Substituted aminoazaheteroaryl compounds as inhibitors of hematopoietic progenitor kinase 1 (HPK1)

Abstract

The present application relates to substituted amino aza-heteroaryl compounds of formula (I) and substituted aza-heteroaryl compounds of formula II or pharma- ceutically acceptable salts, solvates, and / or prodrugs thereof: TIFF2024517771000363.tif67146 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 substituted aminoazaheteroaryl compounds, methods for making substituted aminoazaheteroaryl compounds, compositions containing substituted aminoazaheteroaryl compounds, and their use in therapy. More specifically, this application relates to aminoazaheteroaryl compounds, such as aminopyrazines and aminopyrazine derivatives, that are useful in treating diseases, disorders, or conditions treatable by inhibiting HPK1. [Background technology]

[0002] This application claims the benefit of priority to co-pending U.S. Provisional Patent Application No. 63 / 182,185, filed April 30, 2021, the contents of which are incorporated herein by reference in their entirety.

[0003] Tumors are generally heterogeneous and have evolved mechanisms to hijack cell growth and regulatory pathways, making it unlikely that any single therapy will have a significant effect on patient survival. For this reason, immunotherapy has become an important paradigm for the treatment of several types of cancer. Immune effector cells, such as T cells and B cells, can suppress cancer cell proliferation by targeting aberrant, tumor-expressed antigens. For example, recent clinical trials of novel immunotherapeutic strategies (e.g., anti-PD1 and anti-PDL1) have demonstrated unprecedented and sustained survival benefits, even in patients with advanced metastatic cancer. However, the overall excitement about this therapeutic approach is tempered by the observation that these responses to agents targeting the PD-1 axis are limited to a minority of cancer patients. Therefore, building on the great promise of immunotherapy, there is an urgent need to more rapidly test rational combinations of small molecules and immunotherapies to broaden the response rate in cancer patients. One such approach is the combination of the small molecule hematopoietic progenitor kinase 1 (HPK1) inhibitor with modern anti-PD1 / PDL1 immunotherapy. HPK inhibitors enhance the antitumor immune response by stimulating T cell proliferation and inducing T cell senescence and tumor elimination.

[0004] Hematopoietic progenitor kinase 1 (HPK1, MAP4K1) is a T cell receptor (TCR) proximal kinase involved in regulating the proliferation and survival of primary T cells [Nat Immunol. 2007; 8(1):84-91.] HPK1 is expressed exclusively in hematopoietic tissues and activates the c-Jun N-terminal kinase (JNK) and NF-κB pathways [7]. Transient knockdown of HPK1 in T cells blocks NF-κB activation [Crit Rev Oncol Hematol. 2008; 66(1):52-64]. Most strikingly, mice adoptively transferred with HPKI(- / -) T cells were 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. Antigen receptor crosslinking activates HPK1 in T and B cells, resulting in its relocation to the plasma membrane, autophosphorylation, and transphosphorylation by protein kinase D1 (PKD1). Subsequent transphosphorylation and autophosphorylation by PKD1 within the kinase domain results in full activation of HPK1, which then regulates various cellular responses, including apoptosis, activation-induced cell death, and autoimmunity. HPK1 mediates the regulation of immune responses through phosphorylation of S376 (SL-76). Mutation of lysine 46 to methionine in the ATP-binding site of the kinase domain (designated HPK1-M46) abolishes the catalytic activity of HPK1, resulting in a kinase-dead version of the full-length kinase [Genes Dev. 1996; 10 (18):2251-64]. Inhibition of HPK1 in knock-in mice in which the HPK1 kinase is dead, when treated with anti-PD-1 or anti-PDL1 antibodies, shows improved efficacy in colon cancer models compared to anti-PD-1 or anti-PDL1 treatment alone (Cell Reports 2018, 25, 80-94, and PCT Patent Application Publication Nos. WO2016 / 205942 and WO2016 / 090300).Combining or sequencing immunotherapies targeting distinct immune pathways is therefore a rational strategy to increase the strength of anti-tumor immune responses compared to those generated using single agents.

[0005] HPK1 plays a critical role in regulating lymphocyte receptor signaling and function. In addition, the restricted expression of HPK1 in hematopoietic cells and its role in immune cells suggest that HPK1 may be an ideal drug target for enhancing antitumor immunity. Furthermore, data from preclinical studies suggest that genetic disruption of HPK1 can promote the proliferation, survival, and function of various immune cells (e.g., T cells, NK cells, and dendritic cells (DCs)) and synergistically inhibit tumor growth in combination with anti-PD-1 / PDL-1 monoclonal antibodies. Strong support for this theoretical interpretation was evident from several reports in the literature showing that HPK1 kinase-deficient knock-in mice bearing colorectal tumors (MC38) 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 to treating cancer.

