present invention is a compound of formula (III). Similarly, when one Y is N and the other Y is CR 2 and each X is a CR 3 then the compounds of the invention are compounds of formula (IV).

[0016] [ka]

[0017] The ring containing X and Y may be pyrazinyl, pyridazyl, or pyrimidyl, which means that when two of the four X and Y groups are N, the remaining groups are optionally CR 2 or CR 3 Thus, the compounds can be represented by formulae (V) to (VIII).

[0018] [ka]

[0019] In the compounds of the present invention, it is preferred that zero or one of the X and Y groups is N. This means that preferred compounds of the present invention are compounds of formula (II), formula (III), formula (IV) (most preferably formula (II) or formula (III)), or pharmaceutically acceptable salts, solvates, hydrates, tautomers, enantiomers, diastereoisomers, isotopic forms, N-oxides, and / or prodrugs thereof, with the remaining groups as defined herein. This means that the ring containing X and Y is preferably optionally substituted phenyl or pyridinyl. This means that each Y is preferably CR 3 This means that

[0020] Each R 1 , R 2 , and R 3 is H, halo, (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 3- C9) Cycloalkyl, -OR 4 , -NR 5 R 6 , -C(O)R 7 , 4- to 7-membered non-aromatic heterocycle, 7- to 10-membered spiro, bridged or fused heterocyclic ring systems. 1- C6) alkyl, (C 1- C6) haloalkyl, and (C 3- C9) Cycloalkyl can be one or more R 8 The 4- to 7-membered non-aromatic heterocycle is optionally substituted with one or more R 9 The 7-10 membered spiro, bridged or fused heterocyclic ring systems are optionally substituted with (C 1- C6) alkyl, (C 1- C6) haloalkyl, and optionally substituted with one or more of -NR2.

[0021] The term "optional" or "optionally" means that the subsequently described event or circumstance need not occur, but may occur, and encompasses both instances where the event or circumstance occurs and instances where it does not occur.

[0022] The term "substituted" means that the group to which it refers has one or more hydrogen atoms replaced by a different group. For example, a "substituted alkyl" refers to a monovalent radical of an alkane having one or more hydrogen atoms attached to an alkyl that is substituted by another group.

[0023] In view of the above, the term "optionally substituted" means that the group to which it refers may or may not be substituted, for example, with one or more halo.

[0024] The term "independently selected from" means that each feature is individually selected from the list without regard to the selection of other features.

[0025] As used herein, the term "halo" means a halogen atom, preferably F, Cl, Br, or I, more preferably F or Cl.

[0026] "(C 1- The term "(C6) alkyl" means a straight or branched alkyl group having 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. 1- With respect to the subject matter of "alkyl", all subgroups thereof, e.g., (C 1- C5) alkyl, (C 1- C4) alkyl, (C 1- C3) alkyl, (C 1- C2) alkyl, (C1) alkyl, (C 2- C6) alkyl, (C 2- C5) alkyl, (C 2- C4) alkyl, (C 2- C3) alkyl, (C2) alkyl, (C 3- C6) alkyl, (C 3- C5) alkyl, (C 3- C4) alkyl, (C3) alkyl, (C 4- C6) alkyl, (C 4- C5) alkyl, (C4) alkyl, (C 5-(C6) alkyl, (C5) alkyl, and (C6) alkyl, etc. are contemplated. 1- Examples of "C6) alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, and straight-chain or branched pentyl and hexyl.

[0027] When a term indicates a range, e.g., "(C 1- C6) alkyl 1- "C6" or "1 to 6 carbon atoms" is considered to disclose each integer, i.e., 1, 2, 3, 4, 5, and 6.

[0028] "(C 1- The term "C6)haloalkyl" refers to alkyl groups in which one or more hydrogen atoms are independently replaced with a halo atom, for example, F, Cl, Br, or I, preferably F or Cl, more preferably F. 1- (C6) alkyl group. 1- Each halo-substituted carbon atom in a C6) haloalkyl may be mono-, di-, or, if possible, tri-substituted with an independently selected halo atom. 1- With respect to the subject matter of "haloalkyl", all subgroups thereof, e.g. (C 1- C5) haloalkyl, (C 1- C4) haloalkyl, (C 1- C3) haloalkyl, (C 1- C2) haloalkyl, (C1) haloalkyl, (C 2- C6) haloalkyl, (C 2- C5) haloalkyl, (C 2- C4) haloalkyl, (C 2- C3) haloalkyl, (C2) haloalkyl, (C 3- C6) haloalkyl, (C 3- C5) haloalkyl, (C 3- C4) haloalkyl, (C3) haloalkyl, (C 4- C6) haloalkyl, (C 4- C5) haloalkyl, (C4) haloalkyl, (C 5-(C6)haloalkyl, (C5)haloalkyl, and (C6)haloalkyl, etc. are contemplated. 1- Examples of "C6)haloalkyl" include mono-, di-, and trihalomethyl, where the halo atoms are independently F, Cl, Br, or I, for example, -CH2F, -CF2H, -CF3, -CH2Cl, -CCl2H, -CCl3, -CHFCl, -CF2Cl, -CCl2F, mono-, di- and tribromomethyl, mono-, di- and triiodomethyl, and the like. Also included are ethyl substituted with 1, 2, 3, 4, or 5 independently selected halo atoms; n-propyl and isopropyl substituted with 1, 2, 3, 4, 5, 6, or 7 independently selected halo atoms; n-butyl, isobutyl, sec-butyl, and t-butyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 independently selected halo atoms; straight-chain or branched pentyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 independently selected halo atoms; and straight-chain or branched hexyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 independently selected halo atoms.

[0029] "(C 1- The term "haloalkoxy" refers to -O-(C 1- C3) haloalkyl, wherein "(C 1- The term "(C3)haloalkyl" is as defined above. 1- With respect to the subject matter of "haloalkoxy", all subgroups thereof, e.g. (C 1- C2) haloalkoxy, (C1) haloalkoxy, (C 2- (C3) haloalkoxy, (C2) haloalkoxy, and (C3) haloalkoxy, and the like, are contemplated.

[0030] "(C 3- The term "(C9)cycloalkyl" means a monocyclic alkyl group having 3 to 9 carbon atoms. 3- With respect to the subject matter of "cycloalkyl", all subgroups thereof, e.g. (C 3- C9) cycloalkyl, (C3- C8) cycloalkyl, (C 3- C7) cycloalkyl, (C 3- C6) cycloalkyl, (C 3- C5) cycloalkyl, (C 3- C4) cycloalkyl, (C3) cycloalkyl, (C 4- C9) cycloalkyl, (C 4- C8) cycloalkyl, (C 4- C7) cycloalkyl, (C 4- C6) cycloalkyl, (C 4- C5) cycloalkyl, (C4) cycloalkyl, (C 5- C9) cycloalkyl, (C 5- C8) cycloalkyl, (C 5- C7) cycloalkyl, (C 5- C6) cycloalkyl, (C5) cycloalkyl, (C 6- C9) cycloalkyl, (C 6- C8) cycloalkyl, (C 6- C7) cycloalkyl, (C6) cycloalkyl, (C 7- C9) cycloalkyl, (C 7- C8) cycloalkyl, (C7) cycloalkyl, (C 8- Contemplated are (C9)cycloalkyl, (C8)cycloalkyl, and (C9)cycloalkyl, etc. Examples of these cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and cyclononyl.

[0031] Any R 1 , R 2 , and R 3 but one or more R 8 optionally replaced by (C 3- C9) cycloalkyl. In this case, any R 1 , R 2 , and R 3 is preferably one or more R 8 optionally replaced by (C 3-C6) may be cycloalkyl; more preferably cyclopropyl or cyclobutyl, each of which is optionally substituted with -NR2. The term "heteroatom" means O, N, or S.

[0032] The term "4- to 7-membered non-aromatic heterocycle" refers to a monocyclic non-aromatic ring containing 4, 5, 6, or 7 atoms in the ring, where at least one of the atoms (e.g., 1, 2, 3, 4, preferably 1 or 2) is a heteroatom, such as O, N, S, preferably N or O. Non-aromatic heterocycles containing other ranges of ring atoms, e.g., 4- to 6-membered, 5- to 7-membered, 4- to 5-membered, 5- to 6-membered, etc., contain the appropriate number of atoms. Examples of 4- to 7-membered non-aromatic heterocycles include, but are not limited to, the following: [ka] and each of which may be substituted as defined hereinabove. Further examples contain 3 or 4 heteroatoms.

[0033] Preferred examples of the 4- to 7-membered non-aromatic heterocycle include the following: [ka] and the like, each of which may be substituted as defined hereinabove.

[0034] "-(O) n The term "-(4- to 7-membered non-aromatic heterocycle)" means a "4- to 7-membered non-aromatic heterocycle" as defined herein, optionally linked to the remainder of the compound via an oxygen group. n can be 0 or 1. This means that when "n" is 1, then an oxygen linker is present and "-(O) n "-(4- to 7-membered non-aromatic heterocycle)" means -O-(4- to 7-membered non-aromatic heterocycle). When "n" is 0, there is no oxygen linker, and it refers to "4- to 7-membered non-aromatic heterocycle". When n is 0, "-(O) nNon-limiting examples of "-(4- to 7-membered non-aromatic heterocycle)" include all of those listed above for "4- to 7-membered non-aromatic heterocycle", each of which may be selected from the group consisting of one or more halo or (C 1- C6) optionally substituted with alkyl. When n is 1, "-(O) n Non-limiting examples of "-(4- to 7-membered non-aromatic heterocycle)" include all of the 4- to 7-membered non-aromatic heterocycles listed above, where the heterocycle is linked to the remainder of the compound via an oxygen linker. Thus, when n is 1, "-(O) n Non-limiting examples of -(4- to 7-membered non-aromatic heterocycle) include the following: [ka] and each of which may be selected from the group consisting of one or more halo or (C 1- C6) alkyl. Preferably, when n is 1, "-(O) n Examples of "-(4- to 7-membered non-aromatic heterocycle)" include the following: [ka] and each of which may be selected from the group consisting of one or more halo or (C 1- C6) optionally substituted with alkyl.

[0035] The term "7-10 membered spiro, bridged, or fused heterocyclic ring system" means a non-aromatic ring system containing 7, 8, 9, or 10 atoms in the system (i.e., one or more rings in the system), where at least one of the atoms (e.g., 1, 2, 3, or 4 atoms) is a heteroatom, such as O, N, or S, preferably N or O. These "atoms in the system" do not include any optional substituents. The same is true for "8-10 membered spiro or fused heterocyclic ring system," except that the non-aromatic ring system contains 8, 9, or 10 atoms in the system and the system is a spiro group or a fused ring.

[0036] The heterocyclic ring system may be a spiro group, i.e., a group comprising two rings joined by a shared tetrahedral carbon atom, such as the following non-limiting examples, with further examples comprising two or more heteroatoms within the spiro ring system and / or where the point of attachment to the remainder of the compound may be from any atom within the ring (including the heteroatom): [ka] [ka] Preferred are 7-10 membered spiro heterocyclic ring systems such as those selected from the following: 1- C6) alkyl, (C 1- Preferred examples of 7-10 membered spiro heterocyclic ring systems include those in which each of the following is optionally substituted: (C6) haloalkyl, and -NR2. 1- C6) alkyl, (C 1- C6) haloalkyl, and the following optionally substituted with one or more of -NR2: [ka] Examples include:

[0037] The 6- to 9-membered heterocyclic spiro systems are the same as the spiro heterocycles described above, but contain 6, 7, 8, or 9 ring atoms. The 7- to 9-membered heterocyclic spiro systems are the same as the spiro heterocycles described above, but contain 7, 8, or 9 ring atoms. The 5- to 8-membered heterocyclic spiro systems are the same as the spiro heterocycles described above, but contain 5, 6, 7, or 8 ring atoms. The 6- to 8-membered heterocyclic spiro systems are the same as the spiro heterocycles described above, but contain 5, 6, 7, or 8 ring atoms.

[0038] A heterocyclic ring system may be a bridged group. This is a 7- to 10-membered bridged heterocycle formed from 4- to 9-membered monocyclic rings, in which two non-adjacent atoms are connected by a 1- to 3-membered bridge (and in which the total number of atoms in the system (excluding optional substituents) is 7 to 10). At least one of the atoms in the 7- to 10-membered bridged heterocycle is a heteroatom. The heteroatom may be present in the monocyclic ring, the bridged moiety, or both the monocyclic ring and the bridge. As will be understood, any ring in a bridged group may be considered a "bridge" for that "monocyclic ring," leaving the remaining portion. In this regard, a 6-membered monocyclic ring having a 1-membered bridge between positions 1 and 4 of the monocyclic ring may also be considered a 5-membered monocyclic ring having a 2-membered bridge between positions 1 and 3 of the monocyclic ring. Non-limiting examples of 7- to 10-membered bridged heterocyclic ring systems include those each of which is represented by the formula (C 1- C6) alkyl, (C 1- C6) haloalkyl, and the following optionally substituted with one or more of -NR2: [ka] Preferred examples of the 7- to 10-membered bridged heterocyclic ring system include those in which each of the rings is (C 1- C6) alkyl, (C 1- C6) haloalkyl, and -NR2, preferably (C 1- C3) the following optionally substituted with alkyl, and more preferably methyl: [ka] Examples include:

[0039] The heterocyclic ring system may be a fused ring. As used herein, a "fused" ring system is typically two rings or a bicyclic ring that share two ring atoms, as in the fused ring exemplified below. In this case, a fused bicyclic heterocyclic ring is preferred. The heteroatom may be present in either of the two rings, including the atom shared between the two rings. Non-limiting examples of fused bicyclic heterocyclic ring systems include those in which each of the rings is (C 1- C6) alkyl, (C 1-C6) haloalkyl, and the following optionally substituted with one or more of -NR2: [ka] Preferred examples of the 7- to 10-membered fused heterocyclic ring system include those in which each of them is (C 1- C6) alkyl, (C 1- C6) haloalkyl, and the following optionally substituted with one or more of -NR2: [ka] Examples include:

[0040] "(C 1- The term "C6) alkylene" refers to 1- The range "(C 1- With respect to the subject matter of "alkylene", all subgroups thereof, e.g. (C 1- C5) alkylene, (C 1- C4) alkylene, (C 1- C3) alkylene, (C 1- C2) alkylene, (C1) alkylene, (C 2- C6) alkylene, (C 2- C5) alkylene, (C 2- C4) alkylene, (C 2- C3) alkylene, (C2) alkylene, (C 3- C6) alkylene, (C 3- C5) alkylene, (C 3- C4) alkylene, (C3) alkylene, (C 4- C6) alkylene, (C 4- C5) alkylene, (C4) alkylene, (C 5- (C6) alkylene, (C5) alkylene, and (C6) alkylene are contemplated. 1-Non-limiting examples of "C6) alkylene" include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, t-butylene, and straight-chained or branched pentylene and hexylene.

[0041] Each R in "-NR2" is H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl. In this regard, the term "-NR2" may be a primary amine, a secondary amine, or a tertiary amine. Thus, examples of "-NR2" include, but are not limited to, the following: -NH2, [ka] Examples include:

[0042] Further examples include those in which each R independently represents any straight or branched chain (C 1- Any hydrogen atom in the alkyl chain may be independently replaced by a halo atom. 1- C6) haloalkyl. 1- When the alkyl group is -NR2, then there may be independently 0, 1, 2, or 3 halo atoms present on each carbon atom (where valence allows), provided that at least one halo atom is present. 1- C6) haloalkyl} include, but are not limited to, the following: [ka] Examples include:

[0043] From the above perspective, "(C 1- The term "(C6)alkylene-NR2" means an alkylamine, 1- "(C6) alkylene" and "-NR2" are as defined herein. 1-Preferred examples of C6) alkylene-NR2 include the following: [ka] and more preferably the following: [ka] and most preferably the following: [ka] Examples include:

[0044] "-O-(C 1- The term "(C6) alkylene-NR2" refers to an oxy-linked "(C 1- C)alkylene-NR" group, wherein "(C 1- "-O-(C)alkylene-NR" is as defined above. 1- Preferred, non-limiting examples of C6) alkylene-NR2 include the following: [ka] and most preferably the following: [ka] Examples include:

[0045] "(C 1- The term "alkoxy" refers to -O-(C 1- C alkyl) {wherein (C 1- The range "(C6) alkyl group is as defined above." 1- With regard to the "C6)alkoxy" component, all subgroups thereof, e.g. (C 1- C5) alkoxy, (C 1- C4) alkoxy, (C 1- C3) alkoxy, (C 1- C2) alkoxy, (C1) alkoxy, (C 2- C6) alkoxy, (C2- C5) alkoxy, (C 2- C4) alkoxy, (C 2- C3) alkoxy, (C2) alkoxy, (C 3- C6) alkoxy, (C 3- C5) alkoxy, (C 3- C4) alkoxy, (C3) alkoxy, (C 4- C6) alkoxy, (C 4- C5) alkoxy, (C4) alkoxy, (C 5- (C6)alkoxy, (C5)alkoxy, and (C6)alkoxy, etc. are contemplated. 1- Non-limiting examples of C6)alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, and straight- and branched-chain pentoxy and hexoxy.

[0046] "(C 1- The term "hydroxyalkyl" refers to the (C 1- C6) alkyl group, wherein one or more hydrogen atoms are independently replaced with a hydroxy group (—OH). 1- C6) Each hydroxy-substituted carbon atom in a hydroxyalkyl may be mono-, di-, or, where possible, tri-substituted with a hydroxy group.

[0047] Range "(C 1- With respect to the subject matter of "hydroxyalkyl", all subgroups thereof, e.g., (C 1- C5) hydroxyalkyl, (C 1- C4) hydroxyalkyl, (C 1- C3) hydroxyalkyl, (C 1- C2) hydroxyalkyl, (C1) hydroxyalkyl, (C 2- C6) hydroxyalkyl, (C 2- C5) hydroxyalkyl, (C 2- C4) hydroxyalkyl, (C 2- C3) hydroxyalkyl, (C2) hydroxyalkyl, (C 3- C6) hydroxyalkyl, (C3- C5) hydroxyalkyl, (C 3- C4) hydroxyalkyl, (C3) hydroxyalkyl, (C 4- C6) hydroxyalkyl, (C 4- C5) hydroxyalkyl, (C4) hydroxyalkyl, (C 5- (C6) hydroxyalkyl, (C5) hydroxyalkyl, and (C6) hydroxyalkyl, etc. are contemplated. 1- Examples of "C6)hydroxyalkyl" include mono-, di-, and tri-hydroxymethyl. Also included are ethyl substituted with 1, 2, 3, 4, or 5 hydroxy groups; n-propyl and isopropyl substituted with 1, 2, 3, 4, 5, 6, or 7 hydroxy groups; n-butyl, isobutyl, sec-butyl, and t-butyl substituted with 1, 2, 3, 4, 5, 6, 7, or 8 hydroxy groups; straight-chain or branched pentyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 hydroxy groups; and straight-chain or branched hexyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 hydroxy groups.

[0048] "-N(R)(C 1- The term "(C6)hydroxyalkyl" refers to a nitrogen atom that is connected to the remainder of the compound, where the nitrogen atom is substituted with an R group and is not "(C6)hydroxyalkyl" 1- "-N(R)(C6)hydroxyalkyl" is as defined above. Preferably, "-N(R)(C6)hydroxyalkyl" is as defined above. 1- Non-limiting examples of "C6) hydroxyalkyl" include the following: [ka] and most preferably the following: [ka] Examples include:

[0049] -N(H)(C 1-The term "-NR2" refers to the group "-NR2" where one of the R groups is H and the other is "(C3) alkyl" as defined above. 1- C3) alkyl.

[0050] "-N((C 1- The term "-NR" refers to a group where each R group is independently a "(C) alkyl" as defined above. 1- C3) alkyl.

