Halo-substituted aminoazaheteroaryl compounds as inhibitors of hematopoietic progenitor kinase 1 (HPK1)

Abstract

The present application relates to halo-substituted aza-heteroaryl compounds of formula (I) or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof: TIFF2024516253000822.tif71100 The present invention relates to compositions comprising these compounds or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof, as well as to various uses in the treatment of diseases, disorders, or conditions treatable by inhibiting HPK1, such as cancer.

Description

[Technical Field]

[0001] This application relates to halo-substituted aminoazaheteroaryl compounds, methods for producing halo-substituted aminoazaheteroaryl compounds, compositions containing halo-substituted aminoazaheteroaryl compounds, and their use in therapy. More specifically, this application relates to halo-substituted aminopyrazines. derivative and halo-substituted amino acids Pyridazine This invention relates to halo-substituted azaheteroaryl compounds, such as derivatives, that are useful for treating diseases, disorders, or conditions that can be treated by inhibiting HPK1. [Background technology]

[0002] This application claims priority to the co-pending U.S. Provisional Patent Application No. 63 / 182,249, filed on 30 April 2021, the contents of which the entirety of said U.S. Provisional Patent Application are incorporated by reference into this disclosure.

[0003] Tumors are generally heterogeneous and have evolved mechanisms that hijack cell growth and regulatory pathways, which means that a single factor is influencing patient survival. therapyThe likelihood of significant effects is low. For this reason, immunotherapy has become an important paradigm in the treatment of several types of cancer. Immune effector cells such as T cells and B cells can suppress the proliferation of cancer cells by targeting abnormal antigens expressed in tumors. For example, recent clinical trials of novel immunotherapy strategies (e.g., anti-PD1 and anti-PDL1) have shown unprecedented and long-lasting survival benefits, even in patients with advanced metastatic cancer. However, the overall excitement about this therapeutic approach is dampened by the observation that these responses to PD-1 axis-targeted agents are limited to a minority of cancer patients. Therefore, in order to broaden the response rate in cancer patients, there is an urgent need to more rapidly test rational combinations of small molecules and immunotherapies, based on the great potential of immunotherapy. One such approach is the combination of the small molecule hematopoietic precursor kinase 1 (HPK1) with modern anti-PD1 / PDL1 immunotherapies. HPK inhibitors enhance the anti-tumor immune response by stimulating T cell proliferation and inducing T cells to age cancer cells and eliminate tumors.

[0004] Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a proximal kinase of the T cell receptor (TCR) involved in regulating the proliferation and survival of primary T cells [Nat Immunol. 2007;8(1):84-91.]. HPK1 is expressed only in hematopoietic tissue and activates the c-Jun N-terminal kinase (JNK) and NF-κB pathway [7]. Transient knockdown of HPK1 in T cells blocks NF-κB activation [Crit Rev Oncol Hematol. 2008; 66(1):52-64]. Most notably, mice adopted from HPKI(- / -) T cells became resistant to lung tumor growth [Immunol Res. 2012; 54(1-3):262-5]. HPK1 possesses an N-terminal kinase domain and a C-terminal citron homology domain. Cross-linking of antigens and receptors leads to the activation of HPK1 in T and B cells, resulting in the rearrangement of HPK1 to the cell membrane, autophosphorylation, and transphosphorylation by protein kinase D1 (PKD1). Subsequent transphosphorylation and autophosphorylation by PKD1 within the kinase domain result in complete activation of HPK1, which then regulates various cellular responses, including apoptosis, activation-induced cell death, and autoimmunity. HPK1 also plays a role in immune responses through phosphorylation of SL-76 (S376). negativeIt mediates the control of [unclear]. A mutation from lysine 46 to methionine at the ATP binding site of the kinase domain (represented as HPK1-M46) causes loss of catalytic activity of HPK1, resulting in a full-length kinase version in which the kinase is dead [Genes Dev. 1996; 10 (18):2251-64]. Inhibition of HPK1 in knock-in mice in which the HPKI kinase is dead shows improved efficacy in colon cancer models when treated with anti-PD-1 or anti-PDL1 antibodies compared to anti-PD-1 or anti-PDL1 treatment alone (Cell Reports 2018, 25, 80-94, and PCT patent application publication numbers WO2016 / 205942 and WO2016 / 090300). Combining or sequencing with immunotherapies targeting separate immune pathways is therefore a reasonable strategy to increase the intensity of the antitumor immune response compared to that produced with monotherapy.

[0005] HPK1 plays a crucial role in regulating lymphocyte receptor signaling and function. Furthermore, the restricted expression of HPK1 in hematopoietic cells and its role in immune cells suggest that HPK1 would be an ideal drug target for enhancing anti-tumor immunity. In addition, data from preclinical studies indicate that targeted disruption of the HPK1 gene affects various immune cells (e.g., T cells, NK cells, and dendritic cells). condition It can promote the proliferation, survival, and function of cells (DCs), and it is suggested that it synergistically inhibits tumor growth when combined with anti-PD-1 / PDL-1 monoclonal antibodies. Support for this strong theoretical interpretation is evident from several reports in the literature in which knock-in mice in which HPK1 kinase carrying colorectal tumor (MC38) was dead showed significant growth arrest upon treatment with anti-PD1 or anti-PDL1 antibodies (PCT Patent Application Publication No. WO2016 / 090300). Therefore, combining small molecules that inhibit HPK1 with other immunotherapies appears to be a rational and more effective approach toward the treatment of cancer.

[0006] Therefore, inhibiting kinases such as HPK 1 represents a promising target for immuno-oncology due to the role of these kinases in restricting T cell activation. At the same time, in exploring these targets, it is desirable to have selectivity among other kinases involved in robust T cell activation. Examples of such kinases include, but are not limited to, LcK (Sawasdikosol, et. al. Structure 27, 2019, 1-3).

Summary of the Invention

[0007] Modern cancer immunotherapy strategies seek to overcome immune tolerance by modulating T cell co-receptor signaling or boosting the recognition of tumor-associated antigens by using native biomolecules or monoclonal antibodies. Selective HPK1 inhibitors enhance the anti-tumor activity of immune cells when combined with other immunomodulators. This application discloses novel compounds having such activity.

[0008] Therefore, this application encompasses compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof.

Chemical formula

[0009] This application also includes compositions comprising one or more of the compounds of this application and carriers. In some embodiments, the composition is a pharmaceutical composition comprising one or more of the compounds of this application and pharmaceutically acceptable carriers.

[0010] In some embodiments, the compounds of this application are used as pharmaceuticals. Therefore, this application also includes the compounds of this application for use as pharmaceuticals.

[0011] The compound of this application has been shown to inhibit HPK1. Therefore , book The compounds of the Application are useful for treating diseases, disorders, or conditions that can be treated by inhibiting HPK1 activity. Accordingly, the Application also includes a method for treating diseases, disorders, or conditions that can be treated by inhibiting HPK1, which involves administering one or more of the Compounds of the Application in a therapeutically effective amount to cells or subjects in need of treatment.

[0012] This application also includes the use of one or more of the compounds of this application for the treatment of diseases, disorders or conditions treatable by inhibiting HPK1, and the use of one or more of the compounds of this application for the preparation of pharmaceuticals for the treatment of diseases, disorders or conditions treatable by inhibiting HPK1. This application further includes one or more of the compounds of this application for use in the treatment of diseases, disorders or conditions treatable by inhibiting HPK1.

[0013] In a further embodiment, the disease, disorder, or condition treatable by inhibiting HPK1 is cancer, and the one or more compounds of the present application are administered in combination with one or more additional cancer treatments. In another embodiment, the additional cancer treatments include targeted therapies such as radiotherapy, chemotherapy, antibody therapy, and tyrosine kinase inhibitors. Small molecule therapies such as , immunotherapy, hormone therapy and anti-angiogenic therapy Law Selected ru. Separate In one embodiment, the additional cancer treatment is selected from antibodies that bind to PD-1 or PDL-1.

[0014] This application further provides a process for preparing the compounds of this application. The general and specific processes will be described in more detail in the examples below.

[0015] Other features and advantages of the present application will become apparent from the following detailed description. However, it should be understood that the detailed description and specific examples, while illustrating embodiments of the present application, are provided only as examples, and the claims should not be limited by these embodiments, but rather given the broadest interpretation consistent with the entire specification. [Modes for carrying out the invention]

[0016] I. Definition Unless otherwise noted, the definitions and embodiments described in this section and other sections are intended to be applicable to all embodiments and aspects of the Application described herein, as will be understood by those skilled in the art to be suitable.

[0017] All features disclosed herein, including the claims, abstract, and drawings, and all steps in any disclosed method or process, may be combined in any combination, except for any combination in which at least some of such features and / or steps are mutually exclusive. Each feature disclosed herein, including the claims, abstract, and drawings, may also be replaced by alternative features serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0018] The words “comprising” (and any form of “comprising,” e.g., “comprising” (present tense) (with or without the third-person singular s), “having” (and any form of “having,” e.g., “having” (present tense) (with or without the third-person singular s), “including” (and any form of “including,” e.g., “comprising” (present tense) (with or without the third-person singular s)), and “containing” (and any form of “containing,” e.g., “containing” (present tense) (with or without the third-person singular s)) are inclusive and open, and do not exclude additional, undescribed elements or process steps.

[0019] The terms "consisting of" and their derivatives as used in this disclosure are intended to be closed terms that identify the presence of described features, elements, components, groups, integers, and / or steps, and exclude the presence of other features, elements, components, groups, integers, and / or steps that are not described.

[0020] Where used in this disclosure, the term "essentially" is intended to identify the presence of any feature, element, component, group, integer, and / or step described, and any that does not substantially affect the basic and novel properties (one or more) of these features, elements, components, group, integer, and / or step.

[0021] Terms of degree such as “about,” “substantially,” and “approximately” mean a reasonable amount of deviation of the modified word such that the final result is not significantly changed. These terms of degree should be interpreted as including a deviation of at least ±5% from the modified word, provided that the deviation does not negate the meaning of the word it modifies or the context does not suggest a different interpretation to a person skilled in the art.

[0022] When used in this application, the singular forms "a," "an," and "the" also include multiple subjects unless the context clearly indicates otherwise. For example, an embodiment including "a compound" should be understood to present a configuration having one compound, or a configuration having two or more additional compounds.

[0023] In embodiments including an “additional” or “second” component or effect, such as an additional or second compound, the second compound as used in this disclosure is chemically different from the other compounds or the first compound. The “third” compound is different from the other first and second compounds, and any further listed or “additional” compounds are similarly different.

[0024] Where used in this disclosure, the term “and / or” means that the listed items exist or are used individually or in combination. Substantively, the term means that “at least one” or “one or more” of the listed items are used or exist. With respect to the enantiomers, prodrugs, salts and / or solvates, the term “and / or” means that the compounds of the Application exist as individual enantiomers, prodrugs, salts and solvates, as well as in combination, such as salts of solvates of the compounds of the Application.

[0025] As used in this disclosure, the term “compounds of the application” and similar terms refer to compounds of formula I or formulas IA, IB, IC, ID, IE, IF, IG, IH, IJ, IK, IL, IM, IN, IO, IP, IQ, IR, IS, IT, and IU, or their salts, solvates, and / or prodrugs.

[0026] As used in this disclosure, the term "Composition of the Application" and similar terms refer to a composition comprising one or more of the Compounds of the Application.

[0027] As used in this disclosure, the term “suitable” (or “preferred”) means that the selection of a particular compound or condition depends on the specific synthetic operation to be performed, what the molecule(s) to be transformed is, and / or the specific use of the compound, but the selection is well within the scope of the skills of those skilled in the art.

[0028] This specification refers to many chemical terms and abbreviations used by those skilled in the art. However, for clarity and consistency, definitions of selected terms are provided.

[0029] As used in this disclosure, the terms “protecting group” or “PG” and similar terms refer to a chemical part that protects or masks a reactive part of a molecule to prevent side reactions in those reactive parts of the molecule while different parts of the molecule are being manipulated or reacted. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not destroy or decompose the rest of the molecule. The selection of an appropriate protecting group can be made by those skilled in the art. Many conventional protecting groups are known in the art, for example, “Protective Groups in Organic Chemistry” McOmie, JFW Ed., Plenum Press, 1973, in Greene, TWand Wuts, PGM, “Protective Groups in Organic Synthesis”, JohnWiley & Sons, 3 rd This is mentioned in the 1999 edition and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0030] As used in this disclosure, the term “inert organic solvent” refers to a solvent that is generally considered to be nonreactive with the functional groups present in the compound being bonded in any given reaction, and therefore does not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically nonpolar and dissolve compounds that are insoluble in aqueous solutions.

[0031] As used in this disclosure, the term "alkyl," whether used alone or as part of another group, means a linear or branched saturated alkyl group. The number of carbon atoms possible in the alkyl group of interest is determined by the prefix "C n1~n2 It is represented by "C". For example, the term "C 1~10 "Alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. All alkyl groups are optionally fluorosubstituted.

[0032] The term "alkylene," whether used alone or as part of another group, refers to a linear or branched saturated alkylene group, that is, a saturated carbon chain containing substituents at two of its ends. The number of possible carbon atoms in the alkylene group of interest is indicated by the prefix "C". n1~n2 This is indicated by the term "C 2~6 "Alkylene" refers to an alkylene group having two, three, four, five, or six carbon atoms. All alkylene groups are optionally fluorosubstituted.

[0033] As used in this disclosure, the term "alkenyl," whether used alone or as part of another group, means a linear or branched unsaturated alkyl group containing at least one double bond. The number of carbon atoms possible in the alkylene group of interest is determined by the prefix "C". n1~n2 It is represented by ". Therefore, for example, the term "C 2~6 An "alkenyl" refers to an alkenyl group having two, three, four, five, or six carbon atoms and at least one double bond. All alkenyl groups are optionally fluorosubstituted.

[0034] As used in this disclosure, the term "alkynyl," whether used alone or as part of another group, means a linear or branched unsaturated alkynyl group containing at least one triple bond. The number of carbon atoms possible in the alkyl group of interest is determined by the prefix "C". n1~n2 It is represented by ". For example, term C 2~6 Alkynyl refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. All alkynyl groups are optionally fluorosubstituted.

[0035] As used in this disclosure, the term "cycloalkyl," whether used alone or as part of another group, means a saturated carbocyclic group containing 3 to 20 carbon atoms and one or more rings. The number of carbon atoms possible in the cycloalkyl group of interest is determined by the prefix "C n1~n2 It is represented by ". For example, term C 3~10 A cycloalkyl group refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. All cycloalkyl groups are optionally fluorosubstituted.

[0036] As used in this disclosure, the term "aryl," whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring and comprising 6 to 20 carbon atoms. All aryl groups are optionally fluorosubstituted.

[0037] As used in this disclosure, the term “heterocycloalkyl” refers to a cyclic group comprising at least one non-aromatic ring containing 3 to 20 atoms, where one or more of the atoms are heteroatoms selected from O, S, and N, and the remaining atoms are C, whether used alone or as part of another group. The heterocycloalkyl group may be saturated or unsaturated (i.e., containing one or more double bonds). The heterocycloalkyl group is prefixed with C. n1~n2 When this prefix is ​​included, it represents the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1 to 5, of the ring atoms are replaced by heteroatoms selected from O, S, and N, and the remaining atoms are C. The heterocycloalkyl group is optionally benzo-fused. The heteroatoms in the heterocycloalkyl group are optionally substituted or oxidized, if their valence allows. All heterocycloalkyl groups are optionally fluoro-substituted.

[0038] As used in this disclosure, the term "heteroaryl," whether used alone or as part of another group, refers to a cyclic group comprising at least one heteroaromatic ring containing 5 to 20 atoms, wherein one or more of the atoms are heteroatoms selected from O, S, and N, and the remaining atoms are C. is connected Acronym C n1~n2 When this prefix is ​​included, it represents the number of carbon atoms in the corresponding carbocyclic group, where one or more of the ring atoms, preferably 1 to 5, are replaced by heteroatoms selected from O, S, and N, and the remaining atoms are C. The heteroaryl group is optionally benzo-fused. The heteroatoms in the heteroaryl group are optionally substituted or oxidized, if their valence allows. All heteroaryl groups are optionally fluoro-substituted.

[0039] As used in this disclosure, the term "aza-heteroaryl," whether used alone or as part of another group, refers to a heteroaryl group having only two or more nitrogen atoms as heteroatoms in the group. All aza-heteroaryl groups are optionally fluorosubstituted.

[0040] All cyclic groups, including aryl groups, heteroaryl groups, heterocycloalkyl groups, and cycloalkyl groups, may contain one or more rings (i.e., polycyclic). If a cyclic group contains multiple rings, those rings may be fused, bridged, spirofused, or linked by bonds.

[0041] As used in this disclosure, the term "benzo-fused ring" refers to a polycyclic group in which a benzene ring is fused with another ring.

[0042] The first ring is said to be "fused" with the second ring to mean that the first and second rings share two adjacent atoms between them.

[0043] The statement that the first ring "bridges" the second ring means that the first and second rings share two non-adjacent atoms between them.

[0044] The first ring is said to be "spiro-fused" with the second ring, meaning that the first and second rings share one atom with each other.

[0045] The term "fluorosubstituted" refers to a situation where one or more (or all) of the available hydrogen atoms in the group of interest are replaced by fluorine.

[0046] As used in this disclosure, the terms "halo" or "halogen," whether used alone or as part of another group, refer to a halogen atom and include fluoro, chloro, bromo, and iodine.

[0047] In the terms "available hydrogen atom" or "available atom," the term "available" refers to an atom that would be known to those skilled in the art to be replaceable by substituents.

[0048] When it is stated that a group is substituted by multiple substituents, these substituents are independently selected and therefore may be the same or different.

[0049] As used in this disclosure, the term “cross-coupling” refers to a chemical reaction in which two different starting materials, each typically possessing an activating group, react with each other with the help of a metal catalyst. The result is the loss of two activating groups and the formation of a new covalent bond between the remaining fragments.

[0050] As used in this disclosure, the term “cell” means a single cell or a group of cells, and includes cells in a cell culture medium or cells within a subject.

[0051] As used in this disclosure, the term “Subject” includes all members of the animal kingdom, including mammals, and preferably refers to humans. Therefore, the methods and uses of this application are applicable to both human therapeutic and veterinary applications.

[0052] The term "medically acceptable" means suitable for the treatment of a subject, such as a human being.

[0053] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with an active ingredient to enable the formation of a pharmaceutical composition, i.e., a dosage form that can be administered to a subject.

[0054] The term "medically acceptable salt" refers to an acid-addition salt or base-addition salt that is suitable or appropriate for the treatment of the subject.

[0055] As used in this disclosure, the term “solvate” means a compound or a salt and / or prodrug of a compound in which molecules of a suitable solvent are incorporated into the crystal lattice. The suitable solvent is physiologically acceptable at the administered dose.

[0056] As used in this disclosure, the term “prodrug” means a compound that is converted into an active drug after administration, or a salt and / or solvate of such a compound.

[0057] As used in this disclosure, the terms “to treat” or “treatment” mean a method for obtaining beneficial or desired outcomes, such as clinical outcomes, as is well known in the art. Beneficial or desired clinical outcomes may include, but are not limited to, the reduction or improvement of one or more symptoms or conditions, a decrease in the severity of the disease, a stabilized (i.e., non-worsening) state of the disease, prevention of disease spread, delay or slowing of disease progression, improvement or mitigation of the disease condition, a reduction in disease recurrence, and remission (whether partial or complete), and may be detectable or undetectable. “To treat” and “treatment” may also mean an extended survival time compared to the expected survival time without treatment. As used in this disclosure, “to treat” and “treatment” also include preventive measures. For example, a subject with early-stage cancer may be treated to prevent progression, or a subject in remission may be treated with the compound or composition of the application to prevent recurrence. The treatment method comprises administering one or more of the compounds of this application in a therapeutically effective amount, and optionally consists of a single administration or a series of administrations.

[0058] To “palliate” a disease or disorder means that the degree of the disorder or disease state and / or undesirable clinical findings are reduced and / or the time course of progression is slowed or prolonged compared to when the disorder is left untreated.

[0059] When used in this disclosure , book As used in this disclosure, the terms “prevention” or “prevention,” or their synonyms, refer to a reduction in the risk or probability that a patient will suffer from or exhibit symptoms associated with a treatable disease, disorder, or condition by inhibiting HPK1.

[0060] As used in this disclosure, the terms “effective dose” or “therapeutic dose” mean the amount of one or more of the Compounds of the Application that is effective in the dosage and duration required to achieve the desired result.

[0061] As used in this disclosure, the expression "inhibit HPK1" means inhibiting, blocking, and / or destroying HPK1 enzyme activity in cells, particularly in T cells or B cells. Such inhibition, blocking, and / or destruction produces a therapeutic effect in said cells.

[0062] "Inhibition, blocking, and / or destruction" means any detectable inhibition, blocking, and / or destruction in the presence of the compound compared to the case where the compound is not present under otherwise identical conditions.

[0063] The term “diseases, disorders, or conditions treatable by inhibiting HPK1” means that the diseases, disorders, or conditions to be treated are directly or indirectly affected, modulated, and / or have some biological basis involving HPK1 activity, particularly increased HPK1 activity. These diseases preferably respond when the HPK1 activity associated with the disease, disorder, or condition is inhibited by one or more of the compounds or compositions of this application.

[0064] As used in this disclosure, the term "HPK1" refers to hematopoietic progenitor kinase 1.

[0065] As used in this disclosure, the term “administered” means administering a therapeutically effective amount of a compound of the Application, or one or more compounds of the Application, or a composition of the Application, to cells in a cell culture or subject.

[0066] As used in this disclosure, the term “neoplastic disorder” means a disease, disorder, or condition characterized by cells having the ability to grow or replicate autonomously, such as an abnormal condition or state characterized by proliferative cell growth. As used in this disclosure, the term “neoplasm” means a mass of tissue resulting from abnormal cell proliferation and / or division in an object having a neoplastic disorder. A neoplasm may be benign (e.g., uterine fibroids and pigmented nevi), potentially malignant (carcinoma in situ), or malignant (i.e., cancer).

[0067] As used in this disclosure, the term "cancer" refers to a proliferative disease.

[0068] As used in this disclosure, the term “effective dose” means an effective dose and duration required to achieve the desired result.

[0069] II. Compounds and Compositions This application describes a new class of halo-substituted aminoaza-heteroaryl HPK1 inhibitors.

[0070] Therefore, this application encompasses compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: X 1 N and CR 1 Selected from; X 2 and X 3 N and CR 2 Selected independently from; X 4 and X 5 One of them is N, and the other is CR 3 and; Q is O, S, S(O), SO2, and NR 4 Optionally, a heteroatom selected from is interrupted, and / or one or more R 5 Optionally substituted and / or one carbon is R 5a and R 5b C is optionally substituted by 1~4 It is an alkylene; however, if Q includes the heteromolecule, the heteromolecule is not separated from the ring amide NH by a methylene group; or, Q is one or more R 5c C is optionally replaced 2~4 Alkenirene is; or, Q is optionally selected from C=N and N=C, and R 5c It is optionally replaced by; R 1 H, Halo, OR 6 , NR 7 R 8 , C 1~6 Alkylene NR 7 R 8 and C 1~6 Selected from alkyl groups; R 2 H, Halo, and C 1~6 Selected from alkyl groups; R 3 is a halo; R 4 H and C 1~6 Selected from alkyl groups; Each R 5 is =O, halo, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~6 Alkilen C 3~6Cycloalkyl, C 1~6 Alkilen C 3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl, NR 9 R 10 and C 1~6 Alkylene NR 9 R 10 Selected independently from; R 5a and R 5b They bond together, and together with the carbon atoms between them, form N, NH, NC 1~6 It optionally contains one heteromoon selected from alkyl, O, S, SO, and SO2, and also contains a halo and C 1~6 A 3-6 member molecule optionally substituted with one or more alkyl groups. Saturated or unsaturated Forming a ring; Each R 5c Hello, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~6 Alkilen C 3~6 Cycloalkyl, C 1~6 Alkilen C 3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl NR 9 R 10 , and C 1~6 Alkylene NR 9 R 10 Selected independently from; R 6 H and C 1~6 Selected from alkyl groups; R 7 , R 8 , R 9 and R 10 H and C 1~6 Independently selected from alkyl groups; or, R 7 and R 8 , or R 9 and R 10 , bond together with the nitrogen atom between them, forming a 3-7 member group Saturated or unsaturated A ring of N, NH, NC 1~6It optionally includes one additional heteromoon selected from alkyl, O, S, S(O), and SO2, and also includes a halo and C 1~6 Forming a ring optionally substituted with one or more alkyl groups; Cy 1 C 6~20 Aryl or C 5~20 It is a heteroaryl, and also Cy 1 It is either unsubstituted or has one or more R 11 It is replaced by, or Cy 1 Z-Cy 2 It is replaced by, or Cy 1 is Z-Cy 2 and one or more R 11 Replaced by; Each R 11 is Halo, =O, CN, NO2, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, OR 12 , C(O)R 12 CO2R 12 P(O)R 12 R 13 , P(O)(OR 12 )(OR 13 ), SR 12 SOR 12 SO2R 12 , S(O)(=NR 13 )R 12 SO2NR 12 R 13 , SiR 14 R 14a R 14b , C 1~6 Alkilen OR 12 , OC 1~6 Alkilen OR 12 、 C 1~6 Alkylene NR 12a R 13a , OC 1~6 Alkylene NR 12 R 13 , NR 13a C1~6 Alkylene NR 12 R 13 , NR 13a C 1~6 Alkilen OR 12 , NR 12a R 13a , NR 13a COR 12 , NR 13a CO2R 12 , NR 13a SO2R 12 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~6 Alkilen C 3~7 Cycloalkyl and C 1~6 Alkilen C 3~7 Independently selected from heterocycloalkyl groups, the latter four groups are one or more R groups. 15 It is optionally replaced by; R 12 H, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen OR 16 , and C 1~6 Alkylene NR 16a R 16b Selected from, and also R 12 The alkyl group, alkenyl group, alkynyl group, alkylene group, heterocycloalkyl group, and cycloalkyl group are one or more R 17 It is optionally replaced by; R 13 H and C 1~6 Selected from alkyl groups; or, R 12 and R 13 They bond together, and together with the atoms (one or more) between them, form a 4-6 member group. Saturated or unsaturated A ring of N, NR 18, optionally including one additional heterocomponent selected from O, S, SO, and SO2, and one or more R 17 Forms a ring which is optionally substituted by; R 12a H, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen OR 16 , and C 1~6 Alkylene NR 16a R 16b Selected from, and also R 12a All alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, heterocycloalkyl groups, and cycloalkyl groups are one or more R 17 It is optionally replaced by; R 13a H and C 1~6 Selected from alkyl groups; R 14 , R 14a , and R 14b is OR 19 , C 1~6 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 3~10 Cycloalkyl, and C 1~6 Alkilen C 3~10 Independently selected from heterocycloalkyl groups; Each R 15 Halo, OH, C 1~6 Alkyl, OC 1~6 Alkyl, CN, and NR 15a R 15b Selected independently from; R 15a and R 15b H and C 1~6 Selected independently from alkyl; R16 , R 16a and R 16b H and C 1~6 Selected independently from alkyl; Each R 17 Hello, C 1~6 Alkyl, CN, and NR 17a R 17b Selected independently from; R 17a and R 17b H and C 1~6 Selected independently from alkyl; R 18 H and C 1~6 Selected from alkyl groups; R 19 H, C 1~6 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen OR 20 , and C 1~6 Alkylene NR 20 R 21 Selected from; R 20 and R 21 H and C 1~6 Selected independently from alkyl; Z does not exist, or C 1~6 Alkylene, O, C(O), CO 2、 S, S(O), SO 2、 S(O)(=NR 13b ) and NR 13b , C 1~6 Alkylene O, C 1~6 Alkylene C(O), C 1~6 Alkylene CO2 2、 C 1~6 Alkilen S, C 1~6 Alkylene S(O), C 1~6 Alkylene SO2, C 1~6 Alkylene S(O)(=NR) 13b ), C 1~6 Alkylene NR13b , OC 1~6 Alkylene, C(O)C 1~6 Alkylene, CO2C 1~6 Alkiren, SC 1~6 Alkylene, S(O)C 1~6 Alkylene, SO2C 1~6 Alkylene, S(O)(=NR) 13b )C 1~6 Alkylene and NR 13b C 1~6 Selected from alkylenes; R 13b H and C 1~6 Selected from alkyl groups; Cy 2 C 3~14 Cycloalkyl and C 3~14 Selected from heterocycloalkyl, and also Cy 2 It is either unsubstituted or has one or more R 22 It has been replaced with; Each R 22 Halogen, =O, CN, OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~11 Ariel, C 5~14 Heteroaryl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 6~11 Ariel, C 1~6 Alkilen C 5~14 Heteroaryl, OC 1~6 Alkyl, OC 2~6 Alkenyl, OC 2~6 Alkinyl, C 1~6 Alkilen OR 23 , OC 1~6 Alkilen OR 23 , C 1~6 Alkylene NR 24 R 25 , OC 1~6 Alkylene NR 24R 25 SC 1~6 Alkyl, SC 2~6 Alkenil, SC 2~6 Alkinyl, C(O)C 1~6 Alkyl, C(O)C 2~6 Alkenyl, C(O)C 2~6 Alkinyl, C(O)C 3~10 Cycloalkyl, C(O)C 3~10 Heterocycloalkyl, C(O)C 6~11 Aryl, C(O)C 5~14 Heteroaryl, C(O)C 1~6 Alkilen C 3~10 Cycloalkyl, C(O)C 1~6 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~6 Alkilen C 6~11 Aryl, C(O)C 1~6 Alkilen C 5~14 Heteroaryl, C(O)C 1~6 Alkilenyl OR 23 , C(O)C 1~6 Alkylene NR 24 R 25 , C(O)C 1~6 Alkilen OC 1~6 Alkylene NR 24 R 25 , C(O)NR 24 R 25 CO2C 1~6 Alkyl, CO2C 2~6 Alkenyl, CO2C 2~6 Alkinyl, CO2C 1~6 Alkilen OR 23 CO2C 1~6 Alkilen OC 1~6 Alkylene NR 24 R 25 , NR 24 R 25 , NR 26 C 3~10 Cycloalkyl, NR 26 C 3~10 Heterocycloalkyl, NR 26 C 1~6 Alkilen OR 23 , NR 26 C 1~6Alkylene NR 24 R 25 , NR 26 C 1~6 Alkilen C 3~10 Cycloalkyl, NR 26 C 1~6 Alkilen C 3~10 Heterocycloalkyl, NR 26 C 1~6 Alkilen C 6~11 Ariel, NR 26 C 1~6 Alkilen C 5~14 Heteroaryl, NR 26 SO2C 1~6 Alkyl, SO2C 1~6 Alkyl, SO2C 2~6 Alkenyl, SO2C 2~6 Alkinyl and SO2NR 24 R 25 Selected independently from, and also R 22 The alkyl group, alkenyl group, alkynyl group, alkylene group, aryl group, heteroaryl group, heterocycloalkyl group, and cycloalkyl group are one or more R 27 It is optionally replaced by; R 23 H, C 1~6 Alkyl, C 1~6 Alkilen OC 1~6 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~11 Ariel, C 5~14 Heteroaryl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 6~11 Aryl, and C 1~6 Alkilen C 5~14 Selected from heteroaryls; R 24 H and C 1~6 Selected from alkyl groups; R25 H, C 1~6 Alkyl, C 1~6 Alkilen OC 1~6 Alkyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~11 Ariel, C 5~14 Heteroaryl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 6~11 Aryl, and C 1~6 Alkilen C 5~14 Selected from heteroaryls, or R 24 and R 25 They bond together, and together with the nitrogen atom between them, N, NR 28 , optionally including one additional heterogroup selected from O, S, S(O), and SO2, and also containing a halo and C 1~6 A 4-6 member molecule optionally substituted with one or more alkyl groups. Saturated or unsaturated Forming a ring; R 26 H and C 1~6 Selected from alkyl groups; Each R 27 Hello, C 1~6 Alkyl, CN, and NR 27a R 27b Selected independently from; and R 27a , R 27b , and R 28 H and C 1~6 Selected independently from alkyl; Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

[0071] This application also includes compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof. [ka] During the ceremony: X 1 N and CR 1 Selected from; X 2 and X 3 N and CR 2 Selected independently from ; X 4 and X 5 One of them is N, and the other is CR 3 and; Q is O, S, S(O), SO2, and NR 4 Optionally, a heteroatom selected from is interrupted, and / or one or more R 5 Optionally substituted and / or one carbon is R 5a and R 5b C is optionally substituted by 1~4 It is an alkylene; however, if Q includes the heteromolecule, the heteromolecule is not separated from the ring amide NH by a methylene group; or, Q is one or more R 5c C is optionally replaced 2~4 Alkenirene is; or, Q is optionally selected from C=N and N=C, and R 5c It is optionally replaced by; R 1 H, Halo, OR 6 , NR 7 R 8 , C 1~6 Alkylene NR 7 R 8 and C 1~6 Selected from alkyl groups; R 2 H, Halo, and C 1~6 Selected from alkyl groups; R 3 is a halo; R 4is selected from H and C 1~6 is selected from alkyl; each R 5 is =O, halo, C 1~6 alkyl, C 3~6 cycloalkyl, C 3~6 heterocycloalkyl, C 1~6 alkylene C 3~6 cycloalkyl, C 1~6 alkylene C 3~6 heterocycloalkyl, OH, OC 1~6 alkyl, NR 9 R 10 and C 1~6 alkylene NR 9 R 10 is independently selected from; R 5a and R 5b are combined to optionally contain one additional hetero moiety selected from N, NH, NC 1~6 alkyl, O, S, SO, and SO2, and is optionally substituted by one or more of halo and C 1~6 alkyl to form a 3- to 6-membered y<z Saturated or unsaturated ring; each R 5c is halo, C 1~6 alkyl, C 3~6 cycloalkyl, C 3~6 heterocycloalkyl, C 1~6 alkylene C 3~6 cycloalkyl and C 1~6 alkylene C 3~6 heterocycloalkyl, OH, OC 1~6 alkyl NR 9 R 10 and C 1~6 alkylene NR 9 R 10 is independently selected from; R 6 is selected from H and C 1~6 alkyl; R 7 and R 8 or R 9 and R 10 is selected from H and C 1~6independently selected from alkyl; or, R 7 and R 8 or R 9 and R 10 are joined together with the atoms between them to form a 3- to 7-member Saturated or unsaturated ring which optionally contains one additional hetero moiety selected from N, NH, NC 1~6 alkyl, O, S, S(O), and SO2, and which is optionally substituted by one or more of halo and C 1~6 alkyl; Cy 1 is C 6~20 aryl or C 5~20 heteroaryl, and Cy 1 is unsubstituted or substituted by one or more R 11 s, or Cy 1 is substituted by Z-Cy 2 or Cy 1 is Z-Cy 2 and one or more R 11 s; each R 11 is halo, =O, CN, NO2, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, OR 12 , C(O)R 12 , CO2R 12 , P(O)R 12 R 13 , P(O)(OR 12 )(OR 13 ), SR 12 , SOR 12 , SO2R 12 , S(O)(=NR 13 )R 12 , SO2NR 12 R 13 , SiR 14 R 14a R 14b , C 1~6 alkylene OR 12 , OC1~6 Alkylene OR 12 、 C 1~6 Alkylene NR 12a R 13a , OC 1~6 Alkylene NR 12 R 13 , NR 13a C 1~6 Alkylene NR 12 R 13 , NR 13a C 1~6 Alkylene OR 12 , NR 12a R 13a , NR 13a COR 12 , NR 13a CO2R 12 , NR 13a SO2R 12 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~6 Alkylene C 3~7 Cycloalkyl and C 1~6 Alkylene C 3~7 Independently selected from Heterocycloalkyl, and the latter four groups are optionally substituted by one or more R 15 ; R 12 is H, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkylene C 3~10 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylene OR 17 , and C 1~6 Alkylene NR 16a R 16b selected from, and the alkyl group, alkenyl group, alkynyl group, alkylene group and cycloalkyl group of R 12 are optionally substituted by one or more R 17 ; R 13 is H and C 1~6Selected from alkyl groups; or, R 12 and R 13 They bond together, along with the atoms between them, N, NR 16 , optionally including one additional heterocomponent selected from O, S, SO, and SO2, and one or more R 17 4-6 members are optionally replaced by Saturated or unsaturated Forming a ring; R 12a H, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen OR 14 , and C 1~6 Alkylene NR 11 R 14 Selected from, and also R 10a All alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, and cycloalkyl groups are one or more R 17 It is optionally replaced by; R 13a H and C 1~6 Selected from alkyl groups; R 14 , R 14a , and R 14b is OR 19 , C 1~6 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 3~10 Cycloalkyl, and C 1~6 Alkilen C 3~10 Independently selected from heterocycloalkyl groups; Each R 15 Hello, C 1~6 Alkyl, CN, and NR 15a R 15b Selected independently from; R15a and R 15b H and C 1~6 Selected independently from alkyl; R 16a and R 16b H and C 1~6 Selected independently from alkyl; Each R 17 Hello, C 1~6 Alkyl, CN, and NR 17a R 17b Selected independently from; R 17a and R 17b H and C 1~6 Selected independently from alkyl; R 18 H and C 1~6 Selected from alkyl groups; R 19 H, C 1~6 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl C 1~6 Alkilen OR 20 , and C 1~6 Alkylene NR 20 R 21 Selected from; R 20 and R 21 H and C 1~6 Selected independently from alkyl; Z does not exist, or C 1~6 Alkylene, O, C(O), CO 2、 S, S(O), SO 2、 S(O)(=NR 13b ) and NR 13b Selected from; R 13b H and C 1~6 Selected from alkyl groups; Cy 2 C 3~14 Cycloalkyl and C 3~14 Selected from heterocycloalkyl, and also Cy2 It is either unsubstituted or has one or more R 22 It has been replaced with; Each R 22 Halogen, =O, CN, OH, C 1~6 Alkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, OC 1~6 Alkyl, OC 2~6 Alkenyl, OC 2~6 Alkinyl, C 1~6 Alkilen OR 23 , OC 1~6 Alkilen OR 23 , C 1~6 Alkylene NR 24 R 25 , OC 1~6 Alkylene NR 24 R 25 SC 1~6 Alkyl, SC 2~6 Alkenil, SC 2~6 Alkinyl, C(O)C 1~6 Alkyl, C(O)C 2~6 Alkenyl, C(O)C 2~6 Alkinyl, C(O)C 3~10 Cycloalkyl, C(O)C 3~10 Heterocycloalkyl, C(O)C 1~6 Alkilen C 3~10 Cycloalkyl, C(O)C 1~6 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~6 Alkilenyl OR 23 , C(O)C 1~6 Alkylene NR 24 R 25 , C(O)C 1~6 Alkilen OC 1~6 Alkylene NR 24 R 25 , C(O)NR 24 R 25CO2C 1~6 Alkyl, CO2C 2~6 Alkenyl, CO2C 2~6 Alkinyl, CO2C 1~6 Alkilen OR 23 CO2C 1~6 Alkilen OC 1~6 Alkylene NR 24 R 25 , NR 24 R 25 , NR 26 C 3~10 Cycloalkyl, NR 26 C 3~10 Heterocycloalkyl, NR 26 C 1~6 Alkilen OR 23 , NR 26 C 1~6 Alkilen C 3~10 Cycloalkyl, NR 26 C 1~6 Alkilen C 3~10 Heterocycloalkyl, NR 26 SO2C 1~6 Alkyl, SO2C 1~6 Alkyl, SO2C 2~6 Alkenyl, SO2C 2~6 Alkinyl and SO2NR 24 R 25 Selected independently from, and also R 22 The alkyl group, alkenyl group, alkynyl group, alkylene group and cycloalkyl group are one or more R 27 It is optionally replaced by; R 23 H, C 1~6 Alkyl, C 1~6 Alkilen OC 1~6 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 1~6 Alkilen C 3~10 Cycloalkyl, and C 1~6 Alkilen C 3~10 Selected from heterocycloalkyl groups; R 24H and C 1~6 Selected from alkyl groups; R 25 H, C 1~6 Alkyl, C 1~6 Alkilen OC 1~6 Alkyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkilen C 3~10 Cycloalkyl, and C 1~6 Alkilen C 3~10 Selected from heterocycloalkyls, or R 24 and R 25 They bond together, along with the atoms between them, N, NR 28 , optionally including one additional heterogroup selected from O, S, S(O), and SO2, and halo and C 1~6 A 4-6 member molecule optionally substituted with one or more alkyl groups. Saturated or unsaturated Forming a ring; R 26 H and C 1~6 Selected from alkyl groups; Each R 27 Hello, C 1~6 Alkyl, CN, and NR 27a R 27b Selected independently from; and R 27a , R 27b , and R 28 H and C 1~6 Selected independently from alkyl; Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

[0072] It should be understood that in all the embodiments below, all available hydrogen atoms are optionally substituted with fluorine atoms. This will not be repeated throughout. Therefore, in each embodiment in which groups containing available hydrogen atoms are listed, all such atoms are optionally substituted with fluorine atoms, for example C1~6 Unless otherwise specified, each alkyl group is C 1~6 It should be understood that this also refers to fluoroalkyl compounds.