[0006] Therefore, inhibiting kinases such as HPK represents a promising target for immuno-oncology due to the role of these kinases in limiting T cell activation. At the same time, in exploring these targets, it is desirable to have selectivity between them and 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 subvert immune tolerance by modulating T cell coreceptor signaling or by boosting tumor-associated antigen recognition using innate biomolecules or monoclonal antibodies. Selective HPK1 inhibitors, in combination with other immunomodulators, enhance the antitumor activity of immune cells. This application discloses novel compounds with such activity.

[0008] Accordingly, this application encompasses compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] where: X 1 N and CR 1 Selected from; X 2 and X 3 are independently N and CR 2 and; X 4 and X 5 are each independently selected from N and CH, with the proviso that X 4 and X 5 at least one of is N; Q is C 1~4 Alkylene is O, S, S(O), SO2 and NR 3 and / or one or more R 4 and / or on one carbon R 4a and R 4b C optionally disubstituted by 1~4 alkylene, with the proviso that if Q contains said hetero moiety, said hetero moiety is separated from the ring amide NH by other than a methylene; or Q is one or more R 4c C optionally replaced by 2~4alkenylene; or Q is R 4c C=N or N=C optionally substituted by R 1 H, halo, OR 3a , N.R. 5a R 6a , C 1~6 Alkylene NR 5a R 6a and C 1~6 alkyl; R 2 H, halo and C 1~6 alkyl; R 3 is H and C 1~6 alkyl; Each R 4 =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 5 R 6 and C 1~6 Alkylene NR 5 R 6 are independently selected from; R 4a and R 4b and together with the carbon atoms between them form a 3- to 6-membered saturated or unsaturated ring, which may be N, NH, NC 1~6 Optionally containing one hetero moiety selected from alkyl, O, S, S(O), and SO2, and halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Each R 4c Ha, Halo, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~6 Alkylene C 3~6Cycloalkyl and C 1~6 Alkylene C 3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl, NR 5 R 6 , and C 1~6 Alkylene NR 5 R 6 are independently selected from; R 5 , R 5a , R 6 and R 6a are independently H and C 1~6 alkyl, or R 5 and R 6 , or R 5a and R 6a and are bonded together with the nitrogen atom therebetween to form a 3- to 7-membered saturated or unsaturated ring, and are N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Cy 1 is unsubstituted or substituted with one or more R 7 C, which is replaced by 6~10 Aryl or C 5~10 is heteroaryl; Each R 7 , halo, =O, C 1~6 Alkyl, NR 8 R 9 , and C 1~6 Alkylene NR 8 R 9 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~6 Alkylene C 3~7 Cycloalkyl and C 1~6 Alkylene C 3~7 heterocycloalkyl, and the last four groups are independently selected from one or more R 10 optionally replaced by; R8 and R 9 are independently H and C 1~6 alkyl; Each R 10 Ha, Halo, C 1~6 Alkyl, CN and NR 11 R 11a are independently selected from; R 11 and R 11a are independently H and C 1~6 alkyl; Cy 2 is one or more R 12 Monocyclic C substituted by 3~7 heterocycloalkyl, or unsubstituted or containing one or more R 12 Bicyclic C substituted by 6~12 is heterocycloalkyl; Each R 12 Halo, CN, =O, OH, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkylene C 3~10 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylene OR 13 , C 1~6 Alkylene NR 13 R 14 , O.C. 1~6 Alkylene OR 13 , O.C. 1~6 Alkylene NR 13 R 14 , S.R. 13 , C(O)R 13 , C(O)C 1~6 Alkylene OR 13 , C(O)C 1~6 Alkylene NR 13 R 14 , C(O)C 1~6 Alkylene OC 1~6 Alkylene NR 13 R14 , C(O)NR 13 R 14 , CO2R 13 , CO2C 1~6 Alkylene OR 13 , CO2C 1~6 Alkylene OC 1~6 Alkylene NR 13 R 14 , N.R. 13 R 14 , N.R. 15 SO2R 13 , S(O)R 13 , SO2R 13 , SO2NR 13 R 14 and S(O)(NR 15 )R 13 are independently selected from; R 13 is H, C 1~6 Alkyl, C 1~6 Alkylene OR 14 , C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkylene C 3~10 Cycloalkyl and C 1~6 Alkylene C 3~10 heterocycloalkyl; R 14 is H and C 1~6 alkyl; or R 13 and R 14 and are bonded together with the nitrogen atom therebetween to form a 4- to 6-membered saturated or unsaturated ring, 16 , forming a ring optionally containing one additional hetero moiety selected from O, S, S(O), and SO; and R 15 and R 16 is H and C 1~6 independently selected from alkyl; wherein all available hydrogen atoms are optionally replaced by fluorine atoms; However, Cy 1 When is unsubstituted phenyl, Cy 2 teeth [ka] Instead, here [ka] Cy 1 represents the point of covalent attachment to