[0051] -N(H)(C 1- The term "--C)haloalkyl" refers to the group "--NR" where one of the R groups is H and the other is a "(C)haloalkyl" as defined above. 1- Preferably, "-N(H)(C 1- Non-limiting examples of "C3) haloalkyl" include the following: [ka] and most preferably the following: [ka] Examples include:

[0052] "(C 1- C3) alkylene-N((C 1- The term "(C3) alkyl)" means an alkylamine, 1- C3) alkylene" and "-N((C 1- C)alkyl)" is as defined herein. Preferably, "(C 1- C3) alkylene-N((C 1- Non-limiting examples of C3)alkyl)2 include the following: [ka] and (C 1- Further examples include where the (C3) alkylene is ethylene or propylene. Most preferably, "(C 1-C3) alkylene-N((C 1- C3) alkyl)2" is one of the following: [ka] is.

[0053] In a preferred aspect of the invention, R 1 is one or more R 9 a 4- to 7-membered non-aromatic heterocycle optionally substituted with (C 1- C6) alkyl, (C 1- C6) haloalkyl, and a 7-10 membered spiro, bridged, or fused heterocyclic ring system optionally substituted with one or more of -NR2, where R 9 is halo, (C 1- C3) alkyl, (C 1- C3) haloalkyl, (C 3- C6) cycloalkyl, (C 1- C3)alkoxy, -NR2, (C 1- C3) may be selected from alkylene-NR2, 4- to 6-membered non-aromatic heterocycles, and 5- to 8-membered heterocyclic spiro systems. (C 3- C6)cycloalkyl, 4-6 membered non-aromatic heterocycles, and 5-8 membered heterocyclic spiro systems are also included with halo and (C 1- Further, each R is optionally substituted with one or more of H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl. Preferably, R 1 is R 1 is linked to the remainder of the compound by a heteroatom (preferably N) of the heterocycle or heterocyclic ring system.

[0054] In a more preferred aspect of the invention, R 9 But -NR2, (C 1- C3) alkylene-NR2, a 4- to 6-membered non-aromatic heterocycle, and a 5- to 8-membered heterocyclic spiro system, wherein the 4- to 6-membered non-aromatic heterocycle and the 5- to 8-membered heterocyclic spiro system are selected from halo and (C 1- C6) alkyl. Most preferably, R9 is F, methyl, methoxy, -NH2, -N(H)Me, -N(H)Et, -N(H) i Pr, -NMe2, -N(Me)Et, [ka] is selected from.

[0055] More preferably, R 1 is the following: [ka] and halo, (C 1- C3) alkyl, (C 1- C3)alkoxy, -NH2, -N(H)(C 1- C3) alkyl, -N((C 1- C3) alkyl)2, -N(H)(C 1- C3) haloalkyl, -(C 1- C3) alkylene-N((C 1- C3) alkyl)2, [ka] is optionally replaced by one or more of:

[0056] Each R 10 is halo and (C 1- C3) alkyl. m can be 0, 1, 2, or 3. This means that 0, 1, 2, or 3 carbon atoms on the ring are independently selected from R 10 p can be 0, 1 or 2. This means that 0, 1 or 2 carbon atoms on the ring can be substituted with R 10 In spiro systems, the tetrahedral carbon atom shared by the two rings can be substituted with R 10 cannot be replaced by

[0057] Most preferably, R 1 is the following: [ka] and F, methyl, methoxy, -NH2, N(H)Me, -N(H)Et, -N(H) i Pr, -NMe2, -N(Me)Et, [ka] is optionally replaced by one or more of:

[0058] In an alternative aspect of the invention, R 1 is one or more R 8 optionally replaced by (C 1- C3) alkyl, preferably methyl, in which case R 8 is -NR2, and (O) n -(4- to 7-membered non-aromatic heterocycle), wherein the 4- to 7-membered non-aromatic heterocycle is selected from halo and (C 1- Further, n is 0 or 1, and each R is optionally substituted with one or more of H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl. In this aspect, R 1 is most preferably one of the following: [ka] where: [ka] is optionally replaced by F.

[0059] In an alternative aspect of the invention, R 1 is -NR 5 R 6 In this feature, R 5 is H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl, preferably H and (C 1- C6) alkyl, more preferably selected from H and Me. 6 is H, (C 1-C6) alkyl, (C 1- C6) haloalkyl, and a 4- to 7-membered non-aromatic heterocycle, wherein the 4- to 7-membered non-aromatic heterocycle is selected from halo and (C 1- C6) optionally substituted with one or more alkyl. Preferably, R 6 is one or more (C 1- C3) a 5- or 6-membered non-aromatic heterocycle optionally substituted with alkyl, more preferably R 6 is the following: [ka] Most preferably, R 5 is H or methyl, and R 6 is the following: [ka] is.

[0060] Alternatively, R 1 -OR 4 and (C 1- C6) alkyl, (C 1- C6) haloalkyl, (C 1- C6) R is selected from alkylene-NR2, a 4- to 6-membered non-aromatic heterocycle, and a 6- to 9-membered heterocyclic spiro system. 4 4-6 membered non-aromatic heterocyclic rings, 6-9 membered heterocyclic spiro systems are also included, including halo and (C 1- C6) optionally substituted with one or more alkyls.

[0061] In this aspect of the invention, each R is selected from the group consisting of H, (C 1- C6) alkyl, and (C 1- C6) independently selected from haloalkyl and preferably H.

[0062] More preferably, R 4 is (C 1- C3) alkylene-NR2, a 4- to 5-membered non-aromatic heterocycle, and a 7- to 9-membered heterocyclic spiro system, wherein the 4- to 5-membered non-aromatic heterocycle and the 7- to 9-membered heterocyclic spiro system are selected from halo and (C1- wherein each R is optionally substituted with one or more of H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl, preferably each R is H. Most preferably, R 4 is the following: [ka] and each of which is optionally substituted with halo, preferably F.

[0063] In an alternative aspect of the invention, R 1 is -C(O)R 7 and R 7 is H, (C 1- C6) alkyl, (C 1- C6) haloalkyl, —NR2, and a 4- to 7-membered non-aromatic heterocycle, wherein the 4- to 7-membered non-aromatic heterocycle is selected from halo and (C 1- and each R is optionally substituted with one or more of H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl. Preferably, R 7 is a 4- to 7-membered non-aromatic heterocycle, and is one or more (C 1- C3) optionally substituted with alkyl. Most preferably, R 7 is the following: [ka] is.

[0064] R 2 is a group in which at least one X group is CR 2 i.e., at least one of the X groups is not N. Two R 2 groups are present (i.e., both X groups are CR 2 ), then for each R 2 are independently selected. In a particularly preferred embodiment, R2 is H, halo, (C 1- C3) alkyl, (C 1- C3) haloalkyl, (C 1- C3) alkoxy, (C 1- C3)haloalkoxy (preferably -OCF3), -NR2, and -O(C 1- C) alkylene-NR (preferably -O-propylene-NH), and R is selected from H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl. More preferably, R 2 is H, halo, (C 1- C3) alkyl (preferably methyl), (C 1- C3) haloalkyl (preferably -CF3), and -NR2 (preferably -NMe2). Even more preferably, R 2 is H or halo, most preferably H or F. For the reasons set out below, R 2 But (C 1- C3) It is preferable that it is not alkoxy, and particularly that it is not methoxy.

[0065] It is also preferred that one X is N or CH. This means that one X can be N or CH and the other X can be N or CR. 2 When one X is N or CH, the compound of the present invention may be: [ka] In this case, examples of compounds of the present invention include the following: [ka] Examples include:

[0066] Without wishing to be bound by any theory, it has been surprisingly found that when one X is N or CH, the activity of the compound is improved. 2This may be due to the reduced steric hindrance provided by the smaller groups at the positions, which may allow the compounds to bind more effectively to their targets, potentially leading to improved Chk1 inhibition.

[0067] The compounds of the present invention are characterized by the presence of (single or multiple) R 2 Located at the position (C 1- C3)alkoxy is acceptable. However, their (C 1- C3) the presence of alkoxy groups, especially R 2 The presence of a methoxy group at position 1 is not essential to the activity of the compound. If so, it may affect the inhibition of Chk1 and therefore the ability to treat Chk1-related diseases, such as cancer, when compared to other compounds of the present invention. However, the presence of one or two R 2 But (C 1- C3) Compounds of the invention that are alkoxy (ie, methoxy) may still have advantages over previously known compounds.

[0068] R 3 is a group in which at least one of the Y groups is CR 3 In the compounds of the present invention, at least one of the Y groups is not N. 3 groups are present (i.e., both Y groups are CR 3 ) then, for each R 3 are independently selected.

[0069] In a particularly preferred aspect of the invention, R 3 is H, halo (preferably F or Cl), (C 1- C6) alkyl (preferably methyl), (C 1- C6) haloalkyl (preferably —CF3), —OR 4 ; one or more R 9 5- to 7-membered non-aromatic heterocycles optionally substituted with; and halo and (C 1- C3) an 8-10 membered spiro or fused heterocyclic ring system optionally substituted with one or more of alkyl.

[0070] The 5- to 7-membered non-aromatic heterocycle is preferably one of the following: [ka] and each of which is selected from one or more R 9 is optionally replaced by

[0071] The 8-10 membered spiro or fused heterocyclic ring system is preferably one of the following: [ka] and each of which is selected from halo and (C 1- C3) optionally substituted with one or more alkyl, preferably F or methyl.

[0072] In this case, R 4 is preferably (C 1- C6) alkylene-NR2, a 4- to 6-membered non-aromatic heterocycle, and a 6- to 8-membered heterocyclic spiro system, wherein each of the 4- to 6-membered non-aromatic heterocycle or the 6- to 8-membered heterocyclic spiro system is selected from one or more (C 1- C3) optionally substituted with alkyl or halo. Preferably, R 4 is (C 1- C3) alkylene-NH2 (more preferably, propylene-NH2); [ka] where: [ka] Each of the 1- C3) optionally substituted with alkyl or halo.

[0073] Further in this aspect of the invention, R 9 is halo, (C 1- C3) alkyl (preferably methyl), -NR2, -NR((C 1-C3) hydroxyalkyl), and (C 1- C) alkylene-NR (preferably methylene-NR); and each R is selected from H, (C 1- C6) alkyl and (C 1- C6) haloalkyl, preferably independently selected from H or methyl.

[0074] In a feature of the present invention, R 1 is H or methyl, and at least one Y is CR 3 In this case, R 3 is preferably -OR 4 and the 5- to 7-membered non-aromatic heterocycle is selected from one or more R 9 and the 8-10 membered spiro or fused heterocyclic ring system is optionally substituted with halo and (C 1- C3) optionally substituted with one or more alkyl, where R 4 is (C 1- C6) alkylene-NR2, a 4- to 6-membered non-aromatic heterocycle, and a 6- to 8-membered heterocyclic spiro system, wherein each of the 4- to 6-membered non-aromatic heterocycle or the 6- to 8-membered heterocyclic spiro system may be selected from one or more (C 1- C3) optionally substituted with alkyl or halo. 9 is halo, (C 1- C3) alkyl, -NR2, -NR((C 1- C3) hydroxyalkyl), and (C 1- and each R may be selected from H, (C 1- C6) alkyl, and (C 1- C6) haloalkyl. Even more preferably, R 3 is the following: [ka] and each of which is optionally substituted with one or more halo, preferably F.

[0075] Particularly advantageous compounds of the present invention are: 5-((1-(4-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-chloro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-fluoro-1-methylpiperidin-4-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)-6-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0076] 5-((1-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2,4-dimethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0077] 5-((1-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(((4-fluoro-1-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-chloro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2,4-dimethylpiperazin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0078] 5-((1-(3-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(methyl((1-methylpiperidin-4-yl)methyl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-ethyl-2-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-ethylpiperidin-4-yl)amino)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0079] 5-((1-(2-methoxy-4-(-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-(tert-butyl)azetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((1-propylazetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-([1,3'-bipyrrolidin]-1'-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyrazin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-(tert-butyl)azetidin-3-yl)oxy)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0080] 5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2-methyl-6-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((-4-fluoro-1-methylpyrrolidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2,6-dimethylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-(dimethylamino)pyrrolidin-1-yl)-4-methylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-6-methylpyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-3-(dimethylamino)-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0081] 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2-((dimethylamino)methyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-morpholinopyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-3-(dimethylamino)-4-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-4-(dimethylamino)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)-4-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0082] 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)-3-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-3-fluorophenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-(3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-(dimethylamino)-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(Bis(methyl-d3)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(-4-(dimethylamino)-2-methylpyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-3-(dimethylamino)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(ethylamino)-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(ethyl(methyl)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0083] 5-((1-(5-(3-(ethyl(methyl)amino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-fluoro-4-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-((3,3,3-trifluoropropyl)amino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(isopropylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3,3,4-trimethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(azetidin-1-yl)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(6-methyl-1,6-diazaspiro[3.3]heptan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methyl-1,7-diazaspiro[3.5]nonan-7-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0084] 5-((1-(4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(azetidin-1-yl)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)-3-methylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylmorpholin-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(2-((dimethylamino)methyl)morpholino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-((2-hydroxyethyl)(methyl)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-((dimethylamino)methyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0085] 5-((1-(4-(6-methyl-1,6-diazaspiro[3.4]octan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(3,3-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(3-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methyl-1,6-diazaspiro[3.4]octan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(3-fluoroazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(2-azaspiro[3.3]heptan-2-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(3-isopropylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(2-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(2,2-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 1-(4-(4-((5-cyanopyrazin-2-yl)amino)-1H-imidazol-1-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine oxide 5-((1-(4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0086] 5-((1-(4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-([1,3'-bipyrrolidin]-1'-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-aminopropoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2-aminoethoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0087] 5-((1-(3-((3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-aminopyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(7-amino-5-azaspiro[2.4]heptan-5-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-amino-3-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(aminomethyl)azetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(aminomethyl)-3-fluoroazetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1,6-diazaspiro[3.3]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3,6-diazabicyclo[3.2.0]heptan-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(ethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0088] 5-((1-(4-(3-methoxy-4-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-fluoro-4-(methylamino)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-amino-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(4-amino-3,3-difluoropiperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-(3-aminopropoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile) 5-((1-(4-((ethylamino)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((4,4-difluoropiperidin-1-yl)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0089] 5-((1-(4-((4-fluoropiperidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methylazetidin-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-(diethylamino)cyclopropyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0090] 5-((1-(4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, diastereoisomer, isotopic form, N-oxide, and / or prodrug thereof.

[0091] More preferred compounds of the present invention include the following: 5-((1-(4-((1R,5R)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(3-chloro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-fluoro-1-methylpiperidin-4-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(2-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)-6-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(2-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0092] 5-((1-(3-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (S)-5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(2,4-dimethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (S)-5-((1-(4-(2,4-dimethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0093] 5-((1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((((3S,4S)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-chloro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0094] 5-((1-(4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (S)-5-((1-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (S)-5-((1-(4-(2,4-dimethylpiperazin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (S)-5-((1-(3-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(methyl((1-methylpiperidin-4-yl)methyl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(3-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0095] (R)-5-((1-(4-(4-ethyl-2-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-ethylpiperidin-4-yl)amino)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-((1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-(tert-butyl)azetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((1-propylazetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0096] 5-((1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-([1,3'-bipyrrolidin]-1'-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyrazin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-(tert-butyl)azetidin-3-yl)oxy)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2-methyl-6-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-((3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(((3R,4S)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2,6-dimethylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(3-(3-(dimethylamino)pyrrolidin-1-yl)-4-methylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-6-methylpyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0097] 5-((1-(4-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3S,4R)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3S,4S)-3-(dimethylamino)-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (S)-5-((1-(4-(2-((dimethylamino)methyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1R,5S)-3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0098] (R)-5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-morpholinopyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3R,4S)-3-(dimethylamino)-4-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((2R,4R)-4-(dimethylamino)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((2S,4R)-4-(dimethylamino)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3R,4R)-3-(dimethylamino)-4-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(dimethylamino)-3-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-3-fluorophenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0099] 5-((1-(2-fluoro-4-((1R,5S)-3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-((1S,5R)-3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(2-(dimethylamino)-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(Bis(methyl-d3)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-((2R,4R)-4-(dimethylamino)-2-methylpyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((2R,3R)-3-(dimethylamino)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3aR,6aR)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3S,4R)-3-(ethylamino)-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(ethyl(methyl)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(5-(3-(ethyl(methyl)amino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0100] 5-((1-(4-((3aR,6aR)-4-methylhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(5-(3-((3,3,3-trifluoropropyl)amino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (S)-5-((1-(4-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(isopropylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3,3,4-trimethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((2R,4R)-4-(azetidin-1-yl)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(6-methyl-1,6-diazaspiro[3.3]heptan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methyl-1,7-diazaspiro[3.5]nonan-7-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3aR,6aS)-5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(5-(3-(azetidin-1-yl)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0101] (R)-5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)-3-methylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylmorpholin-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(4-methylmorpholin-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(3-(2-((dimethylamino)methyl)morpholino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(3-(2-((dimethylamino)methyl)morpholino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(3-(3-((2-hydroxyethyl)(methyl)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(3-(3-((2-hydroxyethyl)(methyl)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(3-(3-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1)

[0102] 5-((1-(3-(3-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-((dimethylamino)methyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(3-((dimethylamino)methyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(6-methyl-1,6-diazaspiro[3.4]octan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(6-methyl-1,6-diazaspiro[3.4]octan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1)

[0103] 5-((1-(4-(3-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-(3,3-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(3-(3,3-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-(3-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(3-(3-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(1-methyl-1,6-diazaspiro[3.4]octan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(1-methyl-1,6-diazaspiro[3.4]octan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-(3-fluoroazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(3-(3-fluoroazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-(2-azaspiro[3.3]heptan-2-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1)

[0104] 5-((1-(4-(3-(2-azaspiro[3.3]heptan-2-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-(3-isopropylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(3-(3-isopropylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(4-(3-((R)-2-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (diastereomer 1) 5-((1-(4-(3-((R)-2-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (diastereomer 2) 5-((1-(4-(3-((S)-2-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (diastereomer 1) 5-((1-(4-(3-((S)-2-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (diastereomer 2) 5-((1-(4-(3-(2,2-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(4-(3-(2,2-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) (R)-1-(4-(4-((5-cyanopyrazin-2-yl)amino)-1H-imidazol-1-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine oxide 5-((1-(4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0105] 5-((1-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((((3S,4R)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-([1,3'-bipyrrolidin]-1'-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-aminopropoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2-aminoethoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((3R,4S)-3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0106] (R)-5-((1-(4-(3-aminopyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(7-amino-5-azaspiro[2.4]heptan-5-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-amino-3-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(aminomethyl)azetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(aminomethyl)-3-fluoroazetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1,6-diazaspiro[3.3]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1R,5R)-3,6-diazabicyclo[3.2.0]heptan-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-(3-(ethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3R,4S)-3-methoxy-4-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0107] 5-((1-(4-((3R,4S)-3-fluoro-4-(methylamino)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((2R,4R)-4-amino-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(4-amino-3,3-difluoropiperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 1) 5-((1-(3-(4-amino-3,3-difluoropiperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (enantiomer 2) 5-((1-(2-(3-aminopropoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile (R)-5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile) 5-((1-(4-((ethylamino)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((4,4-difluoropiperidin-1-yl)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((4-fluoropiperidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0108] 5-((1-(3-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methylazetidin-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1R,5S)-9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-(diethylamino)cyclopropyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile

[0109] 5-((1-(4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile or pharmaceutically acceptable salts, solvates, hydrates, tautomers, enantiomers, diastereoisomers, isotopic forms, N-oxides, and / or prodrugs thereof. In some cases, certain stereoisomers of the compounds of the present invention have particularly advantageous properties. For some compounds in the above list, the enantiomers and diastereomers have been separated into "Enantiomer 1" and "Enantiomer 2" or "Diastereomer 1" and "Diastereomer 2." It is understood that one of "Enantiomer 1" and "Enantiomer 2" is the R-enantiomer and the other is the S-enantiomer. Similarly, while the absolute configuration of one or more chiral centers in compounds listed as "Diastereomer 1" and "Diastereomer 2" is known, one chiral center may be R- or S- in one diastereomer and the opposite configuration in the other diastereomer. Details on how to prepare these enantiomers and diastereomers are detailed in the Examples below. In any case, one skilled in the art would know how to prepare and separate the specific enantiomers and diastereomers of the above compounds and would identify their stereochemistry using techniques and methods known in the art.