[0073] In one embodiment, X 1 It is N.

[0074] In one embodiment, X 1 CR 1 That is the case.

[0075] In one embodiment, R 1 H, F, Cl, OR 6 , NR 7 R 8 , C 1~4 Alkylene NR 7 R 8 and C 1~4 Selected from alkyl groups. In one embodiment, R 1 These are H, F, Cl and C 1~4 Selected from alkyl groups. In one embodiment, R 1 is selected from H, F, Cl, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H and CH2CF2H. In one embodiment, R 1 is selected from H, F, CF3, CF2H, CH2CF2H and CH3. In one embodiment, R 1 is selected from H, F, CF3, CF2H and CH2CF2H. In one embodiment, R 1 is selected from H, F, CF3 and CH3. In one embodiment, R 1 is selected from H and F. In one embodiment, R 1 is F. In one embodiment, R 1 H is H.

[0076] In one embodiment, R 1 is OR 6 In one embodiment, R 6 is selected from H, CH3, CH2CH3, CF3, CFH2, CF2H, CH2CF2H, and CH2CF2H. In one embodiment, R 6 H and C1~4 Selected from alkyl groups. In one embodiment, R 6 is selected from H, CH3, CH2CH3, CF3, CFH2, CF2H, CH2CF2H, and CH2CH2F. In one embodiment, R 6 is CF2H. Therefore, in one embodiment, R 1 OH, OCH3, OCH2CH 3、 Selected from OCF3, OCFH2, OCHF2, OCH2CF2H, and OCH2CF2H.

[0077] In one embodiment, R 1 , NR 7 R 8 and C 1~4 Alkylene NR 7 R 8 Selected from. In one embodiment, R 7 and R 8 H and C, respectively. 1~4 Selected independently from alkyl. In one embodiment, R 1 , NR 7 R 8 and C 1~2 Alkylene NR 7 R 8 Selected from.

[0078] In one embodiment, R 7 and R 8 H and C, respectively. 1~4 Selected independently from alkyl. In one embodiment, R 7 and R 8 These are independently selected from H, CH3, and CF3, respectively. In one embodiment, R 7 and R 8 One of them is H, and the other is CH3. In one embodiment, R 7 and R 8 Both are CH3. In one embodiment, R 7 and R 8 Both are H.

[0079] In one embodiment, R 7 and R 8They bond together, and together with the nitrogen atom between them, form N, NH, NC 1~6 It optionally includes one additional heteromoon selected from alkyl, O, S, S(O), and SO2, and also includes a halo and C 1~6 A 3- to 7-membered molecule optionally substituted with one or more alkyl groups. Saturated or unsaturated It forms a ring. In one embodiment, R 7 and R 8 It binds together with the nitrogen atom between them, selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), morpholinyl and azepanyl, and also halo and C 1~6 It forms a 3- to 7-membered heterocycle that is optionally substituted by one or more alkyl groups. In one embodiment, R 7 and R 8 They bond together, forming a 4-6 member saturated ring with the nitrogen atom between them, and then the halo and C 1~6 It is optionally substituted with one or more alkyl groups. In one embodiment, R 7 and R 8 They bond together, along with the nitrogen atom between them, to form aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl, and halo and C 1~6 It is optionally substituted with one or more alkyl groups.

[0080] In one embodiment, X 2 and X 3 One of them is N, and the other is CR 2 In one embodiment, X 2 is N, and also X 3 CR 2 In one embodiment, X 2 and X 3 Both are independent, CR 2 In one embodiment, each R 2 H, Halo, and C 1~4Selected independently from alkyl groups. In one embodiment, each R 2 These are H, F, Cl and C 1~4 Selected independently from alkyl groups. In one embodiment, each R 2 R is independently selected from H, F, Cl, CH3, CF3, CH2F, and CHF2. In one embodiment, each R 2 R is independently selected from H, F, Cl, CH3 and CF3. In one embodiment, each R 2 is selected from H and F. In one embodiment, X 2 and X 3 One of them is N and the other is CH. In one embodiment, X 2 is N, and also X 3 is CH. In one embodiment, X 2 It is selected from CH, CF, CCl, CCH3 and CCF3, and also X 3 is CH. In one embodiment, X 2 is CF or CCl, and X 3 is CH. In one embodiment, X 2 CH is X 3 This is selected from CH, CF, CCl, CCH3 and CCF3. In one embodiment, X 2 and X 3 One of them is CF and the other is CH. In one embodiment, X 2 is CF, and also X 3 is CH. In one embodiment, X 2 and X 3 Both are CF. In one embodiment, X 2 and X 3 Both are CH. In one embodiment, X 2 and X 3 Both are N.

[0081] In one embodiment, X 1 CR 1 And also X 2 and X 3 Both are independent, CR 4 In one embodiment, X 1 is N, and also X 1and X 2 Both are independent, CR 4 In one embodiment, X 1 is N, and also X 1 and X 2 Both are CH. In one embodiment, X 1 CR 1 And also X 1 and X 2 One of them is N, and the other is CR 4 In one embodiment, X 1 CR 1 And also X 1 and X 2 One of them is N and the other is CH. In one embodiment, X 1 CR 1 And also X 2 and X 3 Both are N.

[0082] In one embodiment, X 4 is N, and also X 5 CR 3 In one embodiment, X 5 is N, and also X 4 CR 3 That is the case.

[0083] In one embodiment, R 3 is Cl, F, or Br. In one embodiment, R 3 is Cl or F. In one embodiment, R 3 It is F.

[0084] In one embodiment, X 4 is N, and also X 5 It is CF.

[0085] In one embodiment, Q is O, S, S(O), SO2, and NR 2 The heterogeneous portion selected from is optionally interrupted and / or one or more R 5 C is optionally replaced by 1~3It is an alkylene.

[0086] In certain embodiments, Q is C interrupted optionally by a hetero moiety selected from O, S, S(O), SO2, and NR 4 which is an alkylene. In certain embodiments, Q is C interrupted optionally by a hetero moiety selected from O, SO2, and NR 1~3 which is an alkylene. In certain embodiments, Q is C interrupted optionally by a hetero moiety selected from O or NR 4 which is an alkylene. In certain embodiments, Q is C interrupted optionally by O 1~3 which is an alkylene. In certain embodiments, Q is C interrupted optionally by O 4 which is an alkylene. In certain embodiments, Q is C interrupted optionally by O 1~3 which is an alkylene. 1~3 which is an alkylene.

[0087] In certain embodiments, R 4 is selected from H and C 1~4 alkyl. In certain embodiments, R 4 is selected from CH3, CH2CH3, CH(CH3)2, C(CH3)4, and CH2CH(CH3)2. In certain embodiments, R 4 is selected from CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In certain embodiments, R 4 is selected from CF2H, CH3, and CF3. In certain embodiments, R 4 is selected from CH3 and CF3.

[0088] In certain embodiments, Q is C [[ID=XXX]] 1~3 alkylene and is optionally substituted by one to three R 5 . In certain embodiments, Q is CH2 or CH2CH2 and is optionally substituted by one or two R 5 . In certain embodiments, Q is C1 alkylene and is also optionally substituted by one or two R 5It is optionally substituted by. In one embodiment, Q is CH2. In another embodiment, Q is CH2CH2.

[0089] In one embodiment, each R 5 is = O, F, Cl, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~6 Alkilen C 3~6 Cycloalkyl, C 1~6 Alkilen C 3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl, NR 9 R 10 , and C 1~6 Alkylene NR 9 R 10 Selected independently from R. In one embodiment, each R 5 is = O, F, Cl, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkilen C 3~6 Cycloalkyl, C 1~4 Alkilen C 3~6 Heterocycloalkyl, OH, OC 1~4 Alkyl, NR 9 R 10 , and C 1~4 Alkylene NR 9 R 10 It is independently selected from. In one embodiment, Q is one R 5 It is replaced by R 5 The value is O.

[0090] In one embodiment, each R 5 F, Cl, OH, C 1~4 Alkyl OC 1~4 Alkyl and NR 9 R 10 Selected independently from R. In one embodiment, each R 5These are F, Cl, OH, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, OCH3, OCH2CH3, OCF3, OCF2H, OCH(CH3)2 and NR 9 R 10 Selected independently from R. In one embodiment, each R 5 These are F, Cl, OH, CH3, CF2H, CF3, CFH2, OCH3, OCF3, OCF2H and NR 9 R 10 It is independently selected from R. In one embodiment, R 5 One to three of these are F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H, and NR 9 R 10 It is independently selected from R. In one embodiment, R 5 One to three of these are independently selected from F, Cl, CH3, CF2H, CF3, OCH3, OCF3, and OCF2H. In one embodiment, R 5 One to four of these are independently selected from F, CH3, and OCH3.

[0091] In one embodiment, each R 5 F, Cl, and C 1~4 Selected independently from alkyl groups. In one embodiment, each R 5 R is independently selected from F, Cl, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CH2F. In one embodiment, each R 5 R is independently selected from F, Cl, CH3, CF2H, CF3, and CH2CF2H. In one embodiment, each R 5 R is independently selected from F, Cl, CH3, and CF3. In one embodiment, each R 5 R is independently selected from F, CH3, and CF3. In one embodiment, each R 5 R is independently selected from F, CH3, and CF3. In one embodiment, each R 5 is independently selected from F and CH3. In one embodiment, at least one R 5 is F. In one embodiment, R 5 One or two of them are F. In one embodiment, R 5One or more, one to four, one to three, one or two, or one of them is CH3.

[0092] In one embodiment, R 5 One or two of them are C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkilen C 3~6 Cycloalkyl and C 1~4 Alkilen C 3~6 Selected independently from heterocycloalkyls. In one embodiment, one R 5 C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~2 Alkilen C 3~6 Cycloalkyl and C 1~2 Alkilen C 3~6 Heterocycloalkyl or and others They are selected independently. In one embodiment, R 5 The cycloalkyl in is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, R 5 The cycloalkyl in the above is selected from cyclopropyl and cyclobutyl.

[0093] In one embodiment, R 5The heterocycloalkyl in is selected from azilidinyl, oxylanil, thyranil, oxaxyllidinyl, dioxylanil, azetidinyl, oxetanil, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, piperidinyl, triazolyl, flazanil, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranil, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanil, and dithianyl. In one embodiment, R 5 The heterocycloalkyl in is selected from azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, and pyrazolidinyl.

[0094] In one embodiment, each R 5 These are OH and OC 1~4 Selected independently from alkyl groups. In one embodiment, each R 5 These are OH and OC 1~4 Selected independently from alkyl groups. In one embodiment, each R 5 R is independently selected from OH, OCH3, OCF3, OCF2H, OCH2CH3, and OCH(CH3)2. In one embodiment, R 5 One or two of these are independently selected from OH, OCH3, OCF3, and OCF2H.

[0095] In one embodiment, one R 5 , NR 9 R 10 and C 1~4 Alkylene NR 9 R 10 Selected from. In one embodiment, R 5 One of them is NR 9 R 10or C 1~2 Alkylene NR 9 R 10 In one embodiment, R 5 One of them is NR 9 R 10 In one embodiment, R 5 One of them is C 1~4 Alkylene NR 9 R 10 In one embodiment, R 5 of NR 9 R 10 or C 1~2 Alkylene NR 9 R 10 In R 9 and R 10 Both are CH3 or both are H. In one embodiment, one R 5 is NR 9 R 10 And also R 5 In R 9 and R 10 Both are H.

[0096] In one embodiment, R 5 In R 9 and R 10 H and C are respectively 1~4 Selected independently from alkyl. In one embodiment, R 5 In R 9 and R 10 Each is independently selected from H, CH3, and CF3. In one embodiment, R 5 In R 9 and R 10 One of them is H, and the other is CH3. In one embodiment, R 5 In R 9 and R 10 Both are CH3. In one embodiment, one R 5 is NR 9 R 10 And also R 5 In R 9and R 10 Both are CH3 or both are H. In one embodiment, one R 5 is NR 9 R 10 And also R 6 In R 9 and R 10 Both are H.

[0097] In one embodiment, R 9 and R 10 They bond together, and together with the nitrogen atom between them, form N, NH, NC 1~6 It optionally includes one additional heteromoon selected from alkyl, O, S, S(O), and SO2, and also includes a halo and C 1~6 A 3- to 7-membered molecule optionally substituted with one or more alkyl groups. Saturated or unsaturated It forms a ring. In one embodiment, R 9 and R 10 Together, with the nitrogen atoms between them, they form a 3-7 membered heterocycle, selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), morpholinyl, and azepanyl, with halo and C 1~6 A heterocycle is formed which is optionally substituted by one to four alkyl groups. In one embodiment, R 9 and R 10 They bond together, along with the nitrogen atom between them, forming a halo and C 1~4 It forms a 4-6 heterocycloalkyl ring which is optionally substituted by one to four alkyl groups. In one embodiment, R 9 and R 10 They bond together, along with the nitrogen atom between them, forming Cl, F, and C 1~4 They form azilidinyl, azetidinyl, pyrrolidinyl, or piperidinyl molecules, which are optionally substituted with one to four alkyl groups.

[0098] In one embodiment, Q is unsubstituted. In another embodiment, Q is C 1~3 It is an alkylene, with one or two R 5 It is replaced by C. In one embodiment, Q is C 1~3 It is an alkylene, with one or two R 5 It is replaced by R 5 is C 1~4 It is alkyl. In one embodiment, Q is C 1~3 It is an alkylene, with one or two R 5 It is replaced by R 5 is CH3. In one embodiment, Q is C 1~3 It is an alkylene, with 1 to 4 R 5 It is replaced by and each R 5 Q is independently selected from F, Cl, CH3, CF2H, CF3, OCH3, OCF3 and OCF2H. In one embodiment, Q is C 1~3 It is an alkylene, with 1 to 4 R 5 It is replaced by and each R 5 It is selected independently from F, CH3, and OCH3.

[0099] In one embodiment, Q is C 1~3 It is an alkylene, and also has R on one carbon atom. 5a and R 5b It is optionally disubstituted by [a specific compound]. In one embodiment, Q is a C1 alkylene or a C2 alkylene, and also R on one carbon atom. 5a and R 5b It is optionally substituted by . In one embodiment, Q is CR 5a R 5b That is the case.

[0100] In one embodiment, R 5a and R 5b They bond together, and together with the carbon atoms between them, form a 3-6 member group. Saturated or unsaturated A ring of N, NH, NC 1~6It optionally contains one heteromoon selected from alkyl, O, S, S(O), and SO2, and includes a halo and C 1~4 It forms a ring optionally substituted with one or more alkyl groups.

[0101] In one embodiment, R 5a and R 5b They bond together, forming a 3-6 membered cycloalkyl ring with the carbon atoms between them, and then the halo and C 1~4 It is optionally substituted with one or more alkyl groups. In one embodiment, R 5a and R 5b They bond together, along with the carbon atoms between them. , Selected from chloropropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and also halo and C 1~4 A 3-6 member molecule optionally substituted with one or more alkyl groups. Cycloalkyl It forms a ring. In one embodiment, R 5a and R 5b They are bonded together, and together with the carbon atoms between them, they form a 3-5 membered cycloalkyl ring, and the halo and C 1~4 It is optionally substituted with one to four alkyl groups. In one embodiment, R 5a and R 5b They bond together, and together with the carbon atoms between them, form a cyclopropyl ring, a cyclobutyl ring, or a cyclopentyl ring, and halo and C 1~4 It is optionally substituted with one to four alkyl groups. In one embodiment, R 5a and R 5b They are bonded together, and together with the carbon atoms between them, they form a cyclopropyl ring or a cyclobutyl ring, and the halo and C 1~4 It is optionally substituted with one to three alkyl groups. In one embodiment, R 5a and R 5b They are bonded together, and together with the carbon atoms between them, they form a cyclopropyl ring, and Cl, F and C 1~4It is optionally substituted with one to three alkyl groups. In one embodiment, R 5a and R 5b They are bonded together, and together with the carbon atoms between them, they form a cyclopropyl ring or a cyclobutyl ring. In one embodiment, R 5a and R 5b They are bonded together, forming a cyclopropyl ring with the carbon atoms between them.

[0102] In one embodiment, R 5a and R 5b They bond together, forming a 3-6 membered heterocycloalkyl ring with the carbon atoms between them, and also halo and C 1~4 It is optionally substituted with one or more alkyl groups. In one embodiment, R 5a and R 5b It is bonded together with the carbon atoms between them to form a 3-6 membered heterocycloalkyl ring, such as azilidinyl, oxyranil, thyranil, oxaxyllidinyl, dioxyranil, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxythiolidinyl It forms a heterocycloalkyl ring selected from iolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, piperidinyl, triazolyl, flazanil, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranil, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanil and dithianyl. In one embodiment, R 5a and R 5b They bond together, forming a 3- to 5-membered heterocycloalkyl ring with the carbon atoms between them. In one embodiment, R 5a and R 5bThey bond together, together with the carbon atoms between them, to form a 3-5 membered heterocycloalkyl ring, which is selected from oxyranyl, oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydrothiophenyl rings. In one embodiment, R 5a and R 5b They are bonded together, and together with the carbon atoms between them, they form an oxetanyl ring or an azetidinyl ring. In one embodiment, R 5a and R 5b They bond together, and together with the atoms between them, form an oxetanyl ring. In one embodiment, R 5a and R 5b They bond together, along with the carbon atoms between them, [ka] This forms a , where "●" represents the connection point to Q.

[0103] In one embodiment, Q is one or two R 5c C is optionally replaced by 2~4 It is an alkenylene. In one embodiment, Q is one or more (e.g., one or two) R 5c It is optionally substituted by —C=C—.

[0104] In one embodiment, Q is selected from C=N and N=C, and R 5c It is optionally substituted by. In one embodiment, Q is C=N or N=C.

[0105] In one embodiment, each R 5c F, Cl, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~6 Alkilen C 3~6 Cycloalkyl, C 1~6 Alkilen C3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl, NR 9 R 10 , and C 1~6 Alkylene NR 9 R 10 Selected independently from R. In one embodiment, each R 5c F, Cl, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkilen C 3~6 Cycloalkyl, C 1~4 Alkilen C 3~6 Heterocycloalkyl, OH, OC 1~4 Alkyl, NR 9 R 10 , and C 1~4 Alkylene NR 9 R 10 Selected independently from.

[0106] In one embodiment, each R 5c F, Cl, OH, C 1~4 Alkyl, OC 1~4 Alkyl, C 1~2 Alkylene NR 9 R 10 and NR 9 R 10 Selected independently from R. In one embodiment, each R 5c is F, Cl, OH, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, OCH3, OCH2CH3, OCF3, OCF2H, OCH(CH3)2, C 1~2 Alkylene NR 9 R 10 and NR 9 R 10 Selected independently from R. In one embodiment, each R 5c is F, Cl, OH, CH3, CF2H, CF3, CFH2, OCH3, OCF3, OCF2H, C 1~2 Alkilen R 9 R 10 and NR 9 R 10 Selected independently from R. In one embodiment, each R5c is F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H, C 1~2 Alkylene NR 9 R 10 and NR 9 R 10 Selected independently from R. In one embodiment, each R 5c is F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H, C 1~2 Alkilen R 9 R 10 and NR 9 R 10 Selected independently from.

[0107] In one embodiment, each R 5c F and C 1~4 Selected independently from alkyl groups. In one embodiment, each R 5c R is independently selected from F, Cl, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CH2F. In one embodiment, each R 5c R is independently selected from F, Cl, CH3, CF2H, CF3, and CH2CF2H. In one embodiment, each R 5c is independently selected from F, Cl, CH3, and CF3. In one embodiment, R 5c is selected from F, CH3, and CF3. In one embodiment, each R 5c is selected from F and CH3. In one embodiment, at least one R 5c is F. In one embodiment, R 5c One or more, one to four, one to three, one or two, or one of them is CH3. In one embodiment, each R 5c is CH3. In one embodiment, one or two R 5c C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkilen C 3~6 Cycloalkyl and C 1~4 Alkilen C 3~6 Selected independently from heterocycloalkyls. In one embodiment, one R 5c C3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~2 Alkilen C 3~6 Cycloalkyl and C 1~2 Alkilen C 3~6 Selected from heterocycloalkyl groups. In one embodiment, R 5c The cycloalkyl in is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In one embodiment, R 5c The cycloalkyl in the above is selected from cyclopropyl and cyclobutyl.

[0108] In one embodiment, R 5c The heterocycloalkyl in is selected from azilidinyl, oxylanil, thyranil, oxaxyllidinyl, dioxylanil, azetidinyl, oxetanil, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, piperidinyl, triazolyl, flazanil, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranil, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanil, and dithianyl. In one embodiment, R 5c The heterocycloalkyl in is selected from azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, and pyrazolidinyl.

[0109] In one embodiment, each R 5c These are OH and OC 1~4 Selected independently from alkyl groups. In one embodiment, each R 5c These are OH and OC 1~4Selected independently from alkyl groups. In one embodiment, each R 5c This is independently selected from OH, OCH3, OCF3, OCF2H, OCH2CH3, and OCH(CH3)2. In one embodiment, one R 5c The component is selected from OH, OCH3, OCF3, and OCF2H.

[0110] In one embodiment, one or two R 5c C 1~4 Alkylene NR 9 R 10 In one embodiment, one R 5c C 1~2 Alkylene NR 9 R 10 In one embodiment, R 5c One of them is NR 9 R 10 In one embodiment, R 5c , NR 9 R 10 And also R 5c In R 9 and R 10 Both are CH3 or both are H. In one embodiment, one R 5c is NR 9 R 10 And also R 5c In R 9 and R 10 Both are H.

[0111] In one embodiment, R 5c In R 9 and R 10 H and C, respectively. 1~4 Selected independently from alkyl. In one embodiment, R 5c In R 9 and R 10 These are independently selected from H, CH3, and CF3, respectively. In one embodiment, R 5c In R 9 and R 10 One of them is H, and the other is CH3. In one embodiment, R 5c In R 9and R 10 Both are CH3.

[0112] In one embodiment, R 5c In R 9 and R 10 They bond together, and together with the nitrogen atom between them, form N, NH, NC 1~6 It optionally includes one additional heteromoon selected from alkyl, O, S, S(O), and SO2, and also includes a halo and C 1~6 A 3- to 7-membered molecule optionally substituted with one or more alkyl groups. Saturated or unsaturated It forms a ring. In one embodiment, R 5c In R 9 and R 10 Together, along with the nitrogen atoms between them, are selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), morpholinyl, and azepanyl, and halo and C 1~6 It forms a 3-7 member heteroring, which is optionally substituted by one to four alkyl groups. In one embodiment, R 5c In R 9 and R 10 They bond together, along with the nitrogen atom between them, forming a halo and C 1~6 It forms a 4-6 member heterocycle which is optionally substituted by one to four alkyl groups. In one embodiment, R 5c In R 9 and R 10 They bond together, and together with the nitrogen atom between them, F, Cl and C 1~4 They form azilidinyl, azetidinyl, pyrrolidinyl, or piperidinyl molecules, which are optionally substituted with one to three alkyl groups.

[0113] In one embodiment, Q is NR 4 C with an optional interrupt 1~3It is an alkylene. 4 H and C 1~4 Selected from alkyl groups. Therefore, in one embodiment, Q is NR 4 C with an optional interrupt 1~3 It is alkylene, and also R 4 H and C 1~4 Selected from alkyl groups. In one embodiment, R 4 The following are selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3.

[0114] In one embodiment, Q is O, S, S(O), SO2, and NR 4 An interrupted C with an optionally selected heterogeneous portion. 1~3 It is an alkylene. In one embodiment, Q is O, SO2, and NR 4 An interrupted C with an optionally selected heterogeneous portion. 1~3 It is an alkylene. In one embodiment, Q is O and NR 4 A heterogeneous part selected from is optionally inserted into the interrupted C. 1~3 It is an alkylene. In one embodiment, Q is an interrupted C with an optional heteropolymer selected from O and SO2. 1~3 It is an alkylene. In one embodiment, Q is an interrupted C with O optionally in between. 1~3 It is an alkylene. In one embodiment, Q is an interrupted C with O optionally in between. 1~3 It is an alkylene. In one embodiment, Q is an interrupted C with SO2 optionally in between. 1~2 It is alkylene.

[0115] In one embodiment, R 4 H and C 1~4Selected from alkyl groups. In one embodiment, R 4 The following are selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3.

[0116] In one embodiment, Q is C 1~3 It is an alkylene, and also has R on one carbon atom. 5a and R 5b It is optionally substituted by R 5a and R 5b They bond together, and together with the nitrogen atom between them, form a 3-6 member group. Saturated or unsaturated A ring of N, NH, NC 1~6 It optionally includes one additional heteromoon selected from alkyl, O, S, S(O), and SO2, and contains halo and C 1~4 It forms a ring optionally substituted by one or more alkyl groups. In some embodiments, Q is a C1 alkylene or a C2 alkylene, and also R on one carbon atom. 5a and R 5b It is bisubstituted by R 5a and R 5b They are bonded together, forming a 3-5 membered cycloalkyl ring with the carbon atoms between them, and also halo and C 1~4 It is optionally substituted with one or more alkyl groups. In one embodiment, Q is a C1 alkylene or a C2 alkylene, and R is present on one carbon atom. 5a and R 5b It is substituted by two. In one embodiment, Q is CR 5a R 5b In one embodiment, R 5a and R 5b They are bonded together, and together with the carbon atoms between them, they form a cyclopropyl ring or a cyclobutyl ring, and the halo and C 1~4 It is optionally substituted with one to four alkyl groups. In one embodiment, Q is CR 5a R 5b In one embodiment, R 5a and R5b They are bonded together, and together with the carbon atoms between them, they form a cyclopropyl ring or a cyclobutyl ring, and the halo and C 1~4 It is optionally substituted with one to three alkyl groups, one or two, or one alkyl group.

[0117] In one embodiment, Q is one or two R 5c C is optionally replaced by 2~4 It is an alkenylene, and each R 5c F, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkilen C 3~6 Cycloalkyl, C 1~4 Alkilen C 3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl, NR 9 R 10 , and C 1~4 Alkylene NR 9 R 10 Independently selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms. In some embodiments, Q is one or two R 5c C is optionally replaced by 2~4 It is an alkenylene, and each R 5c F, Cl, C 1~4 Alkyl and OC 1~4 It is independently selected from alkyl groups. In one embodiment, Q is one or two R groups. 5c C=C is optionally substituted by and each R 5c F, Cl, C 1~4 Alkyl and OC 1~4 It is independently selected from alkyl groups. In one embodiment, Q is one or two R groups. 5c C=C, which is optionally substituted by, and each R 5cQ is independently selected from F, Cl, CH3, and OCH3OCF3 and OCF2H. In some embodiments, Q is one or two R 5c C=C and R are optionally substituted by 5c F and C 1~4 Selected from alkyl groups. In one embodiment, R 5c Q is selected from F and CH3. In some embodiments, Q is C=C substituted with F. In some embodiments, Q is C=C substituted with Cl. In some embodiments, Q is C=C substituted with OCH3. In some embodiments, Q is C=C substituted with CH3. In some embodiments, Q is C=C substituted with F and CH3.

[0118] In one embodiment, Q is selected from C=N and N=C, and R 5c It is optionally substituted by and each R 5c F, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkilen C 3~6 Cycloalkyl, C 1~4 Alkilen C 3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl, NR 9 R 10 and C 1~4 Alkylene NR 9 R 10 Independently selected from, where all available hydrogen atoms are optionally replaced by fluorine atoms. In one embodiment, Q is selected from C=N and N=C, and one or two R 5c It is optionally substituted by and each R 5c F, Cl, C 1~4 Alkyl, OC 1~4 Alkyl, NR 9 R 10, independently selected from cyclopropyl and cyclobutyl. In some embodiments, Q is selected from C=N and N=C, and one or two R 5c It is optionally substituted by and each R 5c F, Cl, CH3, OCH3, OCF3, OCF2H, NR 9 R 10 , independently selected from cyclopropyl and cyclobutyl. In some embodiments, Q is selected from C=N and N=C, and one or two R 5c It is optionally replaced by 、 Also, each R 5c Q is independently selected from F, Cl, CH3, OCH3, OCF3 and OCF2H. In some embodiments, Q is selected from C=N and N=C, and R 5c It is optionally replaced by 、 Also R 5c Q is selected from F and CH3. In one embodiment, Q is selected from C=N or N=C, and R 5c It is optionally replaced by R 5c Q is selected from cyclopropyl and cyclobutyl. In some embodiments, Q is selected from C=N or N=C, and R 5c It is optionally replaced by R 5c F and C 1~4 Selected from alkyl groups. In some embodiments, Q is selected from C=N or N=C, and also one or two R groups. 5c It is optionally substituted by and one R 5c is NR 9 R 10 In one embodiment, Q is selected from C=N or N=C, and one or two R 5c It is optionally substituted by and one R 5c is C 1~2 Alkylene NR 9 R 10 That is the case.

[0119] In one embodiment, Cy 1 C 6~16 Aryl or C 5~17 It is a heteroaryl, and also Cy 1 is unsubstituted. In one embodiment, Cy 1 C 6~16 Aryl or C 5~17 It is a heteroaryl, and also Cy 1 This is 1 to 3 R 11 It is replaced by Cy 1 C 6~16 Aryl or C 5~17 It is a heteroaryl, and also Cy 1 is Z-Cy 2 It is replaced by Cy 1 is C 6~16 Aryl or C 5~17 It is a heteroaryl, and also Cy 1 Z-Cy 2 and 1 to 3 R 11 It has been replaced by.

[0120] In one embodiment, Cy 1 is C 6~10 It is an arrow. Therefore, in one embodiment, Cy 1 is C 6~10 It is aryl, and also Cy 1 It is either unsubstituted or has one or more R 9 Is it being replaced by 、 or Z-Cy 2 It is replaced by or Z-Cy 2 and one or more R 11 It is replaced by Cy 1 is phenyl, indanyl, or naphthyl. In one embodiment, Cy 1 It is phenyl.

[0121] In one embodiment, Cy 1 This is a biring C 9~11 It is an aryl group, where the aryl group is fused to a heterocycloalkyl group, and also Cy1 It is either unsubstituted or has one or more R 11 It is replaced by or Z-Cy 2 It is replaced by or Z-Cy 2 and one or more R 11 It is replaced by Cy 1 This is a benzo-fused bicyclic C 9~11 It is heterocycloalkyl. In one embodiment, Cy 1 C 4~8 A benzo-fused ring is formed on a heterocycloalkyl group. In one embodiment, Cy 1 This is selected from indolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzofuranol, 1,1-dioxide-dihydrobenzothiophenyl, benzodioxolyl, benzodioxanyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 1-oxo-tetrahydroisoquinolinyl, 1-oxo-tetrahydroquinolinyl, dihydrobenzodioxepinyl, benzoxazinyl, isochromanil, chromanil, chromanonil, isoclomenyl, clomenil, and clomenonil. In one embodiment, Cy 1 teeth, [ka] Selected from, Here, [ka] Cy to the rest of the molecule 1 It represents the connection point of and the Cy 1 It is either unsubstituted or has one or more R 11 It is replaced with, or Z-Cy 2 It is replaced by R here 11a H, R 11 and Z-Cy 2 Selected from.