[0009] The present application also encompasses compounds of formula (II) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] where X 6 N and CR 17 Selected from; X 7 and X 8 are independently N and CR 18 Selected from; X 9 and X 10 are each independently selected from N and CH, with the proviso that X 9 and X 10 at least one of is N; Q' is C 1~4 Alkylene is O, S, S(O), SO2 and NR 19 and / or one or more R 20 and / or on one carbon R 21 and R 21a C optionally disubstituted by 1~4 alkylene, with the proviso that when Q contains said hetero moiety, said hetero moiety is separated from the ring amide NH by other than methylene; or Q' is one or more R 22 C optionally replaced by 2~4alkenylene; or Q' is R 22 C=N or N=C optionally substituted by R 17 H, halo, OR 23 , N.R. 24 R 25 , C 1~6 Alkylene NR 24 R 25 and C 1~6 alkyl; R 18 H, halo and C 1~6 alkyl; R 19 is H and C 1~6 alkyl; Each R 20 =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 26 R 27 and C 1~6 Alkylene NR 26 R 27 are independently selected from; R 21 and R 21a and together with the carbon atoms between them form a 3- to 6-membered saturated or unsaturated ring, which may be N, NH, NC 1~6 Optionally containing one hetero moiety selected from alkyl, O, S, S(O), and SO2, and halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Each R 22 Ha, Halo, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~6 Alkylene C 3~6Cycloalkyl, C 1~6 Alkylene C 3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl, NR 26 R 27 and C 1~6 Alkylene NR 26 R 27 are independently selected from; R 24 , R 25 , R 26 and R 27 are independently H and C 1~6 alkyl, or R 24 and R 25 , or R 26 and R 27 means, when bonded together with the atoms between them, a 3- to 7-membered saturated or unsaturated ring, which is N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Cy 3 is one or two R 28 and one to three R 29 C optionally further replaced by 6~10 Aryl or C 5~10 is heteroaryl; Each R 28 is NR 30 R 31 , C 1~6 Alkylene NR 30 R 31 、 C 3~7 Heterocycloalkyl and C 1~6 Alkylene C 3~7 heterocycloalkyl, and the latter two groups are independently selected from one or more R 32 optionally replaced by; Each R 29 Ha, Halo, C 1~6 Alkyl, C3~7 Cycloalkyl, and C 1~6 Alkylene C 3~7 cycloalkyl, and the latter two groups are independently selected from one or more R 32 optionally replaced by; R 30 and R 31 are independently H and C 1~6 alkyl; Each R 32 Ha, Halo, C 1~6 Alkyl, CN and NR 33 R 34 are independently selected from; R 33 and R 34 are independently H and C 1~6 alkyl; Cy 4 is C 3~14 Heterocycloalkyl, and Cy 4 is unsubstituted or substituted with one or more R 35 has been replaced by; Each R 35 Halo, =O, CN, OH, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkylene C 3~10 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylene OR 36 , C 1~6 Alkylene NR 36 R 37 , O.C. 1~6 Alkylene OR 36 , O.C. 1~6 Alkylene NR 36 R 37 , S.R. 36 , C(O)R 36 C(O)C 1~6 Alkylene OR 36 , C(O)C 1~6 Alkylene NR36 R 37 , C(O)C 1~6 Alkylene OC 1~6 Alkylene NR 36 R 37 , C(O)NR 36 R 37 , CO2R 36 , CO2C 1~6 Alkylene OR 36 , CO2C 1~6 Alkylene OC 1~6 Alkylene NR 36 R 37 , N.R. 36 R 37 , N.R. 38 SO2R 36 , S(O)R 36 , SO2R 36 , SO2NR 36 R 37 and S(O)(NR 38 )R 36 are independently selected from; R 36 is H, C 1~6 Alkyl, C 1~6 Alkylene OR 14 , C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkylene C 3~10 Cycloalkyl and C 1~6 Alkylene C 3~10 heterocycloalkyl; R 37 is H and C 1~6 alkyl; or R 36 and R 37 and are bonded together with the nitrogen atom therebetween to form a 4- to 6-membered saturated or unsaturated ring, 39 , forming a ring optionally containing one additional hetero moiety selected from O, S, SO, and SO2; and R 38 and R 39 is H and C 1~6 independently selected from alkyl; wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