[0110] The compounds of the present invention can be used per se or, where appropriate, as their pharmacologically acceptable salts (acid or base addition salts). The pharmacologically acceptable addition salts described below are intended to include the therapeutically active non-toxic acid and base addition salt forms that the compounds can form. Compounds having basic properties can be converted to their pharmaceutically acceptable acid addition salts by treating the base form with an appropriate acid. Exemplary acids include inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, glycolic acid, maleic acid, malonic acid, oxalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, fumaric acid, succinic acid, malic acid, tartaric acid, citric acid, salicylic acid, p-aminosalicylic acid, pamoic acid, benzoic acid, and ascorbic acid. Exemplary base addition salt forms are sodium, potassium, calcium salts, and salts of pharmaceutically acceptable amines, such as ammonia, alkylamines, benzathine, and amino acids, such as arginine and lysine. The term addition salts as used herein also includes solvates, such as hydrates, alcoholates, etc., which the compounds and their salts are able to form.

[0111] Throughout this disclosure, a given chemical formula or name also encompasses all pharmaceutically acceptable salts, solvates, hydrates, tautomers, enantiomers, diastereoisomers, isotopic forms, N-oxides, and / or prodrug forms thereof. It should be understood that the compounds of the present invention include any and all hydrates and / or solvates of the compound formula. It is understood that certain functional groups, such as hydroxy, amino, and similar groups, form complexes and / or coordination compounds with water and / or various solvents in the various physical forms of the compound. Thus, the above formula should be understood to include and represent various hydrates and / or solvates thereof.

[0112] The compounds of the present invention also include tautomeric forms. Tautomers result from the swapping of a single bond with an adjacent double bond with the concomitant migration of a proton. Tautomers include protic tautomers, which are isomeric protonation states with the same empirical formula and total charge. Examples of protic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy more than one position on a heterocyclic ring system, such as 1H- and 3H-imidazole, 1H, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms may be in equilibrium or sterically locked into one form by appropriate substitution.

[0113] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are contemplated unless otherwise specified. The terms "diastereoisomer" and "diastereomer" are used interchangeably herein. Compounds of the present invention containing asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials, such as by resolution of racemic mixtures or stereoselective synthesis, are known in the art. Many geometric isomers of olefins, C=N double bonds, and the like, can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as a mixture of isomers or as separated isomeric forms.

[0114] In the case of compounds containing asymmetric carbon atoms, the present invention relates to D-forms, L-forms and D,L mixtures, and also to diastereoisomeric forms when two or more asymmetric carbon atoms are present. Compounds of the present invention containing asymmetric carbon atoms, which are in principle present as racemates, can be separated into optically active isomers in a known manner, for example, using an optically active acid. However, it is also possible to use optically active starting materials from the beginning, and then obtain the corresponding optically active or diastereoisomeric compounds as final products.

[0115] The term "isotopic form" refers to the fact that the compounds of the present invention can include isotopically labeled and / or isotopically enriched forms of the compounds. The compounds of the present invention herein can contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. Examples of isotopes that can be incorporated into the disclosed compounds include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 O. 17 O. 32 P, 35 S, 18 F, 36 Included are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, chlorine, etc., such as Cl. As used herein, a deuterium-labeled compound may include "-d" to indicate that deuterium is included, i.e., "methyl-d" refers to the group -CD.

[0116] The term "N-oxide" refers, for example, to the following examples: [ka] and the like means a compound containing an N+-O- functional group.

[0117] The term "prodrug" refers to a compound that can be converted into a biologically active compound of the present invention under physiological conditions or by solvolysis. Prodrugs may be inactive when administered to a subject in need thereof, but are converted in vivo to an active compound of the present invention. Prodrugs are typically rapidly converted in vivo, such as by hydrolysis in blood, to produce the parent compound of the present invention. Prodrug compounds typically offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Silverman, RB, The Organic Chemistry of Drug Design and Drug Action, 2nd Ed., Elsevier Academic Press (2004), pp. 498-549). Prodrugs of the compounds of the present invention can be prepared by modifying functional groups, such as hydroxy, amino, or mercapto groups, present in the compounds of the present invention to the parent compound of the present invention such that the modification is cleaved either by routine manipulation or in vivo. Examples of prodrugs include, but are not limited to, acetate, formate, and succinate derivatives of hydroxy functional groups, or phenylcarbamate derivatives of amino functional groups.

[0118] For clinical use, the compounds disclosed herein are formulated into pharmaceutical compositions (or formulations) for various modes of administration. It is understood that the compounds of the present invention can be administered together with physiologically acceptable carriers, excipients, and / or diluents (i.e., one, two, or all three of these). The pharmaceutical compositions disclosed herein can be administered by any appropriate route, preferably oral, rectal, nasal, topical (including buccal and sublingual), sublingual, transdermal, intrathecal, transmucosal, or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration. Other formulations can be conveniently presented in unit dosage form, such as tablets and sustained-release capsules, and liposomes, and can be formulated by any method well known in the pharmaceutical arts. Pharmaceutical formulations are typically formulated by mixing the active substance or a pharmaceutically acceptable salt thereof with a conventional pharmaceutically acceptable carrier, diluent, or excipient. Examples of excipients include water, gelatin, arabic gum, lactose, microcrystalline cellulose, starch, sodium starch glycolate, calcium hydrogen phosphate, magnesium stearate, talc, colloidal silicon dioxide, etc. Such formulations may also contain other pharmacologically active agents and conventional additives such as stabilizers, wetting agents, emulsifiers, flavoring agents, buffers, etc. Typically, the amount of active compound is preferably 0.1 to 95% by weight of the formulation, 0.2 to 20% by weight for formulations for parenteral use, and more preferably 1 to 50% by weight for formulations for oral administration. The formulations can be further formulated by known methods such as granulation, compression, microencapsulation, spray coating, etc. The formulations can be formulated by conventional methods into tablets, capsules, granules, powders, syrups, suspensions, suppositories, or injectable dosage forms. Liquid formulations can be formulated by dissolving or suspending the active substance in water or other suitable vehicles. Tablets and granules can be coated by conventional methods. To maintain therapeutically effective plasma concentrations for extended periods of time, the compounds disclosed herein can be incorporated into sustained release formulations.

[0119] The dosage level and frequency of administration of a particular compound will vary depending on a variety of factors, including the potency of the particular compound used, the metabolic stability and duration of action of that compound, the patient's age, weight, general health, sex, diet, mode and time of administration, excretion rate, drug combination, the severity of the condition being treated, and the patient being treated. Daily dosages can range, for example, from about 0.001 mg to about 100 mg per kilogram of body weight, and can be administered in single or multiple doses, for example, from about 0.01 mg to about 25 mg each. Typically, such dosages are administered orally, although parenteral administration may also be selected.

[0120] A subject of the present invention relates to the compounds of the invention for use as a medicament. The term "medicament" means a substance or medicine used for medical treatment.

[0121] The compounds of the present invention can be useful as inhibitors of Chk1. As such, they are useful in the treatment or prevention of medical conditions (conditions or diseases) affected by Chk1. Thus, there is provided a method for treating a disease or condition responsive to Chk1 inhibition, such as cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention.

[0122] The compounds of the invention may be for use in medicine, which may be in the treatment of cancer.

[0123] The compounds of the invention may also be useful in the manufacture of a medicament, which may be for use in the treatment of cancer.

[0124] The compounds of the present invention may be useful in treating various cancers, particularly cancers that are susceptible to Chk1 inhibition. Non-limiting examples of cancers include CNS cancers (including glioblastoma multiforme, glioma, neuroblastoma, medulloblastoma, DIPG, and secondary brain tumors such as brain metastases), sarcomas (including osteosarcoma, rhabdomyosarcoma, Kaposi's sarcoma, and leiomyosarcoma), ovarian cancer (including high-grade serous ovarian cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, pancreatic cancer, renal cell carcinoma, colorectal cancer (including colon cancer, rectal cancer, and anal cancer), gastrointestinal cancer (including gastric cancer), thyroid cancer, bladder cancer, kidney cancer, melanoma, squamous cell carcinoma (including squamous cell carcinoma of the head and neck), leukemia, and lymphoma.

[0125] Preferably, the compounds of the invention are useful in the treatment of CNS cancers (including glioblastoma multiforme, glioma, neuroblastoma, medulloblastoma, DIPG and secondary brain tumors such as brain metastases), sarcoma (including osteosarcoma, rhabdomyosarcoma, Kaposi's sarcoma, leiomyosarcoma), bladder cancer, endometrial cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), breast cancer, squamous cell carcinoma (including squamous cell carcinoma of the head and neck), colorectal cancer (including colon cancer, rectal cancer, anal cancer), gastric cancer, or ovarian cancer (including high-grade serous ovarian cancer).

[0126] The terms "treatment" and "treating," as used herein, can include prevention of the named disorder or condition, or the amelioration or elimination of the disorder or condition after it has been established. The term "prevention" refers to the prevention of the named disorder or condition.

[0127] As used herein, the term "administration" or "administering" refers to a route of administration of a compound disclosed herein. Exemplary routes of administration include, but are not limited to, oral, intravenous, intraperitoneal, intraarterial, and intramuscular. The preferred route of administration may vary depending on various factors, such as the components of a pharmaceutical composition comprising a compound disclosed herein, the site of potential or actual disease, and the severity of the disease.

[0128] The terms "subject" and "patient" are used interchangeably herein. They refer to a human or another mammal (e.g., a mouse, rat, rabbit, dog, cat, cow, pig, sheep, horse, or primate) that is afflicted with or susceptible to a disease or disorder, but may or may not be afflicted with the disease or disorder. Preferably, the subject is a human.

[0129] A "therapeutically effective amount" refers to that amount of a compound of the invention that confers a therapeutic effect on the treated subject. The therapeutic effect can be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject gives an indication of or feels an effect).

[0130] The methods described herein include methods in which a subject is identified as being in need of a particular described treatment. Identifying a subject as being in need of such a treatment can be the judgment of the subject or a medical professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[0131] In other aspects, the methods herein include methods further comprising monitoring the subject's response to the administration of the treatment. Such monitoring can include periodic sampling of the subject's tissues, fluids, specimens, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of the treatment regimen. In other methods, subjects are pre-screened or identified as in need of such treatment by assessment of relevant markers or indicators of suitability for such treatment.

[0132] The compounds of the present invention can be used as monotherapy.They can also be used as part of combination therapy.When used as combination therapy, they can be administered in combination with one or more of the following anti-cancer treatments: ionizing radiation; DNA topoisomerase I or II inhibitor; antimetabolite or thymidylate synthase inhibitor; agents related to DNA damage and repair mechanism; microtubule targeting agent; platinum-based antitumor drug; alkylating agent and immune checkpoint inhibitor.

[0133] Anticancer agents related to DNA damage and repair mechanisms include, but are not limited to, Wee1 inhibitors such as Adavosertib; PARP inhibitors such as Olaparib, Veliparib, Niraparib, Rucaparib, Talazoparib, and Senaparib; ATR inhibitors such as ceralasetib and Galtisertib; HDAC inhibitors such as Entinostat and Vorinostat; PARG inhibitors such as PDD00017273 and JA2131; and ATM inhibitors such as AZD0156 and AZD1390.

[0134] Topoisomerase inhibitors are exemplified by doxorubicin, irinotecan, camptothecin, and etoposide. Antimetabolites are exemplified by gemcitabine, pemetrexed, and cytarabine. Platinum-based antitumor drugs are exemplified by cisplatin and carboplatin. Alkylating agents are exemplified by temozolomide. Immune checkpoint inhibitors are exemplified by ipilimumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, and cemiplimab. Other chemotherapeutic agents that may be used in combination therapy include paclitaxel, MEK inhibitors such as binimetinib, cobimetinib, and trametinib, and farnesyltransferase inhibitors such as tipifarnib and rapamycin. As used herein, "administered in combination with" one or more anti-cancer therapies means that the compounds are administered simultaneously or sequentially, and in any suitable order, as will be understood by one of skill in the art.

[0135] The present invention provides methods for monitoring the progress of a treatment. The methods include determining the level or diagnostic measurement (e.g., screening, assay) of a diagnostic marker (e.g., any target or cell type described herein that is modulated by a compound described herein) in a subject suffering from or susceptible to a disorder or symptom described herein, wherein the subject has been administered a therapeutically effective amount of a compound described herein sufficient to treat the disease or its symptoms. The level of the marker determined in this manner can be compared to the level of a known marker in either healthy normal controls or other afflicted patients to establish the disease status of the subject. In preferred aspects of the invention, a second level of the marker in the subject is determined at a later time point than the determination of the first level, and the two levels are compared to monitor the course of the disease or the effectiveness of the treatment. In certain preferred aspects of the invention, a pre-treatment level of the marker in the subject is determined before initiating treatment according to the present invention. This pre-treatment level of the marker can then be compared to the level of the marker in the subject after initiation of treatment to determine the effectiveness of the treatment.

[0136] The level of a marker or marker activity in a subject can be determined at least once. Comparison of marker levels, for example, with other measurements of marker levels obtained before or after from the same patient, another patient, or a normal subject, can be useful in determining whether a treatment according to the present invention has the desired effect, thereby allowing for adjustment of dosage levels accordingly. Determining marker levels can be performed using any suitable sampling / expression assay method known in the art or described herein. Preferably, a tissue or fluid sample is first removed from the subject. Examples of suitable samples include blood, urine, tissue, mouth or cheek cells, and hair samples, including roots. Other suitable samples are known to those skilled in the art. Determining protein and / or mRNA levels (e.g., marker levels) in a sample can be performed using any suitable technique known in the art, including enzyme-linked immunosorbent assays, ELISA, radiolabeling / assay techniques, blotting / chemiluminescence, real-time PCR, etc.

[0137] The compounds of the present invention may be disclosed by name or by chemical structure. If there is a discrepancy between the name of a compound and its associated chemical structure, the chemical structure shall prevail.

[0138] The present invention will now be further described by the following non-limiting examples. The specific examples below are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. All references and publications cited herein are incorporated by reference in their entirety.

[0139] Preparation of Compounds of the Invention The compounds of the present invention can be prepared by or in analogy with conventional methods. The preparation of intermediates and compounds according to embodiments of the present invention can be easily understood, particularly by the following schemes. The definitions of variables in the structures in the schemes herein are the same as the definitions of variables at the corresponding positions in the formulas depicted herein.

[0140] The following abbreviations are used: AcOH acetic acid AdBrettPhos 2-(di-1-adamantylphosphino)-3,6-dimethoxy-2',4',6'-tri-propyl-1,1'-biphenyl AdBrettPhos Pd G3 Methanesulfonato[2-(di-1-adamantylphosphino)-3,6-dimethoxy-2',4',6'-tri-propyl-1,1'-biphenyl](2'-amino-1,1'-biphenyl-2-yl)palladium(II) aq water-based BCRP Breast Cancer Resistance Protein BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene Boc tert-butyloxycarbonyl n-BuLi n-butyllithium Cbz benzyloxycarbonyl CNS central nervous system Cu(OAc)2Copper(II) acetate Cu(OTf)2 Copper(II) trifluoromethanesulfonate DAD Diode Array Detector DAST (Diethylamino) Sulfur Trifluoride DCM dichloromethane DEA N,N-diethylaniline DIAD Diisopropyl azodicarboxylate DIEA N,N-Diisopropylethylamine DMF n,n-dimethylformamide DMSO dimethyl sulfoxide DXN 1,4-dioxane EDTA Ethylenediaminetetraacetic acid Ephos Dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl)phosphane Ephos Pd G4 Methanesulfonate{dicyclohexyl[3-(1-methylethoxy)-2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]phosphine}(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) ES + Electrospray ionization EtI Iodoethane Et3N Triethylamine EtOAc ethyl acetate EtOH ethanol Example: Example FA formic acid h time HBD H-bond donor HEPES N'-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid Hex HPLC High Performance Liquid Chromatography Int. Intermediate IPA Isopropyl Alcohol IV KOAc Potassium Acetate LCMS Liquid Chromatography Mass Spectrometry mCPBA 3-chloroperbenzoic acid MDCK Madin-Darby canine kidney MDR1 multidrug resistance protein 1 MeCN acetonitrile MeI iodomethane MeOH Methanol Me4tBuXPhos 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2',4'6'-triisopropyl-1,1'biphenyl Min MTBE Methyl tert-butyl ether NaOAc Sodium Acetate NaOtBu Sodium tert-butoxide NP normal phase n / r No record OTf Trifluoromethanesulfonate P app Apparent Permeability Coefficient PDA Photodiode Array Detector Pd2dba3tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2·DCM [1,1'-bis(diphenylphosphino)ferrocene complexed with dichloromethane]dichloropalladium(II) PE Petroleum Ether P-gp P-glycoprotein PhMe Toluene PPh3 Triphenylphosphine Prep-HPLC Preparative High Performance Liquid Chromatography Prep-SFC Preparative Supercritical Fluid Chromatography Prep-TLC (preparative thin-layer chromatography) RP reverse phase RT room temperature Rt retention time sat saturation SFC Supercritical Fluid Chromatography STAB Sodium triacetoxyborohydride tBuXPhos Pd G3 [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TFA trifluoroacetic acid THF tetrahydrofuran tPSA topological polar surface area UPLC Ultra-High Performance Liquid Chromatography XPhos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0141] Scheme 1: General synthetic route for the preparation of compounds of formula (I) [ka] In the formula, R 1 , X, and Y are as defined herein; Q 1 is a halo and M 1 and M 2 is H, alkyl, or M 1 and M 2 may together form a ring, such as a pinacol ester.

[0142] Compounds of formula (I) can be prepared by the Buchwald-Hartwig cross-coupling reaction of 5-aminopyrazine-2-carbonitrile with compounds of general formula 1-3. Compounds of formula 1-3 can be prepared from compounds of general formula 1-1 by the SNAr reaction with 4-bromo-1H-imidazole. Alternatively, compounds of general formula 1-3 can be prepared from compounds of general formula 1-2 by the Cheng-Lamb reaction with 4-bromo-1H-imidazole. Compounds of general formula 1-2 can be prepared by the same general formula but with R using standard chemistries including Mitunobu, SNAr, and reduced amination reactions. 1 Alternatively, compounds of general formula 1-2 can be prepared from commercially available boronic acid / ester reagents with suitable functional group handles at X, Y, or Y. Alternatively, compounds of general formula 1-2 can be prepared by lithium-halogen exchange followed by reaction with a suitable electrophile and alkylation, followed by Br(Q) to the corresponding boronic acid / ester. 1 ) can be converted to R 1, by transformation of X or Y with a suitable functional group handle, 1 It can be prepared from the compound

[0143] Compounds of general formula 1-3 or (I) can be converted into other compounds of the same formula in one or more synthetic steps using standard chemical reactions. For example, R 1 If X or Y contain a suitable halogen, then SNAr or Buchwald-Hartwig coupling reactions can be used with appropriate commercially available amines, or amines of general formula 2-2 (Scheme 2), to provide other compounds of general formula 1-3 or (I). Alternatively, R 1 If X or Y contains a suitable aldehyde or ketone, then a reductive amination or carbonyl reduction reaction can be carried out to give other compounds of general formula 1-3 or (I). Alternatively, R 1 If X or Y contains a suitable OH group, then a Mitsunobu, Appel, alkylation or oxidation reaction can be carried out to obtain other compounds of general formula 1-3 or (I). Alternatively, R 1 If X or Y contains a suitable amine, then N-oxidation, reductive amination, or alkylation reactions can be utilized to provide other compounds of general formula 1-3 or (I). If necessary, the amine can be introduced via the corresponding NO group using standard chemical transformations or via an SN2 reaction using suitable reactants. Standard protecting group strategies can be applied at any stage as needed to facilitate the aforementioned chemical transformations. If the compound contains one or more chiral centers, the compound can be prepared as a racemate, as a single enantiomer, or as a diastereomeric mixture of known or unknown absolute stereochemistry. Enantiomeric or diastereomeric mixtures may optionally be separated by standard techniques at any stage in the synthetic sequence.