[0122] In one embodiment, Cy 1 This is a three-ring type C 11~17 It is an aryl group, where the aryl group is fused to one or two heterocycloalkyl groups and / or spirofused to Cy 1 It is either unsubstituted or has one or more R 11 It is replaced with, or Z-Cy 2 It is replaced by or Z-Cy 2 and one or more R 11 It is replaced by Cy 1 This is a benzo-fused spiro-fused tricyclic C 11~17 It is an arrow. In one embodiment, Cy 1 This is selected from spirobenzodioxin piperidinyl, oxospirochroman piperidinyl, and spirochroman piperidinyl. In one embodiment, Cy 1 teeth, [ka] Selected from, Here [ka] Cy to the rest of the molecule 1 Represents the connection point of and the Cy 1 It is either unsubstituted or has 1 to 3 R 11 It is replaced by or Z-Cy 2 It is replaced by R here 11a H, R 11 and Z-Cy 2 Selected from.

[0123] In one embodiment, Cy 1 C 5~6 It is a heteroaryl, and also Cy 1 This is either unsubstituted or one or more R 11 It is replaced by or Z-Cy 2It is replaced by or Z-Cy 2 and R 11 It is replaced by one or more of the following.

[0124] In one embodiment, Cy 1 The is selected from pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl, pyridadinyl and pyrimidinyl. In one embodiment, Cy 1 The is selected from pyrrolyl, pyrazolyl, thiazolyl, pyridinyl, pyrazinyl and pyrimidinyl. In one embodiment, Cy 1 This is selected from pyrazolyl, pyridinyl, pyrazinyl and pyrimidinyl. In one embodiment, Cy 1 is pyridinyl. In one embodiment, Cy 1 It is pyrazolyl.

[0125] In one embodiment, Cy 1 is a biring type C 9~11 It is a heteroaryl, and also Cy 1 It is either unsubstituted or has one or more R 11 It is replaced by or Z-Cy 2 It is replaced by or Z-Cy 2 and one or more R 11 It is replaced by Cy 1 The compound is selected from benzofuranyl, benzothiophenyl, benzodioxolyl, quinolinyl, and isoquinolyl.

[0126] In one embodiment, Cy 1 This is pyrazolodiazepinonil. In one embodiment, Cy 1 teeth, [ka] And here, [ka] Cy to the rest of the molecule 1 It represents the connection point of and the Cy 1 It is either unsubstituted or has one or more R 11 It is replaced with, or Z-Cy 2 It is replaced by R here 11a H, R 11 and Z-Cy 2 Selected from.

[0127] In one embodiment, Cy 1 It is either unsubstituted or has 1 to 4 R 11 It is replaced by Cy 1 It is either unsubstituted or has 1 to 3 R 11 It is replaced by Cy 1 It is either unsubstituted or has one or two Rs. 11 It is replaced by Cy 1 is either unsubstituted or one R 11 It is replaced by Cy 1 is either unsubstituted or Z-Cy 2 and 1 to 4 R 11 It is replaced by Cy 1 is either unsubstituted or Z-Cy 2 and 1 to 3 R 11 It is replaced by Cy 1 is either unsubstituted or Z-Cy 2 and one to two R 11 It is replaced by Cy 1 is either unsubstituted or Z-Cy 2 and one R 11 It has been replaced by.

[0128] In one embodiment, each R 11 is Halo, =O, CN, NO2, C 1~6 Alkyl, C 2~6 Alkenil, C2~6 Alkinyl, OR 12 , C(O)R 12 CO2R 12 P(O)R 12 R 13 , P(O)(OR 12 )(OR 13 ), SR 12 S(O)R 12 SO2R 12 , S(O)(=NR 13 )R 12 SO2NR 12 R 13 , SiR 14 R 14a R 14a , C 1~6 Alkilen OR 12 , OC 1~6 Alkilen OR 12 、 C 1~6 Alkylene NR 12a R 13a , OC 1~6 Alkylene NR 12 R 13 , NR 13a C 1~6 Alkylene NR 12 R 13 , NR 13a C 1~6 Alkilen OR 12 , NR 12a R 13a , NR 13a COR 12 , NR 13a CO2R 12 , NR 13a SO2R 12 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Independently selected from heterocycloalkyl groups, where the rear four groups are 1 to 3 R groups. 15 It is optionally replaced by [this].

[0129] In one embodiment, each R 11F, Cl, =O, CN, NO2, C 1~4 Alkyl, OR 12 , C(O)R 12 CO2R 12 P(O)R 12 R 13 , P(O)(OR 12 )(OR 13 ), SR 12 S(O)R 12 SO2R 12 , S(O)(=NR 13 )R 12 SO2NR 12 R 13 , SiR 14 R 14a R 14b , C 1~64 Alkilen OR 12 , OC 1~6 Alkilen OR 12 、 C 1~6 Alkylene NR 12a R 13a , OC 1~4 Alkylene NR 12 R 13 , NR 13a C 1~4 Alkylene NR 12 R 13 , NR 13a C 1~4 Alkilen OR 12 , NR 12a R 13a , NR 13a COR 12 , NR 13a CO2R 12 , and NR 13a SO2R 12 , and NR 13a SO2R 12 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Independently selected from heterocycloalkyl groups, where the rear four groups are 1 to 3 R groups. 15 It is optionally replaced by [this].

[0130] In one embodiment, each R 11 F, Cl, CN, NO2, CH3, CH2CH 3、 CH(CH3)2, OR 12 , C(O)R 12 CO2R 12 P(O)R 12 R 13 , P(O)(OR 12 )(OR 13 ), SR 12 SOR 12 SO2R 12 , S(O)(=NR 13 )R 12 SO2NR 12 R 13 , SiR 14 R 14a R 14b , C 1~6 Alkilen OR 12 , OC 1~6 Alkilen OR 13 、 C 1~6 Alkylene NR 12a R 13a , OC 1~6 Alkylene NR 12 R 13 , NR 13a C 1~6 Alkylene NR 12 R 13 , NR 13a C 1~6 Alkilen OR 12 , NR 12a R 13a , NR 13a COR 12 , NR 13a CO2R 12 , NR 13a SO2R 12 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Independently selected from heterocycloalkyl groups, where the rear four groups are 1 to 3 R groups. 15It is optionally replaced by [this].

[0131] In one embodiment, each R 11 F, CH3, CH2CH 3、 CH(CH3)2, P(O)R 12 R 13 SO2NR 12 R 13 , SiR 14 R 14a R 14b , OC 1~4 Alkilen OR 12 , C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 , NR 13a SO2R 12 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Independently selected from heterocycloalkyl groups, where the rear four groups are 1 to 3 R groups. 15 It is optionally replaced by. In one embodiment, each R 11 F, CH3, CH2CH 3、 CH(CH3)2, SO2NR 12 R 13 , OC 1~6 Alkilen OR 12 , NR 13a C 1~6 Alkylene NR 12 R 13 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Independently selected from heterocycloalkyl groups, where the rear four groups are 1 to 3 R groups. 15It is optionally replaced by one R. In one embodiment, one R 11 SO2NR 12 R 13 That is the case.

[0132] In one embodiment, each R 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 SO2NR 12 R 13 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Independently selected from heterocycloalkyl groups, where the rear four groups are 1 to 3 R groups. 15 It is optionally replaced by. In one embodiment, each R 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 SO2NR 12 R 13 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Independently selected from heterocycloalkyl groups, where the rear four groups are 1 to 4 R groups. 15 It is optionally replaced by one R. In one embodiment, one R 11 SO2NR 12 R 13In one embodiment, one or two R 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two rear groups are 1 to 4 R groups. 15 It is optionally replaced by one or two R. In some embodiments, one or two R 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two rear groups are 1 to 4 R groups. 15 It is optionally replaced by one R. In one embodiment, one R 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , and NR 13a C 1~4 Alkylene NR 12 R 13 Selected from. In one embodiment, one R 11 , NR 13 C 1~6 Alkylene NR 12 R 13 In one embodiment, one R 11 C 1~4 Alkylene NR 12a R 13a That is the case.

[0133] In one embodiment, R11 One of them is NR 12a R 13a And also R 12a H and C 1~4 Selected from alkyl, where C 1~4 Alkyl groups have 1 to 3 R's. 17 It is optionally replaced by R 13a H and C 1~4 Selected from alkyl groups. In one embodiment, R 11 One of them is NR 12a R 13a And also R 12a The R is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, where CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3 are 1 to 3 R 17 It is optionally replaced by R 13a is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF. In one embodiment, R 11 One of them is NR 12a R 13a And also R 12a and R 13a is independently selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 11 One of them is NR 12a R 13a And also R 12a and R 13a R is independently selected from H, CF3, CH3, and CH2CH3. Therefore, in one embodiment, R 11 is selected from NH2, N(CH3)2, NH(CH3), N(CH3)(CH2CH2), NH(CH2CH2), and N(CH2CH2). In one embodiment, R 11 One of these is selected from NH2, N(CH3)2, and NH(CH3).

[0134] In one embodiment, R 11 One of them is C 1~4Alkylene NR 12a R 13a And also R 12a H, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen OR 16 , and C 1~6 Alkylene NR 16a R 16b Selected from, and also R 12a All alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, and cycloalkyl groups within the group have 1 to 3 R 17 It is optionally replaced by R 13a H and C 1~4 Selected from alkyl groups. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a H, C 1~4 Alkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~4 Alkilen C 3~10 Heterocycloalkyl, C 1~4 Alkilen OR 16 , and C 1~4 Alkylene NR 16a R 16b Selected from, and also R 12a Each alkyl group, alkylene group, and cycloalkyl group has 1 to 3 R 17 It is optionally replaced by R 13a H and C 1~4 Selected from alkyl groups.

[0135] In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R12a H and C 1~4 Selected from alkyl, where C 1~4 Alkyl groups have 1 to 3 R's. 17 It is optionally replaced by R 13a H and C 1~4 Selected from alkyl groups. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a The R is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, where CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3 are 1 to 3 R 17 It is optionally replaced by R 13a is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a and R 13a is independently selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 11 One of them is C 1~3 Alkylene NR 12a R 13a And also R 12a and R 13a R is independently selected from H, CF3, CH3, and CH2CH3. Therefore, in one embodiment, R 11 These are CH2N(CH2CH3)2, C(CH3)2NH2, CH2N(CH3)2, CH2CH2N(CH3)2, and CH2N(CH3)2 and CH2N(CH3)2. In one embodiment, R 11 This is CH2N(CH3)2. In one embodiment, R 11 One of them is C 1~3 Alkylene NR 12a R 13a And also R12a and R 13a is independently selected from H and CH3. In one embodiment, R 11 One of them is C 1~3 Alkylene NR 12a R 13a And also R 12a and R 13a Both are either H or both are CH3.

[0136] In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~6 Alkilen OR 16 and C 1~6 Alkylene NR 16a R 16b Selected from, and also R 12a All alkylene groups in this product have 1 to 3 R 17 It is optionally replaced by R. 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~4 Alkilen OR 16 and C 1~4 Alkylene NR 16a R 16b Selected from, and also R 12a All alkylene groups in this product have 1 to 3 R 17 It is optionally replaced by R. 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~4 Alkilen OR 16 and C 1~4 Alkylene NR 16a R 16b Selected from, and also R 13a H and C 1~4 Selected from alkyl, and also R12a All alkylene groups in this product have 1 to 3 R 17 It is optionally replaced by R. Therefore, in one embodiment, 11 One of them is C 1~4 Alkylene N(R) 13a )(C 1~6 Alkilen OR 16 ) and also R 13a H and C 1~4 Selected from alkyl, and also R 12a All alkylene groups in this product have 1 to 3 R 15 It is optionally replaced by [this].

[0137] In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~4 Alkilen OR 16 and C 1~4 Alkylene NR 16a R 16b Selected from, and also R 13a H and C 1~4 Selected from alkyl groups. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~4 Alkilen OR 16 and C 1~4 Alkylene NR 16a R 16b Selected from, and also R 13a is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~4 Alkilen OR 16 and C 1~4 Alkylene NR16a R 16b Selected from, and also R 13a is selected from H, CH3 and CH2CH3. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~4 Alkilen OR 16 Selected from, and also R 13a This is selected from H and CH3.

[0138] In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~6 Alkilen OR 16 Selected from, and also R 12a In R 16 H and C 1~4 Selected from alkyl groups. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~6 Alkilen OR 16 Selected from, and also R 12a In R 16 is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C 1~6 Alkilen OR 16 Selected from, and also R 12a In R 16 is selected from H, CF3 and CH3. In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a C1~6 Alkilen OR 16 Selected from, and also R 12a In R 16 This is selected from H and CH3.

[0139] Therefore, in one embodiment, R 11 One of them is C 1~4 Alkylene NH(C) 1~6 Alkylene OH), C 1~4 Alkylene NCH3(C) 1~6 Alkylene OH), C 1~4 Alkylene NH(C) 1~6 Alkylene OCH3), C 1~4 Alkylene NCH3(C) 1~6 Selected from alkylene OCH3). In one embodiment, R 11 One of them is C 1~4 Alkylene NH(C) 1~4 Alkylene OH), C 1~4 Alkylene NCH3(C) 1~6 Alkylene OH), C 1~4 Alkylene NH(C) 1~4 Alkylene (OCH3) and C 1~4 Alkylene NCH3(C) 1~6 Selected from alkylene OCH3). In one embodiment, R 11 One of them is C 1~4 Alkylene NR 12a R 13a And also R 12a is C 1~6 Alkilen C 3~7 It is heterocycloalkyl, and also R 13a H and C 1~4 Selected from alkyl groups. In one embodiment, R 11 One of them is C 1~4 Alkilen C 3~7 It is heterocycloalkyl, and also R 12a is C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl, and also R 13a H and C 1~4 Selected from alkyl groups. In one embodiment, R 11 One of them is C 1~4Alkilen C 3~7 It is heterocycloalkyl, and also R 12a is C 1~2 Alkilen C 3~7 It is heterocycloalkyl, and also R 13a H and C 1~4 Selected from alkyl groups. In one embodiment, R 12a of the aforementioned C 1~4 Alkilen C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyls are selected from azetidinyl, oxetanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidine-2-onyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranil, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, thiepanyl, azabicyclohexanyl, azabicycloheptanyl, oxabicyclohexanyl, and oxabicycloheptanyl. In one embodiment, R 12a of the aforementioned C 1~4 Alkilen C 3~7 C in heterocycloalkyl 3~7 The heterocycloalkyl group is selected from azetidinyl, tetrahydrofuranil, pyrrolidinyl, pyrrolidine-2-onyl, piperidinyl, piperazinyl, and morpholinyl.

[0140] In one embodiment, one or two R 11 This is 1 to 3 R 15 C is optionally replaced by 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Selected independently from heterocycloalkyls. In one embodiment, one R 11 C1~3 Alkilen C 3~7 Cycloalkyl and C 3~7 Selected from cycloalkyl groups, with one or two R groups 15 It is optionally replaced by R. 11 of the aforementioned C 1~3 Alkilen C 3~7 Cycloalkyl and C 3~7 C in cycloalkyl 3~7 Cycloalkyls have one or two R 15 C selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hexanyl and bicyclo[2.2.1]heptanyl, which are optionally substituted by 3~7 Selected from cycloalkyl. In one embodiment, one R 11 This is 1 to 3 R 15 C is optionally replaced by 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups. In one embodiment, one R 11 is one or two R 15 C is optionally replaced by 1~3 Alkilen C 3~7 Cycloalkyl and C 3~7 Selected from cycloalkyl groups. In one embodiment, R 11 of the aforementioned C 1~3 Alkilen C 3~7 Cycloalkyl and C 3~7 C in cycloalkyl 3~7 Cycloalkyls have one or two R 15 C selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hexanyl and bicyclo[2.2.1]heptanyl, which are optionally substituted by3~7 Selected from cycloalkyl groups.

[0141] In one embodiment, one R 11 This is 1 to 3 R 15 C is optionally replaced by 3~7 Heterocycloalkyl and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups. In one embodiment, R 11 of the aforementioned C 3~7 Heterocycloalkyl and C 1~4 Alkilen C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl groups have 1 to 3 R 15 Selected from azetidinyl, oxetanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranil, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, thiepanyl, azabicyclohexanyl, azabicycloheptanyl, oxabicyclohexanyl, and oxabicycloheptanyl, which are optionally substituted by R. 11 C 4~6 Heterocycloalkyl and C 1~4 Alkilen C 4~6 Selected from heterocycloalkyl, and also R 11 of the aforementioned C 4~6 Heterocycloalkyl and C 1~4 Alkilen C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl groups have 1 to 3 R 15Selected from azetidinyl, oxetanyl, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanil, dithiolanil, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, and dioxanyl, which are optionally substituted by R. 11 of the aforementioned C 4~6 Heterocycloalkyl and C 1~4 Alkilen C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl groups have 1 to 3 R 15 Selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, and isothiazolidinyl, which are optionally substituted by R. 11 of the aforementioned C 4~6 Heterocycloalkyl and C 1~4 Alkilen C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl groups have 1 to 3 R 15 Selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl and thiazolidinyl, isothiazolidinyl, which are optionally substituted by R. 11 of the aforementioned C 4~6 Heterocycloalkyl and C 1~4 Alkilen C 4~6 C in heterocycloalkyl 4~6 The heterocycloalkyl is selected from pyrrolidine-2-onyl, azabicyclohexanyl, and azabicycloheptanyl. In some embodiments, R 11 of the aforementioned C 4~6 Heterocycloalkyl and C 1~4 Alkilen C 4~6 C in heterocycloalkyl 4~6The heterocycloalkyl group is pyrrolidine-2-onyl.

[0142] In one embodiment, R 11 of the aforementioned C 3~7 Heterocycloalkyl and C 1~4 Alkilen C 3~7 C in heterocycloalkyl 3~7 The heterocycloalkyl group contains at least one N atom. In one embodiment, R 11 of the aforementioned C 3~7 Heterocycloalkyl and C 1~4 Alkilen C 3~7 C in heterocycloalkyl 3~7 Each heterocycloalkyl group has one or two R 15 Selected from azetidinyl, pyrrolidinyl, pyrrolidine-2-onyl, azabicyclohexanyl, azabicycloheptanyl, piperidinyl, piperazinyl and morpholinyl, which are optionally substituted by R. 11 of the aforementioned C 4~6 Heterocycloalkyl and C 1~4 Alkilen C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyls have one or two R 15 It is a pyrrolidinyl that is optionally substituted by [the specified compound].

[0143] In one embodiment, R 11 One of them is 1 to 4 R 15 C is optionally replaced by 3~7 It is heterocycloalkyl, and also the C 3~7 Heterocycloalkyl groups have 1 to 4 R 15 Selected from azabicyclohexanyl, azabicycloheptanyl, pyrrolidinyl, and pyrrolidine-2-onyl, which are optionally substituted by R. 11 One of them is 1 to 4 R 15 C is optionally replaced by 4~6It is heterocycloalkyl, and also the C 4~6 The heterocycloalkyl is pyrrolidine-2-onyl. In one embodiment, R 11 One of them is 1 to 3 R 15 Pyrrolidine-2-onyl, which is optionally substituted by [ka] Selected from, here R 15d H and R 15 Selected from, and also, [ka] Cy 1 Represents a covalent bond point to R. In one embodiment, one R 11 is one or two R 15 C is optionally replaced by 4~6 It is heterocycloalkyl, and also the C 4~6 The heterocycloalkyl is pyrrolidinyl. In one embodiment, one R 11 is one or two R 15 Pyrrolidines that are optionally substituted by [ka] and [ka] Selected from, here R 15d H and R 15 Selected from, and also, [ka] Cy 1Represents a covalent bond point to R. In one embodiment, one R 11 is C 4~6 It is heterocycloalkyl, and also the C 4~6 Heterocycloalkyls have one or two R 15 Pyrrolidinyl that is optionally substituted by [ka] and [ka] Selected from, here R 15d H and R 15 Selected from, and also, [ka] Cy 1 Represents a covalent bond point to R. In one embodiment, R 15d is H. In one embodiment, R 15d is R 15 That is the case.

[0144] In one embodiment, R 11 One of them is 1 to 4 R 15 C is optionally replaced by 1~6 Alkilen C 3~7 It is heterocycloalkyl, and also the C 1~6 Alkilen C 3~7 C in heterocycloalkyl 3~7 The heterocycloalkyl is selected from azetidinyl, pyrrolidinyl, pyrrolidine-2-onyl, piperidinyl, piperazinyl, and morpholinyl. In one embodiment, R 11 One of them is 1 to 4 R 15 C is optionally replaced by 1~3 Alkilen C 4~7It is heterocycloalkyl, and also the C 1~6 Alkilen C 3~7 C in heterocycloalkyl 4~7 The heterocycloalkyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Therefore, in one embodiment, R 11 One of them is 1 to 4 R 15 C is optionally replaced by 1~3 Alkylene azetidinil, C 1~3 Alkilenpyrrolidinil, C 1~3 Alkylene piperidinyl, C 1~3 Alkylenepiperazinyl and C 1~3 Selected from alkylene morpholinyl. In one embodiment, R 11 One of them is 1 to 4 R 15 Selected from CH2 azetidinyl, CH2 pyrrolidinyl, CH2 piperidinyl, CH2 piperazinyl, and CH2 morpholinyl, which are optionally substituted by R. 11 One of them is one or two R 15 It is optionally replaced by [ka] Selected from, here R 15d H and R 15 Selected from, and also, [ka] Cy 1 This represents a common bond point.

[0145] In one embodiment, one R 11 is one or two R 15 C is optionally replaced by 1~6 Alkilen C 3~7 It is heterocycloalkyl, and also the C1~6 Alkilen C 3~7 C in heterocycloalkyl 3~7 The heterocycloalkyl is pyrrolidinyl. In one embodiment, one R 11 This is 1 to 3 R 15 C is optionally replaced by 1~4 It is alkylene pyrrolidinyl. In one embodiment, one R 11 This is 1 to 3 R 15 C is optionally replaced by 1~4 It is alkylene pyrrolidinyl, where at least one R 15 is F. In one embodiment, R 11 One of them is 1 to 4 R 15 Selected from CH2 pyrrolidinyl which is optionally substituted by R. 11 One of them is, [ka] And here [ka] Cy 1 This represents a common bond point.

[0146] In one embodiment, each R 15 F, Cl, CN, OH, C 1~4 Alkyl, OC 1~4 Alkyl and NR 15a R 15b Selected independently from R. In one embodiment, each R 15 F, Cl, OC 1~4 Alkyl, C 1~4 Alkyl and NR 15a R 15b Selected independently from.

[0147] In one embodiment, one R 15 These are OH and OC1~4 Alkyl and NR 15a R 15b Selected from. In one embodiment, R 15 One of them is OH and OC. 1~4 Selected from alkyl groups. In one embodiment, one R 15 is OC 1~4 It is alkyl. In one embodiment, R 15 One of them is OCH3.

[0148] In one embodiment, R 11 One of them is one or two R 15 The above C is replaced by 1~6 Alkilen C 3~7 It is heterocycloalkyl and also has one R 15 These are OH and OC 1~4 Selected from alkyl groups. In one embodiment, R 11 One of them is one R 15 The above C is replaced by 1~6 Alkilen C 3~7 It is heterocycloalkyl, and also R 15 It is OCH3.

[0149] In one embodiment, each R 15 F, Cl, CN, C 1~4 Alkyl and NR 15a R 15b Selected independently from R. In one embodiment, each R 15 F, C 1~4 Alkyl and NR 15a R 15b Selected independently from. In one embodiment, at least one R 15 is F. In one embodiment, one R 15 is NR 15a R 15b That is the case.

[0150] In one embodiment, R 15a and R 15b H and C 1~4 Selected independently from alkyl. In one embodiment, R 15a and R15b is independently selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 15a and R 15b is independently selected from H, CF3 and CH3. In one embodiment, R 15a and R 15b It is selected independently from H and CH3.

[0151] In one embodiment, Cy 1 is one R 11 It is replaced by R 11 C is unsubstituted. 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkilen C 3~7 Cycloalkyl and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups. In one embodiment, Cy 1 is one R 11 It is replaced by R 11 This is unsubstituted, as defined above, C 3~7 It is heterocycloalkyl. In one embodiment, Cy 1 is one R 11 It is replaced by R 11 The unsubstituted compound is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, and isothiazolidinyl. In one embodiment, Cy 1 is one R 11 It is replaced by R 11 This is an unsubstituted pyrrolidinyl. In one embodiment, Cy 1 is one R 11 It is replaced by R 11 It is the unsubstituted pyrrolidine-2-onyl.

[0152] In one embodiment, Cy 1 is one R 11 It is replaced by R 11 teeth, [ka] and [ka] Selected from, here [ka] Cy 1 Represents a covalent bond point to Cy 1 is one R 11 It is replaced by R 11 teeth, [ka] and [ka] Selected from, here [ka] Cy 1 This represents a common bond point.

[0153] In one embodiment, one to three R 11 These are F, Cl, CN, NO2 and C 1~4 Selected independently from alkyl. In some embodiments, one to three R 11 F, Cl, CN, NO2, CH3, CH2CH 3、 CH2CH2CH3CH2CH2CH2CH 3、 Independently selected from CH(CH3)2, CH2CH(CH3)2, C(CH3), and CH(CH3)2. In some embodiments, one to three R 11The following are independently selected from F, Cl, CN, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, CH2CH2CH2CH3, CF2H, CF3, CFH2, CH2CH2F, CH2CF2H, CH2CH2F2H, CH2CH2CH2F2H, and CH(CH3)2. In one embodiment, one to three R 11 The R is independently selected from F, Cl, CN, CH3, CH2CH3, CF3, CF2H, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, and CH(CH3)2. In one embodiment, one to three R 11 The R is independently selected from CH3, CH2CH3, CF3, CF2H, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, and CH(CH3)2. In one embodiment, one or two R 11 The R is selected from CF2H, CH2CF2H, CH2CH2F2H, and CH2CH2CH2F2H. In one embodiment, one or two R 11 The R is selected from CH2CH2F2H and CH2CH2CH2F2H. In one embodiment, one to three R 11 The R is independently selected from F, Cl, CN, CH3, CH2CH3, CF3, CH2CF2H, CH2CF3, and CH(CH3)2. In some embodiments, one to three R 11 This is independently selected from F, CN, CH3, CH2CH3, CF3, CH2CF2H, CH2CF3, and CH(CH3)2. In one embodiment, one R 11 is CN. In one embodiment, one to three R 11 These are independently selected from CF3, CH2CF3, and F. In some embodiments, one to three R 11 These are independently selected from CF2H, CH2CF2H, CH2CF2H, CH2CH2F2H, and CH2CH2CH2F2H. In one embodiment, one to three R 11 It is F.

[0154] In one embodiment, each R 11 F, CH3, CH2CH 3、 CH(CH3)2, OR 12 , C(O)R12 CO2R 12 , SR 12 SO2R 12 , S(O)(=NR 13 )R 12 , C 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 , C 1~4 Alkylene NR 12 R 13 , OC 1~4 Alkilen OR 12 , NR 13a C 1~4 Alkilen OR 12 , NR 13a COR 12 , and NR 13a SO2R 12 Selected independently from, and also R 12 is H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkylalkylene OR 16 , and C 1~2 Alkylalkylene NR 16a R 16b Selected from, and also R 11 All alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, heterocycloalkyl groups, and cycloalkyl groups have 1 to 3 R 17 It is optionally replaced by one to three R. In some embodiments, one to three R 11 is OR 12 , C(O)R 12 CO2R 12 , SR 12 SO2R 12 , S(O)(=NR 13 )R 12 , C 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 , NR 13a C 1~4 Alkilen OR12 , NR 13a COR 12 , and NR 13a SO2R 12 Selected independently from.

[0155] In one embodiment, R 12 and R 12a H, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~6 Alkilen C 3~10 Heterocycloalkyl, C 1~6 Alkilen OR 16 and C 1~6 Alkylene NR 16a R 16b Selected independently from, and also R 12 or R 12a All alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, heterocycloalkyl groups, and cycloalkyl groups have 1 to 3 R 17 It is optionally replaced by R. 12 and R 12a H, C 1~4 Alkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~4 Alkilen C 3~10 Heterocycloalkyl, C 1~4 Alkilen OR 16 , and C 1~4 Alkylene NR 16a R 16b Selected independently from, and also R 12 or R 12a All alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, and cycloalkyl groups have 1 to 3 R 17 It is optionally replaced by R. 12 and R 12a is H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, C 1~2 Alkilen C3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR 16 , and C 1~2 Alkylene NR 16a R 16b Selected independently from, R 12 or R 12a All alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, heterocycloalkyl groups, and cycloalkyl groups have 1 to 3 R 17 It is optionally replaced by. In one embodiment, each R 12 is H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, C(CH3), C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR 16 , and C 1~2 Alkylene NR 16a R 16b Selected from, also CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, C(CH3), C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR 16 , and C 1~2 Alkylene NR 16a R 16b This is 1 to 3 R 17 It is optionally replaced by [this].

[0156] In one embodiment, R 13 and R 13a H and C 1~4Selected independently from alkyl. In one embodiment, R 13 and R 13a is independently selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 13 and R 13a is independently selected from H, CF3 and CH3. In one embodiment, R 13 and R 13a is selected from H and CH3. In one embodiment, R 13 H and C 1~4 Selected independently from alkyl groups. In one embodiment, each R 13 R is independently selected from H, CH3, CH2CH3, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, each R 13 R is independently selected from H, CF3 and CH3. In one embodiment, each R 13 It is selected independently from H and CH3.

[0157] In one embodiment, R 12 and R 13 They bond together, and together with the nitrogen atom between them, form a 4-6 member group. Saturated or unsaturated It forms a ring, and this ring is N, NR 18 , optionally including one additional heterogroup selected from O, S, S(O), and SO2, and one to three R 17 It is optionally replaced by R. 12 and R 13 The atoms are bonded together, along with the nitrogen atom between them, to form a 4-6 membered heterocycloalkyl ring, which is selected from diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), and morpholinyl, and also contains 1-3 R atoms. 17 It is optionally replaced by R. 12 and R13 It binds together with the nitrogen atom between them, selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), and morpholinyl, and also contains 1 to 3 R 17 It forms a 5-6 member heterocycloalkyl ring that is optionally substituted by [a specific compound].

[0158] In one embodiment, one or two R 11 is OR 12 , C(O)R 12 CO2R 12 , SR 12 SO2R 12 , S(O)(=NR 13 )R 12 , C 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 , NR 13a C 1~4 Alkilen OR 12 , NR 13a COR 12 , and NR 13a SO2R 12 Selected independently from, and each R 12 H, C 1~4 Alkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~4 Alkilen C 3~10 Heterocycloalkyl, C 1~4 Alkilen OR 16 , and C 1~4 Alkylene NR 16a R 16b Selected independently from, and also R 12 The alkylene group, heterocycloalkyl group, and cycloalkyl group have 1 to 3 R 17 It is optionally replaced by R 13a H and C 1~4 Selected from alkyl groups. In some embodiments, one or two R groups are selected. 11 is OR 12, C(O)R 12 CO2R 12 , SR 12 SO2R 12 , S(O)(=NR 13 )R 12 , C 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 , NR 13a C 1~4 Alkilen OR 12 , NR 13a COR 12 , and NR 13a SO2R 12 Selected independently from, and also R 12 t, H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF 3、 CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR 16 , and C 1~2 Alkylene NR 16a R 16b Selected from, and also R 12 CH3 group, CH2CH3 group, CF2H group, CF3 group, CFH2 group, CH2CF2H group, CH2CF3 group 、 CH2CH2F2H group, CH2CH2CH2F2H group, CH(CH3)2 group, CH2CH(CH3)2 group, C(CH3)3 group, C 1~2 Alkilen C 3~10 Cycloalkyl groups, C 1~2 Alkilen C 3~10 Heterocycloalkyl groups, C 1~2 Alkilen OR 16 Base, and C 1~2 Alkylene NR 16a R 16b The base is 1 to 3 R 17 It is optionally replaced by R 13a H and C 1~4Selected from alkyl groups.

[0159] In one embodiment, one or two R 11 , SR 12 SO2R 12 , S(O)(=NR 13 )R 12 , NR 13a COR 12 , and NR 13a SO2R 12 Selected independently from, and also R 12 is H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH(CH3)2, CH2CH(CH3)2, C(CH3), C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR 16 , and C 1~2 Alkylene NR 16a R 16b Selected from, and also R 12 CH3 group, CH2CH3 group, CF2H group, CF3 group, CFH2 group, CH2CF2H group, CH2CF3 group, CH(CH3)2 group, CH2CH(CH3)2 group, C(CH3) group, C 1~2 Alkilen C 3~10 Cycloalkyl groups, C 1~2 Alkilen C 3~10 Heterocycloalkyl groups, C 1~2 Alkilen OR 16 Base, and C 1~2 Alkylene NR 16a R 16b The base is 1 to 3 R 17 It is optionally replaced by R 13a H and C 1~4 Selected from alkyl groups.

[0160] In one embodiment, one or two R 11 , SR 12 and SO2R 12 Selected independently from, R 12is H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, C(CH3), C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR 16 , and C 1~2 Alkylene NR 16a R 16b Selected from, and also R 12 All CH3 groups, CH2CH3 groups, CF2H groups, CF3 groups, CFH2 groups, CH2CF2H groups, CH2CF3 groups, CH2CH2F2H groups, CH2CH2CH2F2H groups, CH(CH3)2 groups, CH2CH(CH3)2 groups, C(CH3)3 groups, C 1~2 Alkilen C 3~10 Cycloalkyl groups, C 1~2 Alkilen C 3~10 Heterocycloalkyl groups, C 1~2 Alkilen OR 16 and C 1~2 Alkylene NR 16a R 16b The base is 1 to 3 R 17 It is optionally replaced by one or two R. In some embodiments, one or two R 11 , SR 12 and SO2R 12 Selected independently from, R 12 The R is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2 and C(CH3)3, where CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, and C(CH3)3, with 1 to 3 R 17 It is optionally replaced by [this].

[0161] In one embodiment, one or two R 11 is OR 12 , C(O)R 12 CO2R 12 , C 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 , NR 13a C 1~4 Alkilen OR 12 Selected independently from, and also R 12 is H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR 16 , and C 1~2 Alkylene NR 16a R 16b Selected from, and also R 12 All CH3 groups, CH2CH3 groups, CF2H groups, CF3 groups, CFH2 groups, CH2CF2H groups, CH2CF3 groups, CH2CH2F2H groups, CH2CH2CH2F2H groups, CH(CH3)2 groups, CH2CH(CH3)2 groups, C(CH3)3 groups, C 1~2 Alkilen C 3~10 Cycloalkyl groups, C 1~2 Alkilen C 3~10 Heterocycloalkyl groups, C 1~2 Alkilen OR 16 Base, and C 1~2 Alkylene NR 16a R 16b The base is 1 to 3 R 17 It is optionally replaced by R 13a H and C 1~4 Selected from alkyl groups.