[0010] The present application also encompasses compositions comprising one or more compounds of the present application and a carrier. In one embodiment, the composition is a pharmaceutical composition comprising one or more compounds of the present application and a pharmaceutically acceptable carrier.

[0011] In some embodiments, the compounds of the present application are used as pharmaceuticals. Thus, the present application also encompasses the compounds of the present application for use as pharmaceuticals.

[0012] The compounds of the present application have been shown to inhibit HPK1. Accordingly, in some embodiments, the compounds of the present application are useful for treating diseases, disorders, or conditions that are treatable by inhibiting HPK1 activity. Accordingly, the present application also encompasses methods for treating diseases, disorders, or conditions that are treatable by inhibiting HPK1, comprising administering to a cell or subject in need of treatment a therapeutically effective amount of one or more compounds of the present application.

[0013] The present application also encompasses the use of one or more compounds of the present application for the treatment of a disease, disorder, or condition treatable by inhibiting HPK1, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a disease, disorder, or condition treatable by inhibiting HPK1. The present application further encompasses one or more compounds of the present application for use in the treatment of a disease, disorder, or condition treatable by inhibiting HPK1.

[0014] In further embodiments, 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 therapies. In other embodiments, the additional cancer therapies are selected from radiation therapy, chemotherapy, targeted therapies such as antibody therapy, and small molecule therapies such as tyrosine kinase inhibitor therapy, immunotherapy, hormonal therapy, and anti-angiogenic therapy. In other embodiments, the additional cancer therapies are selected from antibodies that bind to PD-1 or PDL-1.

[0015] The present application further provides processes for preparing the compounds of the present application, the general and specific processes being described in more detail in the examples below.

[0016] Other features and advantages of the present application will become apparent from the following detailed description, but it should be understood that the detailed description and specific examples, while illustrating embodiments of the present application, are given by way of example only, and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the entire specification. DETAILED DESCRIPTION OF THE INVENTION

[0017] I. Definition Unless otherwise stated, the definitions and embodiments set forth in this and other sections are intended to be applicable to all embodiments and aspects of the present application described in this disclosure as understood by those of skill in the art to be suitable.

[0018] All features disclosed in this specification, including the claims, abstract, and drawings, and all steps in any disclosed method or process, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. Each feature disclosed in this specification, including the claims, abstract, and drawings, may also be replaced by an alternative feature serving the same, equivalent, or similar purpose, unless expressly stated otherwise.

[0019] The words "comprising" (and any form of comprising, e.g., "comprise" (present tense), with or without third person singular-s), "having" (and any form of having, e.g., "have" (present tense), with or without third person singular-s), "including" (and any form of including, e.g., "include" (present tense), with or without third person singular-s), and "containing" (and any form of containing, e.g., "including" (present tense), with or without third person singular-s)) are inclusive and open-ended and do not exclude additional, unrecited elements or process steps.

[0020] As used in this disclosure, the term "consisting of" and its derivatives are intended to be closed terminology that specifies the presence of stated features, elements, components, groups, integers, and / or steps and excludes the presence of other, unrecited features, elements, components, groups, integers, and / or steps.

[0021] As used in this disclosure, the term "consisting essentially of" is intended to specify the presence of stated features, elements, components, groups, integers, and / or steps, and that do not materially affect the basic and novel characteristic(s) of those features, elements, components, groups, integers, and / or steps.

[0022] Terms of degree, such as "about," "substantially," and "approximately," refer to a reasonable amount of deviation from the modified word that does not significantly change the end result. These terms of degree should be interpreted as including deviations of at least ±5% from the modified word unless the deviation negates the meaning of the word it modifies or the context suggests a different interpretation to one of ordinary skill in the art.

[0023] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to present an aspect having one compound, or an aspect having two or more additional compounds.