[0144] Scheme 2: General synthetic route for the preparation of amines of general formula 2-2 [ka] wherein PG is a protecting group and Q 2 is H or methyl.

[0145] Compounds of general formula 2-2 can be prepared from compounds of general formula 2-1 by reductive amination or alkylation followed by protecting group (PG) removal using standard conditions. To obtain other compounds of general formula 1-3, amines of general formula 2-2 can be converted to intermediate compounds of general formula 1-3 (Scheme 1, where R 1 is a halogen).

[0146] Examples and intermediate compounds Experimental Method Unless otherwise noted, all reactants and reagents were commercially sourced, and in that case, the synthetic route is provided. All reagents were commercial grade and, unless otherwise noted, were used as received without further purification. Reagent-grade solvents were used unless otherwise noted. Anhydrous solvents were used where necessary. Solvent ratios are by volume. Reactions were carried out at RT unless otherwise noted. n-BuLi was used as a 2.5 M solution in hexane unless otherwise noted. Formaldehyde was used as a 37 wt% solution in water unless otherwise noted. NaH was used as a 60% dispersion in mineral oil unless otherwise noted. Reactions facilitated by microwave heating were performed on a Biotage Initiator+ system using process vials equipped with aluminum caps and septa. The amounts of reagents used and product yields were typically adjusted for purity, if known. Intermediates and examples are named using IUPAC nomenclature.

[0147] Column chromatography was performed using a Teledyne ISCO CombiFlash® RF200, CombiFlash® RF+, or CombiFlash® RF+ Lumen system equipped with RediSep® Rf, RediSep® Rf C18 Reverse Phase, or RediSep® Silver Silica columns. Preparative RP HPLC was performed on either a Teledyne Isco ACCQPrep HP125 system equipped with an Avantor® ACE® 5AQ, 100 x 100 x 21.2 mm, 5 μm column, an Avantor® ACE® SuperC18™, 100 x 21.2 mm, 5 μm column, or a Phenomenex® Kinetex® EVO C18, 100 x 21.2 mm, 5 μm column, and a CombiFlash® Purlon™ S mass spectrometer with a 200-400 nm UV variable wavelength detector, or an ACCQPrep HP150 system with a 200-400 nm UV variable wavelength detector. RP column chromatography and RP HPLC modifiers used included TFA, FA, and NH3. Capture and elute purification was performed using Biotage ISOLUTE® Flash SCX-2 cartridges unless otherwise stated. A typical capture and elute procedure was to dissolve the raw material in DCM, add the solution to the cartridge, wash with MeOH, elute with approximately 1 N NH3 in MeOH, and then concentrate in vacuo.

[0148] Chiral Prep-HPLC was performed using a Gilson GX-281 Chiral Prep-HPLC with a 159 UV-VIS detector and a 322 pump using the following method: Chiral Prep-HPLC Method 1: Column: CHIRALPAK IG, 2 x 25 cm, 5 μm; Mobile Phase A: Hex:MTBE = 1:1 (0.5% 2M NH3-MeOH), Mobile Phase B: MeOH Chiral Prep-HPLC Method 2: Column: CHIRALCEL AY H, 2 x 25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH Chiral Prep-HPLC Method 3: Column: CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 μm; Mobile Phase A: Hex (10 mM NH3-MeOH), Mobile Phase B: EtOH Chiral Prep-HPLC Method 4: Column: CHIRALPAK 1A-3, 4.6 x 5 mm, 3 μm; Mobile phase A: MTBE (0.1% DEA):EtOH = 70:30 Chiral Prep-HPLC Method 5: Column: CHIRALPAK ID-3, 4.6 x 50 mm, 3 μm; Mobile phase A: MTBE (0.1% DEA):MeOH = 70:30 Chiral Prep-HPLC Method 6: Column: CHIRALPAK IA, 2.12 x 15 cm, 5 μm; Mobile Phase A: MTBE (10 mM NH3-MeOH), Mobile Phase B: MeOH Chiral Prep-HPLC Method 7: Column: Chiral ART Amylose SA, 3 x 25 cm, 5 μm; Mobile phase A: MTBE:DCM = 1:1 (10 mM NH3), Mobile phase B: MeOH Chiral Prep-HPLC Method 8: Column: Chiral ART Amylose SA, 3 x 25 cm, 5 μm; Mobile Phase A: MTBE (10 mM NH3-MeOH), Mobile Phase B: MeOH Chiral Prep-HPLC Method 9: Column: CHIRALPAK ID, 3 x 25 cm, 5 μm; Mobile Phase A: MTBE (2 mM NH3-MeOH), Mobile Phase B: MeOH Chiral Prep-HPLC Method 10: Column: CHIRALPAK IA-3, 4.6 x 50 mm, 3 μm; Mobile Phase A: MTBE (0.1% DEA):MeOH = 50:50

[0149] Prep-SFC was performed on a Waters SFC-150 with a Waters 2489 UV detector, a Waters preparative fraction selector, a Waters 2545 cosolvent pump, and a Waters P200X CO2 pump using the following method: Prep-SFC method 1: Column: CHIRALPAK IH, 3 x 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH Prep-SFC method 2: Column: CHIRALPAK IH, 3 x 25 cm, 5 μm; Mobile phase A: CO2, Mobile phase B: MeOH (0.1% 2M NH3-MeOH) Prep-SFC method 3: Column: (R,R)-WHELK-01-Kromasil, 5 x 25 cm, 5 μm; Mobile phase A: MTBE:DCM=1:1, Mobile phase B: MeOH Prep-SFC method 4: Column: Lux 5μm Cellulose-3, 2.12 x 25cm, 5μm; Mobile phase A: Hex (10mM NH3-MeOH), Mobile phase B: EtOH Prep-SFC method 5: Column: CHIRALPAK IA, 2 x 25 cm, 5 μm; Mobile phase A: MeOH:DCM=2:1 (0.1% 2M NH3-MeOH), Mobile phase B: MeOH Prep-SFC Method 6: Column: CHIRALPAK ID, 2 x 25 cm, 5 μm; Mobile Phase A: MTBE (10 mM NH3-MeOH), Mobile Phase B: MeOH

[0150] Compound analysis was performed by UPLC, HPLC, and LCMS. UPLC data was collected using an Agilent 1290 Infinity or Infinity II system with a DAD using a Phenomenex Kinetex XB-C18 column. HPLC and LCMS data were collected using a Waters ACQUITY H-class HPLC with a Phenomenex Kinetex XB-C18 column and an ACQUITY QDa mass detector connector, or a Shimadzu LCMS-2020 system with a PDA: SPD-M20A or SPD-MP40.

[0151] Intermediates Intermediate 1 tert-Butyl (3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propyl)carbamate [ka] To 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.00 g, 4.50 mmol), tert-butyl N-(3-hydroxypropyl)carbamate (1.19 g, 6.8 mmol), and PPh3 (1.79 g, 6.82 mmol) in THF (20 mL) at 0 °C was added dropwise DIAD (1.38 g, 6.82 mmol). The mixture was allowed to warm to RT and stirred for 4 h. The mixture was quenched with water, then concentrated in vacuo and purified by RP column chromatography to give the title compound (570 mg, 33.3%) as a pale yellow solid. LCMS (ES) + ):378.3 [MH] + .

[0152] Intermediate 2 (4-(morpholinomethyl)phenyl)boronic acid [ka] 4-Formylphenylboronic acid (1.00 g, 6.67 mmol) and morpholine (0.58 g, 6) in MeOH (15 mL) were stirred for 1 h at RT. To the mixture was added NaBHCN (0.42 g, 6.67 mmol) at 0 °C. The mixture was then warmed to RT and stirred for an additional 12 h. The reaction was quenched with water and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (100 mL), dried (NaSO), and concentrated in vacuo. Purification by RP column chromatography afforded the title compound (451 mg, 30.6%) as a white solid. LCMS (ES) + ):225.3 [MH] + .

[0153] Intermediate 3 (4-(4-fluoro-1-methylpiperidin-4-yl)phenyl)boronic acid [ka] Step 1: To dibromobenzene (2.00 g, 8.48 mmol) in THF (20 mL) was added n-BuLi (3.40 mL, 8.50 mmol) dropwise at -78 °C. The mixture was then stirred for 30 min, after which 1-methylpiperidin-4-one (0.96 g, 8.48 mmol) was added dropwise. The mixture was allowed to warm to RT and stirred for an additional 1 h. The reaction was quenched with water and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried (NaSO), and concentrated in vacuo. Purification by RP column chromatography afforded 4-(4-bromophenyl)-1-methylpiperidin-4-ol (1.66 g, 72.5%) as a yellow oil. LCMS (ES) + ):270.3 [MH] + .

[0154] Step 2: To a mixture of 4-(4-bromophenyl)-1-methylpiperidin-4-ol (1.00 g, 3.70 mmol) in THF (10 mL) was added dropwise at −78° C. under N. The mixture was warmed to RT and stirred for 5 h. The reaction was quenched with ice water and extracted with EtOAc (2×10 mL). The combined organic layers were washed with water (2×10 mL), dried (NaSO), and concentrated in vacuo. Purification by NP column chromatography afforded 4-(4-bromophenyl)-4-fluoro-1-methylpiperidine (760 mg, 75.4%) as a brown solid. LCMS (ES) + ):272.3 [MH] + .

[0155] Step 3: A mixture of 4-(4-bromophenyl)-4-fluoro-1-methylpiperidine (760 mg, 2.79 mmol), bis(pinacolato)diboron (1.42 g, 5.58 mmol), Pd(dppf)Cl₂·DCM (1.14 g, 1.40 mmol), and KOAc (548 mg, 5.58 mmol) in DXN (10 mL) was stirred at 100° C. under N₂ for 16 h. The mixture was filtered, washed with DXN, and the filtrate was concentrated in vacuo. Purification by RP column chromatography afforded 4-fluoro-1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (400 mg, 44.9%) as a yellow oil. LCMS (ES) + ):320.2[MH] + .

[0156] Step 4: A mixture of 4-fluoro-1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine (400 mg, 1.26 mmol) and NaIO4 (810 mg, 3.76 mmol) in THF (4.0 mL) and water (1.0 mL) was stirred for 4 h. The mixture was filtered, washed with MeOH, and the filtrate was concentrated in vacuo. Purification by RP column chromatography afforded the title compound (240 mg, 80.8%) as a yellow oil. LCMS (ES) + ):238.1[MH] + .

[0157] Intermediate 4 (4-(4-methylmorpholin-2-yl)phenyl)boronic acid [ka] Step 1: To a mixture of methylethanolamine (1.62 g, 21.6 mmol) at 0 °C under N was added FA (1.0 mL) dropwise. Next, 2-bromo-1-(4-bromophenyl)ethanone (3.00 g, 10.8 mmol) was added, and the mixture was heated to 100 °C and stirred for 16 h. The reaction was quenched with water and extracted with EtOAc (50 mL). Excess KCO was added to the aqueous solution, and further extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried (NaSO), and concentrated in vacuo. Purification by RP column chromatography afforded 2-(4-bromophenyl)-4-methylmorpholine (1.42 g, 51.4%) as a yellow oil. LCMS (ES) + ):256.1 [MH] + .

[0158] Step 2: 2-(4-bromophenyl)-4-methylmorpholine (1.42 g, 5.54 mmol), bis(pinacolato)diboron (2.11 g, 8.32 mmol), Pd(dppf)Cl₂·DCM (230 mg, 0.282 mmol), and NaOAc (1.53 mg, 18.7 mmol) in DXN (20 mL) were stirred at 80 °C under N₂ for 16 h. The mixture was concentrated in vacuo and purified by RP column chromatography to give 4-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (704 mg, 41.9%) as a brown oil. LCMS (ES) + ):304.3 [MH] + .

[0159] Step 3: 4-Methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (704 mg, 2.32 mmol) and NaIO (2.44 g, 11.4 mmol) in THF (20 mL) and water (4.0 mL) were stirred for 36 h. The mixture was concentrated in vacuo and purified by RP column chromatography to give the title compound (432 mg, 84.1%) as a yellow solid. LCMS (ES)+ ):222.2 [MH] + .

[0160] Intermediate 5 (4-(1-(tert-butoxycarbonyl)azetidin-3-yl)phenyl)boronic acid [ka] To tert-butyl 3-(4-bromophenyl)azetidine-1-carboxylate (500 mg, 1.60 mmol) in THF (10 mL) was added n-BuLi (0.75 mL, 1.92 mmol) dropwise at −78° C. under N. The mixture was stirred for 30 minutes, after which triisopropylborate (451 mg, 2.40 mmol) was added dropwise. The mixture was then warmed to RT and stirred for an additional 2 hours. The mixture was concentrated in vacuo and purified by NP column chromatography to give the title compound (227 mg, 51.2%) as a yellow oil. LCMS (ES) + ):278.1 [MH] + .

[0161] Intermediate 6 (6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)boronic acid [ka] 6-Fluoropyridin-3-ylboronic acid (3.00 g, 21.3 mmol), N-methylhomopiperazine (4.86 mL, 42.6 mmol), and K2CO3 (4.41 g, 31.9 mmol) in DMF (50 mL) was heated to 110 °C and stirred for 16 h. The mixture was concentrated in vacuo to give the title compound (2.80 g, 56.0%) as a yellow solid. LCMS (ES) + ):236.1 [MH] + .

[0162] Intermediate 7 (3-Fluoro-4-(4-methylpiperazin-1-yl)phenyl)boronic acid [ka] Step 1: 1-(4-bromo-2-fluorophenyl)-4-methylpiperazine (1.00 g, 3.66 mmol), bis(pinacolato)diboron (1.39 g, 5.48 mmol), Pd(dppf)Cl (26.8 mg, 0.37 mmol), and NaOAc (601 mg, 7.32 mmol) in DXN (25 mL) was heated to 100 °C and stirred under N for 12 h. The mixture was concentrated in vacuo to give crude 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine, which was used in the next step without further purification. LCMS (ES) + ):321.2 [MH] + .

[0163] Step 2: Crude 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-methylpiperazine and NaIO4 (3.22 g, 15.1 mmol) in THF (20 mL) was heated to 40 °C and stirred for 5 h. The mixture was filtered, washed with EtOAc, and the filtrate was concentrated in vacuo. Purification by RP column chromatography afforded the title compound (130 mg, 19% yield over two steps) as a pale yellow oil. LCMS (ES) + ):239.2 [MH] + .

[0164] Intermediate 8 (2-(3-((tert-butoxycarbonyl)amino)propoxy)-6-methoxyphenyl)boronic acid [ka] Step 1: 2-Bromo-3-methoxyphenol (3.00 g, 14.8 mmol), tert-butyl N-(3-bromopropyl)carbamate (3.52 g, 14.8 mmol), NaI (2.21 g, 14.8 mmol), and K2CO3 (4.08 g, 29.6 mmol) in DMF (20 mL) were stirred at 60 °C for 16 h. The reaction was quenched with water and extracted with EtOAc (2 × 200 mL). The combined organics were washed with brine, dried (Na2SO4), and concentrated in vacuo. Purification by NP column chromatography afforded tert-butyl (3-(2-bromo-3-methoxyphenoxy)propyl)carbamate (3.20 g, 60.1%) as a colorless oil. LCMS (ES) + ):360.1 [MH] + .

[0165] Step 2: To tert-butyl (3-(2-bromo-3-methoxyphenoxy)propyl)carbamate (1.00 g, 2.78 mmol) in THF (10 mL) was added n-BuLi (2.50 mL, 6.25 mmol) dropwise at −78° C. under N. To the mixture was added trimethyl borate (288 mg, 2.78 mmol) dropwise. The mixture was then warmed to RT and stirred for an additional 1 h. The reaction was quenched with water and extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine, dried (NaSO), and concentrated in vacuo. Purification by NP column chromatography afforded the title compound (460 mg, 51.0%) as a colorless oil. LCMS (ES) + ):326.2 [MH] + .

[0166] Intermediate 9 (3R,5R)-N,N,5-trimethylpyrrolidin-3-amine [ka] Step 1: tert-Butyl (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylate (1.00 g, 4.99 mmol) and formaldehyde (1.12 mL, 15.0 mmol) in MeOH (20 mL) were stirred at RT for 30 min. The mixture was cooled to 0 °C, and STAB (4.23 g, 20.0 mmol) was added portionwise. The mixture was then warmed to RT and stirred for an additional 2 h. The mixture was concentrated in vacuo and purified by NP column chromatography. Drying in a vacuum oven at 60 °C for 1 h gave tert-butyl (2R,4R)-4-(dimethylamino)-2-methylpyrrolidine-1-carboxylate (778 mg, 68.2%) as a colorless oil. LCMS (ES) + ):229.2 [MH] + UPLC: Rt 3.23 min, 100% purity.

[0167] Step 2: To tert-butyl (2R,4R)-4-(dimethylamino)-2-methylpyrrolidine-1-carboxylate (778 mg, 3.40 mmol) in DCM (11 mL) was added TFA (2.5 mL). The mixture was stirred for 2 hours. The mixture was concentrated in vacuo to give the crude title compound (763 mg) as a brown oil, which was used directly in the next step without further purification. LCMS (ES) + ):129.1 [MH] + .

[0168] Intermediate 10 (2R,4R)-4-(azetidin-1-yl)-2-methylpyrrolidine [ka] Step 1: tert-butyl (2R,4R)-4-amino-2-methylpyrrolidine-1-carboxylate (3.00 g, 15.0 mmol), 1,3-dibromopropane (2.50 mL, 24.6 mmol), and KCO (10.4 g, 75.2 mmol) in MeCN (200 mL) was heated to 90° C. and stirred for 21 h. The mixture was filtered, washed with MeCN, and the filtrate was concentrated in vacuo and purified by NP column chromatography to give crude tert-butyl (2R,4R)-4-(azetidin-1-yl)-2-methylpyrrolidine-1-carboxylate, which was used directly in the next step without further purification.

[0169] Step 2: To crude tert-butyl (2R,4R)-4-(azetidin-1-yl)-2-methylpyrrolidine-1-carboxylate in DCM (12 mL) was added TFA (4.0 mL). The mixture was concentrated in vacuo, and the crude was purified by capture and release cartridge to give the title compound (617 mg, 29.4% over two steps) as a brown oil. LCMS (ES) + ):141.0 [MH] + .

[0170] Intermediate 11 (R)-3-(azetidin-1-yl)pyrrolidine [ka] Step 1: To benzyl (R)-3-aminopyrrolidine-1-carboxylate (15.0 g, 68.1 mmol) and DIEA (35.6 mL, 205 mmol) in MeCN (500 mL) was added 1,3-dibromopropane (11.0 mL, 108 mmol) dropwise. The mixture was then heated to 80° C. and stirred for 12 hours. The mixture was concentrated in vacuo and purified by RP column chromatography to give benzyl (R)-3-(azetidin-1-yl)pyrrolidine-1-carboxylate (6.70 g, 37.8%) as a yellow oil. LCMS (ES) + ):261.2 [MH]+ .

[0171] Step 2: To benzyl (R)-3-(azetidin-1-yl)pyrrolidine-1-carboxylate (6.30 g, 24.2 mmol) in EtOAc (200 mL) was added Pd / C (10% by weight, 6.31 g, 5.93 mmol). The mixture was stirred under an H atmosphere for 3 hours. The mixture was filtered, washed with EtOAc, and the filtrate was concentrated in vacuo to give the crude title compound (2.60 g) as a yellow oil, which was used in the next step without further purification. LCMS (ES) + ):127.3 [MH] + .