[0162] In one embodiment, one or two R 11 is OR 12 , C(O)R12 CO2R 12 , C 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 , NR 13a C 1~4 Alkilen OR 12 Selected independently from, and also R 12 is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, and C(CH3)3, where R 12 In CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, and C(CH3)3 are 1 to 3 R 17 It is optionally replaced by R 13a H and C 1~4 Selected from alkyl groups. In some embodiments, one or two R groups are selected. 11 is OR 12 , C(O)R 12 CO2R 12 , C 1~4 Alkilen OR 12 and OC 1~4 Alkilen OR 12 Selected independently from, and also R 12 is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, and C(CH3)3, where R 12 In the above CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, and C(CH3)3 are 1 to 3 R 17 It is optionally replaced by one R. In one embodiment, one R11 is OR 12 , C 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 Selected from, and also R 12 is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, and C(CH3)3, where R 12 In the above CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH2CH2F2H, CH2CH2CH2F2H, CH(CH3)2, CH2CH(CH3)2, and C(CH3)3 are 1 to 3 R 17 It is optionally replaced by one R. In one embodiment, one R 11 is OH, OCH3, OCFH2, OCH2CF2H, OCH2CH2F2H, OCH2CH2CH2F2H, C 1~4 Alkylene OH, C 1~4 Alkylene OCH3, OC 1~4 Alkylene OH and OC 1~4 Selected from alkylene OCH3. In one embodiment, one R 11 The group is selected from OH, OCH3, OCFH2, OCH2CF2H, OCH2CH2F2H, OCH2CH2CH2F2H, CH2OH, CH2CH2OH, CH2CH2OCH3, CH2OCH3, OCH2CH2OH, and OCH2CH2OCH3.

[0163] In one embodiment, one R 11 is OR 12 , C 1~4 Alkilen OR 12 , OC 1~4 Alkilen OR 12 Selected from, and also R 12 C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR16 , and C 1~2 Alkylene NR 16a R 16b Selected from, and also R 12 In this, alkylene groups, heterocycloalkyl groups, and cycloalkyl groups have 1 to 3 R 17 It is optionally replaced by one R. In one embodiment, one R 11 is OR 12 , C 1~4 Alkilen OR 12 and OC 1~4 Alkilen OR 12 Selected from, and also R 12 C 1~2 Alkilen C 3~6 Cycloalkyl, C 1~2 Alkilen C 4~7 Heterocycloalkyl, and C 1~2 Alkylene NR 16a R 16b Selected from, and also R 12 In this, alkylene groups, heterocycloalkyl groups, and cycloalkyl groups have 1 to 3 R 17 It is optionally replaced by R. 12 In the C 4~7 The cycloalkyl group is selected from cyclopropyl and cyclobutyl. Therefore, in one embodiment, one R 11 is OR 12 , C 1~4 Alkilen OR 12 and OC 1~4 Alkilen OR 12 Selected from, and also R 12 C 1~2 Alkylenecyclopropyl, C 1~2 Alkylenecyclobutyl, and C 1~2 Alkilen C 4~7 Selected from heterocycloalkyl groups. In one embodiment, one R 11 is OR 12 and C 1~4 Alkilen OR 12 Selected from, and also R 12 C 1~2Alkylenecyclopropyl, C 1~2 Alkylenecyclobutyl, and C 1~2 Alkilen C 4~7 Selected from heterocycloalkyls. Therefore, in one embodiment, one R 11 OC 1~2 Alkylenecyclopropyl, OC 1~2 Alkylenecyclobutyl, C 1~4 Alkilen OC 1~2 Alkylenecyclobutyl, C 1~2 Alkilen C 4~7 Heterocycloalkyl and OC 1~2 Alkilen C 4~7 Selected from heterocycloalkyl groups.

[0164] In one embodiment, one or two R 11 Each of these has 1 to 3 R's. 17 C(O)R, which is optionally substituted by 12 and CO2R 12 Selected independently from, and each R 12 The R is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, CH(CH3)2, CH2CH(CH3)2, and C(CH3)3. In one embodiment, one or two R 11 This is independently selected from C(O)CH3, C(O)C(CH3)3, CO2CH3, and CO2C(CH3)3.

[0165] In one embodiment, each R 17 F, Cl, CN, C 1~4 Alkyl and NR 17a R 17b Selected independently from R. In one embodiment, each R 17 F, C 1~4 Alkyl and NR 17a R 17b Selected independently from. In one embodiment, at least one R 17 is F. In one embodiment, one R 17 is NR 17a R 17b That is the case.

[0166] In one embodiment, R 17a and R 17b H and C 1~4 Selected independently from alkyl. In one embodiment, R 17a and R 17b is independently selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 17a and R 17b is independently selected from H, CF3 and CH3. In one embodiment, R 17a and R 17b It is selected independently from H and CH3.

[0167] In one embodiment, R 14 , R 14a and R 14b is OR 19 , C 1~4 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 It is independently selected from heterocycloalkyls. In one embodiment, R 14 , R 14a and R 14b is OR 19 , C 1~4 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 It is independently selected from heterocycloalkyls. In one embodiment, R 14 , R 14a and R 14b One of them is OR 19 And also R 14 , R 14a and R 14b The remaining two are OR 19 , C 1~4Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 Selected from heterocycloalkyl groups. In one embodiment, R 14 , R 14a and R 14b One of them is OR 19 And also R 14 , R 14a and R 14b The remaining two are C 1~4 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 It is independently selected from heterocycloalkyls. In one embodiment, R 14 , R 14a and R 14b One of them is OR 19 And also R 14 , R 14a and R 14b The remaining two are OR 19 , C 1~4 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 Selected from heterocycloalkyl groups.

[0168] In one embodiment, R 16 , R 16a , R 16b , and R 18 H and C 1~4 The alkyl group is independently selected, and the alkyl group is optionally fluorosubstituted. In one embodiment, R 16a , R 16b , and R 18is independently selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 16 , R 16a , R 16b , and R 18 is independently selected from H, CF3 and CH3. In one embodiment, R 16 , R 16a , R 16b , and R 18 It is selected independently from H and CH3.

[0169] In one embodiment, R 19 H, C 1~4 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~4 Alkilen C 3~10 Heterocycloalkyl C 1~4 Alkilen OR 20 , and C 1~4 Alkylene NR 20 R 21 Selected from. In one embodiment, R 19 H and C 1~4 Selected from alkyl groups. In one embodiment, R 19 is H. In one embodiment, R 19 It is CH3.

[0170] In one embodiment, R 20 and R 21 H and C 1~4 It is selected independently of alkyl.

[0171] In one embodiment, Cy 1 Z-Cy 2 and one or two R 11 It is a phenyl, pyrrole, or pyridinyl substituted by Cy 1 Z-Cy 2 and one or two R 11A phenyl, pyrrole, or pyridinyl substituted by, and at least one R 11 is F. In one embodiment, Cy 1 Z-Cy 2 and one or two R 11 A phenyl compound that is substituted by and also contains at least one R 11 It is F.

[0172] In one embodiment, Cy 1 is one or two R 11 Replaced by, or Z-Cy 2 and one or two R 11 A phenyl, pyrrole, or pyridinyl substituted by. In one embodiment, Cy 1 is one or two R 11 By Z-Cy 2 and one or two R 11 A phenyl, pyrrole, or pyridinyl compound substituted with at least one R 11 is F. In one embodiment, Cy 1 is one or two R 11 It is replaced by or Z-Cy 2 and one or two R 11 A phenyl compound that is substituted by and also contains at least one R 11 It is F.

[0173] In one embodiment, Cy 1 is one or two R 11 Replaced by, or Z-Cy 2 and 1 to 3 R 11 A phenyl, pyrrole, or pyridinyl substituted by, and at least one R 11 is OR 12 , C(O)R 12 CO2R 12 , SR 12 SO2R 12 , S(O)(=NR 13 )R 12 , NR 13a COR12 , and NR 13a SO2R 12 Selected from. In one embodiment, Cy 1 is one or two R 11 Replaced by; or Z-Cy 2 and 1 to 3 R 11 A phenyl compound that is substituted by and also contains at least one R 11 However, OR 12 , C(O)R 12 CO2R 12 , SR 12 SO2R 12 , S(O)(=NR 13 )R 12 , NR 13a COR 12 , and NR 13a SO2R 12 Selected from. In one embodiment, R 12 is H, CH3, CH2CH3, CH(CH3)2, C(CH3)3, C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~2 Alkilen OR 16 , and C 1~2 Alkylene NR 13 R 16 Selected from. In one embodiment, R 12 C 1~2 Alkilen C 3~10 Cycloalkyl, and C 1~2 Alkilen C 3~10 Selected from heterocycloalkyl groups.

[0174] In one embodiment, Cy 1 is 1 to 3 R 11 Replaced by, or Z-Cy 2 and 1 to 3 R 11 A phenyl, pyrrole, or pyridinyl substituted by, and at least one R 11 SO2NR 12 R 13 and NR 13a C1~6 Alkylene NR 12 R 13 Selected from. In one embodiment, Cy 1 This is 1 to 3 R 11 Replaced by, or Z-Cy 2 and 1 to 3 R 11 A phenyl compound that is substituted with and also has one or two R 11 SO2NR 12 R 13 and NR 13a C 1~6 Alkylene NR 12 R 13 Selected from. In one embodiment, Cy 1 This is 1 to 3 R 11 Replaced by, or Z-Cy 2 and 1 to 3 R 11 It is a phenyl substituted with R 11 One of them is SO2NR 12 R 13 In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 It is a phenyl that is substituted by and also has one R 11 , NR 13a C 1~6 Alkylene NR 12 R 13 In one embodiment, each R 12 , R 13 and R 13a H and C 1~4 It is selected independently of alkyl.

[0175] In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl, pyrrole, or pyridinyl substituted by, and at least one R 11 is SiR 14 R14a R 14b In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl compound that is substituted with and also has one or two R 11 is SiR 14 R 14a R 14b In one embodiment, R 14 , R 14a and R 14b One of them is OR 19 And the rest are H, OR 19 , C 1~4 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 Selected from heterocycloalkyl groups.

[0176] In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one or two R compounds. 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a SO2NR 12 R 13 , NR 13a COR 12 , NR 13a C 1~4 Alkylene NR 12 R 13 , OR 12 , OC 1~4 Alkilen OR 12 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7Selected from heterocycloalkyl groups, where the two rear groups are 1 to 4 R groups. 15 It is optionally replaced by Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one or two R compounds. 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13aa , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two rear groups are 1 to 4 R groups. 15 It is optionally replaced by Cy 1 This is 1 to 3 R 9 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one or two R compounds. 11 C 1~4 Alkylene NR 12a R 13a Selected from. In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one or two R compounds. 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , OR 12 , C 1~4 Alkilen OR 12 , C3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two rear groups are 1 to 4 R groups. 15 It is optionally replaced by Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one or two R compounds. 11 C 1~4 Alkylene NR 12a R 13a and OR 12 Selected from. In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one or two R compounds. 11 The carbon atom is selected from CH2N(CH2CH3)2, C(CH3)2NH2, CH2N(CH3)2, CH2CH2N(CH3)2, and CH2N(CH3)2. In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one or two R compounds. 11 This is 1 to 4 R 15 C is optionally replaced by 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups.

[0177] In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 A phenyl or pyridinyl substituted by R 11One of them is C 1~4 Alkylene NR 12a R 13a , R 12a C 1~4 Alkilen OR 16 and C 1~4 Alkylene NR 16a R 16b Selected from, and also R 13a H and C 1~4 Selected from alkyl, and also R 12a All alkylene groups in this product have 1 to 3 R 17 It is optionally replaced by Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one R 11 C 1~4 Alkylene N(C) 1~6 Alkilen OR 16 )(R 13a ) is. In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl substituted with one or two R 11 C 1~4 Alkylene NR 12a R 13a Selected from, and also R 12a C 3~7 Heterocycloalkyl and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl, and also R 13a H and C 1~4 Selected from alkyl groups. In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 A phenyl or pyridinyl compound substituted with one or two R compounds.11 C 1~4 Alkylene NR 12a R 13a Selected from, and also R 12a C 3~7 Heterocycloalkyl and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl, and also R 12a H and C 1~4 Selected from alkyl, where C 1~4 Alkilen C 3~7 C in heterocycloalkyl 3~7 The heterocycloalkyl group is selected from azetidinyl, pyrrolidinyl, pyrrolidine-2-onyl, piperidinyl, piperazinyl, and morpholinyl.

[0178] In one embodiment, Cy 1 This is 1 to 3 R 11 Phenyl, pyrrole, or pyridinyl substituted by, and one R 11 is one or more R 15 It is a pyrrolidinyl that is optionally substituted by Cy 1 This is 1 to 3 R 11 It is a phenyl that is substituted by and also has one R 11 This is 1 to 4 R 15 It is a pyrrolidinyl that is optionally substituted by [the specified compound].

[0179] In one embodiment, Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 Phenyl, pyrrole, or pyridinyl substituted by, and one R 11 This is 1 to 4 R 15 C is optionally replaced by 1~4 It is alkylenepyrrolidinil. In one embodiment, Cy 1 This is 1 to 3 R 11It is replaced by or Z-Cy 2 and 1 to 3 R 11 It is a phenyl that is substituted by and also has one R 11 is one or two R 15 C is optionally replaced by 1~4 It is alkylene pyrrolidinil.

[0180] In one embodiment, Cy 1 This is a biring C 9~11 Aryl or tri-ring type C 11~16 It is an aryl group, where the aryl group is fused to one or two heterocycloalkyl groups and / or spirofused to Cy 1 is unsubstituted. In one embodiment, Cy 1 This is a biring C 9~11 Aryl or tri-ring type C 11~16 It is an aryl group, where the aryl group is fused to one or two heterocycloalkyl groups and / or spirofused to Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 It is replaced by and each R 11 F, Cl, CN, NO2, C 1~4 Alkyl, OR 12 , C(O)R 12 CO2R 12 , SR 12 SO2R 12 , C 1~6 Alkilen OR 12 It is independently selected from. In one embodiment, Cy 1 This is a biring C 9~11 It is an aryl group, where the aryl group is fused to a heterocycloalkyl group, and also Cy 1 This is either unsubstituted or one or more R 11 It is replaced by or Z-Cy 2 It is replaced by or Z-Cy 2 and one or more R 11It is replaced by Cy 1 This is a biring C 9~11 It is an aryl group, where the aryl group is fused to a heterocycloalkyl group, and also Cy 1 This is 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 It is replaced by and each R 11 F, Cl, CN, NO2, C 1~4 Alkyl, OR 12 , and C 1~6 Alkilen OR 12 It is independently selected from. In one embodiment, Cy 1 This is a three-ring type C 11~16 It is an aryl group, where the aryl group is fused and / or spirofused to two heterocycloalkyl groups, and Cy 1 This is 1 to 3 R 11 Replaced by; or Z-Cy 2 and 1 to 3 R 11 It is replaced by and each R 11 F, C 1~4 Alkyl, OR 12 , C(O)R 12 CO2R 12 , and C 1~6 Alkilen OR 12 It is independently selected from. In one embodiment, Cy 1 This is a three-ring type C 11~16 It is an aryl group, where the aryl group is fused and / or spirofused to two heterocycloalkyl groups, and Cy 1 is 1 to 2 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 It is replaced by and also has at least one R 11 is OR 12 , C(O)R 12 , and CO2R 12 Selected from. In one embodiment, R 12R is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CF3, and C(CH3)3. In some embodiments, each R 11 C 1~4 Alkylene NR 12a R 13a and NR 12a R 13a Independently selected from. In some embodiments, the aryl is phenyl, and therefore in some embodiments, Cy 1 is a benzo-fused bicyclic or tricyclic aryl group, where phenyl is fused and / or spiro-fused to one or two heterocycloalkyl groups.

[0181] In one embodiment, Cy 1 This is a benzo-fused bicyclic C 9~11 It is an aryl group, where the aryl group is phenyl fused to a heterocycloalkyl group, or a tricyclic C group. 11~16 It is an aryl group, where the aryl group is phenyl fused and / or spiro-fused to one or two heterocycloalkyl groups, all of which are 1 to 3 R 11 It is replaced by or Z-Cy 2 and 1 to 3 R 11 It is replaced by R 11 CH3, CF2H, CFH2, CH2CF2H, CH2CH2F2H, CH2CH2CH2F2H, OCH3, OCF2H, OCFH2, OCH2CF2H, OCH2CH2F2H, OCH2CH2CH2F2H, C 1~4 Alkylene NR 12a R 13a and NR 12a R 13a Selected from.

[0182] In one embodiment, Z does not exist. If Z does not exist, Cy 2 is Cy 1 Those skilled in the art will recognize that the two are covalently bonded by direct connections.

[0183] In one embodiment, Z is C 1~4 Alkylene, O, C(O), CO 2、 SO 2、 S(O)(=NHR 13b ) and NR 13b Selected from. In one embodiment, Z is C 1~4 Selected from alkylene, O, C(O), and SO2. In some embodiments, Z is O. In some embodiments, Z is SO2.

[0184] In one embodiment, Z is C 1~6 Alkylene O, C 1~6 Alkylene C(O), C 1~6 Alkylene CO2 2、 C 1~6 Alkilen S, C 1~6 Alkylene S(O), C 1~6 Alkylene SO2, C 1~6 Alkylene S(O)(=NR) 13b ), C 1~6 Alkylene NR 13b , OC 1~6 Alkylene, C(O)C 1~6 Alkylene, CO2C 1~6 Alkiren, SC 1~6 Alkylene, S(O)C 1~6 Alkylene, SO2C 1~6 Alkylene, S(O)(=NR) 13b )C 1~6 Alkylene and NR 13b C 1~6 Selected from alkylenes. In one embodiment, Z is C 1~4 Alkylene O, C 1~4 Alkylene C(O), C 1~6 Alkylene CO2 2、 C 1~4 Alkilen S, C 1~4 Alkylene S(O), C 1~4 Alkylene SO2, C 1~4 Alkylene S(O)(=NR) 13b ), C 1~4 Alkylene NR 13b , OC 1~4 Alkylene, C(O)C 1~4 Alkylene, CO2C 1~4Alkiren, SC 1~4 Alkylene, S(O)C 1~4 Alkylene, SO2C 1~4 Alkylene, S(O)(=NR) 13b )C 1~4 Alkylene and NR 13b C 1~6 Selected from alkylenes. In one embodiment, Z is C 1~4 Alkylene O, C 1~4 Alkylene C(O), C 1~6 Alkylene CO2 2、 C 1~4 Alkilen S, C 1~4 Alkylene S(O), C 1~4 Alkylene SO2, C 1~4 Alkylene NR 13b , OC 1~4 Alkylene, C(O)C 1~4 Alkylene, CO2C 1~4 Alkiren, SC 1~4 Alkylene, S(O)C 1~4 Alkylene, SO2C 1~4 Alkylene and NR 13b C 1~6 Selected from alkylenes. In one embodiment, Z is C 1~4 Alkylene O, C 1~4 Alkylene C(O), OC 1~4 Alkylene and C(O)C 1~4 Selected from alkylenes. In one embodiment, Z is C 1~4 Alkylene O, C 1~4 Alkylene C(O), C 1~6 Alkylene CO2 2、 C 1~4 Alkilen S, C 1~4 Alkylene S(O), C 1~4 Alkylene SO2, C 1~4 Alkylene NR 13b , OC 1~4 Alkylene, C(O)C 1~4 Alkylene, CO2C 1~4 Alkiren, SC 1~4 Alkylene, S(O)C 1~4 Alkylene, SO2C 1~4 Alkylene and NR 11b C1~6 Selected from alkylenes. In one embodiment, Z is OC 1~4 Alkylene and C(O)C 1~4 Selected from alkylenes. In one embodiment, Z is OC 1~4 It is alkylene.

[0185] In one embodiment, R 13b H and C 1~4 Selected from alkyl groups. In one embodiment, R 13b R13b is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R13b is selected from CH2CH2CF2H and CH2CH2CH2CF2H. In one embodiment, R 13b is selected from H, CF3 and CH3. In one embodiment, R 13b This is selected from H and CH3.

[0186] In one embodiment, Cy 2 is C 3~11 It is cycloalkyl, and also Cy 2 It is either unsubstituted or has one or more R 22 It is replaced by Cy 2 The compound is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one embodiment, Cy 2 It is cyclopropyl.

[0187] In one embodiment, Cy 2 is a single ring C 3~7 It is heterocycloalkyl, and also Cy 2 It is either unsubstituted or has one or more R 22 It is replaced by Cy 2The following are selected from azetidinil, oxetanil, tetrahydrofuranil, tetrahydrothiophenyl, pyrrolidinil, dihydropyrrolyl, imidazolidinil, pyrazolidinil, thiazolidinil, isothiazolidinil, dioxolanil, dithiolanil, 5,6-dihydro-1,2,4-triazinil, 3,4,5,6-tetrahydro-1,2,4-triazinil, dioxidethiomorpholino, tetrahydropyridinil, dihydropyridinil, dihydropyranil, thianil, piperidinil, piperazinil, tetrahydrofuranil, tetrahydropyranil, thiomorpholinil, morpholinil, dioxanil, azepanil, diazepanil, oxepanil and thiepanil, and Cy 2 It is either unsubstituted or has one or more R 22 It is replaced by Cy 2 The following are selected from azetidinil, 5,6-dihydro-1,2,4-triazinil, dioxidethiomorpholino, thiomorpholinil, tetrahydrofuranil, tetrahydropyranil, diazepanil, pyrrolidinil, piperidinil, piperazinil and morpholinil, and Cy 2 It is either unsubstituted or has 1 to 3 R 22 It is replaced by Cy 2 It is selected from tetrahydrofuranil, tetrahydropyranil, pyrrolidinil, piperidinil, piperazinil and morpholinil, and Cy 2 It is either unsubstituted or has 1 to 3 R 22 It is replaced by Cy 2 It is selected from pyrrolidinyl, piperidinyl, piperazinyl and morpholinil, and Cy 2 It is either unsubstituted or has 1 to 3 R 22 It is replaced by Cy 2 is dihydropyranyl. In one embodiment, Cy 2 It is selected from piperidinyl, piperazinyl, and morpholinyl, and Cy 2 It is either unsubstituted or has one or two R 22 It is replaced by Cy2 It is piperazinyl, and also Cy 2 It is either unsubstituted or has one or two R 22 It is replaced by Cy 2 This is 1 to 3 R 22 Selected from tetrahydrofuranyl, dihydropyranyl, morpholinyl, and tetrahydropyranyl, which are substituted by Cy 2 This is 1 to 3 R 22 It is tetrahydropyranyl substituted with [another substance].

[0188] In one embodiment, Cy 2 It is either unsubstituted or has 1 to 4 R values. 22 It is replaced by [ka] Selected from Here again R 22d H and R 22 Selected from; also [ka] This represents a shared bond point to Z.

[0189] In one embodiment, Cy 2 It is either unsubstituted or has 1 to 4 R values. 22 It is replaced by [ka] Selected from Here again R 22d H and R 22 Selected from; also [ka] This represents a shared bond point to Z.

[0190] In one embodiment, Cy 2 This is either unsubstituted or one or more R 22 It is replaced by [ka] Selected from Here again R 22d is H or R 22 Selected from; also [ka] This represents a shared bond point to Z.

[0191] In one embodiment, Cy 2 This is either unsubstituted or one or more R 22 It is replaced by [ka] Selected from And here again, R 22d is H or R 22 Selected from; also [ka] This represents a shared bond point to Z.

[0192] In one embodiment, Cy 2 It is a bicyclic heterocycle, and also Cy 2 It is either unsubstituted or has one or more R 22 It is replaced by Cy 2 It is a bridging biring heterocycle, and also Cy 2It is either unsubstituted or has one or more R 22 It is replaced by Cy 2 It is a fused bicyclic heterocycle or a spiro-fused bicyclic heterocycle, and also Cy 2 It is either unsubstituted or has one or more R 22 It is replaced by Cy 2 This is either unsubstituted or one or more R 22 It is a fused bicyclic heterocycle that is substituted by Cy 2 In this case, one or two of the ring carbon atoms are N, NH, or NR depending on the valence requirement of N. 22 C6~C is replaced by 10 A saturated bicyclic ring, the ring being unsubstituted or having one or more R components. 20 It is replaced by Cy 2 These are azabicyclohexanil, diazabicycloheptanil, or diazabicyclooctanil, and also Cy 2 It is either unsubstituted or has one or more R 22 It is replaced by Cy 2 This is a crosslinked azabicyclohexanil, a crosslinked diazabicycloheptanil, or a crosslinked diazabicyclooctanil. In one embodiment, Cy 2 The following structures are selected: [ka] The structure is either unsubstituted or has one or more R 22 It is replaced by R here 22d is H or R 22 Selected from, and also, [ka] Cy 1 This represents a common bond point.

[0193] In one embodiment, Cy 2 The following structures are selected: [ka] , The structure is either unsubstituted or has one or more R 22 It has been replaced by, and Here R 22d is H or R 22 Selected from, and also, [ka] represents a covalent bond point to Z. In one embodiment, Cy 2 is one or more R 22 It is not substituted by [ka] And here R 22d is H or R 22 Selected from, and also, [ka] This represents a shared bond point to Z.

[0194] In one embodiment, Cy 2 It is selected from tetrahydrofuropyrrolyl, hexapyrazinooxazinyl, hexahydropyrrolopyrazinyl, and hexahydropyrrolodiazepinyl, and Cy 2 It is either unsubstituted or has one or more R 22 It is replaced by Cy 2 This is either unsubstituted or one or more R 22 It is replaced by [ka] Selected from; Here [ka] This represents a shared bond point to Z.

[0195] In one embodiment, Cy 2 It is a spiro-fused bicyclic heterocycle, and also Cy 2 It is either unsubstituted or has 1 to 4 R 22 It is replaced by Cy 2 It is either unsubstituted or has 1 to 4 R values. 22 It is replaced by [ka] Selected from

[0196] ;Also Here, R 22d H and R 22 Selected from, and also,

[0197] [ka] This represents a shared bond point to Z.

[0198] If Z does not exist, Cy 2 In the structure [ka] Cy 1 Those skilled in the art will recognize that this represents a covalent bond point.

[0199] In one embodiment, Cy 2 is unsubstituted. In one embodiment, Cy2 is 1 to 3 R 22 It is replaced by Cy 2 is one or two R 22 It is replaced by Cy 2 is one R 22 It has been replaced by.

[0200] In one embodiment, each R 22 is F, Cl, =O, CN, OH, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~11 Ariel, C 5~14 Heteroaryl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~4 Alkilen C 6~11 Ariel, C 1~4 Alkilen C 5~14 Heteroaryl, C 1~4 Alkilen C 3~10 Heterocycloalkyl, OC 1~4 Alkyl, OC 2~4 Alkenyl, OC 2~4 Alkinyl, C 1~4 Alkilen OR 21 , OC 1~4 Alkilen OR 21 , C 1~4 Alkylene NR 24 R 25 , OC 1~4 Alkylene NR 24 R 25 SC 1~4 Alkyl, SC 2~4 Alkenil, SC 2~4 Alkinyl, C(O)C 1~4 Alkyl, C(O)C 2~4 Alkenyl, C(O)C 2~4 Alkinyl, C(O)C 3~10 Cycloalkyl, C(O)C 3~10 Heterocycloalkyl, C(O)C 6~11 Aryl, C(O)C5~14 Heteroaryl, C(O)C 1~4 Alkilen C 3~10 Cycloalkyl, C(O)C 1~4 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkilen C 6~11 Aryl, C(O)C 1~4 Alkilen C 5~14 Heteroaryl, C(O)C 1~4 Alkirenyl Ure 23 , C(O)C 1~4 Alkylene NR 24 R 25 , C(O)C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 , C(O)NR 24 R 25 CO2C 1~6 Alkyl, CO2C 2~4 Alkenyl, CO2C 2~4 Alkinyl, CO2C 1~4 Alkilen OR 23 CO2C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 , NR 24 R 25 , NR 26 C 3~10 Cycloalkyl, NR 26 C 3~10 Heterocycloalkyl, NR 26 C 6~11 Ariel, NR 26 C 5~14 Heteroaryl, NR 26 C 1~4 Alkilen C 3~10 Cycloalkyl, NR 26 C 1~4 Alkilen C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkilen C 6~11 Ariel, NR 26 C 1~4 Alkilen C 5~14 Heteroaryl, NR 26C 1~4 Alkilen OR 23 , NR 26 SO2C 1~4 Alkyl, SO2C 1~6 Alkyl, SO2C 2~4 Alkenyl, SO2C 2~4 Alkinyl and SO2NR 24 R 25 Selected independently from, and also R 22 Alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, aryl groups, heteroaryl groups, heterocycloalkyl groups, and cycloalkyl groups are 1 to 3 R 27 It is optionally replaced by. In one embodiment, each R 22 is F, Cl, =O, CN, OH, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~4 Alkilen C 3~10 Heterocycloalkyl, OC 1~4 Alkyl, OC 2~4 Alkenyl, OC 2~4 Alkinyl, C 1~4 Alkilen OR 21 , OC 1~4 Alkilen OR 21 , C 1~4 Alkylene NR 24 R 25 , OC 1~4 Alkylene NR 24 R 25 SC 1~4 Alkyl, SC 2~4 Alkenil, SC 2~4 Alkinyl, C(O)C 1~4 Alkyl, C(O)C 2~4 Alkenyl, C(O)C 2~4 Alkinyl, C(O)C 3~10 Cycloalkyl, C(O)C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkilen C 3~10Cycloalkyl, C(O)C 1~4 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkirenyl Ure 23 , C(O)C 1~4 Alkylene NR 24 R 25 , C(O)C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 , C(O)NR 24 R 25 CO2C 1~6 Alkyl, CO2C 2~4 Alkenyl, CO2C 2~4 Alkinyl, CO2C 1~4 Alkilen OR 23 CO2C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 , NR 24 R 25 , NR 26 C 3~10 Cycloalkyl, NR 26 C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkilen C 3~10 Cycloalkyl, NR 26 C 1~4 Alkilen C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkilen OR 23 , NR 26 SO2C 1~4 Alkyl, SO2C 1~6 Alkyl, SO2C 2~4 Alkenyl, SO2C 2~4 Alkinyl and SO2NR 24 R 25 Selected independently from, and also R 22 The alkyl, alkenyl, alkynyl, alkylene, and cycloalkyl groups are 1 to 3 R 27 It is optionally replaced by [this].

[0201] In one embodiment, each R 22 F, Cl, =O, CN, OH, NO2, C 1~4 Alkyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~11 Ariel, C 5~10 Heteroaryl, C 1~4 Alkilen C 3~10 Cycloalkyl, C 1~4 Alkilen C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 6~11 Ariel, C 1~4 Alkilen C 5~14 Heteroaryl, OC 1~4 Alkyl, C 1~4 Alkilen OR 23 , OC 1~4 Alkilen OR 23 , C 1~4 Alkylene NR 24 R 25 , OC 1~4 Alkylene NR 24 R 25 SC 1~4 Alkyl, C(O)C 1~4 Alkyl, C(O)C 3~10 Cycloalkyl, C(O)C 3~10 Heterocycloalkyl, C(O)C 6~11 Aryl, C(O)C 5~10 Heteroaryl, C(O)C 1~4 Alkilen C 3~10 Cycloalkyl, C(O)C 1~4 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkilen C 6~11 Aryl, C(O)C 1~4 Alkilen C 5~10 Heteroaryl, C(O)C 1~4 Alkilen OR 23 , C(O)C 1~4 Alkylene NR 24 R 25 , C(O)C 1~4 Alkilen OC 1~4 Alkylene NR 24 R25 , C(O)NR 24 R 25 CO2C 1~6 Alkyl, CO2C 1~4 Alkilen OR 23 CO2C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 , NR 24 R 25 , NR 26 C 3~10 Cycloalkyl, NR 26 C 3~10 Heterocycloalkyl, NR 26 C 6~11 Ariel, NR 26 C 5~10 Heteroaryl, NR 26 C 1~4 Alkilen C 3~10 Cycloalkyl, NR 26 C 1~4 Alkilen C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkilen C 6~11 Ariel, NR 26 C 1~4 Alkilen C 5~10 Heteroaryl, NR 26 C 1~4 Alkilen OR 23 , NR 26 SO2C 1~4 Alkyl, SO2C 1~6 Alkyl and SO2NR 24 R 25 Selected independently from, and also R 22 Alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, aryl groups, heteroaryl groups, heterocycloalkyl groups, and cycloalkyl groups are 1 to 3 R 27 It is optionally replaced by. In one embodiment, each R 22 F, Cl, CN, OH, NO2, C 1~4 Alkyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10Cycloalkyl, C 1~4 Alkilen C 3~10 Heterocycloalkyl, OC 1~4 Alkyl, C 1~4 Alkilen OR 23 , OC 1~4 Alkilen OR 23 , C 1~4 Alkylene NR 24 R 25 , OC 1~4 Alkylene NR 24 R 25 SC 1~4 Alkyl, C(O)C 1~4 Alkyl, C(O)C 3~10 Cycloalkyl, C(O)C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkilen C 3~10 Cycloalkyl, C(O)C 1~4 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkilen OR 23 , C(O)C 1~4 Alkylene NR 24 R 25 , C(O)C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 , C(O)NR 24 R 25 CO2C 1~6 Alkyl, CO2C 1~4 Alkilen OR 23 CO2C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 , NR 24 R 25 , NR 26 C 3~10 Cycloalkyl, NR 26 C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkilen C 3~10 Cycloalkyl, NR 26 C 1~4 Alkilen C 3~10 Heterocycloalkyl, NR 26C 1~4 Alkilen OR 23 , NR 26 SO2C 1~4 Alkyl, SO2C 1~6 Alkyl and SO2NR 24 R 25 Selected independently from, and also R 22 The alkyl, alkenyl, alkynyl, alkylene, and cycloalkyl groups are 1 to 3 R 27 It is optionally replaced by one R. In one embodiment, one R 22 The value is O.

[0202] In one embodiment, each R 22 F, Cl, =O, CN, OH, NO2, C 1~4 Alkyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 6~11 Ariel, C 5~10 Heteroaryl, C 1~2 Alkilen C 3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 6~11 Ariel, C 1~4 Alkilen C 5~14 Heteroaryl, OC 1~4 Alkyl, C 1~4 Alkilen OR 21 , C(O)C 1~4 Alkyl, C(O)C 3~10 Cycloalkyl, C(O)C 3~10 Heterocycloalkyl, (O)C 6~11 Aryl, C(O)C 5~10 Heteroaryl, C(O)C 1~4 Alkilen C 3~10 Cycloalkyl, C(O)C 1~4 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkilen C 6~11 Aryl, C(O)C 1~4 Alkilen C 5~10 Heteroaryl, C(O)C1~4 Alkilen OR 23 , C(O)C 1~4 Alkylene NR 24 R 25 , C(O)C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 CO2C 1~6 Alkyl, CO2C 1~4 Alkilen OR 23 , NR 24 R 25 , NR 26 C 3~10 Cycloalkyl, NR 26 C 3~10 Heterocycloalkyl, NR 26 C 6~11 Ariel, NR 26 C 5~10 Heteroaryl, NR 26 C 1~2 Alkilen C 3~10 Cycloalkyl, NR 26 C 1~2 Alkilen C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkilen C 6~11 Ariel, NR 26 C 1~4 Alkilen C 5~10 Heteroaryl, NR 26 C 1~4 Alkilen OR 23 , NR 26 SO2C 1~4 Alkyl and SO2C 1~6 Independently selected from alkyl, and also R 22 Alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, aryl groups, heteroaryl groups, heterocycloalkyl groups, and cycloalkyl groups are 1 to 3 R 27 It is optionally replaced by. In one embodiment, each R 22 F, Cl, CN, OH, NO2, C 1~4 Alkyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~2 Alkilen C3~10 Cycloalkyl, C 1~2 Alkilen C 3~10 Heterocycloalkyl, OC 1~4 Alkyl, C 1~4 Alkilen OR 21 , C(O)C 1~4 Alkyl, C(O)C 3~10 Cycloalkyl, C(O)C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkilen C 3~10 Cycloalkyl, C(O)C 1~4 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkilen OR 23 , C(O)C 1~4 Alkylene NR 24 R 25 , C(O)C 1~4 Alkilen OC 1~4 Alkylene NR 24 R 25 CO2C 1~6 Alkyl, CO2C 1~4 Alkilen OR 23 , NR 24 R 25 , NR 26 C 3~10 Cycloalkyl, NR 26 C 3~10 Heterocycloalkyl, NR 26 C 1~2 Alkilen C 3~10 Cycloalkyl, NR 26 C 1~2 Alkilen C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkilen OR 23 , NR 26 SO2C 1~4 Alkyl and SO2C 1~6 Independently selected from alkyl, and also R 22 The alkyl, alkenyl, alkynyl, alkylene, and cycloalkyl groups are 1 to 3 R 27 It is optionally replaced by [this].