[0024] In embodiments that include an "additional" or "second" component or effect, e.g., an additional or second compound, a second compound, as used herein, is chemically distinct from the other or first compounds. A "third" compound is distinct from the other first and second compounds, and further listed or "additional" compounds are similarly distinct.

[0025] As used in this disclosure, the term "and / or" means that the listed items are present or used individually or in combination. In essence, the term means that "at least one" or "one or more" of the listed items are used or present. The term "and / or" with respect to enantiomers, prodrugs, salts and / or solvates thereof means that the compounds of the present application are present as individual enantiomers, prodrugs, salts and solvates, as well as in combinations, such as salts of solvates of the compounds of the present application.

[0026] As used in this disclosure, the term "compounds of the present application" and similar terms refer to compounds of Formula I, IA, IB, IC, ID, IE, II, II-A, II-B, II-C, II-D, and II-E, or salts, solvates, and / or prodrugs thereof.

[0027] As used in this disclosure, the term "composition of the present application" and like terms refer to a composition comprising one or more compounds of the present application.

[0028] As used in this disclosure, the term "suitable" ("preferred") means that the selection of a particular compound or conditions will depend on the particular synthetic operation to be performed, the identity of the molecule(s) being converted, and / or the specific use of the compound, but is well within the skill of one of ordinary skill in the art.

[0029] This specification makes reference to many chemical terms and abbreviations used by those skilled in the art. However, for clarity and consistency, definitions of selected terms are provided.

[0030] As used in this disclosure, the term "protecting group" or "PG" and similar terms refer to a chemical moiety that protects or masks reactive portions of a molecule to prevent side reactions at those reactive portions of the molecule while a different portion of the molecule is being manipulated or reacted. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not destroy or degrade the remaining portions of the molecule. Selection of an appropriate protecting group can be made by one of ordinary skill in the art. Many conventional protecting groups are known in the art, see, for example, "Protective Groups in Organic Chemistry" McOmie, JFW Ed., Plenum Press, 1973, in Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rdEdition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0031] As used in this disclosure, the term "cell" refers to a single cell or multiple cells, including cells in cell culture or in a subject.

[0032] As used in this disclosure, the term "subject" includes all members of the animal kingdom, including mammals, and preferably refers to humans. Thus, the methods and uses herein are applicable to both human therapeutic applications and veterinary applications.

[0033] The term "pharmaceutically acceptable" means compatible with the treatment of a subject, e.g., a human.

[0034] The term "pharmaceutically acceptable carrier" refers to a non-toxic solvent, dispersant, formulation 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.

[0035] The term "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt which is suitable or compatible with the treatment of a subject.

[0036] As used in this disclosure, the term "solvate" means a compound or a salt and / or prodrug of a compound wherein molecules of a suitable solvent are incorporated into the crystal lattice, said suitable solvent being physiologically acceptable at the administered dosage.

[0037] As used in this disclosure, the term "prodrug" means a compound, or a salt and / or solvate of a compound, that is converted into an active drug after administration.

[0038] As used in this disclosure, the term "inert organic solvent" refers to a solvent that is generally considered to be non-reactive with the functional groups present in the compounds being coupled in any given reaction, and thus will not interfere with or inhibit the desired synthetic transformation. Organic solvents are typically non-polar and will dissolve compounds that are insoluble in aqueous solutions.

[0039] As used in this disclosure, the term "alkyl," whether used alone or as part of another group, refers to a straight- or branched-chain saturated alkyl group. The number of carbon atoms possible in the alkyl group in question is determined by the prefix "C n1~n2 For example, the term "C 1~10 "Alkyl" means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. All alkyl groups are optionally fluoro-substituted.

[0040] The term "alkylene," whether used alone or as part of another group, refers to a straight or branched saturated alkylene group, i.e., a saturated carbon chain containing substituents at two of its termini. The number of carbon atoms possible in the alkylene group in question can be determined by the prefix "C n1~n2 For example, the term "C 2~6 "Alkylene" means an alkylene group having 2, 3, 4, 5, or 6 carbon atoms. All alkylene groups are optionally fluoro-substituted.

[0041] As used in this disclosure, the term "alkenyl," whether used alone or as part of another group, refers to a straight or branched chain unsaturated alkyl group containing at least one double bond. The number of carbon atoms possible in the alkylene group in question is indicated by the prefix "C n1~n2 ". Thus, for example, the term "C 2~6"Alkenyl" means an alkenyl group having 2, 3, 4, 5, or 6 carbon atoms and at least one double bond. All alkenyl groups are optionally fluoro-substituted.