[0172] Intermediate 12 1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-4-methylpiperazine [ka] A mixture of 4-(4-methylpiperazin-1-yl)phenylboronic acid (749 mg, 3.40 mmol), 4-bromo-1H-imidazole (200 mg, 1.36 mmol), NaOH (82.0 mg, 2.04 mmol), and CuCl (22.0 mg, 0.16 mmol) in MeOH (10 mL) was stirred at 60 °C overnight under O. The mixture was cooled to RT, filtered, and the filter cake was washed with MeOH (2 × 10 mL). The filtrate was concentrated in vacuo and purified by prep-TLC (DCM / MeOH 10:1) to give the title compound (220 mg, 50.3%) as a yellow solid. LCMS (ES) + ):321.10 [MH] + .

[0173] Intermediate 13 tert-Butyl (3-(2-(4-bromo-1H-imidazol-1-yl)phenoxy)propyl)carbamate [ka] Intermediate 13 was prepared similarly to Intermediate 12 by Cheng-Lam coupling of 4-bromo-1H-imidazole with Intermediate 1 using CuCl and NaOH, followed by purification by NP column chromatography to give the title compound (40.1 mg, 38.2%) as a white solid. LCMS (ES + ):395.9 [MH] + .

[0174] Intermediate 14 (4-(4-Bromo-1H-imidazol-1-yl)phenyl)(4-methylpiperazin-1-yl)methanone [ka] A mixture of 4-(4-methylpiperazine-1-carbonyl)phenylboronic acid (500 mg, 1.51 mmol), 4-bromo-1H-imidazole (300 mg, 2.04 mmol), boric acid (190 mg, 3.07 mmol), and Cu(OAc) (85.0 mg, 0.47 mmol) in MeCN (2.5 mL) was heated in a sealed tube at 80° C. for 28 h. The reaction mixture was diluted with EtOAc (20 mL) and filtered through Celite®, rinsing with additional EtOAc. The filtrate was then concentrated in vacuo and purified by NP column chromatography to give the title compound (121 mg, 21.9%) as a colorless gum. LCMS (ES) + ):349.1 [MH] + .

[0175] Intermediate 15 4-(4-(4-bromo-1H-imidazol-1-yl)benzyl)morpholine [ka] To a stirred solution of intermediate 2 (412 mg, 1.86 mmol) and 4-bromo-1H-imidazole (274 mg, 1.86 mmol) in DMF (15 mL) at RT was added DIEA (723 mg, 5.59 mmol) and Cu(OAc) (677 mg, 3.73 mmol). The resulting mixture was stirred at 60 °C under O for 12 h, then cooled to RT, filtered, and the filtrate was concentrated in vacuo and purified by NP column chromatography to give the title compound (155 mg, 25.8%) as a red solid. LCMS (ES) + ):322.15 [MH] + .

[0176] Intermediates 16-20 Intermediates 16-20 were prepared similarly to intermediate 15 by Cheng-Lam coupling of the appropriate boronic acid or boronic ester with 4-bromo-1H-imidazole using Cu(OAc) and either DIEA or pyridine as the base; see Table 1 below.

[0177] [Table 1]

[0178] Intermediate 21 4-Bromo-1-(4-bromo-2-methoxyphenyl)-1H-imidazole [ka] (4-Bromo-2-methoxy-phenyl)boronic acid (4.92 g, 21.3 mmol), 4-bromo-1H-imidazole (4.70 g, 32.0 mmol), pyridine (5.15 mL, 63.9 mmol), and Cu(OTf) (15.4 g, 42.6 mmol) in DMF (30 mL) was heated to 40 °C and stirred for 17 h. The reaction mixture was concentrated in vacuo, diluted with EtOAc (30 mL) and water (30 mL), the phases were separated, and the aqueous phase was further extracted with EtOAc (30 mL). The combined organic phases were washed with brine (30 mL), concentrated in vacuo, and purified by NP column chromatography to give the title compound (1.36 g, 19.2%) as a white solid. LCMS (ES) + ):330.7 [MH] + .

[0179] Intermediates 22-38 Intermediates 22-38 were prepared similarly to intermediate 21 by Cheng-Lam coupling of the appropriate boronic acid or boronic ester with 4-bromo-1H-imidazole using Cu(OTf) and either pyridine, DIEA, or EtN as the base; see Table 2 below.

[0180] [Table 2-1] [Table 2-2] [Table 2-3]

[0181] Intermediate 39 tert-Butyl 6-(4-(4-bromo-1H-imidazol-1-yl)-3-methoxyphenoxy)-2-azaspiro[3.3]heptane-2-carboxylate [ka] To a stirred mixture of Intermediate 35 (650 mg, 2.42 mmol) in DMF (3.0 mL) was added NaH (116 mg, 4.83 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 0.5 h, and then tert-butyl 6-(methanesulfonyloxy)-2-azaspiro[3.3]heptane-2-carboxylate (1.05 g, 3.62 mmol) was added dropwise at 0° C. The resulting mixture was stirred at 80° C. for an additional 2 h, then concentrated in vacuo and purified by Prep-TLC (PE / EtOAc 1:1) to give the title compound (756 mg, 67.4%) as a yellow oil. LCMS (ES + ):466.10 [MH] + .

[0182] Intermediate 40 4-(4-Bromo-1H-imidazol-1-yl)-2-chlorobenzaldehyde [ka] A mixture of 4-bromo-1H-imidazole (200 mg, 1.36 mmol), 2-chloro-4-fluorobenzaldehyde (216 mg, 1.36 mmol), and K2CO3 (282 mg, 2.04 mmol) in DMSO (2.0 mL) was stirred at 60 °C for 16 h. The reaction mixture was cooled to RT and poured into rapidly stirred water (15 mL). The resulting solid was collected by filtration, washed with water (4 × 30 mL), and then dried in a vacuum oven at 50 °C for 3 h to give the title compound (350 mg, 77.3%) as a white solid. LCMS (ES) + ):284.9 [MH] + .

[0183] Intermediates 41-44 Intermediates 41-44 were prepared similarly to intermediate 40 by nucleophilic aromatic substitution of the appropriate halogenated aromatic substrate with 4-bromo-1H-imidazole in DMSO using KCO as the base; see Table 3 below.

[0184] [Table 3]

[0185] Intermediate 45 4-Bromo-1-(4-bromophenyl)-1H-imidazole [ka] A mixture of 4-bromo-1H-imidazole (5.00 g, 34.0 mmol), 1-bromo-4-fluorobenzene (7.50 mL, 69.3 mmol), and KPO (36.3 g, 171 mmol) in DMF (100 mL) was heated to 150 °C for 20 h. The reaction mixture was slowly poured into rapidly stirred water (400 mL), filtered, and the residue was then washed with water (20 mL) and dried in a vacuum oven at 60 °C for 5 h to give the title compound (7.93 g, 74.3%) as a white solid. LCMS (ES) + ):300.8 [MH] + .

[0186] Intermediates 46-48 Intermediates 46-48 were prepared similarly to intermediate 45 by nucleophilic aromatic substitution of the appropriate halogenated aromatic substrate with 4-bromo-1H-imidazole in DMF using KPO as the base; see Table 4 below.

[0187] [Table 4]

[0188] Intermediate 49 5-Bromo-2-(4-bromo-1H-imidazol-1-yl)pyridine [ka] To a stirred mixture of 5-bromo-2-fluoropyridine (1.00 g, 5.68 mmol) and 4-bromo-1H-imidazole (1.25 g, 8.52 mmol) in DMF (20 mL) was added CsCO (3.70 g, 11.4 mmol) at RT. The resulting mixture was stirred at 100 °C for 1 h, then quenched with water (100 mL), extracted with EtOAc (5 × 100 mL), and the combined organic layers were washed with brine (50 mL), dried (NaSO), concentrated in vacuo, and purified by NP column chromatography to give the title compound (1.10 g, 63.9%) as a yellow solid. LCMS (ES) + ):304.1 [MH] + .

[0189] Intermediate 50 2-(4-bromo-1H-imidazol-1-yl)-5-chloropyrazine [ka] To a solution of 4-bromo-1H-imidazole (493 mg, 3.36 mmol) in DMF (10 mL) at 0° C. was added NaH (162 mg, 4.05 mmol). The mixture was stirred for 1 h, then 2,5-dichloro-pyrazine (500 mg, 3.36 mmol) was added. The mixture was warmed to 100° C. and stirred for 1 h, then quenched with water and extracted with DCM (3×25 mL). The combined organic layers were washed with brine, dried (NaSO), concentrated in vacuo, and purified by NP column chromatography to give the title compound (400 mg, 45.9%) as a pale yellow solid. LCMS (ES) + ):259.0 [MH] + .

[0190] Intermediate 51 4-(4-Bromo-1H-imidazol-1-yl)-3-methyl-5-(trifluoromethyl)benzaldehyde [ka] To a stirred mixture of 4-fluoro-3-methyl-5-(trifluoromethyl)benzaldehyde (2.00 g, 9.70 mmol) and 4-bromo-1H-imidazole (2.14 g, 14.6 mmol) in MeCN (5.0 mL) was added dropwise DIEA (3.38 mL, 19.4 mmol) at RT. The mixture was stirred at 80° C. for 16 h, then concentrated in vacuo and purified by NP column chromatography to give the title compound (1.30 g, 40.2%) as a white solid. LCMS (ES) + ):333.0 [MH] + .

[0191] Intermediate 52 4-(4-Bromo-1H-imidazol-1-yl)-3,5-dimethylbenzaldehyde [ka] To a stirred mixture of 4-fluoro-3,5-dimethylbenzaldehyde (1.00 g, 6.57 mmol) and 4-bromo-1H-imidazole (1.93 g, 13.1 mmol) in DMF (50 mL) was added KCO (1.82 g, 13.1 mmol) under N at RT. The resulting mixture was stirred at 100 °C for 2 h, quenched with water, extracted with EtOAc (3 × 25 mL), and the combined organic layers were then washed with brine, dried (NaSO), concentrated in vacuo, and purified by NP column chromatography to give the title compound (103 mg, 5.60%) as a pale yellow powder. LCMS (ES) + ):279.10 [MH] + .

[0192] Intermediate 53 3-Bromo-6-(4-bromo-1H-imidazol-1-yl)-2-methylpyridine [ka] A solution of 3-bromo-6-fluoro-2-methylpyridine (2.00 g, 10.5 mmol), 4-bromo-1H-imidazole (2.19 g, 14.9 mmol), and DIEA (2.58 g, 20.0 mmol) in DMF (10 mL) was stirred at 100° C. overnight, then quenched with water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (3×10 mL), dried (NaSO), concentrated in vacuo, and purified by NP column chromatography to give the title compound (356 mg, 10.7%) as a white solid. LCMS (ES) + ):317.9 [MH] + .

[0193] Intermediate 54 5-Bromo-2-(4-bromo-1H-imidazol-1-yl)pyrimidine [ka] Intermediate 54 was prepared similarly to intermediate 53 by the nucleophilic aromatic substitution reaction of 5-bromo-2-chloropyrimidine with 4-bromo-1H-imidazole in DMF using DIEA as the base, followed by purification by NP column chromatography to give the title compound (420 mg, 17.8%) as a white solid. LCMS (ES + ):304.9 [MH] + .

[0194] Intermediate 55 4-Bromo-1-(4-bromo-2-nitrophenyl)-1H-imidazole [ka] Intermediate 55 was prepared similarly to intermediate 53 by the nucleophilic aromatic substitution reaction of 4-bromo-1-fluoro-2-nitrobenzene with 4-bromo-1H-imidazole in MeCN using DIEA as the base, followed by purification by NP column chromatography to give the title compound (6.30 g, 93.2%) as a yellow solid. LCMS (ES + ):347.6 [MH]+ .

[0195] Intermediate 56 tert-Butyl (3S,4S)-3-((4-(4-bromo-1H-imidazol-1-yl)benzyl)oxy)-4-fluoropyrrolidine-1-carboxylate [ka] Step 1: To a solution of intermediate 42 (1.00 g, 3.98 mmol) in MeOH (20 mL) was added NaBH (301 mg, 7.96 mmol) at 0 °C. The reaction mixture was stirred at RT for 1 h, then quenched with water (50 mL) at 0 °C, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 50 mL), dried (NaSO), and concentrated in vacuo to give [4-(4-bromoimidazol-1-yl)phenyl]methanol (990 mg, 98.2%) as a white solid. LCMS (ES) + ):253.0 [MH] + .

[0196] Step 2: To a stirred mixture of [4-(4-bromoimidazol-1-yl)phenyl]methanol (3.60 g, 14.2 mmol) and CBr (9.43 g, 28.5 mmol) in DCM (30 mL) was added PPh (7.46 g, 28.4 mmol) at 0 °C under N. The mixture was stirred at 0 °C for 4 h, then concentrated in vacuo and purified by NP column chromatography to give 4-bromo-1-[4-(bromomethyl)phenyl]imidazole (3.00 g, 66.8%) as a white solid. LCMS (ES) + ):316.8 [MH] + .

[0197] Step 3: To a solution of tert-butyl (3S,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate (500 mg, 2.44 mmol) in DMF (10 mL) at 0 °C was added NaH (128 mg, 3.20 mmol). The mixture was stirred for 15 seconds, then 4-bromo-1-[4-(bromomethyl)phenyl]imidazole (500 mg, 1.58 mmol) was added, and the mixture was warmed to RT and stirred for 1 hour. The reaction was quenched with water (10 mL), extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with brine (3 × 10 mL), dried (NaSO), concentrated in vacuo, and purified by NP column chromatography to give the title compound (530 mg, 76.1%) as a yellow oil. LCMS (ES) + ):439.9 [MH] + .

[0198] Intermediate 57 tert-Butyl (3S,4R)-3-((4-(4-bromo-1H-imidazol-1-yl)benzyl)oxy)-4-fluoropyrrolidine-1-carboxylate [ka] Intermediate 57 was prepared similarly to intermediate 56 by aldehyde reduction of intermediate 42 using NaBH4, followed by Appel reaction using CBr4 and PPh3, followed by alkylation with tert-butyl (3R,4S)-3-fluoro-4-hydroxypyrrolidine-1-carboxylate to give the title compound (660 mg, 94.7%) as a yellow solid. LCMS (ES) + ):439.9 [MH] + .

[0199] Intermediate 58 1-(4-(4-bromo-1H-imidazol-1-yl)benzyl)-4-methylpiperazine [ka] To a stirred mixture of intermediate 42 (600 mg, 2.39 mmol) and STAB (1.00 g, 4.78 mmol) in DCM (12 mL) under N2 at RT was added 1-methyl-piperazine (359 mg, 3.58 mmol). The mixture was stirred for 2 h, then concentrated in vacuo and purified by NP column chromatography to give the title compound (329 mg, 41.1%) as a yellow solid. LCMS (ES) + ):335.3 [MH] + .

[0200] Intermediate 59 (R)-4-Bromo-1-(3-chloro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-imidazole [ka] Intermediate 40 (50.0 mg, 0.15 mmol, 85.8% purity), (R)-(-)-3-fluoropyrrolidine·HCl (18.9 mg, 0.15 mmol), and MP-trimethylammonium cyanoborohydride resin (3.82 mmol / g, 101 mg, 0.38 mmol) in IPA (1.5 mL) and AcOH (150 μL) were heated for 25 min using a microwave reactor (100 °C). The reaction mixture was diluted with DCM (5.0 mL), passed through a thin Celite® pad, concentrated in vacuo, and purified by RP HPLC. The combined fractions were passed through a capture and elution cartridge to give the title compound (26.0 mg, 48.3%) as a colorless gum. LCMS (ES) + ):357.6 [MH] + .

[0201] Intermediate 60 (R)-4-Bromo-1-(2-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)-6-methoxyphenyl)-1H-imidazole [ka] Intermediate 60 was prepared similarly to Intermediate 59 by reductive amination of Intermediate 43 with (R)-(-)-3-fluoropyrrolidine.HCl using MP-trimethylammonium cyanoborohydride resin to give the title compound (26.0 mg, 35.3%) as a colorless gum. LCMS (ES + ):371.7 [MH] + .

[0202] Intermediate 61 (R)-4-Bromo-1-(2-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-imidazole [ka] Intermediate 61 was prepared analogously to Intermediate 59 by reductive amination of Intermediate 44 with (R)-(-)-3-fluoropyrrolidine·HCl using MP-trimethylammonium cyanoborohydride resin to give the title compound (34.0 mg, 45.5%) as a colorless gum. LCMS (ES + ):341.6 [MH] + .

[0203] Intermediate 62 (R)-4-Bromo-1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2-methyl-6-(trifluoromethyl)phenyl)-1H-imidazole [ka] To a stirred mixture of intermediate 51 (1.30 g, 3.90 mmol) and (3R)-3-fluoropyrrolidine (0.70 g, 7.81 mmol) in MeOH (10 mL) was added NaBHCN (0.49 g, 7.81 mmol) portionwise at 0 °C. The resulting mixture was stirred at RT for 16 h, then quenched with water, concentrated in vacuo, and purified by RP column chromatography to give the title compound (579 mg, 36.5%) as a yellow oil. LCMS (ES) + ):406.1 [MH] + .

[0204] Intermediate 63 (R)-4-Bromo-1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2,6-dimethylphenyl)-1H-imidazole [ka] Intermediate 63 was prepared similarly to Intermediate 62 by reductive amination of Intermediate 52 with (R)-(-)-3-fluoropyrrolidine·HCl using NaBH3CN to give the title compound (100 mg, 77.7%) as a pale yellow solid. LCMS (ES + ):354.1 [MH] + .

[0205] Intermediate 64 (R)-1-(5-(4-bromo-1H-imidazol-1-yl)pyrazin-2-yl)-N,N-dimethylpyrrolidin-3-amine [ka] A mixture of intermediate 50 (400 mg, 1.54 mmol), DIEA (598 mg, 4.62 mmol), and (3R)-N,N-dimethylpyrrolidin-3-amine (176 mg, 1.54 mmol) in DMF (10 mL) was stirred at 100° C. for 2 hours. The resulting mixture was dried under reduced pressure and purified by NP column chromatography to give the title compound (300 mg, 57.7%) as a pale yellow solid. LCMS (ES) + ):337.2 [MH] + .

[0206] Intermediate 65 (R)-1-(5-(4-bromo-1H-imidazol-1-yl)pyridin-2-yl)-N,N-dimethylpyrrolidin-3-amine [ka] DIEA (3.60 mL, 20.7 mmol) was added to a stirred mixture of Intermediate 37 (2.50 g, 10.3 mmol) and (3R)-N,N-dimethylpyrrolidin-3-amine (1.97 mL, 15.5 mmol) in DMF (25 mL) at RT, and the mixture was then stirred for 18 h. Water (100 mL) was added, and the resulting mixture was extracted with EtOAc (4 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL), dried (NaSO), concentrated in vacuo, and purified by NP column chromatography to give the title compound (976 mg, 28.1%) as a purple solid. LCMS (ES) + ):336.2 [MH] + .

[0207] Intermediate 66 4-Bromo-1-(4-((1-(tert-butyl)azetidin-3-yl)oxy)phenyl)-1H-imidazole [ka] To a stirred solution of intermediate 19 (300 mg, 1.26 mmol), 1-tert-butylazetidin-3-ol (243 mg, 1.88 mmol), and PPh3 (494 mg, 1.88 mmol) in THF (5.0 mL) at 0 °C under N2, DIAD (381 mg, 1.88 mmol) was added dropwise. The resulting mixture was stirred at 40 °C under N2 for 2 h, then cooled to RT, quenched with water, concentrated in vacuo, and purified by NP column chromatography to give the title compound (110 mg, 25.0%) as a brown solid. LCMS (ES) + ):345.0 [MH] + .

[0208] Intermediates 67-74 Intermediates 67-74 were prepared similarly to intermediate 66 by Mitsunobu reaction of intermediates 16, 19, and 35 with the appropriate alcohol using DIAD and PPh3; see Table 5 below.