[0203] In one embodiment, each R 27 F, Cl, CN, C 1~4 Alkyl and NR 27a R 27b Selected independently from R. In one embodiment, each R 27 F, C 1~4 Alkyl and NR 27a R 27b Selected independently from. In one embodiment, at least one R 27 is F. In one embodiment, R 27 One of them is NR 27a R 27b That is the case.

[0204] In one embodiment, R 27a and R 27b H and C 1~4 Selected independently from alkyl. In one embodiment, R 27a and R 27b is independently selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, R 27a and R 27b is independently selected from H, CF3 and CH3. In one embodiment, R 27a and R 27b It is selected independently from H and CH3.

[0205] In one embodiment, R 23 H, C 1~4 Alkyl, C 1~4 Alkilen OC 1~6 Alkyl, C 3~11 Cycloalkyl, C 3~10 Heterocycloalkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 Selected from heterocycloalkyl groups. In one embodiment, R 23 H and C 1~4 Selected from alkyl groups. In one embodiment, R 23 C 1~4Alkilen OC 1~6 Alkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 Selected from heterocycloalkyl groups.

[0206] In one embodiment, R 24 H and C 1~4 Selected from alkyl groups.

[0207] In one embodiment, R 25 H, C 1~4 Alkyl, C 1~4 Alkilen OC 1~4 Alkyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkilen C 3~10 Cycloalkyl, and C 1~4 Alkilen C 3~10 Selected from heterocycloalkyl groups.

[0208] In one embodiment, R 24 and R 25 H and C, respectively. 1~4 Selected independently from alkyl. In one embodiment, R 24 and R 25 They bond together, along with the atoms between them, N, NR 28 , optionally including one additional heterogroup selected from O, S, S(O), and SO2, and also containing a halo and C 1~6 A 4-6 member molecule optionally substituted with one to three alkyl groups. Saturated or unsaturated It forms a ring.

[0209] In one embodiment, R 23 , R 26 and R 28 H and C 1~4 It is selected independently of alkyl.

[0210] In one embodiment, each R 22is F, Cl, =O, CN, OH, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF2H, CF3, CFH2, CH2CFH2, CH2CF2H, CH2CH2CF2H, CH2CH2CH2CF2H, CH2CF3, CH2CH2CF3, CH2CH2CH2CF3, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, phenyl, C 5~14 Heteroaryl, C 1~4 Alkilen C 3~6 Cycloalkyl, C 1~4 Alkilen C 3~6 Heterocycloalkyl, C 1~4 Alkylenephenyl, C 1~4 Alkilen C 5~14 Heteroaryl, OC 1~4 Alkyl, C 1~4 Alkylene OH, C 1~4 Alkylene OCH3, C(O)C 1~4 Alkyl, C(O)C 3~6 Cycloalkyl, C(O)C 3~6 Heterocycloalkyl, C(O)phenyl, C(O)C 5~14 Heteroaryl, C(O)C 1~2 Alkilen C 3~6 Cycloalkyl, C(O)C 1~2 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~2 Alkylenephenyl, C(O)C 1~2 Alkilen C 5~14 Heteroaryl, C(O)C 1~4 Alkylene OCH3, C(O)C 1~4 Alkylene OH, C(O)C 1~4 Alkylene NH2, C(O)C 1~4 Alkylene N(CH3)2, C(O)C 1~4 Alkilen OC 1~4 Alkylene N(CH3)2, CO2C 1~6 Alkyl, CO2C 1~4 Alkilen OC 1~6 Alkyl, NHC 1~4 Alkyl, NC 1~4 Alkyl C 1~4 Alkyl, NHC 1~2Alkilen C 3~10 Cycloalkyl, NHC 1~2 Alkylenephenyl, NHC 1~2 Alkilen C 5~14 Heteroaryl, N(CH3)C 1~2 Alkilen C 3~10 Cycloalkyl, N(CH3)C 1~2 Alkilen C 3~10 Heterocycloalkyl, N(CH3)C 1~2 Alkylenephenyl, N(CH3)C 1~2 Alkilen C 5~14 Heteroaryl, NHC 1~2 Alkilen C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkylene OH, NR 26 C 1~4 Alkylene OCH3, NHSO2C 1~4 Alkyl, NCH3SO2C 1~4 Alkyl and SO2C 1~6 Independently selected from alkyl, and also R 22 The alkyl groups, alkylene groups, phenyl groups, heteroaryl groups, heterocycloalkyl and cycloalkyl groups consist of 1 to 3 R groups. 27 It is optionally substituted by and each R 27 F, Cl, and C 1~4 Selected independently from alkyl groups. In one embodiment, each R 22 is F, Cl, =O, CN, OH, CH3, CH2CH3, CH(CH3)2, C(CH3)3, CF2H, CF3, CFH2, CH2CFH2, CH2CF2H, CH2CF3, CH2CH2CF3, CH2CH2CH2CF3, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkilen C 3~6 Cycloalkyl, C 1~4 Alkilen C 3~6 Heterocycloalkyl, OC 1~4 Alkyl, C 1~4 Alkylene OH, C 1~4 Alkylene OCH3, C(O)C 1~4 Alkyl, C(O)C3~6 Cycloalkyl, C(O)C 3~6 Heterocycloalkyl, C(O)C 1~2 Alkilen C 3~6 Cycloalkyl, C(O)C 1~2 Alkilen C 3~10 Heterocycloalkyl, C(O)C 1~4 Alkylene OCH3, C(O)C 1~4 Alkylene OH, C(O)C 1~4 Alkylene NH2, C(O)C 1~4 Alkylene N(CH3)2, C(O)C 1~4 Alkilen OC 1~4 Alkylene N(CH3)2, CO2C 1~6 Alkyl, CO2C 1~4 Alkilen OC 1~6 Alkyl, NHC 1~4 Alkyl, NC 1~4 Alkyl C 1~4 Alkyl, NHC 1~2 Alkilen C 3~10 Cycloalkyl, NCH3C 1~2 Alkilen C 3~10 Cycloalkyl, NCH3C 1~2 Alkilen C 3~10 Heterocycloalkyl, NHC 1~2 Alkilen C 3~10 Heterocycloalkyl, NR 26 C 1~4 Alkylene OH, NR 26 C 1~4 Alkylene OCH3, NHSO2C 1~4 Alkyl, NCH3SO2C 1~4 Alkyl and SO2C 1~6 Independently selected from alkyl, and also R 22 The alkyl groups, alkylene groups, and cycloalkyl groups consist of 1 to 3 R 27 It is optionally substituted by and each R 27 F, Cl, and C 1~4 Selected independently from alkyl groups. In one embodiment, each R 22 This is selected independently from CH2CH2CF2H and CH2CH2CH2CF2H.

[0211] In one embodiment, each R 22 C 3~6 Cycloalkyl, C 3~6 Heterocyclic alkyl, C 1~4 Alkilen C 3~6 Cycloalkyl and C 1~4 Alkilen C 3~6 Independently selected from heterocycloalkyls. In one embodiment, each R 22 C 3~5 Cycloalkyl, C 3~6 Heterocyclic alkyl, C 1~4 Alkilen C 3~5 Cycloalkyl, and C 1~4 Alkilen C 3~5 It is independently selected from heterocycloalkyls. In one embodiment, R 22 All cycloalkyl groups have 1 to 3 R 27 It is optionally replaced by [this].

[0212] In one embodiment, each R 22 R is independently selected from cyclopropyl, cyclobutyl, and cyclopentyl. In some embodiments, each R 22 The compound is independently selected from cyclopropyl and cyclobutyl. In one embodiment, each of the cyclopropyl, cyclobutyl, and cyclopentyl compounds contains 1 to 3 R compounds. 27 It is optionally replaced by [this].

[0213] In one embodiment, each R 22 C 1~4 Alkylenecyclopropyl, C 1~4 Alkylenecyclobutyl and C 1~4 Independently selected from alkylenecyclopentyl. In one embodiment, R 22 All cycloalkyl groups have 1 to 3 R 27 It is optionally replaced by. In one embodiment, each R 22 C 1~4 Alkylenecyclopropyl and C 1~4Independently selected from alkylene C3 cyclobutyl. In one embodiment, each R 22 C 1~4 Alkylenecyclopropyl, C 1~4 Alkylene C3 cyclobutyl and C 1~4 Independently selected from alkylenecyclopentyl, and also R 22 All cycloalkyl groups have 1 to 3 R 27 It is optionally replaced by one R. In one embodiment, one R 22 is C 1~3 It is alkylenecyclopropyl. 22 is 1 to 3 R 27 C is optionally replaced by 1~3 It is alkylenecyclopropyl. In one embodiment, one R 22 is C 1~3 Alkylenecyclopropyl [ka] Selected from.

[0214] In one embodiment, one R 20 is selected from CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CH2CF2H, CH2CH2CH2CF2H and CH2CF3. In one embodiment, each R 22 R is independently selected from CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, each R 22 The R is independently selected from CH3, CH2CH3, and CH(CH3)2. In one embodiment, each R 22 The R is independently selected from CH2CH3 and CH(CH3)2. In one embodiment, each R 22 This is independently selected from optionally fluorosubstituted CH2CH3 and CH(CH3)2. In one embodiment, one R 22The following are selected from CF2H, CH2CF2H, CH2CH2CF2H, and CH2CH2CH2CF2H.

[0215] In one embodiment, R 22 One of them is phenyl, C 6~11 Heteroaryl, C 1~4 Alkilen C 6~11 Aryl and C 1~4 Alkilen C 5~14 Selected from heteroaryls, and also R 22 The aryl and heteroaryl groups are 1 to 3 R 27 It is optionally replaced by R. 22 One of them is phenyl, C 5~7 Heteroaryl, C 1~4 Alkylenephenyl and C 1~4 Alkilen C 5~7 Selected from heteroaryls, and also R 22 All aryl groups, heteroaryl groups, and cycloalkyl groups are 1 to 3 R 27 It is optionally replaced by R. 22 One of them is 1 to 3 R 27 Phenyl and C are optionally substituted by 1~2 Selected from alkylenephenyl. In one embodiment, R 20 One of them is C 5~7 Heteroaryl and C 1~6 Alkilen C 5~7 Selected from heteroaryls, and also R 22 All heteroaryl groups have 1 to 3 R 27 It is optionally replaced by R. 27 C 5~7 Heteroaryl and C 1~6 Alkilen C 5~7The heteroaryl in heteroaryl is selected from pyrrolyl, furanyl, thiophenyl, imidazolyl, pyrazolyl, oxathiolyl, isoxathiolyl, oxaxolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl and tetrazolyl. In one embodiment, R 22 C 5~7 Heteroaryl and C 1~6 Alkilen C 5~7 In heteroaryls, the heteroaryl is triazolyl. In one embodiment, the triazole is 1,2,3-triazole or 1,2,4-triazole.

[0216] In one embodiment, R 22 One of them is C 3~6 Heterocyclic alkyl and C 1~4 Alkilen C 3~6 Selected from heterocycloalkyl groups. In one embodiment, R 22 of the aforementioned C 3~6 Heterocyclic alkyl and C 1~4 Alkilen C 3~6 C in heterocycloalkyl 3~6 The heterocyclic alkyl group is independently selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0217] In one embodiment, one R 22 CO2C 1~6 It is alkyl. In one embodiment, one R 22 The following are selected from CO2CH3, CO2CH2CH3, CO2CF2H, CO2CF3, CO2CFH2, CO2CH2CF2H, CO2CH2CF3, CO2CH2CH2F2H, CO2CH2CH2CH2F2H, CO2CH(CH3)2, and CO2CH2CH(CH3)2. For a certain axial position, one R 22 It is CO2CH3.

[0218] In one embodiment, one R 22 COC 1~6 It is alkyl. In one embodiment, one R 22The following are selected from COCCH3, COCH2CH3, COCF2H, COCF3, COCFH2, COCH2CF2H, COCH2CF3, COCH2CH2F2H, COCH2CH2CH2F2H, COCH(CH3)2, and COCH2CH(CH3)2. For some axial values, one R 22 It is COCH3.

[0219] In one embodiment, each R 22 teeth, [ka] [ka] Selected independently from.

[0220] In one embodiment, each R 22 teeth, [ka] [ka] Selected independently from.

[0221] In one embodiment, Cy 2 These are pyrrolidinyl, piperidinyl, piperazinyl, or morpholinil, and each R 22 These are independently CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, Cy 2 These are pyrrolidinyl, piperidinyl, piperazinyl, or morpholinil, and each R 22 These are independently CH2CH3 or CH(CH3)2.

[0222] In one embodiment, Cy 2These are pyrrolidinyl, piperidinyl, piperazinyl, or morpholinil, and also one R 22 is C 1~3 It is alkylenecyclopropyl.

[0223] In one embodiment, the compound of formula (I) is a compound of formula (IA) or formula (IB), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, R 5 , X 1 , X 2 , X 3 , X 4 , X 5 and Cy 1 This is as defined in equation (I) above; and m is an integer selected from 0 to 4. Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

[0224] In one embodiment, the compound of formula (I) is the compound of formula (IC) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, Q, X 1 , X 2 , X 3 , and R 3 and Cy 1 This is defined in equation (I) above, Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

[0225] In one embodiment, the compound of formula (I) is a compound of formula (ID) and (IE), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, Q, R 11 , R 22 , X 1 , X 2 , X 3 , X 4 , X 5 , Z, Cy 1 and Cy 2 This is defined in equation (I) above; n is an integer selected from 0 to 5; and p and q are independently selected from integers 0 to 4. Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

[0226] In one embodiment, the compound of formula (I) is a compound of formula (ID) and (IE) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, Q, R 3 , R 11 , R 22 , X 1 , X 2 , X 3 , Z, Cy 1 and Cy 2 This is defined in equation (I) above; r is an integer selected from 0 to 5; and s and t are independently selected from integers 0 to 4. Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

[0227] In one embodiment, R 3 It is F.

[0228] In one embodiment, the compound of formula (I) is the compound of formula (IH) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, R 5c , X 1 , X 2 , X 3 , X 4 , X 5 and Cy 1 This is as defined in equation (I) above; and u is an integer selected from 0 to 2. Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

[0229] In one embodiment, the compound of formula (I) is a compound of formula (IJ) or formula (IK), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, R 5c , X 1 , X 2 , X 3 , X 4 , X 5 and Cy 1 This is as defined in equation (I) above; and v is an integer selected from 0 and 1. Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

[0230] In one embodiment, the compound of formula (I) is a compound of formula (IL) or formula (IM) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, R 5c , R 11 , X 1 , X 2 , X 3 , Z, Cy 1 and Cy 2 This is defined in equation (I) above; w and aa are independently selected from integers 0 to 2. y and bb are independently selected from integers 0 to 4, and cc is an integer selected from 0 to 5.

[0231] In one embodiment, R in the formula (IL) or (IM) 5c F, Cl, OH, C 1~4 Alkyl, OC 1~4 Alkyl and NR 9 R 10 Selected from. In one embodiment, one or two R 5c These are F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H and NR 9 R 10 Selected from.

[0232] In one embodiment, the compound of formula (I) is a compound of formula (IN) or formula (IO) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, R 5c , R 11 , X 1 , X 2 , X 3 , Z, Cy 1 and Cy2 This is defined in equation (I) above; dd and ee are independently selected from integers 0 to 4, and ff is an integer selected from 0 to 5.

[0233] In one embodiment, the compound of formula (I) is a compound of formula (IP) or formula (IQ), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, Q, R 22 , X 1 , X 2 , X 3 , Z, Cy 1 , and Cy 2 This is defined in equation (I) above; R 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 SO2NR 12 R 13 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the last four groups are 1 to 4 R groups. 15 It is optionally replaced by R 12 , R 12a , R 13 , R 13a and R 15 This is defined in equation (I) above; ff is an integer selected from 1 to 5; and gg is an integer selected from 1 to 4, and hh is an integer selected from 0 to 5.

[0234] In some embodiments, ff is 1 or 2, preferably 1. In some embodiments, gg is 1 or 2, preferably 1. In some embodiments, one R in formula (IP) or formula (IQ) 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two trailing groups are 1 to 4 R groups as defined by formula (I). 15 It is optionally replaced by. In one embodiment, one or two R in formula (IP) or formula (IQ) 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two trailing groups are 1 to 4 R groups as defined by formula (I). 15 It is optionally substituted by. In one embodiment, one R in formula (IP) or formula (IQ) 11 The C specified above for equation (I) is 1~2 Alkylene NR 12a R 13a In one embodiment, ff and gg are 1 or 2, preferably 1.

[0235] In one embodiment, the compound of formula (I) is a compound of formula (IR) or formula (IS), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, R 5c , X 1 , X 2 , X 3 , Z, Cy 1 and Cy 2 This is defined in equation (I) above; R 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 SO2NR 12 R 13 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the last four groups are 1 to 4 R groups. 15 It is optionally replaced by R 12 , R 12a , R 13 , R 13a and R 15 This is defined in equation (I) above; ii and kk are independently selected from integers 0 to 2. jj and mm are independently selected from integers 1 to 4, and ll is an integer selected from 0 to 5.

[0236] In one embodiment, both ii and kk are 1, and R in the formula (IR) or (IS) 5cis selected from F and Cl. In one embodiment, both ii and kk are 1, and R in the formula (IR) or (IS) 5c It is F.

[0237] In some embodiments, jj is 1 or 2, preferably 1. In some embodiments, ll is 1 or 2, preferably 1. In some embodiments, one R in the formula (IR) or (IS) 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two trailing groups are 1 to 4 R groups as defined by formula (I). 15 It is optionally substituted by. In one embodiment, one or two R in the expression (IR) or (IS) 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two trailing groups are one to four R groups as defined above for formula (I). 13 It is optionally substituted by. In one embodiment, one R in the expression (IR) or (IS) is replaced 11 The C specified above for equation (I) is 1~2 Alkylene NR 12a R 13a That is the case.

[0238] In one embodiment, the compound of formula (I) is a compound of formula (IT) or (IU) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, R 5c , X 1 , X 2 , X 3 , Z, Cy 1 and Cy 2 This is defined in equation (I) above; R 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 SO2NR 12 R 13 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the last four groups are 1 to 4 R groups. 15 It is optionally replaced by R 12 , R 12a , R 13 , R 13a and R 15 This is defined in equation (I) above; nn and pp are independently selected from integers 1 to 4, and oo is an integer selected from 0 to 5.

[0239] In some embodiments, nn is 1 or 2, preferably 1. In some embodiments, oo is 1 or 2, preferably 1. In some embodiments, one R in the formula (IT) or (IU) 11 C1~4 Alkylene NR 12a R 13a , NR 12a R 13a , NR 13a COR 12 , NR 13a C 1~4 Alkylene NR 12 R 13 , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two trailing groups are one to four R groups as defined above for formula (I). 13 It is optionally substituted by. In one embodiment, one or two R in the expression (IT) or (IU) 11 C 1~4 Alkylene NR 12a R 13a , NR 12a R 13a , C 3~7 Heterocycloalkyl, and C 1~4 Alkilen C 3~7 Selected from heterocycloalkyl groups, where the two trailing groups are 1 to 4 R groups as defined by formula (I). 15 It is optionally substituted by. In one embodiment, one R in the expression (IT) or (IU) 11 The C specified above for equation (I) is 1~4 Alkylene NR 12a R 13a That is the case.

[0240] In one embodiment, the compound of formula (I) is selected from the compounds listed in Table 1 or their pharmaceutically acceptable salts, solvates, and / or prodrugs. [Table 1-1] [Table 1-2] Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46

[0241] In certain embodiments of the present application, the compounds described herein may have at least one chiral center. If a compound has two or more chiral centers, the compound may exist as a diastereomer. It should be understood that all such isomers and mixtures thereof in any ratio are encompassed within the scope of the present application. The stereochemistry of a compound may be as shown in a given compound enumerated in the present application, but the compound may be found in a specific amount (e.g., less than 20%, preferably less than 10%, more preferably less than 5%) of the same compound of the present application having an alternative stereochemistry. ) including It should also be understood that this is acceptable. Any optical isomer as separated, pure, or partially purified optical isomers, or racemic mixtures thereof, are intended to be included within the scope of this application.

[0242] The compounds of this application may exist in various tautomer forms, and any tautomers formed by the compounds, as well as mixtures thereof, are intended to be included within the scope of this application.

[0243] The compounds of this invention are various polymorphic It may exist in any form, and any compound that forms polymorphism , or mixtures thereof, are also intended to be included within the scope of this application.

[0244] In some embodiments, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt. The selection of a suitable salt can be made by those skilled in the art (see, for example, S.M. Berge, eta I., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0245] An acid addition salt suitable for the treatment of the target is any non-toxic organic or inorganic acid addition salt of any basic compound. Examples of basic compounds that form acid addition salts include compounds containing an amine group. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as acidic metal salts such as sodium monohydrogen orthophosphate and potassium bisulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids. Examples of such organic acids include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and other sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and 2-hydroxyethanesulfonic acid. In some embodiments, mono-acid salts or di-acid salts are formed, and such salts may exist in hydrated, solvated, or substantially anhydrous forms. Generally, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points compared to their free base forms. The criteria for selecting a suitable salt will be known to those skilled in the art. Other pharmaceutically acceptable salts, such as oxalates, but not limited to them, may be used, for example, in the isolation of the compounds of the present invention for experimental purposes or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0246] A suitable or compatible base addition salt for the treatment of the target is any non-toxic organic or inorganic base addition salt of any acidic compound. Examples of acidic compounds that form base addition salts include compounds containing a carboxylic acid group. Exemplary inorganic bases that form suitable salts include lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, or barium hydroxide, as well as ammonia. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. For example, if ester functional groups are present in other parts of the compound, the selection of an appropriate salt may be useful in preventing the hydrolysis of such ester functional groups. The criteria for selecting an appropriate salt will be known to those skilled in the art.

[0247] Examples of solvates of the compound of this application include those formed with a pharmaceutically acceptable solvent. Examples of such solvents include water (the resulting solvate is called a hydrate) and ethanol, and so on.

[0248] The prodrug of the compound of the present invention may be, for example, a conventional ester formed with an available hydroxyl group, thiol group, amino group, or carboxyl group. Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates, and amino acid esters.

[0249] The compounds of the present application include radioactive and non-radioactive isotopes in any of the atoms, and also include compounds having alternative isotopes. For example, in one embodiment, the compounds of the present application include compounds in which one or more available hydrogen atoms are substituted with deuterium. In one embodiment, the compounds of the present application include compounds in which one or more available carbon atoms are 13 Compounds in which carbon is substituted are also examples.

[0250] The compounds of this application are appropriately formulated into compositions using one or more carriers in a conventional manner. Therefore, this application also encompasses compositions comprising one or more of the compounds of this application and carriers. The compounds of this application are appropriately formulated into pharmaceutical compositions for administration to a subject in a biocompatible form suitable for in vivo administration. Therefore, this application further encompasses pharmaceutical compositions comprising one or more of the compounds of this application and pharmaceutically acceptable carriers.

[0251] The compounds of this application, including their salts and / or solvates, are preferably used alone, but generally, one or more of the compounds of this application (active ingredients) are used together. Allowable It will be administered in the form of a composition with a suitable carrier. Depending on the mode of administration, the composition will contain about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of the active ingredient and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of a suitable carrier. Here, all weight percentage values ​​are based on the entire composition.

[0252] The compounds of this application may be administered to subjects in various forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, the compounds of this application may be administered orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally, and the pharmaceutical composition may be formulated accordingly. Administration may be carried out by pump for periodic or continuous delivery. Conventional procedures and raw materials for selecting and preparing suitable compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999.

[0253] Parenteral administration modes include intravenous, intra-arterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary (e.g., by aerosol), intrathecal, rectal, and topical (including the use of patches or other transdermal delivery devices). Parenteral administration may also be by continuous infusion over a selected period.

[0254] Suitable pharmaceutical forms for injectable use include sterile aqueous solutions or aqueous dispersions and Extermination Examples include sterile powders for the extemporaneous preparation of injectable solutions or dispersions of bacteria. In all cases, the form must be sterile and fluid enough to allow for easy injection.

[0255] The compounds of this application may be administered orally, for example, using an inert diluent or an assimilated edible carrier, or encapsulated in a hard-shell or soft-shell gelatin capsule, or compressed into a tablet, or taken directly with food. For oral therapeutic administration, the compounds may be incorporated with a pharmaceutical excipient and may be used in the form of ingestible tablets, buccal tablets, lozenges, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, aqueous suspensions, etc. In the case of tablets, suitable carriers include lactose, corn starch, sodium citrate, and phosphoric acid salts. pharmaceutically acceptable excipients include binders (e.g., pre-gelatinized corn starch, polyvinylpyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). Tablets may be coated in methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, pH-sensitive enteric coatings such as Eudragits®, designed to control the release of the active ingredient, are optionally used. Oral dosage forms also include modified-release formulations, such as immediate-release and timed-release formulations.Examples of modified release formulations include, for example, sustained-release (SR), extended-release (ER, XR, or XL), time-release or timed-release, controlled-release (CR), or continuous-release (CR or Contin), and are used, for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, aggregated particles (e.g., aggregated particles of molecular sieve type particles), or fine hollow permeable fiber bundles, or chopped hollow permeable fiber groups that are aggregated or held in fibrous packets. Timed-release compositions may be formulated, for example, as liposomes, or as formulations in which the active compound is protected by a coating that is differentially degradable (by microencapsulation, multilayer coating, etc.). Liposome delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes may be formed from various phospholipids, such as cholesterol, stearylamine, or phosphatidylcholine. For oral administration in capsule form, lactose and dried corn starch are useful carriers or diluents.

[0256] Liquid preparations for oral administration may take the form of solutions, syrups, or suspensions, or may be appropriately presented as dry products to be prepared using water or other suitable solvents (vehicles) before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present invention are suitably suspended or dissolved in an oil phase combined with emulsifiers and / or suspending agents. Certain sweeteners and / or flavoring agents and / or colorants may be added as desired. Such liquid preparations for oral administration are prepared by conventional methods using pharmaceutically acceptable additives. Examples of pharmaceutically acceptable additives include suspending agents (e.g., sorbitol syrup, methylcellulose, or edible hydrogenated fats); emulsifiers (e.g., lecithin or acacia); non-aqueous solvents (vehicles) (e.g., almond oil, oily esters, or ethyl alcohol); and preservatives (e.g., methyl p-hydroxybenzoate, propyl p-hydroxybenzoate, or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycol.

[0257] For example, it is possible to freeze-dry the compound of the present invention and use the resulting freeze-dried product for the preparation of an injection product.

[0258] The compound of this application may be administered parenterally. For example, a solution of the compound of this application can be prepared in water, appropriately mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof (with or without alcohol), and in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. Those skilled in the art know how to prepare suitable formulations. For parenteral administration, a sterile solution of the compound of this application is usually prepared and buffered by appropriately adjusting the pH of the solution. For intravenous use, the total concentration of the solute should be controlled so that the preparation is isotonic. For ocular administration, an ointment or instillable liquid may be delivered by an ocular delivery system known in the art, such as an applicator or dropper. Such compositions may contain mucosal mimics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose, or polyvinyl alcohol, preservatives such as sorbic acid, EDTA, or benzalkonium chloride, and a normal amount of diluent or carrier. For pulmonary administration, the diluent or carrier should be selected to be suitable for enabling aerosol formation.

[0259] The compounds of this application may be formulated for parenteral administration by infusion, which includes conventional catheter insertion techniques or infusions. The formulation for infusion may be given, for example, in a unit dose form with added preservatives, for example, in an ampoule or in a multi-dose container. The composition may take the form of a sterile suspension, solution, or emulsion in an oily or aqueous solvent (vehicle), and may contain formulation agents such as suspending agents, stabilizers, and / or dispersants. In all cases, the form must be sterile and fluid enough to be easily injected. Alternatively, the compounds of this application may be preferably in the form of a sterile powder for reconstitution before use using a suitable solvent (vehicle), such as sterile water free of pyrogens.

[0260] Compositions for nasal administration may be formulated as aerosols, drops, gels, and powders for convenience.

[0261] For intranasal or inhalation administration, the compound of the present invention is conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer. The aerosol formulation typically comprises a solution or microsuspension of the active compound in a physiologically acceptable aqueous or non-aqueous solvent, and is usually provided in sterile form as a single dose or multiple dose in a sealed container. The container may take the form of a cartridge or refill for use with a spray device. Alternatively, the sealed container may be a unit dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser fitted with a metering valve intended to be discarded after use. If the drug delivery form includes an aerosol dispenser, it will also include a propellant. The propellant may be a compressed gas, such as compressed air or an organic propellant such as a fluorochloro hydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit is appropriately determined by providing a valve for dispensing the measured amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (e.g., made of gelatin) for use in inhalers or inhalers may be formulated to contain, for example, a powder mixture of the compound of the present invention and a suitable powder base such as lactose or starch. The aerosol dosage form may take the form of a pump atomizer.

[0262] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and troches, in which the active ingredient is formulated with a carrier such as sugar, acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0263] The compounds of this application, in suppository form, are useful for vaginal, urethral, ​​and rectal administration. Such suppositories generally consist of a mixture of substances that are solid at room temperature but melt at body temperature. Substances commonly used to make such vehicles include, but are not limited to, cocoa butter (also known as cocoa oil), glycerin-gelatinized, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For further explanation of suppository administration forms, see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530–1533.

[0264] The compounds of the present invention may be conjugated to soluble polymers as targetable drug carriers. Examples of such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl aspartamido-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present invention may be conjugated to a class of biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyran, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0265] In some embodiments, the compounds of the present application may be coupled with a viral vector, a non-viral vector, or other vector. Examples of viral vectors include retroviruses, lentiviruses, adenoviruses, herpesviruses, poxviruses, alphaviruses, vaccinia viruses, or adeno-associated viruses. Examples of non-viral vectors include nanoparticles, cationic lipids, cationic polymers, metal nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Examples of nanoparticles include silica, lipids, carbohydrates, or other pharmaceutically acceptable polymers.

[0266] In one embodiment, depending on the administration method, the pharmaceutical composition comprises about 0.05% to about 99% by weight or about 0.10% to about 70% by weight of an active ingredient (one or more compounds of the present application), and about 1% to about 99.95% by weight or about 30% to about 99.90% by weight of one or more pharmaceutically acceptable carriers, where all weight percentage values ​​are based on the entire composition.

[0267] In some embodiments, the compounds of the present application are administered simultaneously or sequentially with other therapeutic agents in separate unit dosing forms, or together in a single unit dosing form. Accordingly, the present application provides a single unit dosing form comprising one or more compounds of the present application (e.g., compounds of formula (I)), additional therapeutic agents, and a pharmaceutically acceptable carrier.

[0268] To clarify, in the above, the term "compound" also includes embodiments that refer to one or more types of compounds.

[0269] III. Method and Use of the Application The compounds of this application have been shown to inhibit HPK1 activity. In some embodiments, the HPK1 is human HPK1; see, for example, Hu, MC et al.; Genes Dev. 10 (1):2251-2264, 1996.

[0270] Accordingly, the Application also includes a method for inhibiting HPK1 in cells in a biological sample or in a patient, comprising administering an effective amount of one or more of the Compounds of the Application to the cells. The Application also includes the use of one or more of the Compounds of the Application for inhibiting HPK1 in cells, and the use of one or more of the Compounds of the Application for the preparation of a pharmacopoeia for inhibiting HPK1 in cells. The Application further includes one or more of the Compounds of the Application for use in inhibiting HPK1.

[0271] Since the compounds of this application have been shown to inhibit HPK1, they are useful for treating diseases, disorders, or conditions by inhibiting HPK1. Therefore, the compounds of this application are useful as pharmaceuticals. Accordingly, this application encompasses the compounds of this application for use as pharmaceuticals.

[0272] The present invention also includes a method for treating a disease, disorder, or condition that can be treated by inhibiting HPK1, which involves administering a therapeutically effective amount of one or more of the compounds of the present invention to a subject in need of treatment.

[0273] This application also includes the use of one or more of the compounds of this application for the treatment of diseases, disorders, or conditions treatable by inhibiting HPK1, and the use of one or more of the compounds of this application for the preparation of pharmaceuticals for the treatment of diseases, disorders, or conditions treatable by inhibiting HPK1. This application further includes one or more of the compounds of this application for use in the treatment of diseases, disorders, or conditions treatable by inhibiting HPK1.

[0274] In some embodiments, the disease, disorder, or condition treatable by inhibiting HPK1 is a neoplastic disorder. Therefore, the Application also encompasses a method for treating a neoplastic disorder, comprising administering a therapeutically effective amount of one or more of the Compounds of the Application to a subject in need of treatment. The Application also encompasses the use of one or more of the Compounds of the Application for the treatment of neoplastic disorders, and the use of one or more of the Compounds of the Application for the preparation of a medicament for the treatment of neoplastic disorders. The Application further encompasses one or more of the Compounds of the Application for use in treating neoplastic disorders. In some embodiments, the treatment is an effective amount to alleviate at least one symptom of a neoplastic disorder in a subject in need of such treatment, particularly, for example, reducing cell proliferation or reducing tumor volume.

[0275] The compounds of the present application have been demonstrated to inhibit HPK1 and, therefore, to inhibit cytokine release in immune-derived cells (e.g., Jurkat-T cells). Accordingly, in some other embodiments of the present application, the disease, disorder, or condition that can be treated by inhibiting HPK1 is cancer. Accordingly, the present application also encompasses a method for treating cancer, comprising administering a therapeutically effective amount of one or more of the compounds of the present application to a subject in need of treatment. The present application also encompasses the use of one or more of the compounds of the present application for the treatment of cancer, and the use of one or more of the compounds of the present application for the preparation of a medicament for the treatment of cancer. The present application further encompasses one or more of the compounds of the present application for use in treating cancer. In some embodiments, the compounds are administered for the prevention of cancer in a subject predisposed to cancer, e.g., a mammal predisposed to cancer.

[0276] In one embodiment, the cancer is selected from hematological cancers, breast cancers, ovarian cancers, lung cancers, melanomas, colon cancers, and glioblastomas.

[0277] In some embodiments, the diseases, disorders, or conditions treatable by inhibiting HPK1 are diseases, disorders, or conditions associated with uncontrolled and / or abnormal cellular activity that is directly or indirectly affected by inhibiting HPK1. In other embodiments, the uncontrolled and / or abnormal cellular activity that is directly or indirectly affected by inhibiting HPK1 is proliferative activity in cells. Accordingly, the Application also encompasses methods for inhibiting proliferative activity in cells, comprising administering an effective amount of one or more of the Compounds of the Application to cells. The Application also encompasses the use of one or more of the Compounds of the Application for inhibiting proliferative activity in cells, and the use of one or more of the Compounds of the Application for the preparation of a pharmacopoeia for inhibiting proliferative activity in cells. The Application further encompasses one or more of the Compounds of the Application for use in inhibiting proliferative activity in cells by boosting immune cell function through HPK1 inhibition.

[0278] This application also includes methods for inhibiting uncontrolled and / or abnormal cellular activity directly or indirectly affected by inhibiting HPK1 in cells within a biological sample or subject, comprising administering an effective amount of one or more of the compounds of this application to cells. This application also includes the use of one or more of the compounds of this application for inhibiting uncontrolled and / or abnormal cellular activity directly or indirectly affected by inhibiting HPK1 in cells, and the use of one or more of the compounds of this application for the preparation of pharmaceuticals for inhibiting uncontrolled and / or abnormal cellular activity directly or indirectly affected by inhibiting HPK1 in cells. This application further includes one or more of the compounds of this application for use in inhibiting uncontrolled and / or abnormal cellular activity directly or indirectly affected by inhibiting HPK1 in cells.