[0042] As used in this disclosure, the term "alkynyl," whether used alone or as part of another group, refers to a straight or branched chain unsaturated alkynyl group containing at least one triple bond. The number of carbon atoms possible in the alkyl group in question is indicated by the prefix "C n1~n2 For example, the term C 2~6 Alkynyl refers to alkynyl groups having 2, 3, 4, 5, or 6 carbon atoms. All alkynyl groups are optionally fluoro-substituted.

[0043] As used in this disclosure, the term "cycloalkyl," whether used alone or as part of another group, refers to a saturated carbocyclic group containing a certain number of carbon atoms and one or more rings. The number of possible carbon atoms in a given cycloalkyl group is determined by the prefix "C n1~n2 For example, the term C 3~10 Cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. When a cycloalkyl group contains more than one ring, the rings may be fused, bridged, spirofused, or joined by bonds. All cycloalkyl groups are optionally fluorosubstituted.

[0044] As used herein, the term "aryl," whether used alone or as part of another group, refers to a carbocyclic group containing at least one aromatic ring, containing 6 to 20 carbon atoms, such as phenyl, indanyl, or naphthyl. All aryl groups are optionally fluorosubstituted.

[0045] As used in this disclosure, the term "heterocycloalkyl," whether used alone or as part of another group, refers to a cyclic group containing at least one non-aromatic ring containing 3 to 20 atoms, one or more of which are heteroatoms selected from O, S, and N, with the remaining atoms being C. Heterocycloalkyl groups can be saturated or unsaturated (i.e., contain one or more double bonds). Heterocycloalkyl groups can be formed by adding the prefix C to the ring. n1~n2 When the prefix "" contains the radical "-", this prefix refers to 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 a heteroatom as defined above. All heterocycloalkyl groups are optionally fluoro-substituted. Heteroatoms in heterocycloalkyl groups are optionally substituted or oxidized, if valence permits.

[0046] As used herein, the term "heteroaryl," whether used alone or as part of another group, refers to a cyclic group containing at least one heteroaromatic ring containing 5 to 10 atoms, one or more of which are heteroatoms selected from O, S, and N, with the remaining atoms being C. A heteroaryl group may be identified by the prefix C. n1~n2 When the prefix "-" contains the radical "-", this prefix 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 a heteroatom selected from O, S, and N, and the remaining atoms are C. All heteroaryl groups are optionally fluoro-substituted. Heteroatoms in heteroaryl groups are optionally substituted or oxidized, if valence permits.

[0047] As used in this disclosure, the term "aza-heteroaryl," whether used alone or as part of another group, refers to a heteroaryl group having two or more N atoms as the only heteroatoms in the group.

[0048] All cyclic groups, including aryl and cyclo groups and their hetero versions, contain one ring or multiple rings (i.e., polycyclic). When a cyclic group contains more than one ring, the multiple rings may be fused, bridged, and / or spirofused.

[0049] A first ring is "fused" to a second ring means that the first ring and the second ring share two adjacent atoms between them.

[0050] A first ring is "bridged" to a second ring means that the first ring and the second ring share two non-adjacent atoms between them.

[0051] A first ring is "spirofused" to a second ring means that the first ring and the second ring share one atom between each other.

[0052] The term "fluoro-substituted" means that one or more (including all) of the available hydrogens in the group in question have been replaced with fluorine.

[0053] 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 iodo.

[0054] The term "available" in "available hydrogen atom" or "available atom" refers to an atom that would be known to one of ordinary skill in the art as being available for replacement by a substituent.

[0055] Where a group is stated to be substituted with multiple substituents, the substituents are independently selected and, therefore, may be the same or different.

[0056] As used in this disclosure, the term "cross-coupling" refers to a chemical reaction in which two different starting materials, each usually equipped with an activating group, react with each other with the aid 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.

[0057] As used in this disclosure, the terms "treat" or "treatment" refer to an approach for obtaining beneficial or desired results, such as clinical results, as is well known in the art. Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of disease, stabilized (i.e., not worsening) disease, prevention of disease spread, delay or slowing of disease progression, improvement or palliation of the disease state, reduction in disease recurrence, and remission (whether partial or complete), which may be detectable or undetectable. "Treat" and "treatment" can also mean prolonging survival compared to expected survival in the absence of treatment. As used in this disclosure, "treat" and "treatment" also encompass prophylactic treatment. For example, a subject with early-stage cancer may be treated to prevent progression, or a subject in remission may be treated with a compound or composition of the present application to prevent recurrence. The method of treatment involves administering to the subject a therapeutically effective amount of one or more compounds of the present application, and optionally consists of a single administration or includes a series of administrations.