[0209] [Table 5-1] [Table 5-2]

[0210] Intermediate 75 (1R,4R)-2-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane [ka] Intermediate 45 (500 mg, 1.66 mmol), (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (279 mg, 2.48 mmol), XPhos (79.0 mg, 0.17 mmol), XPhos Pd G3 (140 mg, 0.17 mmol), and Cs2CO3 (1.08 g, 3.32 mmol) in DXN (10 mL) was stirred at 100 °C under N2 overnight, then cooled to RT, concentrated in vacuo, and purified by NP column chromatography to give the title compound (110 mg, 19.9%) as a yellow solid. LCMS (ES) + ):333.1 [MH] + .

[0211] Intermediates 76-161 Intermediates 76-161 were prepared similarly to intermediate 75 by XPhos Pd G3-catalyzed Buchwald-Hartwig coupling of the indicated (hetero)aryl bromide intermediate with the appropriate amine; see Table 6 below.

[0212] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15]

[0213] Intermediates 162 and 163 tert-Butyl 6-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-1,6-diazaspiro[3.4]octane-1-carboxylate [ka] Intermediates 162 and 163 were prepared similarly to intermediate 75 by XPhos Pd G3-catalyzed Buchwald-Hartwig coupling of intermediate 45 (1.76 g, 5.83 mmol) with tert-butyl 1,6-diazaspiro[3.4]octane-1-carboxylate hemioxalate (2.10 g, 4.08 mmol), followed by purification by NP column chromatography to afford the title compound (900 mg, 35.6%) as a yellow solid.

[0214] The racemic products were separated by prep-SFC method 1 to give each enantiomer of the title compound as a single enantiomer of unknown absolute stereochemistry.

[0215] Intermediate 162 (Enantiomer 1): SFC Rt 2.28 min to give the title compound (401 mg, 15.9%) as a yellow solid. LCMS (ES + ):433.1 [MH] + .

[0216] Intermediate 163 (Enantiomer 2): SFC Rt 4.02 min afforded the title compound (430 mg, 17.0%) as a yellow solid. LCMS (ES + ):433.1 [MH] + .

[0217] Intermediate 164 1-(4-(4-bromo-1H-imidazol-1-yl)-3-(trifluoromethoxy)phenyl)-4-methylpiperazine [ka] To a stirred mixture of Intermediate 32 (500 mg, 1.30 mmol) and 1-methyl-piperazine (194 mg, 1.94 mmol) in DXN (10 mL) at RT under N was added tBuXPhos Pd G3 (103 mg, 0.13 mmol), Me4tBuXPhos (60.0 mg, 0.13 mmol), and Cs2CO3 (848 mg, 2.60 mmol). The mixture was heated to 100 °C, stirred for 16 h, filtered, and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo and purified by RP column chromatography to give the title compound (190 mg, 36.2%) as a red solid. LCMS (ES) + ):407.0 [MH] + .

[0218] Intermediate 165 (R)-1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine [ka] Intermediate 45 (2.00 g, 6.56 mmol, 99.1% purity), (R)-(+)-3-(dimethylamino)pyrrolidine (1.00 mL, 7.88 mmol), BINAP (307 mg, 0.49 mmol), and NaOtBu (883 mg, 9.19 mmol) in PhMe (40 mL) were degassed with N for 10 min, then Pd2dba3 (150 mg, 0.16 mmol) was added, and the mixture was degassed for an additional 5 min and then heated to 110 °C under N2 for 18 h. The reaction mixture was diluted with DCM (100 mL), filtered through Celite®, concentrated in vacuo, and purified by NP column chromatography to give the title compound (1.07 g, 46.9%) as a beige solid. LCMS (ES) + ):335.1 [MH] + .

[0219] Intermediates 166-182 Intermediates 166-182 were prepared similarly to intermediate 165 by Pd2dba3-catalyzed Buchwald-Hartwig coupling of the appropriate amine with the designated aryl bromide intermediate; see Table 7 below.

[0220] [Table 7-1] [Table 7-2] [Table 7-3]

[0221] Intermediate 182 (R)-1-(4-(4-bromo-1H-imidazol-1-yl)-3-(dimethylamino)phenyl)-N,N-dimethylpyrrolidin-3-amine [ka] Step 1: To a stirred mixture of intermediate 137 (1.70 g, 4.47 mmol) and iron powder (2.00 g, 35.8 mmol) in EtOH (50 mL) at RT was added NH4Cl (1.91 g, 35.8 mmol) and water (403 μL, 22.4 mmol). The resulting mixture was stirred at 80 °C for 2 h, then filtered, and the filter cake was washed with EtOH (3 × 20 mL). The filtrate was concentrated in vacuo, then diluted with water (100 mL), and extracted with EtOAc (5 × 100 mL). The combined organic layers were washed with brine (5 x 20 mL), dried (NaSO), and the residue was then purified by NP column chromatography to give (R)-1-(3-amino-4-(4-bromo-1H-imidazol-1-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine (936 mg, 59.8%) as a brown solid. LCMS (ES) + ):350.3 [MH] + .

[0222] Step 2: A mixture of (R)-1-(3-amino-4-(4-bromo-1H-imidazol-1-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine (936 mg, 2.67 mmol) in MeOH (20 mL) was treated with formaldehyde (2.20 mL, 22.1 mmol) at RT for 10 min, followed by the addition of NaBH3CN (336 mg, 5.34 mmol). The resulting mixture was stirred at 60 °C for 16 h, concentrated in vacuo, and purified by RP column chromatography to give the title compound (289 mg, 28.6%) as a yellow solid. LCMS (ES) + ):378.3 [MH] + .

[0223] Intermediate 183 (R)-1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-N,N-bis(methyl-d3)pyrrolidin-3-amine [ka] Step 1: To a solution of intermediate 179 (243 mg, 86.0% purity, 0.68 mmol) and pyridine (220 μL, 2.73 mmol) in DCM (5.0 mL) was added p-toluenesulfonyl chloride (388 mg, 2.04 mmol). The reaction mixture was stirred at RT for 64 h, and additional pyridine (220 μL, 2.73 mmol) and p-toluenesulfonyl chloride (388 mg, 2.04 mmol) were added, and the mixture was stirred for an additional 24 h. The reaction mixture was concentrated in vacuo and purified by NP column chromatography to give [(3S)-1-[4-(4-bromoimidazol-1-yl)phenyl]pyrrolidin-3-yl]4-methylbenzenesulfonate (51.4 mg, 12.8%) as a light brown gum. LCMS (ES) + ):462.1 [MH] + .

[0224] Step 2: [(3S)-1-[4-(4-bromoimidazol-1-yl)phenyl]pyrrolidin-3-yl]4-methylbenzenesulfonate (51.4 mg, 78.2% purity, 86.9 μmol), K2CO3 (60.0 mg, 0.43 mmol), and dimethyl-d6-amine HCl (23.0 mg, 0.26 mmol) in MeCN (2.0 mL) were stirred at 80 °C for 18 h in a sealed tube. Additional K2CO3 (60.0 mg, 0.43 mmol) and dimethyl-d6-amine HCl (23.0 mg, 0.26 mmol) were added, and the mixture was stirred at 80 °C for an additional 6 h, then concentrated in vacuo and purified by NP column chromatography to give the title compound (13.8 mg, 46.6%) as a pale yellow solid. LCMS (ES) + ):343.2 [MH] + .

[0225] Intermediate 184 (3S,4R)-1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-4-fluoro-N-methylpyrrolidin-3-amine [ka] Step 1: A mixture of intermediate 123 (520 mg, 1.22 mmol) in DMF (5.0 mL) was treated with NaH (40 wt%, 73.0 mg, 1.83 mmol) under N at 0° C. for 30 min, followed by the dropwise addition of MeI (113 μL, 1.83 mmol) at 0° C. The mixture was warmed to RT, stirred for 16 h, quenched with water (20 mL), and then extracted with EtOAc (6×50 mL). The combined organic layers were washed with brine (6 x 20 mL), dried (Na2SO4), concentrated in vacuo, and purified by Prep-TLC (PE / EtOAc 2:1) to give tert-butyl ((3S,4R)-1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-4-fluoropyrrolidin-3-yl)(methyl)carbamate (380 mg, 70.7%) as a yellow solid. LCMS (ES + ):439.0 [MH] + .

[0226] Step 2: A mixture of tert-butyl N-[(3S,4R)-1-[4-(4-bromoimidazol-1-yl)phenyl]-4-fluoropyrrolidin-3-yl]-N-methylcarbamate (380 mg, 0.87 mmol) and TFA (1.0 mL) in DCM (10 mL) was stirred at RT for 2 h. The mixture was concentrated in vacuo and purified by prep-TLC (DCM / MeOH 20:1) to give the title compound (220 mg, 74.6%) as a yellow solid. LCMS (ES) + ):338.9 [MH] + .

[0227] Intermediate 185 tert-Butyl ((3S,4R)-1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-4-methoxypyrrolidin-3-yl)(methyl)carbamate [ka] A solution of intermediate 149 (156 mg, 0.36 mmol) in DMF (3.0 mL) was treated with NaH (22.0 mg, 0.55 mmol) under N at 0° C. for 40 min, followed by the dropwise addition of MeI (33.0 μL, 0.53 mmol). The resulting mixture was stirred at RT for 1 h, then concentrated in vacuo and purified by RP column chromatography to give the title compound (152 mg, 93.2%) as a yellow solid. LCMS (ES) + ):451.0 [MH] + .

[0228] Intermediate 186 tert-Butyl ((3S,4R)-1-(4-(4-bromo-1H-imidazol-1-yl)-3-methoxyphenyl)-4-fluoropyrrolidin-3-yl)(methyl)carbamate [ka] Intermediate 186 was prepared similarly to intermediate 185 by alkylation of intermediate 157 (220 mg, 0.48 mmol) with MeI (45.0 μL, 0.72 mmol), followed by purification by Prep-TLC (PE / EtOAc 1:1) to give the title compound (200 mg, 88.2%) as a brown solid. LCMS (ES + ):469.1 [MH] + .

[0229] Intermediate 187 tert-Butyl (R)-(1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)pyrrolidin-3-yl)(ethyl)carbamate [ka] Intermediate 187 was prepared similarly to Intermediate 185 by alkylation of Intermediate 118 (200 mg, 0.49 mmol) with EtI (60.0 μL, 0.74 mmol) to give the title compound (200 mg, 93.6%) as a white solid. LCMS (ES + ):435.1 [MH] + .

[0230] Intermediate 188 1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)pyrrolidin-3-one [ka] A solution of DMSO (6.50 mL, 91.5 mmol) in DCM (200 mL) was treated with oxalyl chloride (3.90 mL, 46.1 mmol) under N at −78° C. for 5 min, then Intermediate 181 (10.0 g, 32.5 mmol) in DCM (50 mL) was added dropwise at −78° C. The resulting mixture was warmed to RT and stirred for 1 h. Then EtN (28.0 mL, 202 mmol) was added, and the mixture was stirred for 16 h. DCM (200 mL) was added, then the reaction was quenched by the addition of aq NaHCO (200 mL), washed with water (6×100 mL), dried (NaSO), and concentrated in vacuo. Purification by NP column chromatography afforded the title compound (6.00 g, 60.4%) as a yellow solid. LCMS (ES) + ):306.0 [MH] + .

[0231] Intermediate 189 (2R,3R)-1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-N,N,2-trimethylpyrrolidin-3-amine [ka] Step 1: Intermediate 139 (185 mg, 0.41 mmol) in AcOH (4.0 mL) was treated with HBr (2.0 mL, 40% of AcOH) at RT for 1 h, then concentrated in vacuo. Purification by RP column chromatography afforded (2R,3R)-1-[4-(4-bromoimidazol-1-yl)phenyl]-2-methylpyrrolidin-3-amine (130 mg, 98.8%) as a yellow solid. LCMS (ES) + ):321.0 [MH] + .

[0232] Step 2: A solution of (2R,3R)-1-[4-(4-bromoimidazol-1-yl)phenyl]-2-methylpyrrolidin-3-amine (130 mg, 0.40 mmol) in MeOH (5.0 mL) was treated with formaldehyde (122 μL, 1.23 mmol) at RT for 10 min, followed by the addition of NaBHCN (76.0 mg, 1.22 mmol). The resulting mixture was stirred at RT for 2 h, quenched with water (10 mL), extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with brine (3 × 5.0 mL), dried (NaSO), and then concentrated in vacuo. Purification by prep-TLC (DCM / MeOH 10:1) afforded the title compound (90.0 mg, 64.7%) as a yellow solid. LCMS (ES) + )348.9[MH] + .

[0233] Intermediate 190 (3aR,6aR)-1-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-4-methyloctahydropyrrolo[3,2b]pyrrole [ka] Intermediate 190 was prepared similarly to intermediate 189 by Cbz deprotection of intermediate 144 (300 mg, 0.64 mmol) followed by reductive amination with formaldehyde using NaBH3CN to give the title compound (167 mg, 75.2% over two steps) as a yellow solid. LCMS (ES + ):347.1 [MH] + .

[0234] Intermediate 191 4-Bromo-1-(4-((((3S,4S)-4-fluoro-1-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-1H-imidazole [ka] Step 1: A solution of intermediate 56 (510 mg, 1.16 mmol) and TFA (2.0 mL) in DCM (10 mL) was stirred at RT for 1 h. The resulting mixture was concentrated in vacuo to give 4-bromo-1-(4-((((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)methyl)phenyl)-1H-imidazole (390 mg) as a red oil, which was used directly in the next step without further purification. LCMS (ES) + ):339.9 [MH] + .

[0235] Step 2: To a stirred solution of 4-bromo-1-(4-((((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)methyl)phenyl)-1H-imidazole (390 mg, 1.15 mmol) and formaldehyde (108 μL, 1.09 mmol) in THF (5.0 mL) was added NaBHCN (80.0 mg, 1.27 mmol) at RT. The solution was stirred at RT for 1 h, then concentrated in vacuo and purified by RP column chromatography to give the title compound (210 mg, 51.2% over 2 steps) as a yellow oil. LCMS (ES) + ):353.9 [MH] + .

[0236] Intermediates 192-210 Intermediates 192-210 were prepared similarly to intermediate 191 by Boc deprotection of the indicated amine intermediates using TFA followed by reductive amination with the appropriate aldehyde or ketone using NaBHCN, NaBH, or STAB as the reducing agent; see Table 8 below.

[0237] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4]

[0238] Intermediates 211 and 212 6-(4-(4-bromo-1H-imidazol-1-yl)phenyl)-1-methyl-1,6-diazaspiro[3.4]octane [ka] Intermediates 211 and 212 were prepared from intermediates 162 and 163, respectively, similar to intermediate 191, by Boc deprotection of intermediates 162 and 163 using TFA, followed by reductive amination with formaldehyde using NaBHCN as the reducing agent. Intermediates 162 and 163 were isolated as single enantiomers of unknown absolute stereochemistry, and therefore intermediates 211 and 212 are also single enantiomers of unknown absolute stereochemistry.

[0239] Intermediate 211 (enantiomer 1): Isolated 80.0 mg as a yellow oil, 24.9% over two steps. LCMS (ES + ):347.0 [MH] + .

[0240] Intermediate 212 (enantiomer 2): Isolated 150 mg as a yellow oil, 43.5% over 2 steps. LCMS (ES + ):347.1 [MH] + .

[0241] Intermediate 213 4-Bromo-1-(4-(3-(3,3-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazole [ka] A mixture of intermediate 188 (400 mg, 1.31 mmol), 3,3-dimethylazetidine HCl (175 mg, 1.44 mmol), and STAB (831 mg, 3.92 mmol) in DCM (10 mL) was stirred at RT for 1 h. The resulting mixture was concentrated in vacuo and purified by prep-TLC (DCM / MeOH=50:1) to give the crude product (420 mg) as a yellow solid, which was further purified by prep-HPLC to give the title compound (120 mg, 24.5%) as a yellow solid. LCMS (ES) + ):375.1 [MH] + .

[0242] Intermediate 214 4-Bromo-1-(4-(3-(3-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazole [ka] Intermediate 214 was prepared similarly to intermediate 213 by reductive amination of intermediate 188 (400 mg, 1.31 mmol) with 3-methylazetidine·HCl (155 mg, 1.44 mmol), followed by purification by prep-TLC (EtOAc) to give the title compound (200 mg, 42.4%) as a yellow solid. LCMS (ES) + ):361.1 [MH] + .

[0243] Intermediates 215-226 Intermediates 215-226 were prepared similarly to intermediate 213 by reductive amination of intermediate 188 with the appropriate amine, but with a subsequent isomer separation step using either prep-SFC or chiral prep-HPLC to give the two intermediates as either single enantiomers or single diastereomers with unknown absolute stereochemistry; see Table 9 below.

[0244] [Table 9-1] [Table 9-2] [Example]

[0245] Example 1 5-((1-(4-((1R,5R)-6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Intermediate 192 (181 mg, 95.1% purity, 0.52 mmol), 5-aminopyrazine-2-carbonitrile (78.0 mg, 0.65 mmol), CsCO (336 mg, 1.03 mmol), and AdBrettPhos (33.00 mg, 51.5 μmol) in DXN (3.0 mL) was sparged with N for 5 min, then AdBrettPhos Pd G (52.0 mg, 51.5 μmol) was added, and the mixture was sparged with N for an additional 5 min, then heated to 100 °C in a sealed tube and stirred for 15 h. The reaction mixture was concentrated in vacuo and purified by NP column chromatography. Further purification by NH-buffered RP HPLC followed by drying in a vacuum oven at 60 °C for 16 h afforded the title compound (36.2 mg, 18.6%) as a pale yellow solid. LCMS(ES + ):373.2 [MH] + UPLC: Rt 3.14 min, 99.0% purity.

[0246] Examples 2 to 104 Examples 2-104 were prepared analogously to Example 1 by AdBrettPhos Pd G3-catalyzed Buchwald-Hartwig coupling of 5-aminopyrazine-2-carbonitrile with the indicated (hetero)aryl bromide intermediates; see Table 10 below.

[0247] [Table 10-1]

Table 10-2

Table 10-3

Table 10-4

Table 10-5

Table 10-6

Table 10-7

Table 10-8

Table 10-9

Table 10-10

Table 10-11

Table 10-12

Table 10-13

Table 10-14

Table 10-15

Table 10-16

Table 10-17

[0248] Examples 105 to 126 Examples 105-126 were prepared similarly to Example 1 by AdBrettPhos Pd G3-catalyzed Buchwald-Hartwig coupling of 5-aminopyrazine-2-carbonitrile and the designated aryl bromide intermediates, but with a subsequent enantiomer separation step using either prep-SFC or chiral prep-HPLC to isolate single enantiomers of unknown absolute configuration; see Table 11 below.

[0249] [Table 11-1] [Table 11-2] [Table 11-3]

[0250] Examples 127 to 140 Examples 127-140 were prepared similarly to Example 1 by AdBrettPhos Pd G3-catalyzed Buchwald-Hartwig coupling of 5-aminopyrazine-2-carbonitrile and the designated aryl bromide intermediates. Intermediates 211-212 and 215-226 are single enantiomers or diastereomers of unknown absolute configuration due to a prior isomer separation step using either chiral prep-HPLC or SFC, and therefore Examples 127-140 are also single enantiomers or diastereomers of unknown absolute configuration; see Table 12 below.

[0251] [Table 12-1] [Table 12-2]

[0252] Example 141 (R)-1-(4-(4-((5-cyanopyrazin-2-yl)amino)-1H-imidazol-1-yl)phenyl)-N,N-dimethylpyrrolidine-3-amine oxide [ka] To Example 12 (100 mg, 0.26 mmol) in DCM (8.0 mL) was added mCPBA (75% in water, 90.0 mg, 0.39 mmol). The mixture was stirred at RT for 30 min and then purified by capture and elute cartridge. Further purification by NP column chromatography followed by RP HPLC gave the title compound (15.3 mg, 15.0%) as a green solid. LCMS (ES + ):391.2 [MH] + UPLC: Rt 3.30 min, 99.6% purity.

[0253] Example 142 5-((1-(4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Intermediate 15 (150 mg, 0.47 mmol) was reacted with 5-aminopyrazine-2-carbonitrile (83.9 mg, 0.70 mmol) as in Example 1, except that EPhos Pd G4 and Ephos were used instead of AdBrettPhos Pd G3 and AdBrettPhos, respectively. Purification by RP HPLC gave the title compound (5.4 mg, 3.2%) as a yellow solid. LCMS (ES + ):362.3 [MH] + HPLC: Rt 0.91 min, 98.8% purity.