[0279] The Application also includes a method for treating a disease, disorder, or condition treatable by inhibiting HPK1, comprising administering to a subject in need of treatment one or more of the Compounds of the Application in a therapeutically effective amount, in combination with other known agents useful for treating a disease, disorder, or condition treatable by inhibiting HPK1. The Application also includes the use of one or more of the Compounds of the Application in combination with other known agents useful for treating a disease, disorder, or condition treatable by inhibiting HPK1, for the treatment of a disease, disorder, or condition treatable by inhibiting HPK1, and the use of one or more of the Compounds of the Application in combination with other known agents useful for treating a disease, disorder, or condition treatable by inhibiting HPK1, for the preparation of a medicament for the treatment of a disease, disorder, or condition treatable by inhibiting HPK1. The Application further includes the use of one or more of the Compounds of the Application in combination with other known agents useful for treating a disease, disorder, or condition treatable by inhibiting HPK1, for use in treating a disease, disorder, or condition treatable by inhibiting HPK1. In one embodiment, the disease, disorder, or condition that can be treated by inhibiting HPK1 is cancer.

[0280] In a further embodiment, the disease, disorder, or condition treatable by inhibiting HPK1 is cancer, and the one or more compounds are administered in combination with one or more additional cancer therapies. In another embodiment, the additional cancer therapies are selected from targeted therapies such as radiotherapy, chemotherapy, and antibody therapy, as well as small molecule tyrosine kinase inhibitor therapy, immunotherapy, hormone therapy, and anti-angiogenic therapy.

[0281] When used in combination with other agents or treatments useful for treating a disease, disorder, or condition by inhibiting HPK1, it is one embodiment that the compounds of the Application are administered concurrently with those agents or treatments. In this disclosure, “contemporary administration” of two substances or treatments to a subject means administering each of the two substances or treatments so that they are simultaneously active in the individual. The exact details of the administration will depend on the pharmacokinetics of the two substances or treatments in the presence of each other, but if the pharmacokinetics are suitable, this may include administering the two substances or treatments within a few hours of each other, or even administering one substance or treatment within 24 hours of the administration of the other. Designing an appropriate drug regimen is a routine practice for those skilled in the art. In certain embodiments, the two substances or treatments are administered substantially simultaneously, that is, within a few minutes of each other, or, in the case of administration of two substances, in a single composition. The non-contemporary administration of a combination of agents or treatments is a further embodiment of the Application.

[0282] In one embodiment, the subject is a mammal. In another embodiment, the subject is a human.

[0283] In the context of treating diseases, disorders, or conditions treatable by HPK1 inhibition, the effective dose is, for example, the amount of one or more compounds that inhibits HPK1 compared to inhibition without administration. The effective dose may vary depending on factors such as the disease state, age, sex, and / or weight of the subject. The amount of a given compound that would constitute an effective dose will vary depending on various factors such as the given drug or compound, pharmaceutical formulation, route of administration, condition, type of disease or disorder, and the identity of the person being treated, but can be routinely determined by those skilled in the art. The effective dose is what appears as improvement or reduction of disease symptoms after treatment with that dose. If the disease is cancer, the effective dose may cause a reduction in the number, growth rate, size, and / or distribution of tumors.

[0284] The dosage of the compound in this application varies depending on many factors, including, for example, the compound PharmacodynamicsFactors include the characteristics, mode of administration, the recipient's age, health, and weight, the nature and severity of symptoms, the frequency of treatment, and (if any) the type of concurrent treatment, as well as the clearance rate of the compound within the patient receiving treatment. Those skilled in the art can determine an appropriate dosage based on the above factors. The compound of the present invention may be administered initially at an appropriate dosage, and the dosage may be adjusted as needed in response to the clinical response. The dosage is generally selected to maintain serum levels of the compound of the present invention at approximately 0.01 μg / cc to approximately 1000 μg / cc or approximately 0.1 μg / cc to approximately 100 μg / cc. Typical examples include oral dosages of one or more compounds of the present invention for adults ranging from approximately 1 mg to approximately 1000 mg per day, preferably from approximately 1 mg to approximately 500 mg per day, and more preferably from approximately 1 mg to approximately 200 mg per day. For parenteral administration, typical doses are approximately 0.001 mg / kg to 10 mg / kg, 0.01 mg / kg to 10 mg / kg, 0.01 mg / kg to 1 mg / kg, or 0.1 mg / kg to 1 mg / kg. For oral administration, typical doses are approximately 0.001 mg / kg to 10 mg / kg, 0.1 mg / kg to 10 mg / kg, 0.01 mg / kg to 1 mg / kg, or 0.1 mg / kg to 1 mg / kg. For suppository administration, typical doses are approximately 0.1 mg / kg to 10 mg / kg or 0.1 mg / kg to 1 mg / kg. In some embodiments of the present application, the composition is formulated for oral administration, and the compound is preferably in the form of tablets containing 0.25, 0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0, 70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg of the active ingredient per tablet. The compound of the present application is administered once daily, once weekly, or once monthly, or the total daily dose is divided into two, three, or four doses per day.

[0285] In one embodiment, the compound of the present application is administered at least once a week. However, in another embodiment, the compound is administered to the subject about once every two weeks, about once every three weeks, or about once a month. In yet another embodiment, the compound is administered about once a week to about once a day. In yet another embodiment, the compound is administered once, twice, three, four, five, or six times a day. The length of treatment depends on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration and / or activity of the compound of the present application, and / or combinations thereof. It will also be understood that the effective dosage of the compound used in treatment may increase or decrease in the course of a particular treatment regimen. Changes in dosage can be made and become apparent by standard diagnostic assays known in the art. In some cases, chronic administration is necessary. be For example, the compound is administered to the subject in an amount and for a period sufficient to treat the subject.

[0286] IV. Method for preparing the compound of this application The compounds of this application can be prepared by various synthetic processes. The selection of specific structural features and / or substituents may influence the preference for one process over another. Selecting a particular process for preparing a compound of a given formula (I) is within the scope of those skilled in the art. Several starting materials for preparing the compounds of this application are available from commercial chemical suppliers. Other starting materials, such as those described below, can be readily prepared from available precursors using simple transformations well known to those skilled in the art. In the following schemes illustrating the preparation of the compounds of this application, all variables are as defined in formula I, unless otherwise specified.

[0287] Compounds of formula (I) can generally be prepared by the process shown in the following scheme. In the structural formulas shown below, unless otherwise specified, the symbols (variables) are as defined in formula (I). Those skilled in the art will understand that many of the reactions described in the following scheme are sensitive to oxygen and water, and will know to carry out the reactions in an anhydrous and inert atmosphere if necessary. The reaction temperature and reaction time are shown for illustrative purposes only and may be varied to optimize the yield, as those skilled in the art will understand.

[0288] It should be understood that, through the processes described herein, appropriate protecting groups are added to and subsequently removed from various reactants and intermediates in a manner that will be readily apparent to those skilled in the art, where appropriate. Conventional procedures using such protecting groups and examples of appropriate protecting groups are described, for example, in "Protective groups in Organic Synthesis," TW Green, PGM Wuts, Wiley-Interscience, New York, (1999).

[0289] Furthermore, it should be understood that intermediates or final products in a synthetic pathway leading to the final product can be chemically transformed into other groups or substituents, and that the types of transformations possible are limited only by the fact that other functionalities of the molecule at that stage are inherently incompatible with the conditions or reagents used in the transformation. Such inherent incompatibility, and ways of avoiding it by performing appropriate transformation and synthesis steps in the appropriate order, will be readily understood by those skilled in the art. Examples of transformations are given in this disclosure, and it should be understood that the transformations described are not limited to the generic groups or substituents exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional GroupPreparations” RC Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions can be found in organic chemistry textbooks, for example, “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994).

[0290] Techniques for purifying intermediates and final products Technique and Examples include normal-phase and reverse-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which will be readily apparent to those skilled in the art.

[0291] The products of the process of the present invention may be isolated by known methods, for example, the compounds may be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable methods.

[0292] Generally, the above reactions are carried out in a suitable inert organic solvent at a temperature and time optimized for the yield of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, 2-propanol, dimethylformamide (DMF), 1,4-dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and others.

[0293] The formation of the desired compound salt is achieved using standard techniques. For example, a neutral compound is treated with an acid or base in a suitable solvent, and the resulting salt is isolated by filtration, extraction, or other appropriate method.

[0294] The formation of solvates of the compounds of this application varies depending on the compound and the solvent. Generally, solvates are formed by dissolving the compound in a suitable solvent and then isolating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotropically dried under ambient conditions. The selection of suitable conditions for forming a particular solvate can be made by those skilled in the art.

[0295] The prodrug of the compound of the present invention may be a conventional ester formed with, for example, an available hydroxyl group, thiol group, amino group, or carboxyl group. For example, the available hydroxyl group or amino group may be activated with an activated acid in the presence of a base, and optionally )un The product may be acylated in an active solvent (for example, an acid chloride in pyridine).

[0296] Those skilled in the art will recognize that, when a reaction step of the present invention is carried out in various solvents or solvent systems, the reaction step may be carried out in a suitable mixture of solvents or solvent systems.

[0297] Therefore, in one embodiment, the compound of formula (I) is prepared as shown in scheme 1. [ka]

[0298] Therefore, the aminopyridine compound of formula (A) is monohalogenated to form the compound of formula (B), and then halogenated to form the intermediate compound of formula (C), where Hal 1 and Hal 2 These are independently halogens. The intermediate (C) is then coupled with the boronic acid or boronic acid ester intermediate compound of formula (D) to form the aminopyridine intermediate compound of formula (E). In one embodiment, Hal 1 and Hal 2 Hal is a different halogen selected to have different reactivity in a coupling reaction, as is known to those skilled in the art. In one embodiment, Hal 1 and Hal 2 These are Br and Cl, respectively. In one embodiment, Hal 1 and Hal 2 These are I and Cl, respectively. In one embodiment, Hal 1 and Hal 2 These are I and Br, respectively. In one embodiment, R a and R b or R c and R d All of them are H. In one embodiment, R a and R b or R c and R d It forms a cycloalkyl ring. The compound of formula (E) is then coupled to a boronic acid or an ester compound of formula (F) to form the compound of formula (I). Variable factors Q, X 1 , X 2 , X 3 , X 4 , X 5 Cy 1This is defined in formula (I). In some embodiments, both coupling reactions are carried out under cross-coupling conditions, such as in the presence of a cross-coupling catalyst and in an inert solvent. In some embodiments, the cross-coupling catalyst is a palladium catalyst. In some embodiments, the halogenation conditions include a halogenating reagent such as N-bromosuccinate.

[0299] In a further embodiment, the compound of formula (I) is synthesized as shown in Scheme 2 by first coupling the boronic acid or boronic acid ester compound of formula (F) with the dihalogenated intermediate compound of formula (G) via the Suzuki-Miyaura reaction to form the intermediate compound of formula (H). The intermediate compound of formula (H) is then reacted with a suitable boronic acid or boronic acid ester intermediate compound of formula (D) to form the compound of formula (I). Variation factor X 1 Q, X 2 , X 3 , X 4 , X 5 Cy 1 This is defined in formula (I). In one embodiment, Hal 1 and Hal 2 Hal is a different halogen selected to have different reactivity in a coupling reaction, as is known to those skilled in the art. In one embodiment of the present application, Hal 1 and Hal 2 These are Br and I, respectively. In one embodiment, R a and R b or R c and R d All of them are H. In one embodiment, R a and R b or R c and R d These components together form a cycloalkyl ring. In some embodiments, both coupling reactions are carried out under cross-coupling conditions, such as in the presence of a cross-coupling catalyst and in an inert solvent. In some embodiments, the cross-coupling catalyst is a palladium catalyst. [ka]

[0300] In a further embodiment, the compound of formula (C) is synthesized as shown in scheme 3. Thus, the compound of formula (C) can be prepared by treating the intermediate compound of formula (A) with a halogenating reagent such as NBS to form the monohalogenated intermediate compound of formula B, and then treating this with a halogenating reagent such as N-iodosuccinimide (NIS) to give the compound of formula C. In a further embodiment, Hal 1 and Hal 2 Hal is a different halogen selected to have different reactivity in a coupling reaction, as is known to those skilled in the art. In one embodiment, Hal 1 and Hal 2 These are, for example, Br and I, respectively. [ka]

[0301] In one embodiment, the compound of formula (F) is synthesized as shown in Scheme 4. Thus, the compound of formula (F) is synthesized by converting the intermediate compound of formula (H), in which Hal is a halogen, into an inert solvent such as 1,4-dioxane, in the presence of a suitable catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane, and a suitable boronating agent such as 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane). in It is prepared by processing sequentially. [ka]

[0302] In one embodiment, as shown in scheme 5, Cy 1 is phenyl, and R 11 but [ka] And here R 15a is H or R 15 The compound of formula (I) is prepared by coupling the boronic acid or boronic acid ester compound of formula (J) with the halogenated compound of formula (K) under appropriate conditions, for example, under Suzuki coupling conditions, to form the compound of formula (I). In one embodiment, R 1 The amino protecting group is, for example, tert-butyloxycarbonyl (Boc), which can be removed under appropriate conditions, such as with a strong acid like trifluoroacetic acid, and R 9a It forms a compound of formula (I) where H is present. In one embodiment, Hal 2 is Br. In one embodiment, R i and R j Both are H. In one embodiment, R i and R j Together, they form a cycloalkyl ring. Variation factors Q, X 1 , X 2 , X 3 , X 4 , X 5 Cy 1 and Cy 2 This is defined in formula (I). In one embodiment, the compound of formula I is an S-enantiomer: [ka] That is the case. [ka]

[0303] In one embodiment, as shown in Scheme 6, the intermediate compound of formula (K) in Scheme 5 is synthesized by coupling the dihalogenated ester compound of formula (L) with the halogenated compound of formula (M) under appropriate coupling conditions, such as in the presence of zinc, to form the halogenated ester compound of formula (N). Then, this halogenated ester compound of formula (N) is reduced under appropriate reducing conditions, such as in the presence of lithium aluminum hydride, to form the hydroxy compound of formula (O), which is then oxidized under appropriate oxidizing conditions, such as in the presence of manganese dioxide (MnO2), to give the halogenated aldehyde compound of formula (P). The compound of formula (P) is then coupled with tert-butanesulfinamide (compound of formula (Q)) to form the aldimine compound of formula (R), which is further coupled with (1,3-dioxane-2-ylethyl)(1,3-dioxane-2-ylethyl)manganese bromide (compound of formula (S)) under appropriate Grignard conditions to form the intermediate compound of formula (T), which is then cyclized under appropriate cyclization conditions such as in the presence of trifluoroacetic acid (TFA) and triethylsilane (EtSiH) to form the compound of formula (K). In some embodiments, the tert-butanesulfinamide (compound of formula Q) is S-tert-butanesulfinamide, and the subsequent compounds of formula (R), formula (T), and formula (K) are S-enantiomers. In some embodiments, Hal 3 Hal 4 and Hal 5 These are halogens, respectively, selected to function under specific coupling conditions that would be known to those skilled in the art. In one embodiment, Hal 3 and Hal 4 These are Br and I, respectively. In one embodiment, Hal 5 is any suitable halogen. In one embodiment, Hal 5 It is I. The variable factor Cy 1 and Cy 2 This is defined in Equation I. [ka]

[0304] The above scheme is given for illustrative purposes only. It will be understood by those skilled in the art that the most appropriate reagents may vary depending on the intermediate compounds of formulas (A) to (T), and that the most appropriate route also depends on the intermediates and the target compound of formula (I).

[0305] Intermediates of the compounds of formulas (A) to (t) may be commercially available or prepared using methods known in the art.

[0306] Generally, the above reactions are carried out in a suitable inert organic solvent and at a temperature and time optimized for the yield of the desired compound. Examples of suitable inert organic solvents include, but are not limited to, dimethylformamide (DMF), dioxane, methylene chloride, chloroform, tetrahydrofuran (THF), toluene, and others.

[0307] Salts of the compounds of this application are generally formed by dissolving a neutral compound in an inert organic compound, adding either a desired acid or base, and isolating the resulting salt by filtration or other known means.

[0308] The formation of solvates of the compounds of this application will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or by using a poor solvent. Solvates are typically dried or azeotropically dried under environmental conditions. The selection of appropriate conditions for forming a particular solvate can be made by those skilled in the art. Examples of suitable solvents include ethanol, water, and so on. When water is the solvent, the molecule is called a "hydrate."

[0309] The prodrug of the compound of the present invention may be a conventional ester formed with, for example, an available hydroxyl group, thiol group, amino group, or carboxyl group. For example, the available hydroxyl group or amino group may be activated with an activated acid in the presence of a base, and optionally )un Acylation may be performed in an active solvent (for example, an acid chloride in pyridine). Some common esters that have been used as prodrugs include phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates, and amino acid esters.

[0310] It should be understood that, where appropriate, suitable protecting groups are added to and subsequently removed from various reactants and intermediates in a manner readily understood by those skilled in the art throughout the processes described herein. Conventional methods for using such protecting groups, and examples of suitable protecting groups, are described, for example, in “Protective Groups in Organic Synthesis”, TW Green, PGM Wuts, Wiley-Interscience, New York (1999). It should also be understood that a group or substituent can be chemically converted to another group or substituent on intermediates or final products in the synthetic pathway toward the final product, and that the types of conversions possible are limited only by other functionalities of the molecule at that stage that are essentially incompatible with the conditions or reagents used in the conversion. Such essential incompatibility, and ways of avoiding it by performing appropriate conversion and synthesis steps in the appropriate order, will be readily understood by those skilled in the art. Examples of conversions are given herein, and it should be understood that the conversions described are not limited to the generic groups or substituents exemplified. References and descriptions of other suitable transformations are given in “Comprehensive Organic Transformations - A Guide to Functional Group Preparations” RC Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are given in organic chemistry textbooks, for example, in “Advanced Organic Chemistry”, March, 4th ed. McGraw Hill (1992) or “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniques for purifying intermediates and final products include, for example, normal-phase and reverse-phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which will be readily understood by those skilled in the art.

[0311] The following non-limiting embodiments are illustrative of the present invention. <Examples> Preparation of the Exemplary Compounds of this Application Example 1: 6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one(I-1) [ka] Step 1: 5-Chloro-6-fluoropyrazine-2-amine [ka]

[0312] To a solution of 6-fluoropyrazine-2-amine (0.75 g, 6.6 mmol) in DMF (18 mL) at room temperature (RT), N-chlorosuccinimide (0.90 g, 6.9 mmol) was added. The reaction system was heated to 80°C for 2 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography [0-35% siRNA / hexane] to obtain the product (0.71 g, 72%) as an off-white solid. LCMS: [M - H] - = 146.0. Step 2: 3-Bromo-5-chloro-6-fluoropyrazine-2-amine [ka]

[0313] To a solution of 5-chloro-6-fluoropyrazine-2-amine (0.70 g, 4.7 mmol) in 15 mL of room temperature DCM, N-bromosuccinimide (1.3 g, 7.1 mmol) was added. The reaction system was stirred at room temperature for 18 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography (0-30% Âxane) to obtain the product (0.99 g, 92%). LCMS: [M - H] - = 224.3. Step 3: 6-(3-amino-6-chloro-5-fluoropyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0314] 30 mL of a vial was filled with 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (0.15 g, 0.54 mmol), 3-bromo-5-chloro-6-fluoropyrazine-2-amine (0.081 g, 0.36 mmol), and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II)DCM complex (0.020 g, 0.025 mmol). The vial was sealed with a cap and septum, the reaction vessel was degassed, and backfilled with nitrogen. 1,4-dioxane (5 mL) and 2 M Na2CO3 aqueous solution (0.54 mL, 1.1 mmol) were added, the reaction vessel was degassed again, and backfilled with nitrogen. The reaction mixture was heated in an aluminum block at 90°C for 18 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography (0.5-9.5% MeOH / DCM + 0.5% NH4OH) to obtain the product (0.061 g, 58%). LCMS: [M + H] + = 293.3. Step 4: 6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0315] 4-(4-isopropylpiperazinyl)phenylboronic acid pinacol ester (0.10 g, 0.31 mmol), 6-(3-amino-6-chloro-5-fluoropyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (0.061 g, 0.21 mmol), and XPhos Pd G2 (0.016 g, 0.021 mmol) were added to a 30 mL vial. The vial was sealed with a cap and septum, and the reaction vessel was degassed and backfilled with nitrogen. 1,4-dioxane (3 mL) and K3PO4 aqueous solution (0.40 mL of 1.3 M solution, 0.52 mmol) were added, and the reaction vessel was again degassed and backfilled with nitrogen. The reaction mixture was heated in an aluminum block at 90°C for 18 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography (0.5-9.5% DCM / MeOH + 0.5% NH4OH). The fraction containing the product was concentrated and further concentrated by reverse-phase chromatography (Biotage SNAP C18; 5-60% MeCN / water + 0.1% formic acid). Isolation of the compound described in the heading was achieved by a catch-and-release procedure using Biotage SCX2 silica gel to obtain the compound described in the heading (4.0 mg, 4%). 1 H NMR (500 MHz, DMSO-d6) δ 7.9-8.0 (m, 2H), 7.75 (d, J = 7.9 Hz, 2H), 7.7-7.7 (m, 1H), 7.65(s, 1H), 7.01 (d, J = 9.0 Hz, 2H), 6.71(s, 2H), 3.2-3.2 (m, 4H), 2.99 (t, J = 6.5Hz, 2H), 2.7-2.7 (m, 1H), 2.6-2.6 (m, 4H), 1.01 (d, J = 6.5 Hz, 6H); LCMS: [M + H] + = 461.6. Example 2: 6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-2) [ka] Step 1: 5-Chloro-6-fluoropyrazine-2-amine [ka]

[0316] To a solution of 6-fluoropyrazine-2-amine (0.250 g, 2.211 mmol) in N,N-dimethylformamide (DMF) (6 mL) at room temperature, N-chlorosuccinimide (0.301 g, 2.26 mmol) was added. The reaction system was heated to 80°C for 2 hours. The DMF was removed under reduced pressure (invaccuo), and the residue was dissolved in CH2Cl2 and concentrated on Celite®. Flash chromatography (0-35% siRNA / hexane) yielded the major regioisomer, 5-chloro-6-fluoropyrazine-2-amine (0.708 g, yield 72.4%). LCMS [M - H] - = 146.00. Step 2: 3-Bromo-5-chloro-6-fluoropyrazine-2-amine [ka]

[0317] To a solution of 5-chloro-6-fluoropyrazine-2-amine (0.70 g, 4.74 mmol) in CH2Cl2 (15 ml) at room temperature, N-bromosuccinimide (1.267 g, 7.12 mmol) was added. The reaction system was stirred for 19 hours. The reaction mixture was concentrated on Celite® and the product was obtained by flash chromatography (0-30% siRNA / hexane). LCMS [M + H]+ = 226.02. Step 3: 8-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0318] To 6-bromo-5-fluoro-3,4-dihydroisoquinoline-1(2H)-one (50 mg, 0.205 mmol, 1 eq), bis(pinacolato)diborone (58.2 mg, 0.229 mmol, 1.1 eq), KOAc (61.3 mg, 0.625 mmol, 3 eq), and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.62 mg, 10.41 μmol, 0.05 eq) in 1,4-dioxane (2.5 mL) were added under Ar. This mixture was heated in a microwave at 100°C for 2 hours. LCMS showed less than 10% of the starting material. The reaction mixture was used in the next step without purification. LCMS: [M + H] + = 292.0 Step 4: 6-(3-amino-6-chloro-5-fluoropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0319] Following a procedure similar to Step 3 of Example 1, the product (129 mg, 31%) was obtained using 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (0.579 g, 1.99 mmol), 3-bromo-5-chloro-6-fluoropyrazine-2-amine (0.300 g, 1.33 mmol), [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II), DCM complex (0.076 g, 0.093 mmol), 1,4-dioxane (8 mL), and aqueous Na2CO3 solution (1.99 mL of 2 M solution, 3.97 mmol). LCMS: [M + H] + = 311.37. Step 5: 6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-2) [ka]

[0320] Following a procedure similar to that of Example 1, the compound described in the heading (61 mg, 79% yield) was obtained as a yellow powder by step 4 using 4-(4-isopropylpiperazinyl)phenylboronic acid pinacol ester (0.080 g, 0.241 mmol), 6-(3-amino-6-chloro-5-fluoropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (0.050 g, 0.161 mmol), XPhos Pd G2 (0.013 g, 0.016 mmol), 1,4-dioxane (3 mL), and an aqueous solution of K3PO4 (0.309 mL of 1.3 M solution, 0.402 mmol). 1H NMR (500 MHz, DMSO-d6) δ 8.15 (br s, 1H), 7.70 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 10.1 Hz, 1H), 7.51 (d, J = 6.8 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.67 (s, 2H), 3.42 (brdd, J = 6.6, 2.7 Hz, 3H), 3.2-3.2 (m, 4H), 2.96 (br t, J = 6.4 Hz, 2H), 2.7-2.7 (m, 1H), 2.6-2.6 (m, 4H), 1.01(d, J = 6.5 Hz, 6H); LCMS: [M+H] + = 479.5. Example 3: 6-(3-amino-5-fluoro-6-(4-((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-3) [ka] Step 1: 5-Chloro-6-fluoropyrazine-2-amine [ka]

[0321] To a solution of 6-fluoropyrazine-2-amine (0.75 g, 6.6 mmol) in DMF (18 mL) at room temperature (RT), N-chlorosuccinimide (0.90 g, 6.9 mmol) was added. The reaction system was heated to 80°C for 2 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography (0-35% siRNA / hexane) to obtain the product (0.71 g, 72%) as a colorless solid. LCMS: [MH] - 146.0. Step 2: 3-Bromo-5-chloro-6-fluoropyrazine-2-amine [ka]

[0322] N-bromosuccinimide (1.3 g, 7.1 mmol) was added to a solution of 5-chloro-6-fluoropyrazine-2-amine (0.70 g, 4.7 mmol) in DCM (15 mL) at room temperature. The reaction system was stirred at room temperature for 18 hours, concentrated on Celite®, and purified by flash chromatography (0-30% siRNA / hexane) to obtain the product (0.99 g, 92%). LCMS: [M - H] - = 224.3. Step 3: 6-(3-amino-6-chloro-5-fluoropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0323] 7-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (0.58 g, 2.0 mmol), 3-bromo-5-chloro-6-fluoropyrazine-2-amine (0.30 g, 1.3 mmol), and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II)DCM complex (0.076 g, 0.093 mmol) were added to 30 mL of the reaction vessel. The vial was sealed with a cap and septum, the reaction vessel was degassed, and backfilled with nitrogen. 1,4-Dioxane (8 mL) and 2M Na2CO3 aqueous solution (2.0 mL, 4.0 mmol) were added, and the reaction vessel was degassed again and backfilled with nitrogen. The reaction mixture was heated in an aluminum block at 90°C for 18 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography (0.5–9.5% MeOH / DCM + 0.5% NH4OH) to obtain the product (0.12 g, 28%). LCMS: [M + H] + = 311.3. Step 4: (1R,5S)-1-(4-bromophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane [ka]

[0324] To a solution of (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (0.50 g, 2.1 mmol) in 1:1 MeOH:THF (10 mL), formaldehyde (37 wt%, 0.23 mL, 3.2 mmol) was added, followed by NaBH(OAc)3 (0.67 g, 3.2 mmol). The reaction system was stirred at room temperature for 40 hours. Volatile components were removed under reduced pressure, and the residue was partitioned between 15 mL of 1 M KOH aqueous solution and 15 mL of DCM. The layers were separated, and the aqueous phase was extracted using an additional portion of DCM. The combined extracts were dried over MgSO4 and concentrated to dryness to obtain the product (0.50 g, 95%), which was used in the next step without purification. LCMS: [M + H] + = 252.2. Step 5: 6-(3-amino-5-fluoro-6-(4-((1R,5S)-3-methyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0325] A stock solution of (5-amino-3-fluoro-6-(7-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)boronic acid was prepared as follows: 6-(3-amino-6-chloro-5-fluoropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (0.24 g, 0.77 mmol), bis(pinacorato)diborone (0.29 g, 1.2 mmol), XPhos Pd G2 (0.091 g, 0.12 mmol), and KOAc (0.19 g, 1.9 mmol) were placed in a 30 mL vial. The vial was sealed with a cap and septum, degassed, and backfilled with nitrogen. 1,4-dioxane (8 mL) was added, and the reaction vial was degassed and flushed with N2. The reaction system was heated in an aluminum block at 90°C for 1 hour. After cooling to room temperature, 2.0 mL of this stock solution was transferred to a 30 mL vial that had been sealed with (1R,5S)-1-(4-bromophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane (0.047 g, 0.19 mmol) and XPhos Pd G2 (0.015 g, 0.019 mmol). K3PO4 aqueous solution (0.36 mL of 1.3 M solution, 0.47 mmol) was added by syringe, and the reaction vessel was degassed and backfilled with nitrogen. The reaction mixture was heated in an aluminum block at 90°C for 18 hours. The reaction mixture was concentrated on Celite® and purified by flash chromatography (0.5-9.5% MeOH / DCM + 0.5% NH4OH). The fraction containing the product was concentrated and further purified by reverse-phase chromatography (Biotage SNAP C18; 5-45% MeCN / water + 0.1% formic acid). Isolation of the compound described in the heading was achieved by a catch-and-release procedure using Biotage SCX2 silica gel to obtain the product (0.020 g, 24%). 1H NMR (500 MHz, DMSO-d6) δ 8.08 (br s, 1H), 7.67 (d, J = 7.3 Hz, 2H), 7.57 (d, J = 10.1 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 7.14 (d, J = 8.6 Hz, 2H), 6.76 (s, 2H), 3.35 (brdd, J = 6.6, 2.4 Hz, 4H), 3.20 (br d, J =8.4 Hz, 1H), 2.9-2.9 (m, 3H), 2.33 (br d, J =5.9 Hz, 1H), 2.24 (s, 3H), 1.75 (td, J = 7.8, 3.9 Hz, 1H), 1.30 (t, J = 4.1 Hz, 1H), 0.71(dd, J = 7.9, 3.8 Hz, 1H); LCMS: [M + H] + = 448.6. Example 4: 6-(3-amino-5-fluoro-6-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-4) [ka] Step 1: (1R,5S)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane [ka]

[0326] To a solution of (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (0.500 g, 2.100 mmol) in MeOH / THF (5 mL each), acetone (0.231 mL, 3.15 mmol) and acetic acid (0.012 mL, 0.210 mmol) were added, followed by the addition of NaBH(OAc)3 (0.668 g, 3.15 mmol). The reaction system was stirred at room temperature for 40 hours. Volatile components were removed under reduced pressure, and the residue was partitioned between KOH (1N) and CH2Cl2. The layers were separated, and the aqueous phase was extracted with additional CH2Cl2. The combined extracts were dried over MgSO4 and concentrated to dryness to obtain the product (2.10 mmol, 100%) as amber oil. LCMS: [M + H] + = 280.29. Step 2: 6-(3-amino-5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0327] 6-(3-amino-6-chloro-5-fluoropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (0.240 g, 0.772 mmol), bis(pinacorato)diborone (0.294 g, 1.16 mmol), XPhos Pd G2 (0.091 g, 0.116 mmol), and KOAc (0.190 g, 1.93 mmol) were placed in a 30 mL vial. The vial was sealed with a cap and septum, degassed, and backfilled with nitrogen. 1,4-dioxane (8 ml) was added, the reaction vial was degassed, and N2 was refilled. The reaction system was heated to 90°C in an aluminum block for 1 hour. The reaction system was allowed to cool to room temperature, and the product was allowed to proceed to the next stage of the reaction in solution without isolation. LCMS [M + H]+ = 318.37. Step 3: 6-(3-amino-5-fluoro-6-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0328] Following the same procedure as in Step 5 of Example 3, the compound described in the heading (24 mg, 27%) was obtained using (1R,5S)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane (0.052 g, 0.186 mmol), XPhos Pd G2 (0.015 g, 0.019 mmol)6-(3-amino-5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (0.075 g, 0.186 mmol, newly prepared in Step 2 of Example 4), and an aqueous solution of K3PO4 (0.359 mL, 0.466 mmol). 1H NMR (500 MHz, DMSO-d6) δ 8.08 (br s, 1H), 7.66 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 10.3 Hz, 1H), 7.45 (d, J = 6.7Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.76(s, 2H), 3.35 (br dd, J = 6.2, 2.2 Hz, 4H), 2.98 (d, J = 8.6 Hz, 1H), 2.88 (br t, J = 6.4 Hz, 2H), 2.51 (br d, J =8.3 Hz, 2H,), 2.4-2.4 (m, 2H), 1.76(td, J = 7.8, 3.9 Hz, 1H), 1.25 (t, J = 3.9Hz, 1H), 0.95 (dd, J = 14.7, 6.3 Hz, 6H), 0.69 (dd, J = 7.8, 3.5 Hz, 1H); LCMS [M + H] + =476.5. Example 5: 6-(3-amino-5-fluoro-6-(4-((1S,5R)-3-methyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-5) [ka]

[0329] The compound described in the heading was obtained using the same procedure as in Step 5 of Example 3, with (1S,5R)-1-(4-bromophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane (0.047 g, 0.186 mmol) and XPhos Pd G2 (0.015 g, 0.019 mmol), 6-(3-amino-5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (0.075 g, 0.186 mmol) and an aqueous solution of K3PO4 (0.359 mL of 1.3 M solution, 0.466 mmol). 1H NMR (500 MHz, DMSO-d6) δ 8.08 (br s, 1H), 7.67 (d, J = 7.3 Hz, 2H), 7.57 (d, J = 10.1 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 7.14(d, J = 8.6 Hz, 2H), 6.7-6.8 (m, 2H), 3.3-3.4(m, 4H), 3.19 (d, J = 8.4 Hz, 1H), 2.9-2.9(m, 3H), 2.32 (dd, J = 8.6, 3.4 Hz, 1H), 1.74 (td, J = 7.8, 3.9Hz, 1H), 1.30 (t, J = 4.1 Hz, 1H), 0.71(dd, J = 7.9, 3.8 Hz, 1H); LCMS: [M + H] + = 448.5. Example 6: 6-(3-amino-5-fluoro-6-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-6) [ka] Step 1: (1S,5R)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane [ka]

[0330] Following a procedure similar to Step 1 of Example 4, (1S,5R)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (0.500 g, 2.100 mmol), acetone (0.231 mL, 3.15 mmol), and AcOH (0.012 mL, 0.210 mmol) were used in MeOH / THF (5 mL each), followed by NaBH(OAc)3 (0.668 g, 3.15 mmol) to obtain the product (665 mg, quantitative yield) as amber oil, which was used in the next step without further purification. LCMS: [M + H]+ = 280.29. Step 2: 6-(3-amino-5-fluoro-6-(4-((1S,5R)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-6) [ka]

[0331] In a procedure similar to step 5 of Example 3, (1S,5R)-1-(4-bromophenyl)-3-isopropyl-3-azabicyclo[3.1.0]hexane (0.052 g, 0.186 mmol), XPhos Pd G2 (0.015 g, 0.019 mmol), and 6-(3-amino-5-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (0.075 g, 0.186 mmol) and an aqueous solution of K3PO4 (0.359 mL of 1.3 M solution, 0.466 mmol) were used to obtain the compound described in the heading (9 mg, 10%) as an off-white residue. 1H NMR (500 MHz, DMSO-d6) δ 8.08 (br s, 1H), 7.66 (d, J = 7.3 Hz, 2H), 7.57 (d, J = 10.1 Hz, 1H), 7.45 (d, J = 6.8 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.76 (s, 2H), 3.35 (br dd, J = 6.4, 2.5Hz, 4H), 2.98 (d, J = 8.6 Hz, 1H), 2.88 (br t, J = 6.5 Hz, 2H), 2.51 (br d, J = 8.3 Hz, 2H), 2.4-2.4 (m, 2H), 1.76 (td, 1H, J = LCMS: [M + H] + = 476.5. Example 7: 6-(3-amino-5-chloro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one(I-7) [ka] Step 1: 5-Bromo-6-chloro-3-iodopyrazine-2-amine [ka]