[0058] "Palliating" a disease or disorder means that the severity and / or undesirable clinical findings of the disorder or disease state are reduced and / or the time course of progression is slowed or prolonged compared to what would occur if the disorder were not treated.

[0059] As used in this disclosure, the term "prevention" or "prophylaxis," or synonyms thereof, refers to a reduction in the risk or probability that a patient will suffer from or exhibit symptoms associated with a disease, disorder, or condition treatable by inhibiting HPK1.

[0060] As used in this disclosure, the term "effective amount" or "therapeutically effective amount" means an amount of a compound of the present application, or one or more compounds of the present application, effective, at dosages and for periods of time necessary, to achieve the desired result.

[0061] As used in this disclosure, the phrase "inhibiting HPK1" refers to inhibiting, blocking, and / or disrupting HPK1 enzymatic activity in a cell, particularly a T cell or a B cell, which inhibits, blocks, and / or disrupts the activity of the HPK1 enzyme, causing a therapeutic effect in the cell.

[0062] "Inhibiting, blocking and / or destroying" means any detectable inhibition, blocking and / or destruction in the presence of a compound compared to otherwise identical conditions in the absence of the compound.

[0063] The term "disease, disorder, or condition treatable by inhibiting HPK1" means that the disease, disorder, or condition being treated has some biological basis that is affected by, modulated by, and / or involves, HPK1 activity, particularly increased HPK1 activity, whether directly or indirectly. These diseases respond favorably when HPK1 activity associated with the disease, disorder, or condition is inhibited by one or more compounds or compositions of the present 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 present application, or one or more compounds of the present application, or a composition of the present application to a cell in cell culture or in a subject.

[0066] As used in this disclosure, the term "neoplastic disorder" refers to a disease, disorder, or condition characterized by cells capable of autonomous growth or replication, e.g., an abnormal state or condition characterized by proliferative cell growth. As used in this disclosure, the term "neoplasm" refers to a mass of tissue resulting from the abnormal proliferation and / or division of cells in a subject with a neoplastic disorder. Tumors can be benign (such as 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 cell proliferative condition.

[0068] As used in this disclosure, the term "effective amount" means an amount effective, at dosages and for periods of time necessary, to achieve the desired result.

[0069] II. Compounds and Compositions i) a compound of formula (I) This application describes a new class of substituted heterocyclic HPK1 inhibitors.