[0254] Examples 143 to 147 Examples 143-147 were prepared similarly to Example 142 by EPhos Pd G4 catalyzed Buchwald-Hartwig coupling of 5-aminopyrazine-2-carbonitrile with the designated aryl bromide intermediates; see Table 13 below.

[0255] [Table 13]

[0256] Example 148 5-((1-(3-(3-aminopropoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Step 1: Intermediate 69 (200 mg, 0.51 mmol) was reacted with 5-aminopyrazine-2-carbonitrile (90.9 mg, 0.76 mmol) using AdBrettPhos Pd G3 as in Example 1. Purification by RP column chromatography gave tert-butyl N-[3-(3-{4-[(5-cyanopyrazin-2-yl)amino]imidazol-1-yl}phenoxy)propyl]carbamate (94.8 mg, 43.1%) as a light brown solid. LCMS (ES) + ):436.2 [MH] + .

[0257] Step 2: A mixture of tert-butyl N-[3-(3-{4-[(5-cyanopyrazin-2-yl)amino]imidazol-1-yl}phenoxy)propyl]carbamate (90.0 mg, 0.21 mmol) and TFA (1.0 mL) in DCM (5.0 mL) was stirred at RT for 30 min. The resulting mixture was concentrated in vacuo and purified by RP HPLC to give the title compound (21.0 mg, 28.9%) as a yellow solid. LCMS (ES) + ):336.1 [MH] + HPLC: Rt 1.02 min, 95.4% purity.

[0258] Examples 149 to 165 Examples 149-165 were prepared similarly to Example 148 by AdBrettPhos Pd G3 catalyzed Buchwald-Hartwig coupling of the indicated aryl bromide intermediates with 5-aminopyrazine-2-carbonitrile followed by Boc deprotection using TFA; see Table 14 below.

[0259] [Table 14-1] [Table 14-2] [Table 14-3]

[0260] Examples 166 and 167 5-((1-(3-(4-amino-3,3-difluoropiperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Examples 166 and 167 were prepared analogously to Example 148 by AdBrettPhos Pd G3-catalyzed Buchwald-Hartwig coupling of 5-aminopyrazine-2-carbonitrile with intermediate 110, followed by Boc deprotection using TFA. The enantiomers were separated using chiral Prep-HPLC method 10 to give each enantiomer of the title compound as a single enantiomer of unknown absolute stereochemistry.

[0261] Example 166 (Enantiomer 1): Chiral Prep-HPLC Rt 3.19 min to give the title compound (13.0 mg, 4.7% over 2 steps) as a yellow solid. LCMS (ES + ):397.4 [MH] + HPLC: Rt 0.74 min, 99.5% purity.

[0262] Example 167 (Enantiomer 2): Chiral Prep-HPLC Rt 4.49 min to give the title compound (11.0 mg, 4.0% over 2 steps) as a yellow solid. LCMS (ES + ):397.3 [MH] + HPLC: Rt 0.72 min, 99.9% purity.

[0263] Example 168 5-((1-(2-(3-aminopropoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Example 168 was prepared from Intermediate 13 in a similar manner to Example 148, except that in Step 1, EPhos Pd G4 and Ephos were used instead of AdBrettPhos Pd G3 and AdBrettPhos, respectively. Purification by RP HPLC afforded the title compound (5.8 mg, 19.1% over two steps) as a pale yellow solid. LCMS (ES + ):336.2 [MH] + HPLC: Rt 6.26 min, 97.9% purity.

[0264] Example 169 (R)-5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile) [ka] Step 1: Intermediate 41 (800 mg, 2.85 mmol) was reacted with 5-aminopyrazine-2-carbonitrile (684 mg, 5.69 mmol) using AdBrettPhos Pd G3 as in Example 1. Purification by NP column chromatography gave 5-[[1-(4-formyl-2-methoxy-phenyl)imidazol-4-yl]amino]pyrazine-2-carbonitrile (95.0 mg, 9.6%) as a yellow solid.

[0265] Step 2: 5-[[1-(4-Formyl-2-methoxy-phenyl)imidazol-4-yl]amino]pyrazine-2-carbonitrile (20.0 mg, 57.6 μmol, 92.2% purity), (R)-(−)-3-fluoropyrrolidine·HCl (7.23 mg, 57.6 μmol), and MP-trimethylammonium cyanoborohydride resin (3.82 mmol / g, 37.7 mg, 0.14 mmol) in IPA (0.5 mL) and AcOH (50 μL) were heated for 10 min using a microwave reactor (100 °C). The reaction mixture was purified by trap and elute cartridge. Further purification by RP HPLC afforded the title compound (13.9 mg, 61.2%) as a yellow solid. LCMS (ES) + ):394.1 [MH] + UPLC: Rt 3.21 min, 99.7% purity.

[0266] Examples 170 to 174 Examples 170-174 were prepared similarly to Example 169 by AdBrettPhos Pd G3 catalyzed Buchwald-Hartwig coupling of 5-aminopyrazine-2-carbonitrile with intermediates 41 and 42, followed by reductive amination with the appropriate amine; see Table 15 below.

[0267] [Table 15]

[0268] Example 175 5-((1-(3-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Step 1: Intermediate 72 (60.0 mg, 0.14 mmol) was reacted with 5-aminopyrazine-2-carbonitrile (24.9 mg, 0.21 mmol) as in Example 1. Purification by NP column chromatography afforded tert-butyl 6-(3-{4-[(5-cyanopyrazin-2-yl)amino]imidazol-1-yl}phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate (41.2 mg, 63.0%) as a pale yellow solid. LCMS (ES) + ):474.3 [MH] + .

[0269] Step 2: A solution of tert-butyl 6-(3-{4-[(5-cyanopyrazin-2-yl)amino]imidazol-1-yl}phenoxy)-2-azaspiro[3.3]heptane-2-carboxylate (40.0 mg, 0.08 mmol) and TFA (1.0 mL) in DCM (1.0 mL) was stirred at RT for 30 min. The resulting mixture was concentrated in vacuo to give crude 5-{[1-(3-{2-azaspiro[3.3]heptan-6-yloxy}phenyl)imidazol-4-yl]amino}pyrazine-2-carbonitrile (20.0 mg), which was used directly in the next step without further purification.

[0270] Step 3: A solution of 5-{[1-(3-{2-azaspiro[3.3]heptan-6-yloxy}phenyl)imidazol-4-yl]amino}pyrazine-2-carbonitrile (20.0 mg, 0.05 mmol) and formaldehyde (5.00 μL, 0.05 mmol) in MeOH (1.0 mL) was stirred at RT for 30 min. NaBHCN (6.7 mg, 0.11 mmol) was added at 0° C., and the resulting mixture was stirred at RT for 4 h. The reaction was quenched with water, concentrated in vacuo, and purified by RP HPLC (TFA modifier) ​​to give the title compound as the TFA salt as a yellow solid (2.9 mg, 10.7% over 2 steps). LCMS (ES) + ):388.1 [MH] + HPLC: Rt 1.23 min, 98.9% purity.

[0271] Examples 176 to 180 Examples 176-180 were prepared similarly to Example 175 by AdBrettPhos Pd G3 catalyzed Buchwald-Hartwig coupling of 5-aminopyrazine-2-carbonitrile and the designated aryl bromide intermediate, followed by TFA Boc removal and subsequent reductive amination with the appropriate aldehyde; see Table 16 below.

[0272] [Table 16]

[0273] Example 181 5-((1-(4-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Example 181 was prepared from Intermediate 20 in a similar manner to Example 175, except that EPhos Pd G4 and Ephos were used instead of AdBrettPhos Pd G3 and AdBrettPhos, respectively, in Step 1, and 3,3-difluorocyclobutan-1-one was used instead of formaldehyde in Step 3. Purification by RP HPLC afforded the title compound (4.4 mg, 3.3% over 3 steps) as a pale yellow solid. LCMS (ES + ):437.0 [MH] + HPLC: Rt 0.81 min, 95.1% purity.

[0274] Example 182 5-((1-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Example 182 was prepared from intermediate 20 in a similar manner to Example 181, except that 3-oxetanone was used instead of 3,3-difluorocyclobutan-1-one in step 3. Purification by RP HPLC afforded the title compound (2.2 mg, 1.6% over 3 steps) as a yellow solid. LCMS (ES + ):403.2 [MH] + HPLC: Rt 6.67 min, 95.4% purity.

[0275] Example 183 5-((1-(4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile [ka] Step 1: Intermediate 20 (800 mg, 2.85 mmol) was reacted with 5-aminopyrazine-2-carbonitrile (684 mg, 5.69 mmol) using EPhos Pd G4 as in Example 142. Purification by RP HPLC gave tert-butyl 4-(4-{4-[(5-cyanopyrazin-2-yl)amino]imidazol-1-yl}phenyl)piperazine-1-carboxylate (80.0 mg, 73.0%) as a brown semi-solid. LCMS (ES) + :447.2 [MH] + .

[0276] Step 2: A solution of tert-butyl 4-(4-{4-[(5-cyanopyrazin-2-yl)amino]imidazol-1-yl}phenyl)piperazine-1-carboxylate (75.0 mg, 0.17 mmol) and TFA (0.5 mL) in DCM (2.5 mL) was stirred at RT for 30 min. The resulting mixture was concentrated in vacuo to give 5-({1-[4-(piperazin-1-yl)phenyl]imidazol-4-yl}amino)pyrazine-2-carbonitrile (40.0 mg, 68.74%) as a brown semi-solid. The resulting mixture was used directly in the next step without further purification. LCMS (ES) + ):347.1 [MH]+ .

[0277] Step 3: To a stirred solution of 5-({1-[4-(piperazin-1-yl)phenyl]imidazol-4-yl}amino)pyrazine-2-carbonitrile (40.0 mg, 0.115 mmol) and 1-bromo-2-fluoroethane (29.3 mg, 0.23 mmol) in DXN (2.0 mL) at RT was added NaI (34.6 mg, 0.23 mmol) and DIEA (29.8 mg, 0.23 mmol). The resulting mixture was stirred at 100° C. for 12 h, cooled to RT, filtered, and the filtrate was concentrated in vacuo. Purification by RP HPLC afforded the title compound (4.8 mg, 10.5%) as a yellow solid. LCMS (ES) + ):393.3 [MH] + HPLC: Rt 0.69 min, 99.2% purity.

[0278] Examples 184 to 186 Examples 184-186 were prepared similarly to Example 183 by EPhos Pd G4 catalyzed Buchwald-Hartwig coupling of 5-aminopyrazine-2-carbonitrile with intermediate 20, followed by Boc removal using TFA and subsequent alkylation with the appropriate alkyl halide; see Table 17 below.

[0279] [Table 17]

[0280] Comparative Examples 1 to 4 Four pyrazole-NH-pyrazine-containing Chk1 inhibitors are presented for comparison; see Table 18 below.

[0281] [Table 18]

[0282] High resolution mass spectrometry (HRMS) HRMS Methods This protocol is a non-GLP UPLC-HRMS analytical method for accurate mass analysis. Samples were prepared at a concentration of 250 ng / mL in water:acetonitrile (1:1) and analyzed by UPLC-HRMS using a BEH C18 50 x 2.1 mm, 1.7 μm column and 0.1% formic acid in water + 0.1% acetonitrile as the mobile phase.

[0283] Samples were analyzed on a Waters Synapt XS (Quadruple Time-of-Flight instrument) and Acquity UPLC system and corrected using LockSpray Leucine Enkephalin lockmass. Data were processed using the OpenLynx application software in MassLynx. The estimated and observed mass values ​​generated by OpenLynx are for neutral [M-H], or [M-H] or [M+H] species, and the exact mass error is reported in ppm (parts per million) and is calculated using the following formula: Mass error (ppm) = ((Actual mass - Theoretical mass) / Theoretical mass) × 10 6 was calculated by

[0284] [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4]

[0285] Biological data Human Chk1 HTRF (homogeneous time-resolved fluorescence) enzyme assay method 2 μL of enzyme / substrate solution (1 nM Chk-1 (Carna bioscience # 02-177) in assay buffer (20 mM HEPES pH 7.5, 500 mM NaCl, 0.1% BGG, 1 mM DTT, 0.005% Tween®-20) containing 30 μM ATP, 4 μM STK1 S1 (Cisbio # 62ST1PEB)) and various concentrations of compound were incubated in a 384-well plate (proxiplate-384 plus, Perkin Elmer cat # 6008289) for 30 minutes at room temperature. MgCl cofactor solution (2 μL, 20 mM) was added, and incubation continued for 30 minutes at room temperature. 4 μL of kit detection reagent (Cisbio # 62ST1PEB) was added, and incubation continued for 60 minutes at room temperature. Plates were read on a PHERAstar FS using TR-FRET technology, Channel A: 337 / 665, Channel B: 337 / 620. The % effect of compounds at a given concentration was calculated based on the inhibition occurring in DMSO control wells and inhibition control wells (control wells) within each assay plate. Compound IC 50 was determined using a four-parameter logistic dose-response equation using an 11-point dose-response curve and analyzed within the Dotmatics platform.

[0286] Exemplary compounds of the present invention were tested for their inhibitory potency against human Chk1 kinase in the HTRF assay and pIC 50 The data are shown in Table 20. pIC 50 is the IC when converted to moles 50 All of the exemplified compounds of the present invention have a pIC of >6. 50 This data demonstrates that compounds of the present invention can inhibit Chk1.

[0287] [Table 20-1] [Table 20-2]

[0288] Cancer cell line data In vitro cell viability assay GBM LN18 cells were incubated with increasing concentrations of selected compounds of the invention for 72 hours, after which ATP in metabolically viable cells was measured using Cell Titre® Glo Luminescent reagent. A 10-point concentration-response curve was tested, with a top concentration of 10 μM. The percent (%) effect, i.e., inhibition at each concentration of compound, was calculated based on and compared to the amount of inhibition produced in vehicle and inhibition control wells included in each plate. Log molar concentration and % inhibition values ​​were plotted, and the concentration of compound required for 50% inhibition (IC 50 ) was determined using a four-parameter logistic dose-response equation.

[0289] ELISA Kinase activity against cell-based targets was measured for selected compounds of the present invention using a sandwich ELISA assay kit (pChk1 PathScan ELISA kit, Cell Signaling Technologies, Cat# 7870) with pChk1 (Ser296) as the detection antibody. SW620 cells were seeded in 96-well plates and incubated overnight at 37°C and 5% CO2 before being treated with the DNA damage inducer neocarzinostatin (7.5 μM) and increasing concentrations of test drugs. Cells were returned to the incubator for 2 hours and then lysed in 30 μl of the lysis buffer provided in the kit (a 1:10 dilution of 10x Cell Lysis Buffer #9803, supplemented with protease and phosphatase inhibitors). ELISA assays were performed according to the manufacturer's protocol. However, an alternative detection antibody, pChk1 (Ser296; Cat #2349, Cell Signaling Technology), was used instead of the pChk1 (Ser317) antibody provided in the kit. Selected compounds of the invention were tested as an eight-point concentration response, with a maximum concentration of either 1 μM, 3 μM, or 10 μM. The percent (%) effect, i.e., inhibition at each concentration of compound, was calculated based on and compared to the amount of inhibition produced in vehicle and inhibition control wells included in each plate. Log molar concentrations and % inhibition values ​​for the tested compounds were plotted on a dose-response curve, and the concentration of compound required for 50% inhibition (IC 50 ) was determined using a four-parameter logistic dose-response equation.

[0290] A selection of exemplified compounds of the present invention were tested for their inhibitory potency in human derived glioblastoma (LN18) and colorectal cancer (SW620) cell lines and the data are presented in Table 21. pIC 50 is the IC when converted to moles 50 The negative logarithm of the value. These data demonstrate that compounds of the invention are effective in cancer cell lines at therapeutically relevant concentrations.

[0291] [Table 21]

[0292] Kinome selectivity Selected compounds of the invention were tested for broader kinome selectivity against the Eurofins KinaseProfiler™ kinase screen consisting of 373 human wild-type kinases using nine-point concentration-response curves up to a top concentration of 10 μM. Radiometric kinase activity assays were performed to obtain the approximate ATP K for each kinase. m 10-fold and 100-fold Chk1 IC 50 The number of kinases inhibited within the range of 100-1500 is shown in Table 22, which indicates that these compounds have good selectivity across the broader kinome Chk1.

[0293] [Table 22]

[0294] Human Chk2 HTRF enzyme assay method 2 μL of enzyme / substrate solution (2 nM Chk-2 (Carna bioscience # 02-162) in assay buffer (20 mM HEPES pH 7.5, 500 mM NaCl, 0.1% BGG, 1 mM DTT, 0.005% Tween®-20) containing 200 μM ATP, 4 μM STK1 S1 (Cisbio # 62ST1PEB)) and various concentrations of compound were incubated in a 384-well plate (Proxiplate-384 plus, Perkin Elmer cat # 6008289) for 30 minutes at room temperature. MgCl cofactor solution (2 μL, 20 mM) was added, and incubation continued for 30 minutes at room temperature. 4 μL of kit detection reagent (Cisbio # 62ST1PEB) was added, and incubation continued for 60 minutes at room temperature. Plates were read on a PHERAstar FS using TR-FRET technology, Channel A: 337 / 665, Channel B: 337 / 620. The % effect of compounds at a given concentration was calculated based on the inhibition occurring in DMSO control wells and inhibition control wells (control wells) within each assay plate. Compound IC 50was determined using a four-parameter logistic dose-response equation using an 11-point dose-response curve and analyzed within the Dotmatics platform.

[0295] Exemplary compounds of the present invention were tested for their inhibitory potency against human Chk2 kinase in the HTRF assay and pIC 50 The data are presented in Table 23. All of the exemplified compounds of the present invention had a pIC of <6. 50 This data indicates that the compounds of the present invention are not potent Chk2 inhibitors.

[0296] [Table 23-1] [Table 23-2]

[0297] RSK1-4 kinase assay Selected compounds of the invention were tested for their inhibitory potency of RSK1, RSK2, RSK3, and RSK4 kinases by Eurofins KinaseProfiler™ service using 9-point concentration-response curves up to a top concentration of 10 μM. Radiometric kinase activity assays were performed to obtain the approximate ATP K for each kinase. m and IC 50 The data are shown in Table 24. The data indicate that compounds of the present invention are not potent RSK1-4 inhibitors.

[0298] [Table 24]

[0299] MDCK-MDR1 and MDCK-BCRP efflux assays Assay protocol: Wild-type (WT) MDCK, MDR1-MDCK, and BCRP-MDCK cells were seeded into 24-well Transwell plates and cultured for 3 days to allow monolayer formation. Test compounds were prepared at 1 μM in Hanks' Balanced Salt Solution containing 25 mM HEPES and added to the donor compartment of the Transwell plate carrying the cell monolayer (pH 7.4 in both donor and receiver compartments). Lucifer Yellow was added to the apical buffer of all wells to assess the integrity of the cell monolayer. Duplicate wells were prepared and incubated at 37°C in a CO2 incubator. Samples were removed at time 0 and 60 minutes, and the test compounds were analyzed by LC-MS / MS. The concentration of Lucifer Yellow in the samples was measured using a fluorescence plate reader. The apparent permeation (P) of the test compounds was measured using a fluorescence plate reader. app ) values ​​were determined for both apical to basolateral (A>B) and basolateral to apical (B>A) permeation, and the efflux ratio (B>A:A>B) was determined for each cell line.

[0300] Compounds that freely penetrate the blood-brain barrier (BBB) ​​typically have ≤1 hydrogen bond donor, a tPSA ≤90 Å 2 (Hitchcock, J Med Chem, 2012, 4877-4895), apparent permeability (P app ) value >15×10e -6 It has a high passive permeability of 0.01 cm / s and low efflux by P-glycoprotein (P-gp), encoded by the MDR1 gene, and BCRP with an efflux ratio of ≦2.5 (Doan et al., J Pharmacol Exp Ther, 2002, 1029-1037). The data in Table 25 suggest that many of the compounds of the present invention can effectively cross the blood-brain barrier and may treat cancers of the brain and central nervous system.