[0332] To a solution of 5-bromo-6-chloropyrazine-2-amine (1.6 g, 7.68 mmol) in AcOH (14 mL), N-iodosuccinimide (2.245 g, 9.98 mmol) was added. Then TFA (20 drops) was added, and the mixture was stirred at 50°C for 3 hours. The mixture was allowed to cool to room temperature, and then mixed with water (60 mL). The resulting precipitate was filtered, and the filter cake was washed with water (3x). This solid was then placed in water (60 mL) and based with 28-30% NH4OH solution. The suspension was filtered, the filter cake was washed with water (3x), and the mixture was dried overnight under high pressure (under vacuum) to obtain the product (2.306 g, 90%) as a pale yellow solid. LCMS: [M + H] + = 334.28. Step 2: 6-(3-amino-6-bromo-5-chloropyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0333] Water (12 mL) is mixed with 5-bromo-6-chloro-3-iodopyrazine-2-amine (698 mg, 2.09 mmol), 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (500 mg, 1.83 mmol), and Na2CO3 in CH3CN (28 mL). .The reaction mixture was added to a degassed suspension of H2O (477 mg, 3.84 mmol) and bis(triphenylphosphine)palladium(II) dichloride (154 mg, 0.220 mmol), and the reaction mixture was heated in a microwave reactor at 80°C for 1 hour. This mixture was mixed with water and EA, the organic phase was separated, and the aqueous phase was extracted using a 4:1 mixture of CHCl3 / i-PrOH (4x). The combined organic phase was concentrated on Celite® and purified by elution with CH2Cl2 containing 0-2% MeOH and 0-0.2% NH4OH using silica gel chromatography (12 g column). Appropriate fractions were combined and concentrated to obtain the desired product as a beige solid (447 mg, 69% yield). LCMS: [M + H] + = 355.40. Step 3: 6-(3-amino-5-chloro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one(I-7) [ka]

[0334] A microwave vial containing a mixture of 6-(3-amino-6-bromo-5-chloropyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (50 mg, 0.141 mmol), 4-(4-isopropylpiperazinyl)phenylboronic acid pinacol ester (65.4 mg, 0.198 mmol), [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15.52 mg, 0.021 mmol), and Cs2CO3 (138 mg, 0.424 mmol) in DME (3.5 mL) was degassed with argon. Water (1 mL) was added, and the mixture was heated in a microwave reactor at 90°C for 1.75 hours. This mixture was concentrated on Celite® and purified by elution with CH2Cl2 containing 0-1% MeOH and 0-0.1% NH4OH on a silica gel column (4 g). The crude product was triturated with hot MeOH (1 mL) and the desired product was isolated as a yellow solid (30.5 mg, 43%). 1H NMR (500 MHz, DMSO-d6) δ 8.00 -7.96 (m, 1H), 7.95 - 7.89 (m, 1H), 7.71 - 7.67 (m, 1H), 7.64 (s, 1H), 7.61 -7.55 (m, 2H), 7.00 - 6.96 (m, 2H), 6.78 - 6.69 (m, 2H), 3.43 - 3.41 (m, 2H), 3.22- 3.17 (m, 4H), 2.97 (br t, J = 6.5 Hz, 2H), 2.70 - 2.66 (m, 1H), 2.61- 2.57 (m, 4H), 1.01 (d, J = 6.5 Hz, 6H);LCMS: [M + H] + = 477.63. Example 8: 6-(3-amino-5-chloro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-8) [ka] Step 1: 8-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0335] To 6-bromo-5-fluoro-3,4-dihydroisoquinoline-1(2H)-one (50 mg, 0.205 mmol, 1 eq), bis(pinacolato)diborone (58.2 mg, 0.229 mmol, 1.1 eq), KOAc (61.3 mg, 0.625 mmol, 3 eq), and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.62 mg, 10.41 μmol, 0.05 eq) in 1,4-dioxane (2.5 mL) were added under argon. This mixture was heated in a microwave at 100°C for 2 hours. The reaction mixture was used as a solution in the next step without purification. LCMS: [M + H] + = 292.0 Step 2: 6-(3-amino-6-bromo-5-chloropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0336] Water (12 mL) is mixed with 5-bromo-6-chloro-3-iodopyrazine-2-amine (570 mg, 1.70 mmol), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (500 mg, 1.49 mmol), and Na2CO3 in CH3CN (28 mL). .Added to a degassed suspension of H2O (389 mg, 3.14 mmol) and bis(triphenylphosphine)palladium(II) dichloride (126 mg, 0.179 mmol), and the reaction mixture was heated in a microwave reactor at 80 °C for 90 minutes. Additional 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (150 mg, 0.447 mmol) was added, and the mixture was heated at 80 °C for an additional 2 hours. The reaction system was partitioned between water and EtOAc, the organic phase was separated, and the aqueous phase was extracted with 4:1 CHCl3 / i-PrOH (4x). The combined organic layers were dried over MgSO4, filtered, and concentrated onto Celite®. Purification by flash silica gel chromatography (12 g column, removed in vaccuo, eluted with CH2Cl2 containing 0 - 1.5% MeOH and 0 - 0.15% NH4OH), and combining and concentrating the appropriate fractions gave the desired product as a beige solid (310 mg, 49%). LCMS [M + H] + = 373.39. Step 3: 6-(3-Amino-5-chloro-6-(4-(4-isopropylpiperazin-1-yl)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-8)

Chemical Structure

[0337] A microwave vial containing a mixture of 6-(3-amino-6-bromo-5-chloropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (50 mg, 0.135 mmol), 4-(4-isopropylpiperazinyl)phenylboronic acid pinacol ester (62.2 mg, 0.188 mmol), [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (14.77 mg, 0.020 mmol), and Cs2CO3 (132 mg, 0.404 mmol) in DME (3.5 mL) was degassed with argon. Water (1 mL) was added, and the mixture was heated in a microwave reactor at 90°C for 1.75 hours. This mixture was concentrated on Celite® and purified by flash silica gel chromatography (4g column) with elution using CH2Cl2 containing 0-2% MeOH and 0-0.2% NH4OH. The isolated crude product contained impurities. Therefore, it was triturated with hot MeOH (1mL) to isolate the desired product as a yellow solid (33mg, 47%). 1 H NMR (500 MHz, DMSO-d6) δ 8.18 - 8.11 (m, 1H), 7.66 - 7.60 (m, 1H), 7.58 - 7.53 (m, 2H), 7.52 - 7.48 (m, 1H), 6.99 - 6.95 (m, 2H), 6.76 -6.65 LCMS: [M + H] + = 495.62. Example 9: 6-(3-amino-5-fluoro-6-(4-(1-isopropyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-9) [ka] Step 1: tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate [ka]

[0338] Water (1.5 mL) is mixed with 1-bromo-4-iodobenzene (2.5 g, 8.84 mmol) and Na2CO3 in CH3CN (3.5 mL). . H2O (3.29 g, 26.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.511 g, 0.442 mmol), and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine-1-carboxylate (3.01 g, 9.72 mmol) were added under argon. This mixture was heated in a microwave reactor at 90°C for 1 hour. The mixture was allowed to cool to room temperature, filtered through a thin pad of Celite®, concentrated, and purified by elution with hexane containing 0-5% EA on an Isco column (24 g). Appropriate fractions were combined and concentrated to obtain the desired product (2.477 g, 83%) as brown oil. LCMS: [M + H]+ = 284.38. Step 2: 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine [ka]

[0339] Trifluoroacetic acid (1.250 ml, 16.32 mmol) was added to a solution of tert-butyl 4-(4-bromophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (1.38 g, 4.08 mmol) in CH2Cl2 (10 ml) under argon at room temperature. The reaction mixture was stirred at room temperature for 1 hour. Complete conversion to the desired product was observed by LC-MS. This mixture was concentrated, and the residue was dissolved in MeOH (20 mL), passed through a 5G porapak cation exchange cartridge, and the eluent was removed to obtain the product (854 mg, 88%) as a beige solid. LC-MS: [M + H]+ = 240.36. Step 3: 4-(4-bromophenyl)-1-isopropyl-1,2,3,6-tetrahydropyridine [ka]

[0340] A solution of 4-(4-bromophenyl)-1,2,3,6-tetrahydropyridine (500 mg, 2.10 mmol), propan-2-one (0.311 ml, 4.20 mmol), and AcOH (0.060 mL, 1.05 mmol) in dichloroethane (15 mL) at room temperature was treated with NaBH(OAc)3 (1335 mg, 6.30 mmol). The mixture was stirred at room temperature for 5 hours. The mixture was concentrated to dryness and passed through a porapak cation exchange resin cartridge. The desired product was isolated as an off-white solid (575 mg, 98%). LC-MS: [M + H]+ = 280.43. Step 4: 1-Isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine [ka]

[0341] A mixture of 4-(4-bromophenyl)-1-isopropyl-1,2,3,6-tetrahydropyridine (150 mg, 0.535 mmol), bis(pinacolato)diborone (154 mg, 0.605 mmol), [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (39.2 mg, 0.054 mmol), and KOAc (158 mg, 1.61 mmol) in 1,4-dioxane (6 mL) was flushed with argon. This mixture was heated in a microwave reactor at 100 °C for 1 hour. The reaction mixture was filtered through a thin pad of Celite®, and the filter cake was washed with ELISA. The combined filtrate was concentrated to dryness, and the residue was dissolved in DME to prepare a 10 mL stock solution. Assuming 100% conversion, the concentration is 17.5 mg / mL. LCMS: [M + H] + = 328.64. Step 6: 3-(4-bromo-3-fluorophenyl)propionic acid [ka]

[0342] To a stirred solution of triethylamine (123 mL, 886.6 mmol), formic acid (83.6 mL, 2216.7 mmol) was added in portion wise, and the mixture was stirred at room temperature for 15 minutes. This mixture was diluted with DMF (750 mL) and 3-bromo-4-fluorobenzaldehyde (150 g, 738.9 mmol). Meldrumic acid (106.4 g, 738.9 mmol) was added. The mixture was then heated at 100 °C for 16 hours. The reaction mixture was poured into ice-cold water (3.5 L) and concentrated HCl (350 mL). This mixture was extracted using DCM (2 x 1000 mL). The combined organic layers were washed with 1N NaOH (2 x 1500 mL). The aqueous layer was acidified with concentrated HCl and extracted using RINKAN (2 x 1000 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the product (120 g, 65%) as a brown liquid. This was used directly in the next step. LCMS: [M + H] + = 247.06. Step 7: 5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one [ka]

[0343] To a stirred solution of 3-(4-bromo-3-fluorophenyl)propionic acid (120 g, 487.8 mmol) in DCM (1000 mL), oxalyl chloride (146.5 mL, 1707.3 mmol) and DMF (16 mL) were added at room temperature for 30 minutes. The solvent was concentrated under reduced pressure to obtain the crude residue. The residue was dissolved in DCM (1000 mL) and added dropwise to a stirred solution of aluminum chloride (227 g, 1707.3 mmol) in DCM (4000 mL). This mixture was stirred at room temperature for 2 hours. This mixture was poured into ice-cold water (4000 mL) and extracted using DCM (2 x 1000 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using column chromatography with silica gel (230-400 mesh) with 0-10% ethyl phosphate in petroleum ether as the eluent, and the product (60 g, 64%) was obtained as an off-white solid. LCMS: [M + H] + =229.05. Step 8: Synthesis of 6-bromo-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0344] To a stirred solution of 5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (60 g, 263.1 mmol) in DCM (900 mL) and methanesulfonic acid (240 mL, 4V), NaN3 (51.3 g, 789.4 mmol) was added in portion wise at 0°C for 4 hours. This mixture was based with 20% NaOH aqueous solution (600 mL) and extracted using DCM (2 x 800 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography using silica gel (230-400 mesh) with 0-90% siRNA in hexane as the eluent to obtain the product (30 g, 46.9%) as an off-white solid. LCMS: [M + H] + = 244.06. Step 9: 7-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0345] To a stirred solution of 6-bromo-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (30 g, 123.4 mmol) in 1,4-dioxane (300 mL), KOAc (36.3 g, 370.3 mmol)bis(pinacorato)diborone (46.8 g, 185.1 mmol) was added at room temperature, the mixture was degassed with argon for 30 minutes, and then Pd(dppf)Cl2.DCM(0) (10.1 g, 12.3 mmol) was added. The reaction mixture was heated at 90 °C for 16 hours and then cooled to room temperature. The reaction mixture was filtered through a Celite bed, washed with ELISA (1000 mL), and the filtrate was concentrated under reduced pressure to obtain the crude compound. This crude compound was washed with diethyl ether (300 mL), filtered, and dried to obtain the product (26 g, 72%) as a dark brown solid. TLC (100% HCl): R f = 0.4 Step 10: 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline 1(2H)-one [ka]

[0346] To a stirred solution of 5-bromo-6-fluoro-3-iodopyrazine-2-amine (9 g, 28.4 mmol) in 1,4-dioxane (180 mL), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (12.4 g, 42.6 mmol), Na2CO3 (9 g, 85.1 mmol, and 42 mL of water) were added at room temperature. The mixture was degassed with argon for 30 minutes, followed by Pd(dppf)Cl 2. DCM (2.3 g, 2.8 mmol) was added, and the reaction mixture was heated at 80°C for 16 hours, then cooled to room temperature. The reaction mixture was filtered through a Celite bed and washed with ethyl acetate (2 x 500 mL). The filtrate was washed with cold water (1000 mL), the organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude compound. This was purified by column chromatography (neutral alumina) using 0-100% siRNA in petroleum ether and 0-5% MeOH in DCM as eluents, and the product (4.5 g, 45%) was obtained as a light brown solid. TLC (5% MeOH in DCM)R f =0.4 Step 11: 6-(3-amino-5-fluoro-6-(4-(1-isopropyl-1,2,3,6-tetrahydropyridine-4-yl)phenyl)pyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0347] A microwave vial containing a mixture of 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-7-fluoro-3,4-dihydroisoquinoline-1(2H)-one (23 mg, 0.065 mmol), 1-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,3,6-tetrahydropyridine (1.58 mL, 0.084 mmol), [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.11 mg, 9.71 μmol), and Cs2CO3 (63.3 mg, 0.194 mmol) in DME (4 mL) was degassed with argon. Water (1 mL) was added, and the mixture was heated in a microwave reactor at 90°C for 1.75 hours. This mixture was concentrated on Celite® and purified by elution with CH2Cl2 containing 0-2.5% MeOH and 0-0.25% NH4OH using silica gel chromatography (4g column). The resulting crude product was further purified by preparative HPLC elution with water / CH3CN / HCOOH (0.1%) to obtain the desired product (8 mg, 26%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.18 - 8.14 (m, 1H), 7.81 (br d, J = 7.8Hz, 2H), 7.65 (d, J = 10.1 Hz, 1H), 7.57 - 7.50 (m, 3H), 6.99- 6.77 (m,2H), 6.32 - 6.19 (m, 1H), 3.54 - 3.52 (m, 4H), 3.19 (br d, J = 2.6 Hz, 2H), 2.99 - 2.95 (m, 2H), 2.81 - 2.76 (m, 1H), 2.69 (br t, J = 5.5 Hz, 2H), 1.07- 1.02 (m, 6H); LCMS: [M + H] + = 476.63. Example 10: 6-(3-amino-5-fluoro-6-(4-(1-isopropylpiperidine-4-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-10) [ka] Step 1: 8-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0348] 6-Bromo-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (896 mg, 3.67 mmol), bis(pinacolato)diborone (1025 mg, 4.04 mmol), and KOAc (1081 mg, 11.01 mmol) were added to a 100 mL round-bottom flask, to which anhydrous 1,4-dioxane (40 mL) was added. The system was flushed with nitrogen, and then PdCl2dppf (269 mg, 0.367 mmol) was added. This mixture was further flushed with nitrogen and then heated overnight at 100 °C. LC-MS analysis showed a 58:42 mixture of boronic acid and boronate. The reaction system was diluted with acetonitrile, filtered through a Celite® pad, and concentrated under reduced pressure (in vacuo). Assuming complete conversion to boronate, the crude material was used directly in the next step. Boronate LCMS: [M + H]+ = 292.34, Boronic acid LCMS: [M + H]+ = 210.39. Step 2: 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0349] A solution of 5-bromo-6-fluoro-3-iodopyrazine-2-amine (760 mg, 2.39 mmol) and 8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (835 mg, 2.87 mmol) in acetonitrile (15 mL) is prepared in a microwave vial, with Na2CO3 in water (3.8 mL) added. . A solution of H2O (623 mg, 5.02 mmol) was added. The system was degassed, and bis(triphenylphosphine)palladium(II) dichloride (201 mg, 0.287 mmol) was added. The reaction system was heated in a microwave apparatus at 80°C for 3 hours. The reaction system was concentrated on Celite® and purified by silica gel chromatography by elution with 0-100% siRNA / hexane, followed by elution with 0-10% MeOH / CH2Cl2 + 1% NH4OH, to obtain the product (536 mg, 63%) as a beige solid. LCMS: [M + H]+ = 355.28. Step 3: tert-butyl 4-(4-(5-amino-3-fluoro-6-(8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)phenyl)piperidine-1-carboxylate [ka]

[0350] PdCl2dppf (20.60 mg, 0.028 mmol) was added to a degassed suspension of 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (100 mg, 0.282 mmol), 4-(N-Boc-piperidino)phenylboronic acid pinacol ester (131 mg, 0.338 mmol), and Cs2CO3 (229 mg, 0.704 mmol) in a 3:1 mixture of DME (4 mL):water (1.3 mL). This mixture was then flashed with nitrogen and heated in a microwave apparatus at 90°C for 2 hours. The reaction system was concentrated on Celite® and purified by silica gel chromatography using elution with 0-10% MeOH / CH2Cl2 + 1% NH4OH, yielding the product (151 mg, 100%) as a brown solid. LCMS: [M + H]+ = 534.54. Step 4: 6-(3-amino-5-fluoro-6-(4-(piperidine-4-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0351] To a solution of tert-butyl 4-(4-(5-amino-3-fluoro-6-(8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)phenyl)piperidine-1-carboxylate (151 mg, 0.282 mmol) in CH2Cl2 (5 mL), TFA (0.65 mL, 8.46 mmol) was added. The reaction system was stirred overnight at room temperature. The reaction system was concentrated under reduced pressure (in vacuo) to remove volatile components. The crude product was dissolved in methanol and eluted with 3% NH3 / MeOH through an Isolute SCX-2 cation exchange resin cartridge to obtain the product (120 mg, 98%) as a beige solid. LCMS: [M + H]+ = 436.58. Step 5: 6-(3-amino-5-fluoro-6-(4-(1-isopropylpiperidine-4-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0352] 6-(3-amino-5-fluoro-6-(4-(piperidine-4-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (30 mg, 0.069 mmol) and N,N-diisopropylethylamine (0.120 mL, 0.689 mmol) in DMF (1 mL) were mixed with 2-iodopropane (58.6 mg, 0.344 mmol). The reaction system was stirred at room temperature for 2.5 days. The reaction system was concentrated on Celite® and purified by silica gel chromatography using 0-10% MeOH / CH2Cl2 + 1% NH4OH followed by reverse-phase chromatography (C18, 0-100% ACN / H2O). The desired fraction was then passed through an Isolute SCX-2 cation exchange resin cartridge and eluted with 3% NH3 in MeOH to obtain the compound described in the heading (14.6 mg, 44%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.05 (br s, 1H), 7.79 (br d, J = 7.6Hz, 2H), 7.50 (s, 1H), 7.44 (br d, J = 11.9 Hz, 1H), 7.34(d, J = 8.2 Hz, 2H), 6.98 (s, 2H), 2.98 (br t, J = 6.2Hz, 2H), 2.90 (br d, J = 11.1 Hz, 2H), 2.73 (td, J = 6.5, 13.1 Hz, 1H), 2.24 (brt, J = 10.8 Hz, 2H), 1.78 (br d, J = 12.2 Hz, 2H), 1.68 -1.59 (m, 2H), 1.24 (s, 1H), 1.00 (d, J = 6.5 Hz, 6H); LCMS:[M + H]+ = 478.57. Example 11: 6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-3-((methylamino)methyl)-3,4-dihydroisoquinoline-1(2H)-one(I-11) [ka] Step 1: 3-(3-bromophenyl)-1-methoxy-1-oxopropane-2-aminium chloride: [ka]

[0353] To a stirred solution of 2-(3-bromophenyl)-1-carboxyethane-1-aminium chloride (10 g, 35.7 mmol) in MeOH (300 mL), SOCl2 (7.7 mL, 107.3 mmol) was added dropwise at 0°C. The reaction mixture was then heated at 100°C for 16 hours and subsequently cooled to room temperature. The solvent was concentrated under reduced pressure to obtain the product (10.4 g, quantitative) as an off-white solid. The crude compound was used in the next step without purification. LCMS: [M + H] + = 258.09. Step 2: Methyl 3-(3-bromophenyl)-2-(((trichloromethoxy)carbonyl)amino)propanoate: [ka]

[0354] To a stirred solution of 3-(3-bromophenyl)-1-methoxy-1-oxopropane-2-aminium chloride (10.5 g, 35.7 mmol) in 1,4-dioxane (115 mL), add trichloromethyl chloroformate (5.9 mL, 50 mmol) at room temperature. andThe mixture was then heated at 100°C for 16 hours and then cooled to room temperature. The solvent was concentrated under reduced pressure to obtain the product (14.8 g, quantitative) as a pale brown, gum-like liquid, which was used in the next step without purification. TLC: 10% MeOH: CH2Cl2; R f = 0.7. Step 3: Methyl 6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate: [ka]

[0355] To a stirred solution of methyl 3-(3-bromophenyl)-2-(((trichloromethoxy)carbonyl)amino)propanoate (14.8 g, 35.5 mmol, quantitative) in DCM (150 mL), AlCl3 (9.3 g, 71.1 mmol) was added in multiple portions at 0°C. The mixture was then heated at 45°C for 3 hours and subsequently cooled to room temperature. The reaction mixture was quenched with water (100 mL), extracted with CH2Cl2 (2 x 300 mL), and the resulting organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude residue. This crude compound was purified by column chromatography using silica gel (100-200 mesh) with 0-60% siRNA in hexane as the eluent, yielding the product (2.9 g, 29%) as an off-white solid. LCMS: [M + H] + = 284.05. Step 4: 6-Bromo-3-(hydroxymethyl)-3,4-dihydroisoquinoline-1(2H)-one: [ka]

[0356] To a stirred solution of methyl 6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (2.9 g, 10.2 mmol) in EtOH (30 mL), LiBH4 (450 mg, 20.4 mmol) was added in portion at 0°C. The reaction system was stirred at room temperature for 16 hours, and the solvent was concentrated under reduced pressure to obtain the crude residue. The crude compound was diluted with water (100 mL) and extracted with CH2Cl2 (2 x 300 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude residue. The crude compound was triturated with diethyl ether (100 mL), filtered, and dried under reduced pressure to obtain the product (2.5 g, 95%) as an off-white solid. LCMS: [M+H] + = 256.03. Step 5: (6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methylmethanesulfonate: [ka]

[0357] To a stirred solution of 6-bromo-3-(hydroxymethyl)-3,4-dihydroisoquinoline-1(2H)-one (2.5 g, 9.8 mmol) in CH2Cl2 (30 mL), triethylamine (2.6 mL, 19.6 mmol), methanesulfonyl chloride (1.5 mL, 19.6 mmol), and DMAP (110 mg, 0.98 mmol) were added at 0°C. The reaction mixture was then stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure to obtain the crude residue. This crude compound was diluted with water (100 mL) and extracted with CH2Cl2 (2 x 300 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the crude residue. The crude compound was triturated with diethyl ether (100 mL), filtered, and dried under reduced pressure (under vacuum) to obtain the product (2.2 g, 68%) as an off-white solid. LCMS: [M + H]+ = 334.03. Step 6: 6-Bromo-3-((methylamino)methyl)-3,4-dihydroisoquinoline-1(2H)-one: [ka]

[0358] To a stirred solution of (6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methylmethanesulfonate (2.2 g, 6.6 mmol) in THF (25 mL), triethylamine (13.5 mL, 99 mmol) and a 40% aqueous methylamine solution (13.5 mL) were added in a sealed tube at room temperature. The resulting mixture was stirred at 100 °C for 16 hours and then cooled to room temperature. The solvent was concentrated under reduced pressure to obtain the crude residue. The crude compound was purified by column chromatography (neutral alumina) using 0-5% MeOH in CH2Cl2 as the eluent, and the product (0.85 g, 48%) was obtained as an off-white solid. 1 H NMR (400 MHz, DMSO-d6): δ 7.82 (s, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 10.4, 2.4Hz, 2H), 3.68-3.60 (m, 1H), 2.99 (dd, J = 16, 4.8 Hz, 1H), 2.88-2.78(m, 1H), 2.61-2.52 (m, 2H), 2.27 (s, 3H); LCMS: [M + H] + = 269.04. Step 7: tert-butyl ((6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)(methyl)carbamate [ka]

[0359] 6-Bromo-3-((methylamino)methyl)-3,4-dihydroisoquinoline-1(2H)-one (200 mg, 0.743 mmol) was dissolved in CH2Cl2 (6 mL) at room temperature, and di-tert-butyl dicarbonate (178 mg, 0.817 mmol) was added in one portion, followed by N,N-diisopropylethylamine (0.272 mL, 1.56 mmol). The mixture was stirred at room temperature for 1 hour, concentrated on Celite®, and purified by flash silica gel chromatography by elution with hexane containing 0-20% EA. The product was isolated as a colorless oil (359 mg, quantitative yield). LCMS: [M + H] + = 371.45. Step 8: tert-butylmethyl((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)carbamate [ka]

[0360] A mixture of tert-butyl((6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)(methyl)carbamate (138 mg, 0.374 mmol), bis(pinacolato)diborone (107 mg, 0.422 mmol), [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.3 mg, 0.037 mmol), and KOAc (110 mg, 1.12 mmol) in 1,4-dioxane (10 mL) was flushed with argon. This mixture was heated in a microwave reactor at 100 °C for 1 hour. This mixture was filtered through a thin pad of Celite®, the filter cake was washed with ethyl acetate, the combined filtrate was concentrated, and a 16 mg / mL stock solution was prepared in CH3CN, which was used in the next step. LCMS: [M + H] + = 417.58. Step 9: tert-butylmethyl((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)carbamate [ka]

[0361] Water (1.5 mL) is mixed with tert-butylmethyl((1-oxo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl) carbamate (6.3 mL solution at a concentration of 16 mg / mL, 100 mg, 0.239 mmol), 5-bromo-6-fluoro-3-iodopyrazine-2-amine (80 mg, 0.252 mmol), and Na2CO3. . The reaction mixture was added to a degassed suspension of H2O (65.5 mg, 0.528 mmol) and bis(triphenylphosphine)palladium(II) dichloride (21.20 mg, 0.030 mmol), and the reaction mixture was flushed with argon. This mixture was heated in a microwave reactor at 80°C for 1 hour. The reaction mixture was concentrated on Celite® and purified by silica gel chromatography by elution with hexane containing 0-60% butyl. The product (80 mg, 60%) was isolated as a yellowish-brown solid. LCMS: [M + H] + = 480.39. Step 10: tert-butyl ((6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)(methyl)carbamate [ka]

[0362] A microwave vial containing a mixture of tert-butyl ((6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)(methyl)carbamate (38 mg, 0.079 mmol), 4-(4-isopropylpiperazinyl)phenylboronic acid pinacol ester (36.6 mg, 0.111 mmol), [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.68 mg, 0.012 mmol), and Cs2CO3 (77 mg, 0.237 mmol) in DME (4 mL) was degassed with argon. Water (1 mL) was added, and the mixture was heated in a microwave reactor at 90°C for 1.75 hours. This mixture was concentrated on Celite® and purified by flash silica gel chromatography, eluting with hexane containing 0-100% EA. The product was isolated as a yellow solid (32 mg, 67%). LC-MS: [M + H]+ = 604.73. Step 11: 6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-3-((methylamino)methyl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0363] Trifluoroacetic acid (0.107 mL, 1.39 mmol) was added at room temperature to a solution of tert-butyl((6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)(methyl)carbamate (42 mg, 0.070 mmol) in CH2Cl2 (1.5 mL). The mixture was stirred at room temperature for 1 hour and then concentrated using a rotary evaporator. The residue was dissolved in MeOH and 26 mg of the product was collected through a 2 G porapak cation exchange cartridge. This crude product was triturated from CH2Cl2 / hexane to obtain the desired product as a yellow solid (16 mg, 43%). 1 H NMR (500 MHz, DMSO-d6) δ 7.9-8.0 (m, 1H), 7.7-7.8 (m, 3H), 7.7-7.7(m, 1H), 7.6-7.6 (m, 1H), 7.0-7.0 (m, 2H), 6.6-6.8 (m, 2H), 3.7-3.7(m, 1H), 3.18 (br s, 4H), 3.0-3.1 (m, 1H), 2.9-2.9 (m, 1H), 2.6-2.7(m, 3H), 2.58 (br s, 4H), 2.3-2.3 (m, 3H), 1.0-1.0 (m, 6H). LCMS: [M+H] + =504.58. Example 12: 6-(3-amino-5-fluoro-6-(4-morpholinophenyl)pyrazine-2-yl)-3-((methylamino)methyl)-3,4-dihydroisoquinoline-1(2H)-one(I-12) [ka] Step 1: tert-butyl ((6-(3-amino-5-fluoro-6-(4-morpholinophenyl)pyrazine-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)(methyl)carbamate [ka]

[0364] A microwave vial containing a mixture of tert-butyl ((6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)(methyl)carbamate (38 mg, 0.079 mmol), 4-(morpholino)phenylboronic acid (22.93 mg, 0.111 mmol), [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8.68 mg, 0.012 mmol), and Cs2CO3 (77 mg, 0.237 mmol) in DME (4 mL) was degassed with argon. Water (1 mL) was added, and the mixture was heated in a microwave reactor at 90°C for 1.5 hours. This mixture was concentrated on Celite® and purified by flash silica gel chromatography, eluting with hexane containing 0-100% toluene. The product was isolated as a yellow solid (31 mg, 70%). LCMS: [M + H] + = 563.62. Step 2: 6-(3-amino-5-fluoro-6-(4-morpholinophenyl)pyrazine-2-yl)-3-((methylamino)methyl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0365] Trifluoroacetic acid (0.084 mL, 1.10 mmol) was added at room temperature to a solution of tert-butyl ((6-(3-amino-5-fluoro-6-(4-morpholinophenyl)pyrazine-2-yl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-yl)methyl)(methyl)carbamate (31 mg, 0.055 mmol) in CH2Cl2 (1.5 mL). The mixture was stirred at room temperature for 1 hour, and the residue was dissolved in MeOH. The desired product was collected as a yellow solid (23 mg, 86%) through a 2 g porapak cation exchange cartridge. 1H NMR (500 MHz, DMSO-d6) δ 7.99 - 7.91 (m, 1H), 7.84 - 7.73 (m, 3H), 7.72- 7.67 (m, 1H), 7.64 (s, 1H), 7.08 - 6.99 (m, 2H), 6.81 - 6.64 (m, 2H), 3.79-3.71 (m, 5H), 3.20 - 3.15 (m, 4H), 3.10 - 3.05 (m, 1H), 2.93 - 2.86 (m, 1H), 2.64 (br s, 2H), 2.41 - 2.27 (m, 3H). LCMS: [M + H] + = 463.53. Example 13: 6-(3-amino-6-(4-(1-(cyclopropylmethyl)piperidine-4-yl)phenyl)-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one formate(I-13) [ka] Step 1: 5-bromo-6-fluoropyrazine-2-amine [ka]

[0366] To an ice-cold solution of 6-fluoropyrazine-2-amine (550 mg, 4.86 mmol) in CH2Cl2 (30 mL) and CH3CN (5.0 mL), a cold solution of recrystallized N-bromosuccinimide (883 mg, 4.96 mmol) in CH2Cl2 (10 mL) in CH3CN (5.00 mL) was added dropwise over 10 minutes. After stirring at 0°C for 5 minutes, the reaction system was quenched with ice / MeOH and concentrated on Celite®. The crude material was purified by flash silica gel chromatography using 0-40% Â / hexane. The desired fraction was collected, concentrated, and dried under high pressure at room temperature to obtain the product as a pale yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.62 (d, J = 4.4 Hz, 1H), 7.13 (br s, 2H). Step 2: 5-Bromo-6-fluoro-3-iodopyrazine-2-amine [ka]

[0367] To a solution of 5-bromo-6-fluoropyrazine-2-amine (934 mg, 4.86 mmol) in AcOH (10 mL), N-iodosuccinimide (1313 mg, 5.84 mmol) was added in multiple portions. Trifluoroacetic acid (55.5 mg, 0.486 mmol) was added, and the reaction mixture was heated at 50°C for 1 hour. The reaction mixture was concentrated under reduced pressure (in vacuo) and neutralized with aqueous NaHCO3 (aq) and saturated sodium thiosulfate aqueous solution. The aqueous layer was extracted using CH2Cl2. The combined organic extract was concentrated on Celite® and purified by flash silica gel chromatography by elution with 0-30% Â / hexane. The desired fraction was collected, concentrated, and dried under reduced pressure (under vacuum) to obtain the product (2.85 mmol, 59%) as a pale yellow solid. LCMS: [M + H] + = 318.29. Step 3: 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0368] To a degassed solution of 5-bromo-6-fluoro-3-iodopyrazine-2-amine (760 mg, 2.391 mmol) and 8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (835 mg, 2.87 mmol) in CH3CN (15 mL), a solution of Na2CO3 (623 mg, 5.02 mmol) in water was added in a microwave vial. This container was degassed, and bis(triphenylphosphine)palladium(II) dichloride (201 mg, 0.287 mmol) was added. The reaction system was heated in a microwave apparatus at 80°C for 3 hours. The reaction system was concentrated on Celite® and purified by flash silica gel chromatography with elution of 0-100% siRNA / hexane. The desired fraction was collected, concentrated, and re-purified by silica gel chromatography with elution of 0-10% MeOH / CH2Cl2 + 1% NH4OH. The desired fraction was collected, concentrated, and dried under high pressure (under vacuum) to obtain the product (1.51 mmol, 63%) as a beige solid (throughout the two steps). LCMS: [M + H] + = 355.28. Step 4: tert-butyl 4-(4-(5-amino-3-fluoro-6-(8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)phenyl)piperidine-1-carboxylate [ka]

[0369] 6-Bromo-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (700 mg, 2.87 mmol), bis(pinacolato)diborone (801 mg, 3.15 mmol), and KOAc (844 mg, 8.60 mmol) were added to a microwave vial with anhydrous 1,4-dioxane (40.0 mL). The reaction system was degassed, and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (210 mg, 0.287 mmol) was added. The mixture was degassed and then heated at 100°C for 3 hours. The reaction system was diluted with CH3CN, filtered through a Celite® pad, concentrated under reduced pressure (in vacuo), and used in the next step without further purification. LCMS: [M + H] + = 292.40. Step 5: tert-butyl 4-(4-(5-amino-3-fluoro-6-(8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)phenyl)piperidine-1-carboxylate [ka]

[0370] To a degassed suspension of 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (100 mg, 0.282 mmol) and Cs2CO3 (229 mg, 0.704 mmol) in a mixture of 1,2-DME (4 mL):H2O (1.33 mL), 4-(N-Boc-piperidino)phenylboronic acid pinacol ester (131 mg, 0.338 mmol) was added. This mixture was heated in a microwave apparatus at 90°C for 2 hours. The reaction system was concentrated on Celite® and purified by flash silica gel chromatography with elution of 0-10% MeOH / DCM + 1% NH4OH. The desired fraction was collected, concentrated, and dried under reduced pressure (en vacuo) to obtain the product (0.282 mmol, 100%) as a brown solid. LCMS: [M + H] += 480.58. Step 6: 6-(3-amino-5-fluoro-6-(4-(piperidine-4-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0371] To a solution of tert-butyl 4-(4-(5-amino-3-fluoro-6-(8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)phenyl)piperidine-1-carboxylate (151 mg, 0.282 mmol) in CH2Cl2 (5.0 mL), TFA (0.648 mL, 8.46 mmol) was added. The reaction system was stirred at room temperature for 16 hours. The reaction system was concentrated under reduced pressure (en vacuo) to remove volatile components. The crude product was dissolved in methanol and eluted with 3% NH3 / MeOH after passing through an Isolute flash SCX-2 500 mg replacement column. The mixture was then concentrated and dried under high pressure (under vacuum) to obtain the product (0.276 mmol, 98%). LCMS [M + H] + = 436.58. Step 7: 6-(3-amino-6-(4-(1-(cyclopropylmethyl)piperidine-4-yl)phenyl)-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one formate [ka]

[0372] To a solution of 6-(3-amino-5-fluoro-6-(4-(piperidine-4-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (30 mg, 0.069 mmol) and N,N-diisopropylethylamine (0.120 mL, 0.689 mmol) in DMF (1 mL), (bromomethyl)cyclopropane (46.5 mg, 0.344 mmol) was added. The reaction system was stirred at room temperature for 72 hours. This mixture was concentrated under reduced pressure (en vacuo) and purified by Waters preparative HPLC (XBridge Prep C18 5 μm, 10 x 100 mm column, 0.1% formic acid in 90-70% water / 0.1% formic acid in CH3CN) to obtain the formate salt (18.8 mg, 51%) of the compound described in the heading as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.25 - 8.12 (m, 2H), 7.95 (br s, 1H), 7.69 (br d, J = 7.5 Hz, 2H), 7.40 (s, 1H), 7.33 (brd, J = 12.0 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 6.88 (s, 2H), 3.26 (br d, J = 2.8 Hz, 2H), 3.01 (br d, J =11.2 Hz, 2H), 2.87 (br t, J = 6.2 Hz, 2H), 2.14(d, J = 6.5 Hz, 2H), 1.96 (br t, J = 10.6 Hz, 2H), 1.70 - 1.55 (m, 4H), 0.82 - 0.71 (m, 1H), 0.44- 0.34 (m, 2H), 0.00 (br d, J = 4.3 Hz, 2H); LCMS: [M + H]+ = 490.54. Example 14: 6-(3-amino-5-fluoro-6-(4-(4-isopropylpiperazine-1-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-14) [ka]

[0373] PdCl2dppf (8.24 mg, 0.011 mmol) was added to a suspension of 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (40 mg, 0.113 mmol), 4-(4-isopropylpiperazinyl)phenylboronic acid pinacol ester (44.6 mg, 0.135 mmol), and Cs2CO3 (92 mg, 0.282 mmol) in a 3:1 mixture of DME (4 mL):water (1.3 mL). This suspension was then mixed with PdCl2dppf (8.24 mg, 0.011 mmol). The mixture was flushed with nitrogen and heated in a microwave at 90°C for 2 hours. The reaction system was concentrated on Celite® and purified by silica gel chromatography by elution with 0-10% MeOH / CH2Cl2 + 1% NH4OH. The combined concentrated fraction was triturated from MeOH to obtain the compound described in the heading (43.8 mg, 81%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.04 (br s, 1H), 7.75 (d, J = 7.9 Hz, 2H), 7.50 (s, 1H), 7.43 (d, J = 12.1 Hz, 1H), 7.02 (d, J = 8.9 Hz, 2H), 6.83 (s, 2H), 3.38 - 3.35 (m, 2H), 3.22 - 3.17 (m, 4H), 2.98 (br t, J = 6.3 Hz, 2H), 2.68 (td, J = 13.1, 6.5 Hz, 1H), 2.61 - 2.56 (m, 4H), 1.01 (d, J = 6.6 Hz, 6H); LCMS: [M+H]+ = 479.57. Example 15: 6-(3-amino-5-fluoro-6-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one formate [ka] Step 1: (1R,5S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane [ka]

[0374] (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (130 mg, 0.546 mmol), bis(pinacolato)diborone (152 mg, 0.601 mmol), and KOAc (161 mg, 1.64 mmol) were added to a microwave vial, to which anhydrous 1,4-dioxane (6 mL) was added. The system was degassed, and PdCl2dppf (39.9 mg, 0.055 mmol) was added. This mixture was flushed with nitrogen and then heated at 100°C for 3 hours. The reaction system was diluted with CH3CN, filtered through a Celite® pad, concentrated under reduced pressure (in vacuo), and used in the next step without further purification. LCMS: [M + H]+ = 286.51. Step 2: 6-(6-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-3-amino-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0375] PdCl2dppf (19.57 mg, 0.027 mmol) was added to a suspension of 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (95 mg, 0.267 mmol), (1R,5S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-azabicyclo[3.1.0]hexane (3.52 mL, 0.321 mmol, 26 mg / ml in CH3CN) and Cs2CO3 (218 mg, 0.669 mmol) in a 3:1 mixture of DME (5 mL):water (1.7 mL). The mixture was flashed with nitrogen and heated in a microwave oven at 90°C for 2 hours. The reaction system was concentrated on Celite® and purified by silica gel chromatography using elution with 0-10% MeOH / CH2Cl2 + 1% NH4OH to obtain the product (96 mg, 83%) as a brown solid. LCMS: [M + H]+ = 434.57. Step 3: 6-(3-amino-5-fluoro-6-(4-((1R,5S)-3-isopropyl-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0376] 6-(6-(4-((1R,5S)-3-azabicyclo[3.1.0]hexane-1-yl)phenyl)-3-amino-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (30 mg, 0.069 mmol) and N,N-diisopropylethylamine (0.121 mL, 0.692 mmol) were dissolved in DMF (1 mL), to which 2-iodopropane (58.8 mg, 0.346 mmol) was added. The reaction system was stirred at room temperature for 3 days, then concentrated on Celite®, and purified by silica gel chromatography using 0-10% MeOH / CH2Cl2 + 1% NH4OH followed by reverse-phase chromatography (C18, 0-100% ACN / H2O). The desired fraction was then passed through an Isolute SCX-2 cation exchange resin cartridge and eluted with 3% NH3 in MeOH. This material was then purified by Waters preparative HPLC (XBridge Prep C18 5 μm, 10 x 100 mm column, 90-70% 0.1% formic acid in water / 0.1% formic acid in acetonitrile) to obtain the formate (11 mg, 31%) of the compound described in the heading as an orange solid. 1 H NMR (500 MHz, DMSO-d6) δ 8.32 (br s, 2H), 8.05 (br s, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.50 (s, 1H), 7.43 (br d, J = 11.9Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H), 6.98 (s, 2H), 3.06 (br d, J = 8.6Hz, 1H), 2.98 (br t, J = 6.2 Hz, 2H), 2.60 (d, J = 8.4 Hz, 1H), 2.48 - 2.45 (m, 2H), 1.84 (td, J = 7.8, 3.9 Hz, 1H), 1.33 (t, J = LCMS:[M + H]+ = 476.56 Example 16: 6-(3-amino-6-(4-(4-(cyclopropylmethyl)piperazine-1-yl)phenyl)-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one(I-16) [ka] Step 1: tert-butyl 4-(4-(5-amino-3-fluoro-6-(8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)phenyl)piperazine-1-carboxylate [ka]

[0377] PdCl2dppf (14.42 mg, 0.020 mmol) was added to a suspension of 6-(3-amino-6-bromo-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (70 mg, 0.197 mmol), tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]tetrahydro-1(2H)-pyrazinecarboxylate (92 mg, 0.237 mmol), and Cs2CO3 (161 mg, 0.493 mmol) in a 3:1 mixture of DME (4 mL):water (1.3 mL). This mixture was heated in a microwave apparatus at 90°C for 2 hours. The reaction system was concentrated on Celite® and purified by silica gel chromatography using elution with 0-10% MeOH / CH2Cl2 + 1% NH4OH, yielding the product as a yellow solid. This material was directly carried over to the next step. LCMS: [M + H] + = 537.55. Step 2: 6-(3-amino-5-fluoro-6-(4-(piperazine-1-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0378] To a solution of tert-butyl 4-(4-(5-amino-3-fluoro-6-(8-fluoro-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-yl)pyrazine-2-yl)phenyl)piperazine-1-carboxylate (106 mg, 0.197 mmol) in CH2Cl2 (4 mL), trifluoroacetic acid (0.45 mL, 5.91 mmol) was added. The reaction system was stirred overnight at room temperature. The reaction system was concentrated under reduced pressure (in vacuo) to remove volatile components. The crude product was dissolved in MeOH and eluted with 3% NH3 in MeOH via an isolute SCX-2 cation exchange resin cartridge to obtain the product (84 mg, 98%) as a bright yellow solid. LCMS: [M + H] + = 437.45. Step 3: 6-(3-amino-6-(4-(4-(cyclopropylmethyl)piperazine-1-yl)phenyl)-5-fluoropyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0379] Using 6-(3-amino-5-fluoro-6-(4-(piperazin-1-yl)phenyl)pyrazine-2-yl)-8-fluoro-3,4-dihydroisoquinoline-1(2H)-one (30 mg, 0.069 mmol), N,N-diisopropylethylamine (0.120 mL, 0.687 mmol), and (bromomethyl)cyclopropane (27.8 mg, 0.206 mmol) in DMF (1 mL), the compound described in the heading (3.46 mg, 10%) was obtained as a yellow solid in a procedure similar to step 3 of Example 15. 1H NMR (500 MHz, DMSO-d6) δ 8.03 (br s, 1H), 7.75 (br d, J = 8.2Hz, 2H), 7.50 (s, 1H), 7.42 (br d, J = 12.2 Hz, 1H), 7.02(br d, J = 8.8 Hz, 2H), 6.83 (s, 2H), 3.22 (br s, 4H), 2.97(br t, J = 6.1 Hz, 2H), 2.61 (br s, 4H), 2.26 (br s, 2H), 0.87(br d, J = 6.4 Hz, 1H), 0.49 (br d, J = 7.3 Hz, 2H), 0.11 (br d, J = 3.7Hz, 2H); LCMS: [M + H]+ = 491.54. Example 17: 6-(3-amino-5-fluoro-6-(4-morpholinophenyl)pyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one(I-17) [ka]

[0380] To a degassed suspension of 6-(3-amino-6-chloro-5-fluoropyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one (80 mg, 0.273 mmol), 4-(morpholino)phenylboronic acid (85 mg, 0.410 mmol), and K3PO4 (145 mg, 0.683 mmol) in an 8:1 mixture of 1,4-dioxane (9.0 mL):water (1.1 mL), XPhos Pd G2 (32.3 mg, 0.041 mmol) was added. The system was degassed, and the mixture was heated at 90°C for 16 hours. The mixture was concentrated on Celite® and purified by flash chromatography (silica gel) with elution of 0-10% MeOH / CH2Cl2 + 1% NH4OH. The desired fraction was collected and concentrated. This yellow solid was triturated with MeOH:SiO (9:1, 15 mL) and dried under reduced pressure (under vacuum) to obtain the compound described in the heading (46.4 mg, 41%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 7.98 (br. s., 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 7.8 Hz, 1H), 7.65 (s, 1H), 7.03 (d, J = LCMS: [M+H] + = 420.55. Example 18: (S)-6-(3-amino-5-fluoro-6-(3-(pyrrolidine-2-yl)-4-(tetrahydro-2H-pyran-4-yl)phenyl)pyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one(I-18) [ka] Step 1: 1-(4-bromophenyl)-3-chloropropan-1-one [ka]

[0381] To a stirred solution of AlCl3 (699 g, 5254.8 mmol) in DCM (2.5 L), bromobenzene (500 mL, 4777.1 mmol) and 3-chloropropanoyl chloride (456 mL, 4777.1 mmol) in DCM (2.5 L) were added dropwise at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The mixture was quenched with ice water (5 L) and extracted using DCM (3 x 3.0 L). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to obtain the product (700 g, quantitative) as a pale yellow semi-solid. TLC: (20% EA in petroleum ether) R f = 0.4. Step 2: 5-bromo-2,3-dihydro-1H-idden-1-one [ka]

[0382] A solution of 1-(4-bromophenyl)-3-chloropropan-1-one (350 g, 1422.8 mmol) in H2SO4 (3.5 L) was stirred at room temperature, then heated to 100°C and stirred for 4 hours, after which it was cooled to room temperature. The reaction mixture was diluted with ice water and extracted with ELISA (3 x 5.0 L). The combined organic layers were washed with aqueous salt solution (4.0 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the product (500 g, quantitative) as a brown solid. LCMS: [M+H] + = 211.06 Step 3: 6-Bromo-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0383] To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (500 g, 2369.7 mmol) in DCM (4.0 L), methanesulfonic acid (2.0 L) was added at 0°C. Then, NaN3 (539 g, 8.293 mmol) was added in several portions. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was slightly based with 20% NaOH solution and extracted using DCM (2 x 5.0 L). The combined organic layers were dried over sodium sulfate and concentrated to obtain the crude compound; this crude compound was purified by column chromatography using 100-200 silica and 30-40% ethyl acetate in petroleum ether as the eluent to obtain the product (100 g, yield 37.0%) as a light brown solid. LCMS: [M+H] + = 226.09 Step 4: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-1(2H)-one [ka]

[0384] To a stirred solution of 6-bromo-3,4-dihydroisoquinoline-1(2H)-one (10 g, 44.3 mmol) in 1,4-dioxane (100 mL), B2Pin2 (16.8 g, 66.4 mmol) and KOAc (8.7 g, 88.5 mmol) were added, and the mixture was bubbling with argon at room temperature for 15 minutes. Then, Pd(dppf)Cl2.DCM (1.85 g, 2.21 mmol) was added, and the mixture was heated at 80 °C for 16 hours, after which it was cooled to room temperature. The reaction system was filtered through a Celite bed, washed with SiO2 (300 mL), and concentrated under reduced pressure to obtain the crude material, which was purified with 100-200 silica and SiO2 as the eluent to obtain the product (10 g, 83.0%) as a gray solid. LCMS: 274.22 [M + H] + = 274.22. Step 5: 2-6-difluoropyrazine [ka]

[0385] To a stirred solution of 2,6-dichloropyrazine (7 g, 47.2 mmol) in DMSO (35 mL), CsF (14.4 g, 94.5 mmol) was added. This mixture was then heated in a sealed tube at 120°C for 16 hours and subsequently cooled to room temperature. The reacti...

Claims

1. Compounds of formula (I) or their enantiomers, or pharmaceutically acceptable salts and / or solvates thereof, 【Chemistry 1】 During the ceremony: X １ N and CR １ Selected from; X ２ and X ３ N and CR ２ Selected independently from ； X ４ and X ５ One of them is N and the other is CR ３ ; Q is one or more R ５ It is optionally substituted and / or R on one carbon ５ａ and R ５ｂ C is optionally substituted by １～４ It is alkylene; or Q is one or more R ５ｃ C is optionally replaced ２～４ It is an alkenylene; or Q is optionally selected from C=N and N=C, and R ５ｃ It is optionally replaced by; R １ H, Halo, OR ６ , NR ７ R ８ , C １～６ Alkilen NR ７ R ８ and C １～６ Selected from alkyl groups; R ２ H, halo and C １～６ Selected from alkyl groups; R ３ It is a halo; R ４ H and C １～６ Selected from alkyl groups; Each R ５ H is = O, halo, C １～６ Alkyl, C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl, C １～６ Alkilen C ３～６ Cycloalkyl, C １～６ Alkilen C ３～６ Heterocycloalkyl, OH, OC １～６ Alkyl, NR ９ R １０ and C １～６ Alkilen NR ９ R １０ Selected independently from; R ５ａ and R ５ｂ They bond together, and together with the carbon atoms between them, form a 3-6 member saturated or unsaturated ring consisting of N, NH, NC １～６ Alkyl, O, S, S(O), and SO ２ A ring is formed that optionally includes one heteromorph selected from, and the halo and C １～６ It is optionally substituted with one or more alkyl groups; Each R ５ｃ Hello, C １～６ Alkyl, C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl, C １～６ Alkilen C ３～６ Cycloalkyl, C １～６ Alkilen C ３～６ Heterocycloalkyl, OH, OC １～６ Alkyl NR ９ R １０ , and C １～６ Alkilen NR ９ R １０ Selected independently from; R ６ H and C １～６ Selected from alkyl groups; R ７ , R ８ , R ９ and R １０ H and C １～６ Independently selected from alkyl; or, R ７ and R ８ , or R ９ and R １０ They bond together, and together with the nitrogen atom between them, form N, NH, NC １～６ Alkyl, O, S, SO, and SO ２ It optionally includes one additional heteromorph selected from and includes Halo and C. １～６ Forming a 3- to 7-membered saturated or unsaturated ring optionally substituted by one or more alkyl groups; Cy １ is a phenyl substituted with one to three R11 groups, wherein at least one R11 is selected from C1-4 alkylene NR12aR13a, NR12aR13a, and NR13aC1-4 alkylene NR12R13; or at least one R11 is CN; or Cy 1 is a benzo-fused C9-11 heterocycle, and Cy １ It is either unsubstituted or has one to three R's. １１ It is replaced by, or Cy １ These are all Z-Cy ２ Selected from phenyl and C5-6 heteroaryls substituted by, or Cy １ These are all Z-Cy ２ and one to three R １１ Selected from phenyl and C5-6 heteroaryls substituted by; Each R １１ is halo, =O, CN, NO ２ , C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, OR １２ , C(O)R １２ , CO ２ R １２ , SR １２ , S(O)R １２ , SO ２ R １２ , S(O)(=NR １３ )R １２ , SO ２ NR １２ R １３ , C １～６ alkylene OR １２ , OC １～６ alkylene OR １２ 、 C １～６ alkylene NR １２ａ R １３ａ , OC １～６ alkylene NR １２ R １３ , NR １３ａ C １～６ alkylene NR １２ R １３ , NR １３ａ C １～６ alkylene OR １２ , NR １２ａ R １３ａ , NR １３ａ COR １２ , NR １３ａ , CO ２ R １２ , NR １３ａ , SO ２ R １２ , C ３～７ cycloalkyl, C ３～７ heterocycloalkyl, C １～６ alkylene C ３～７ cycloalkyl and C １～６ alkylene C ３～７ [[ID=, 103]]heterocycloalkyl are independently selected from, and the latter four groups are optionally substituted by one or more R １５ ; R １２ H, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkilen C ３～１０ Cycloalkyl, C １～６ Alkilen C ３～１０ Heterocycloalkyl, C １～６ Alkilen OR １６ , and C １～６ Alkilen NR １６ａ R １６ｂ Selected from, and also R １２ The alkyl group, alkenyl group, alkynyl group, alkylene group, heterocycloalkyl group, and cycloalkyl group are one or more R １７ It is optionally replaced by; R １３ H and C １～６ Selected from alkyl groups; or, R １２ and R １３ They bond together, together with the atoms (one or more) between them, forming a 4-6 member saturated or unsaturated ring, N, NR １８ , O, S, SO, and SO ２ Optionally includes one additional heteromorph selected from and one or more R １７ Forms a ring which is optionally substituted by; R １２ａ H, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkilen C ３～１０ Cycloalkyl, C １～６ Alkilen C ３～１０ Heterocycloalkyl, C １～６ Alkilen OR １６ , and C １～６ Alkilen NR １６ａ R １６ｂ Selected from, and also R １２ａ All alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, heterocycloalkyl groups, and cycloalkyl groups are one or more R １７ It is optionally replaced by; R １３ａ H and C １～６ Selected from alkyl groups; R １４ , R １４ａ , and R １４ｂ is OR １９ , C １～６ Alkyl, C ３～１１ Cycloalkyl, C ３～１０ Heterocycloalkyl, C １～６ Alkilen C ３～１０ Cycloalkyl, and C １～６ Alkilen C ３～１０ Independently selected from heterocycloalkyl groups; Each R １５ is Halo, OH, C １～６ Alkyl, OC １～６ Alkyl, CN and NR １５ａ R １５ｂ Selected independently from; R １５ａ and R １５ｂ H and C １～６ Independently selected from alkyl groups; R １６ , R １６ａ and R １６ｂ H and C １～６ Independently selected from alkyl groups; Each R １７ Hello, C １～６ Alkyl, CN and NR １７ａ R １７ｂ Selected independently from; R １７ａ and R １７ｂ H and C １～６ Independently selected from alkyl groups; R １８ H and C １～６ Selected from alkyl groups; R １９ H, C １～６ Alkyl, C ３～１１ Cycloalkyl, C ３～１０ Heterocycloalkyl, C １～６ Alkilen C ３～１０ Cycloalkyl, C １～６ Alkilen C ３～１０ Heterocycloalkyl C １～６ Alkilen OR ２０ , and C １～６ Alkilen NR ２０ R ２１ Selected from; R ２０ and R ２１ H and C １～６ Independently selected from alkyl groups; Z does not exist, or C １～６ Alkylene, O, C(O), CO ２、 S, S(O), SO ２、 S(O)(=NR １３ｂ ), NR １３ｂ , C １～６ Alkylene O, C １～６ Alkylene C(O), C １～６ Alkylene CO2 ２、 C １～６ Alkilen S, C １～６ Alkylene S(O), C １～６ Alkylene SO1 ２ , C １～６ Alkylene S(O) (=NR) １３ｂ ), C １～６ Alkilen NR １３ｂ , OC １～６ Alkylene, C(O)C １～６ Alkylene, CO ２ C １～６ Alkiren, SC １～６ Alkylene, S(O)C １～６ Alkilen, SO ２ C １～６ Alkylene, S(O)(=NR) １３ｂ ) C １～６ Alkylene and NR １３ｂ C １～６ Selected from alkylene; R １３ｂ H and C １～６ Selected from alkyl groups; Cy ２ C ３～１４ It is heterocycloalkyl, and also Cy ２ is either unsubstituted or has one or more R ２２ It has been replaced with; Each R ２２ H is, =O,CN,OH,C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～１０ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１１ Ariel, C ５～１４ Heteroaryl, C １～６ Alkilen C ３～１０ Cycloalkyl, C １～６ Alkilen C ３～１０ Heterocycloalkyl, C １～６ Alkilen C ６～１１ Ariel, C １～６ Alkilen C ５～１４ Heteroaryl, OC １～６ Alkyl, OC ２～６ Alkenil, OC ２～６ Alkinyl, C １～６ Alkilen OR ２３ , OC １～６ Alkilen OR ２３ , C １～６ Alkilen NR ２４ R ２５ , OC １～６ Alkilen NR ２４ R ２５ SC １～６ Alkyl, SC ２～６ Alkenil, SC ２～６ Alkinyl, C(O)C １～６ Alkyl, C(O)C ２～６ Alkenyl, C(O)C ２～６ Alkinyl, C(O)C ３～１０ Cycloalkyl, C(O)C ３～１０ Heterocycloalkyl, C(O)C ６～１１ Ariel, C(O)C ５～１４ Heteroaryl, C(O)C １～６ Alkilen C ３～１０ Cycloalkyl, C(O)C １～６ Alkilen C ３～１０ Heterocycloalkyl, C(O)C １～６ Alkilen C ６～１１ Ariel, C(O)C １～６ Alkilen C ５～１４ Heteroaryl, C(O)C １～６ Alkirenyl OR ２３ , C(O)C １～６ Alkilen NR ２４ R ２５ , C(O)C １～６ Alkilen OC １～６ Alkilen NR ２４ R ２５ , C(O)NR ２４ R ２５ CO ２ C １～６ Alkyl, CO ２ C ２～６ Alkenyl, CO ２ C ２～６ Alkinyl, CO ２ C １～６ Alkilen OR ２３ CO ２ C １～６ Alkilen OC １～６ Alkilen NR ２４ R ２５ , NR ２４ R ２５ , NR ２６ C ３～１０ Cycloalkyl, NR ２６ C ３～１０ Heterocycloalkyl, NR ２６ C ６～１１ Aryl, NR ２６ C ５～１４ Heteroaryl, NR ２６ C １～６ Alkilen OR ２３ , NR ２６ C １～６ Alkilen NR ２４ R ２５ , NR ２６ C １～６ Alkilen C ３～１０ Cycloalkyl, NR ２６ C １～６ Alkilen C ３～１０ Heterocycloalkyl, NR ２６ C １～６ Alkilen C ６～１１ Aryl, NR ２６ C １～６ Alkilen C ５～１４ Heteroaryl, NR ２６ SO ２ C １～６ Alkyl, SO ２ C １～６ Alkyl, SO ２ C ２～６ Alkenil, SO ２ C ２～６ Alkinyl and SO ２ NR ２４ R ２５ Selected independently from, and also R ２２ The alkyl group, alkenyl group, alkynyl group, alkylene group, aryl group, heteroaryl group, heterocycloalkyl group and cycloalkyl group are one or more R ２７ It is optionally replaced by; R ２２ｂ and R ２２ｃ H and C １～６ Independently selected from alkyl groups; R ２３ H, C １～６ Alkyl, C １～６ Alkilen OC １～６ Alkyl, C ３～１１ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１１ Ariel, C ５～１４ Heteroaryl, C ２～６ Alkenil, C ２～６ Alkinyl, C １～６ Alkilen C ３～１０ Cycloalkyl, C １～６ Alkilen C ３～１０ Heterocycloalkyl, C １～６ Alkilen C ６～１１ Aryl, and C １～６ Alkilen C ５～１４ Selected from heteroaryls; R ２４ H and C １～６ Selected from alkyl groups; R ２５ H, C １～６ Alkyl, C １～６ Alkilen OC １～６ Alkyl, C ３～１０ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１１ Ariel, C ５～１４ Heteroaryl, C １～６ Alkilen C ３～１０ Cycloalkyl, C １～６ Alkilen C ３～１０ Heterocycloalkyl, C １～６ Alkilen C ６～１１ Aryl, and C １～６ Alkilen C ５～１４ Selected from heteroaryls, or R ２４ and R ２５ They bond together, and together with the nitrogen atom between them, N, NR ２８ , O, S, S(O), and SO ２ It optionally includes one additional heteromorph selected from, and also includes Halo and C. １～６ Forming a 4- to 6-membered saturated or unsaturated ring optionally substituted by one or more alkyl groups; R ２６ H and C １～６ Selected from alkyl groups; Each R ２７ Hello, C １～６ Alkyl, CN and NR ２７ａ R ２７ｂ Selected independently from; and R ２７ａ , R ２７ｂ and R ２８ H and C １～６ Selected independently from alkyl Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

2. X １ Is it N, or X １ CR １ And R １ H, F, Cl, C １～４ Alkyl, OR ６ , NR ７ R ８ , C １～４ Alkilen NR ７ R ８ and C １～４ Selected from alkyl groups, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 1.

3. Q is one to three R's ５ C is optionally replaced by １～３ It is alkylene, and each R ５ is = O, F, Cl, C １～４ Alkyl, C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl, C １～４ Alkilen C ３～６ Cycloalkyl, C １～４ Alkilen C ３～６ Heterocycloalkyl, OH, OC １～４ Alkyl, NR ９ R １０ and C １～４ Alkilen NR ９ R １０ Selected independently from, R ９ and R １０ H and C, respectively. １～４ Independently selected from alkyl groups, or Q is C １～３ It is an alkylene, and R on one carbon atom ５ａ and R ５ｂ It is optionally substituted by R ５ａ and R ５ｂ They bond together, along with the nitrogen atom between them, to form a 3-6 member saturated or unsaturated ring, N, NH, NC １～６ Alkyl, O, S, S(O), and SO ２ It optionally includes one additional heteromorph selected from, and also includes Halo and C. １～４ It forms a ring that is optionally substituted by one or more alkyl groups, Q is one or two R ５ｃ C is optionally replaced by ２～４ It is an alkenylene, and each R ５ｃ F, C １～４ Alkyl, C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl, C １～４ Alkilen C ３～６ Cycloalkyl, C １～４ Alkilen C ３～６ Heterocycloalkyl, OH, OC １～６ Alkyl, NR ９ R １０ , and C １～４ Alkilen NR ９ R １０ Either selected independently from, Q is selected from C=N and N=C, and R ５ｃ It is optionally substituted by each R ５ｃ F, C １～４ Alkyl, C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl, C １～４ Alkilen C ３～６ Cycloalkyl, C １～４ Alkilen C ３～６ Heterocycloalkyl, OH, OC １～６ Alkyl, NR ９ R １０ and C １～４ Alkilen NR ９ R １０ Selected independently from, R ９ and R １０ H and C, respectively. １～４ Selected independently from alkyl, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 1.

4. X ２ and X ３ One of them is N, and the other is CR ２ is or, X ２ and X ３ Both are CR ２ And each R ２ is independently selected from H and F. The compound according to claim 1.

5. X ４ is N, and also X ５ CR ３ The compound according to claim 1.

6. X ４ is N, X ５ CR ３ And also, R ３ The compound according to claim 1, wherein is F.

7. Cy １ is a phenyl molecule substituted with one to three R11 groups, where at least one R11 group is selected from C1-4 alkylene NR12a R13a, NR12a R13a, and NR13a C1-4 alkylene NR12 R13, or Cy １ is a benzo-fused ring C ９～１１ It is a heterocycle, Cy １ It is either unsubstituted or has one to three R's. １１ It is replaced by The compound according to claim 1.

8. Cy １ is phenyl and C ５～６ Selected from heteroaryls, and Cy １ is Z-Cy ２ It is replaced by or Z-Cy ２ and one to three R １１ It is replaced by The compound according to claim 1.

9. Each R １１ F, Cl, =O, CN, NO ２ , C １～４ Alkyl, OR １２ , C(O)R １２ CO ２ R １２ , SR １２ , SOR １２ SO ２ R １２ , S(O)(=NR １３ ) R １２ SO ２ NR １２ R １３ , C １～６４ Alkilen OR １２ , OC １～６ Alkilen OR １２ 、 C １～６ Alkilen NR １２ａ R １３ａ , OC １～４ Alkilen NR １２ R １３ , NR １３ａ C １～４ Alkilen NR １２ R １３ , NR １３ａ C １～４ Alkilen OR １２ , NR １２ａ R １３ａ , NR １３ａ COR １２ , NR １３ａ CO ２ R １２ , and NR １３ａ SO ２ R １２ , and NR １３ａ SO ２ R １２ , C ３～７ Cycloalkyl, C ３～７ Heterocycloalkyl, C １～４ Alkilen C ３～７ Cycloalkyl and C １～４ Alkilen C ３～７ Independently selected from heterocycloalkyl groups, where the rear four groups are 1 to 3 R groups. １５ It is optionally replaced by Each R １５ F, Cl, CN, OH, C １～４ Alkyl, OC １～４ Alkyl and NR １５ａ R １５ｂ Selected independently from, and also R １５ａ and R １５ｂ H and C, respectively. １～４ Selected independently from alkyl, Here C １～４ In alkyl groups, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 1.

10. Each R １７ F, Cl, CN, C １～４ Alkyl and NR １７ａ R １７ｂ Selected independently from, and also R １７ａ and R １７ｂ H and C １～４ Independently selected from alkyl, where C １～４ The compound according to claim 1, wherein all available hydrogen atoms in the alkyl group are optionally replaced by fluorine atoms.

11. R １４ , R １４ａ and R １４ｂ One of them is OR １９ And R １４ , R １４ａ and R １４ｂ The remaining two are C １～４ Alkyl, C ３～１１ Cycloalkyl, C ３～１０ Heterocycloalkyl, C １～４ Alkilen C ３～１０ Cycloalkyl, and C １～４ Alkilen C ３～１０ Independently selected from heterocycloalkyls, where all available hydrogen atoms are optionally replaced by fluorine atoms, or R １９ H, C １～４ Alkyl, C ３～１１ Cycloalkyl, C ３～１０ Heterocycloalkyl, C １～４ Alkilen C ３～１０ Cycloalkyl, C １～４ Alkilen C ３～１０ Heterocycloalkyl C １～４ Alkilen OR ２０ , and C １～４ Alkilen NR ２０ R ２１ Selected from, R ２０ and R ２１ H and C １～４ Selected independently from alkyl, Here C １～４ In alkyl groups, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 1.

12. Z does not exist, or Z is C １～４ Alkylene, O, C(O), and SO ２ Selected from, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 1.

13. Z is C １～４ Alkylene O, C １～４ Alkylene C(O), C １～６ Alkylene CO2 ２、 C １～４ Alkilen S, C １～４ Alkylene S(O), C １～４ Alkylene SO1 ２ , C １～４ Alkilen NR １３ｂ , OC １～４ Alkylene, C(O)C １～４ Alkylene, CO ２ C １～４ Alkiren, SC １～４ Alkylene, S(O)C １～４ Alkilen, SO ２ C １～４ Alkylene and NR １３ｂ C １～６ The compound according to claim 1, selected from alkylenes, wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

14. Cy ２ is a single ring C ３～７ It is heterocycloalkyl, and also Cy ２ It is either unsubstituted or has one to three R's. ２２ It is either replaced by, Cy ２ It is a bicyclic heterocycle, and Cy ２ It is either unsubstituted or has one to three R's. ２２ It is replaced by The compound according to claim 1.

15. Each R ２２ F, Cl, CN, OH, C １～４ Alkyl, C ３～１０ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１１ Ariel, C ５～１４ Heteroaryl, C １～２ Alkilen C ３～１０ Cycloalkyl, C １～２ Alkilen C ３～１０ Heterocycloalkyl, C １～４ Alkilen C ６～１１ Ariel, C １～４ Alkilen C ５～１４ Heteroaryl, OC １～４ Alkyl, C １～４ Alkilen OR ２１ , C(O)C １～４ Alkyl, C(O)C ３～１０ Cycloalkyl, C(O)C ３～１０ Heterocycloalkyl, C(O)C １～４ Alkilen C ３～１０ Cycloalkyl, C(O)C １～４ Alkilen C ３～１０ Heterocycloalkyl, C(O)C １～４ Alkilen OR ２３ , C(O)C １～４ Alkilen NR ２４ R ２５ , C(O)C １～４ Alkilen OC １～４ Alkilen NR ２４ R ２５ CO ２ C １～６ Alkyl, CO ２ C １～４ Alkilen OR ２３ , NR ２４ R ２５ , NR ２６ C ３～１０ Cycloalkyl, NR ２６ C ３～１０ Heterocycloalkyl, NR ２６ C １～２ Alkilen C ３～１０ Cycloalkyl, NR ２６ C １～２ Alkilen C ３～１０ Heterocycloalkyl, NR ２６ C １～４ Alkilen OR ２３ , NR ２６ SO ２ C １～４ alkyl and SO ２ C １～６ Independently selected from alkyl, and also R ２２ The alkyl groups, alkenyl groups, alkynyl groups, alkylene groups, aryl groups, heteroaryl groups, heterocycloalkyl groups, and cycloalkyl groups consist of one to three R groups. ２７ It is optionally substituted by, where all available hydrogen atoms are optionally replaced by fluorine atoms, R ２７ F, Cl, CN, C １～４ Alkyl and NR ２７ａ R ２７ｂ Selected from, and also R ２７ａ and R ２７ｂ H and C １～４ Independently selected from alkyl, where C １～４ In alkyl groups, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 14.

16. R ２４ H and C １～４ Selected from alkyl groups, R ２５ H, C １～４ Alkyl, C １～４ Alkilen OC １～４ Alkyl, C ３～１０ Cycloalkyl, C ３～１０ Heterocycloalkyl, C １～４ Alkilen C ３～１０ Cycloalkyl, and C １～４ Alkilen C ３～１０ Selected from heterocycloalkyls, where all available hydrogen atoms are optionally replaced by fluorine atoms, or R ２４ and R ２５ They bond together, along with the nitrogen atom between them, to form a 4-6 member saturated or unsaturated ring, and this ring is NR ２８ , optionally including one additional heteromorph selected from O and S, and also including Halo and C １～６ Alkyl and C １～６ It is optionally substituted with one to three alkyl groups, and, R ２８ H and C １～４ Selected independently from alkyl, Here C １～４ Alkyl or C １～６ The compound according to claim 15, wherein all available hydrogen atoms in the alkyl group are optionally replaced by fluorine atoms.

17. The compound of formula (I) is one of the compounds listed in Table 1. Table 1 Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 The compound according to claim 1, or selected from pharmaceutically acceptable salts and / or solvates thereof.

18. An agent for use in the treatment of cancer, comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt and / or solvate thereof.

19. An agent for inhibiting growth activity, comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt and / or solvate thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier and / or diluent.

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