[0301] [Table 25]

[0302] Measurement of CNS penetration in vivo Male Sprague Dawley rats (Charles River, UK), weighing 300–350 g, were group-housed (n=2) and operated on a 12-h light / dark cycle with free access to food and water. Two days before dosing, animals were anesthetized with inhaled isoflurane, and the right jugular vein was exposed and surgically cannulated. Animals were then housed singly for recovery and throughout the remainder of the procedure. On the day of dosing, animals were weighed, tail-marked, and administered 0.25 mg / kg of compound intravenously via an indwelling cannula in a volume of 3 mL / kg. Animals were culled 15 seconds after administration by intravenous administration of pentobarbital. Postmortem blood was collected by cardiac puncture and briefly stored on ice in K2 EDTA blood tubes before centrifugation at 14,000 g for 4 minutes at 4°C. Plasma was collected in a 96-well plate, placed on dry ice, and stored at -80°C. Brains were quickly dissected and placed on dry ice before being stored at -80°C.

[0303] Following intravenous administration of test compounds to male Sprague-Dawley rats, the animals were sacrificed at 15 seconds. Plasma was separated from whole blood immediately after cardiac exsanguination by centrifugal blood fractionation, and whole brains were dissected. Samples were stored on ice and transferred to the Bioanalytical Laboratory's storage at -80°C. Bioanalysis of plasma and brain samples was performed as detailed below.

[0304] Plasma bioanalysis Typically, a 1.00 mg / mL DMSO stock was used to prepare calibration standards for test compounds in the range of 1.00 to 6,000 ng / mL. Calibration series were prepared by printing known masses of specimens into a 96-well plate in the range of 25 to 150,000 pg. A volume of 25 μL of control male Sprague-Dawley rat plasma was added to each well to prepare calibration standards of appropriate concentrations across the calibration range. Experimental samples were thawed to room temperature, and 25 μL aliquots were added to a 96-well precipitation plate along the calibration series. Samples were extracted using protein precipitation (300 μL of MeCN containing 25 ng / mL tolbutamide as an internal standard, agitated at RT for at least 5 minutes). The protein precipitate was separated from the extracted test compound by centrifugation at 4000 rpm for 5 minutes at 4°C. The resulting supernatant was diluted with diluent, 1:1 MeOH:H2O, in a ratio of 1:2.

[0305] Samples were analyzed by UPLC-MS / MS on either an AB Sciex API6500 QTrap or a Waters TQ-S mass spectrometer using a previously optimized analytical MRM (multiple reaction monitoring) method specific to the test compound.

[0306] The concentrations of test compounds in the separated samples were determined following analysis of samples against two replicates of the calibration curve, injected before and after the sample set using appropriate regression and weighting. Only calibrators within ±15% of the expected test concentration value were included in the calibration curve (±20% at LLoQ); samples beyond the limits of the calibration curve were considered below or above the limit of quantitation (LLoQ / ALoQ).

[0307] Brain bioanalysis Typically, a 1.00 mg / mL DMSO stock was used to prepare calibration standards of test compounds in the range of 3.00 to 18,000 ng / mL. Calibration series were prepared by printing known masses of analytes into a 96-well plate in the range of 25 to 150,000 pg. A volume of 25 μL of control male Sprague-Dawley rat brain homogenate (containing 8.33 mg of brain tissue) was added to each well to prepare calibration standards of appropriate concentrations across the calibration range.

[0308] To prepare control and experimental brain homogenates, brains were thawed at room temperature, weighed, and a volume of diluent (50:50 MeCN / HO) was added at a ratio of 2 mL per gram of brain. Brain homogenization was performed by bead-beater homogenization using Precellys Evolution and CKMix50 7 mL mixed ceramic bead homogenization tubes.

[0309] Aliquots of 25 μL of experimental samples were extracted along the calibration curve using protein precipitation (300 μL of MeCN containing 25 ng / mL of tolbutamide as an internal standard, stirred at RT for at least 5 minutes). The protein precipitate was separated from the extracted test compound by centrifugation at 4000 rpm for 5 minutes at 4° C. The resulting supernatant was diluted 1:2 with diluent, 1:1 MeOH:water.

[0310] Samples were analyzed by UPLC-MS / MS on either an AB Sciex API6500 QTrap or a Waters TQ-S mass spectrometer using a pre-optimized analytical MRM (multiple reaction monitoring) method specific to the test compound.

[0311] The concentrations of test compounds in the separated samples were determined following analysis of samples against two replicates of the calibration curve, injected before and after the sample set using appropriate regression and weighting. Only calibrators within 15% of the expected test concentration value were included in the calibration curve (±20% at LLoQ); samples beyond the limits of the calibration curve were considered below or above the limit of quantitation (LLoQ / ALoQ).

[0312] Determination of unbound brain-to-plasma ratio The free drug hypothesis states that only unbound compounds can interact and exert pharmacological effects. Therefore, it is desirable for compounds to have high free brain concentrations. To calculate the free concentration in each matrix, the measured concentration is multiplied by the % free value determined by plasma protein binding and brain tissue binding studies using rapid equilibrium dialysis.

[0313] K puu is calculated as the ratio of the free drug fraction unbound in the brain to the free drug unbound in plasma. The results (Table 26) show that compounds of the present invention have high free brain concentrations (K puu ), i.e., they have a higher ratio of unbound free drug fraction in the brain to unbound free drug in plasma, which allows them to exert their pharmacological effects better in the brain.

[0314] [Table 26]

Claims

1. The following formula (I): 【Chemical 1】 {During the ceremony, Each X is independently N or CR ２ and Each Y is independently N or CR ３ and 0, 1, or 2 of X or Y are N; R １ , R ２ , and R ３ are independently the following: (a) H, halo, (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, (C ３－ C ９ ) cycloalkyl, -OR ４ , -NR ５ R ６ , -C(O)R ７ , where (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, and (C ３－ C ９ ) Cycloalkyl is one or more R ８ optionally replaced by; (b) one or more R ９ a 4- to 7-membered non-aromatic heterocycle optionally substituted with (c) Each of them (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, and -NR ２ a 7-10 membered spiro, bridged or fused heterocyclic ring system optionally substituted with one or more of: Selected from: R ４ is (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, (C １－ C ６ ) Alkylene-NR ２ , 4- to 6-membered non-aromatic heterocycles, and 6- to 9-membered heterocyclic spiro systems, wherein the 4- to 6-membered non-aromatic heterocycles and 6- to 9-membered heterocyclic spiro systems are selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; R ５ is H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl; R ６ is H, (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, and 4- to 7-membered non-aromatic heterocycle, wherein the heterocycle is selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; R ７ is H, (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, -NR ２ and 4- to 7-membered non-aromatic heterocycles, wherein the heterocycle is selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; R ８ is -NR ２ , and (O) ｎ -(4- to 7-membered non-aromatic heterocycle), wherein the 4- to 7-membered non-aromatic heterocycle is selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; R ９ is halo, (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, (C ３－ C ６ ) cycloalkyl, (C １－ C ６ ) alkoxy, -NR ２ , -N(R)(C １－ C ６ ) hydroxyalkyl, (C １－ C ６ ) Alkylene-NR ２ , 4- to 6-membered non-aromatic heterocycles, and 5- to 8-membered heterocyclic spiro systems, wherein the (C ３－ C ６ ) cycloalkyl, 4-6 membered non-aromatic heterocycles, 5-8 membered heterocyclic spiro systems are also included, including halo and (C １－ C ６ ) optionally substituted with one or more alkyl; and Each R is independently H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl} or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, diastereoisomer, isotopic form, N-oxide, and / or prodrug thereof.

2. R １ but one or more R ９ a 4- to 7-membered non-aromatic heterocycle optionally substituted with (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, and -NR ２ 7-10 membered spiro, bridged or fused heterocyclic ring systems optionally substituted with one or more of: Here, the R ９ is halo, (C １－ C ３ ) alkyl, (C １－ C ３ ) haloalkyl, (C ３－ C ６ ) cycloalkyl, (C １－ C ３ ) alkoxy, -NR ２ , (C １－ C ３ ) Alkylene-NR ２ , 4- to 6-membered non-aromatic heterocycles, and 5- to 8-membered heterocyclic spiro systems, wherein the (C ３－ C ６ ) cycloalkyl, 4- to 6-membered non-aromatic heterocycles, and 5- to 8-membered heterocyclic spiro systems are substituted with halo and (C １－ C ６ ) optionally substituted with one or more alkyl; and Each R is H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl; 2. The compound of claim 1.

3. R ９ But, -NR ２ , (C １－ C ３ ) Alkylene-NR ２ , 4- to 6-membered non-aromatic heterocycles, and 5- to 8-membered heterocyclic spiro systems, wherein the 4- to 6-membered non-aromatic heterocycles and 5- to 8-membered heterocyclic spiro systems are selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; 3. The compound of claim 2.

4. R １ but the following: 【Chemistry 2】 And halo, (C １－ C ３ ) alkyl, (C １－ C ３ ) alkoxy, -NH ２ , -N(H)(C １－ C ３ ) alkyl, -N((C １－ C ３ )Alkyl) ２ , -N(H)(C １－ C ３ ) haloalkyl, -(C １－ C ３ ) alkylene-N((C １－ C ３ )Alkyl) ２ , 【Chemistry 3】 optionally substituted with one or more of; m is 0, 1, 2 or 3; p is 0, 1 or 2; and Each R １０ However, halo and (C １－ C ３ ) alkyl, 4. The compound of claim 2 or 3.

5. R １ but one or more R ８ optionally replaced by (C １－ C ３ ) alkyl; R ８ But, -NR ２ , and (O) ｎ -(4- to 7-membered non-aromatic heterocycle), wherein the 4- to 7-membered non-aromatic heterocycle is selected from halo and (C １－ C ３ ) optionally substituted with one or more alkyl; n is 0 or 1; and Each R is H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl; 2. The compound of claim 1.

6. R １ But, -NR ５ R ６ and R ５ However, H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl, preferably H and (C １－ C ６ ) alkyl, more preferably selected from H and Me; R ６ However, H, (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, and 4- to 7-membered non-aromatic heterocycle, wherein the 4- to 7-membered non-aromatic heterocycle is selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; Preferably, R ６ However, one or more (C １－ C ３ ) a 5- or 6-membered non-aromatic heterocycle optionally substituted with alkyl; 2. The compound of claim 1.

7. R １ But, -OR ４ and R ４ However, (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, (C １－ C ６ ) Alkylene-NR ２ , 4- to 6-membered non-aromatic heterocycles, and 6- to 9-membered heterocyclic spiro systems, wherein the 4- to 6-membered non-aromatic heterocycles and 6- to 9-membered heterocyclic spiro systems are selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; Preferably, R ４ is (C １－ C ３ ) Alkylene-NR ２ , 4- to 5-membered non-aromatic heterocycles, and 7- to 9-membered heterocyclic spiro systems, wherein the 4- to 5-membered non-aromatic heterocycles and 7- to 9-membered heterocyclic spiro systems are selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; and Each R is H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl, preferably each R is H; 2. The compound of claim 1.

8. R １ But -C(O)R ７ and R ７ However, H, (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, -NR ２ and 4- to 7-membered non-aromatic heterocycle, wherein the 4- to 7-membered non-aromatic heterocycle is selected from halo and (C １－ C ６ ) optionally substituted with one or more alkyl; Preferably, where R ７ is a 4- to 7-membered non-aromatic heterocycle, and is one or more (C １－ C ３ ) optionally substituted with alkyl; and Each R is H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl; 2. The compound of claim 1.

9. R ２ But H, halo, (C １－ C ３ ) alkyl, (C １－ C ３ ) haloalkyl, (C １－ C ３ ) alkoxy, (C １－ C ３ ) haloalkoxy, -NR ２ , and -O(C １－ C ６ ) Alkylene-NR ２ , preferably H, halo, (C １－ C ３ ) alkyl, (C １－ C ３ ) haloalkyl, and -NR ２ , more preferably selected from H and halo, most preferably H and F; and R is H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl; A compound according to any one of claims 1 to 8.

10. R ３ but the following: (i) H, halo, (C １－ C ６ ) alkyl, (C １－ C ６ ) haloalkyl, -OR ４ ; (ii) one or more R ９ a 5- to 7-membered non-aromatic heterocycle optionally substituted with (iii) Halo and (C １－ C ３ ) an 8-10 membered spiro or fused heterocyclic ring system optionally substituted with one or more alkyl; Selected from: R ４ However, (C １－ C ６ ) Alkylene-NR ２ , a 4- to 6-membered non-aromatic heterocycle, and a 6- to 8-membered heterocyclic spiro system, wherein each of the 4- to 6-membered non-aromatic heterocycle or the 6- to 8-membered heterocyclic spiro system is selected from one or more (C １－ C ３ ) optionally substituted with alkyl or halo; R ９ But, Halo, (C １－ C ３ ) alkyl, -NR ２ , -NR((C １－ C ３ ) hydroxyalkyl), and (C １－ C ３ ) Alkylene-NR ２ is selected from: Each R is H, (C １－ C ６ ) alkyl, and (C １－ C ６ ) haloalkyl; A compound according to any one of claims 1 to 9.

11. 11. The compound of any one of claims 1 to 10, wherein one of X is N or CH.

12. The compound is represented by the following formulas (II) to (VIII): 【Chemistry 4】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, enantiomer, diastereoisomer, isotopic form, N-oxide, and / or prodrug thereof, preferably a compound of formula (II) or formula (III), wherein R １ , R ２ , and R ３ A compound according to any one of claims 1 to 11, wherein is as defined in any one of claims 1 to 10.

13. The compound is selected from the group consisting of: 5-((1-(4-(6-methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-chloro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-fluoro-1-methylpiperidin-4-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)-6-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((4-methylpiperazin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-((1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2,4-dimethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(6-(4-methyl-1,4-diazepan-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(((4-fluoro-1-methylpyrrolidin-3-yl)oxy)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-chloro-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-ethylpiperazin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-methyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylpiperazin-1-yl)-2-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2,4-dimethylpiperazin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)azetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(4-methyl-1,4-diazepan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(5-methyl-2,5-diazaspiro[3.4]octan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(methyl((1-methylpiperidin-4-yl)methyl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-ethyl-2-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-ethylpiperidin-4-yl)amino)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(5-methyl-2,5-diazabicyclo[2.2.2]octan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(methyl(1-methylpiperidin-4-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-(tert-butyl)azetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(6-methyl-2,6-diazaspiro[3.3]heptan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((1-propylazetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-propylazetidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-([1,3'-bipyrrolidin]-1'-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyrazin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((1-(tert-butyl)azetidin-3-yl)oxy)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2-methyl-6-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((-4-fluoro-1-methylpyrrolidin-3-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2,6-dimethylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-(dimethylamino)pyrrolidin-1-yl)-4-methylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-6-methylpyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(8-methyl-2,8-diazaspiro[4.5]decan-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methyl-1,6-diazaspiro[3.3]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-3-(dimethylamino)-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(6-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-3-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2-((dimethylamino)methyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-3-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-(trifluoromethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-morpholinopyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-3-(dimethylamino)-4-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-4-(dimethylamino)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)-4-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)-6-(trifluoromethyl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)-3-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)pyrrolidin-1-yl)-3-fluorophenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-fluoro-4-(3-methyl-3,6-diazabicyclo[3.2.0]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyrimidin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-(dimethylamino)-4-(3-(dimethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(Bis(methyl-d3)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(-4-(dimethylamino)-2-methylpyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(-3-(dimethylamino)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methylhexahydropyrrolo[3,4-b]pyrrol-5(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(ethylamino)-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(ethyl(methyl)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(ethyl(methyl)amino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylhexahydropyrrolo[3,2-b]pyrrol-1(2H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-fluoro-4-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-((3,3,3-trifluoropropyl)amino)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(methyl(1-methylpyrrolidin-3-yl)amino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(isopropylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3,3,4-trimethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(azetidin-1-yl)-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(6-methyl-1,6-diazaspiro[3.3]heptan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methyl-1,7-diazaspiro[3.5]nonan-7-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(5-(3-(azetidin-1-yl)pyrrolidin-1-yl)pyridin-2-yl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)-3-methylphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylmorpholin-2-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(2-((dimethylamino)methyl)morpholino)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-((2-hydroxyethyl)(methyl)amino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(azetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-((dimethylamino)methyl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(6-methyl-1,6-diazaspiro[3.4]octan-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(dimethylamino)piperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(3,3-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(3-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methyl-1,6-diazaspiro[3.4]octan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(3-fluoroazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(2-azaspiro[3.3]heptan-2-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(3-isopropylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(2-methylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(2,2-dimethylazetidin-1-yl)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 1-(4-(4-((5-cyanopyrazin-2-yl)amino)-1H-imidazol-1-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine oxide 5-((1-(4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-methylpiperazine-1-carbonyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methyl-4-(4-methylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-([1,3'-bipyrrolidin]-1'-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(3-aminopropoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-(3-aminopropoxy)-6-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(2-aminoethoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-aminopyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(7-amino-5-azaspiro[2.4]heptan-5-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-amino-3-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-amino-4-fluoropyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(aminomethyl)azetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(aminomethyl)-3-fluoroazetidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1,6-diazaspiro[3.3]heptan-6-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3,6-diazabicyclo[3.2.0]heptan-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-(ethylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-methoxy-4-(methylamino)pyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(3-fluoro-4-(methylamino)pyrrolidin-1-yl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-amino-2-methylpyrrolidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-(4-amino-3,3-difluoropiperidin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-(3-aminopropoxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((3-fluoropyrrolidin-1-yl)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile) 5-((1-(4-((ethylamino)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(pyrrolidin-1-ylmethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((4,4-difluoropiperidin-1-yl)methyl)-2-methoxyphenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-(morpholinomethyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((4-fluoropiperidin-1-yl)methyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(3-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-methylazetidin-3-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(9-methyl-3-oxa-7,9-diazabicyclo[3.3.1]nonan-7-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(1-(diethylamino)cyclopropyl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(2-methoxy-4-((2-methyl-2-azaspiro[3.3]heptan-6-yl)oxy)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(3,3-difluorocyclobutyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(oxetan-3-yl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(2-fluoroethyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-(3,3,3-trifluoropropyl)piperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-ethylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 5-((1-(4-(4-isopropylpiperazin-1-yl)phenyl)-1H-imidazol-4-yl)amino)pyrazine-2-carbonitrile 10. The compound of claim 1, wherein:

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and an excipient.

15. A compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 for use as a medicament.

16. A compound according to any one of claims 1 to 13 or a pharmaceutical composition according to claim 14 for use in the treatment of cancer.

17. 14. Use of a compound according to any one of claims 1 to 13 in the manufacture of a medicament for use in the treatment of cancer.

18. 15. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 13 or a pharmaceutical composition of claim 14.

19. 19. The compound or pharmaceutical composition for use according to claim 16, the use of the compound according to claim 17, or the method of treatment according to claim 18, wherein the cancer is CNS cancer (including glioblastoma multiforme, glioma, neuroblastoma, medulloblastoma, DIPG and secondary brain tumors such as brain metastases), sarcoma (including osterosarcoma, rhabdomyosarcoma, Kaposi's sarcoma, leiomyosarcoma), ovarian cancer (including high-grade serous ovarian cancer), lung cancer (including small cell lung cancer and non-small cell lung cancer), breast cancer, endometrial cancer, prostate cancer, pancreatic cancer, renal cell carcinoma, colorectal cancer (including colon cancer, rectal cancer, and anal cancer), gastrointestinal cancer (including gastric cancer), thyroid cancer, bladder cancer, kidney cancer, melanoma, squamous cell carcinoma (including squamous cell carcinoma of the head and neck), leukemia, or lymphoma.

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