[0070] Accordingly, this application encompasses compounds of formula (I) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] (I) where: X 1 N and CR 1 Selected from; X 2 and X 3are independently N and CR 2 Selected from; X 4 and X 5 are each independently selected from N and CH, with the proviso that X 4 and X 5 at least one of is N; Q is C 1~4 Alkylene is O, S, S(O), SO2 and NR 3 and / or one or more R 4 and / or on one carbon R 4a and R 4b optionally disubstituted by C 1~4 alkylene, with the proviso that when Q contains said hetero moiety, said hetero moiety is separated from the ring amide NH by other than methylene; or Q is one or more R 4c C optionally replaced by 2~4 alkenylene; or Q is R 4c C=N or N=C optionally substituted by R 1 H, halo, OR 3a , N.R. 5a R 6a , C 1~6 Alkylene NR 5a R 6a and C 1~6 alkyl; R 2 H, halo and C 1~6 alkyl; R 3 is H and C 1~6 alkyl; Each R 4 =O, halo, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~6Alkylene C 3~6 Cycloalkyl, C 1~6 Alkylene C 3~6 Heterocycloalkyl, OH, OC 1~6 Alkyl, NR 5 R 6 and C 1~6 Alkylene NR 5 R 6 are independently selected from; R 4a and R 4b and together with the carbon atoms between them form a 3- to 6-membered saturated or unsaturated ring, which may be N, NH, NC 1~6 Optionally containing one hetero moiety selected from alkyl, O, S, S(O), and SO2, and halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Each R 4c Ha, 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 5 R 6 , and C 1~6 Alkylene NR 5 R 6 are independently selected from; R 5 , R 5a , R 6 and R 6a are independently H and C 1~6 alkyl, or R 5 and R 6 , or R 5a and R 6a are bonded together with the nitrogen atom therebetween to form a 3- to 7-membered saturated or unsaturated ring, and are selected from the group consisting of N, NH, NC 1~6Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Cy 1 is unsubstituted or substituted with one or more R 7 C, which is replaced by 6~10 Aryl or C 5~10 is heteroaryl; Each R 7 , halo, =O, C 1~6 Alkyl, NR 8 R 9 , and C 1~6 Alkylene NR 8 R 9 , C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~6 Alkylene C 3~7 Cycloalkyl and C 1~6 Alkylene C 3~7 heterocycloalkyl, and the last four groups are independently selected from one or more R 10 optionally replaced by; R 8 and R 9 are independently H and C 1~6 alkyl; Each R 10 Ha, Halo, C 1~6 Alkyl, CN and NR 11 R 11a are independently selected from; R 11 and R 11a are independently H and C 1~6 alkyl; Cy 2 is one or more R 12 Monocyclic C substituted by 3~7 heterocycloalkyl, unsubstituted, or containing one or more R 12 Bicyclic C 6~12 is heterocycloalkyl; Each R 12 Halo, CN, =O, OH, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkylene C 3~10 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylene OR 13 , C 1~6 Alkylene NR 13 R 14 , O.C. 1~6 Alkylene OR 13 , O.C. 1~6 Alkylene NR 13 R 14 , S.R. 13 , C(O)R 13 , C(O)C 1~6 Alkylene OR 13 , C(O)C 1~6 Alkylene NR 13 R 14 , C(O)C 1~6 Alkylene OC 1~6 Alkylene NR 13 R 14 , C(O)NR 13 R 14 , CO2R 13 , CO2C 1~6 Alkylene OR 13 , CO2C 1~6 Alkylene OC 1~6 Alkylene NR 13 R 14 , N.R. 13 R 14 , N.R. 15 SO2R 13 , S(O)R 13 , SO2R 13 , SO2NR 13 R 14 and S(O)(NR 15 )R 13 are independently selected from; R 13 is H, C 1~6 Alkyl, C1~6 Alkylene OR 14 , C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkylene C 3~10 Cycloalkyl and C 1~6 Alkylene C 3~10 heterocycloalkyl; R 14 is H and C 1~6 alkyl; or R 13 and R 14 and are bonded together with the nitrogen atom therebetween to form a 4- to 6-membered saturated or unsaturated ring, 16 , forming a ring optionally containing one additional hetero moiety selected from O, S, S(O) and SO2; and R 15 and R 16 is H and C 1~6 independently selected from alkyl; wherein all available hydrogen atoms are optionally replaced by fluorine atoms; However, Cy 1 When is unsubstituted phenyl, Cy 2 teeth [ka] Instead, here [ka] Cy 1 represents the point of covalent attachment to

[0071] In all of the following embodiments, it should be understood that all available hydrogen atoms are optionally substituted with fluorine atoms. This will not be repeated throughout. Thus, in each embodiment where a group containing available hydrogen atoms is listed, all such atoms are optionally substituted with fluorine atoms, e.g., C 1~6 Unless otherwise specified, each description of alkyl is C 1~6 It should be understood that this also describes fluoroalkyl.

[0072] In one embodiment, X 2 is N. In one embodiment, X 2 is CR 1 is.

[0073] In one embodiment, R 1 are H, F, Cl, OR 4a , N.R. 5a R 6a , C 1~4 Alkylene NR 5a R 6a and C 1~4 alkyl.

[0074] In one embodiment, R 1 are H, F, Cl and C 1~4 In one embodiment, R 1 is selected from H, F, Cl, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In some embodiments, R 1 is selected from H, F, CF, CFH, CHCFH, and CH. In some embodiments, R 1 is selected from H, F, CF, CFH, and CHCFH. In some embodiments, R 1 is selected from H, F, CF3, and CH3. In some embodiments, R 1 is selected from H and F. In some embodiments, R 1 is F. In one embodiment, R 1 is H.

[0075] In one embodiment, R 1 is OR 3a In one embodiment, R 3a is selected from H, CH, CHCH, CF, CFH, CFH, CHCFH, and CHCFH. In certain embodiments, R 3a is H and C 1~4 In one embodiment, R 3a is selected from H, CH3, and CH2CH3. In some embodiments, R 3a is selected from H, CH, CHCH, CF, CFH, CHCFH, and CHCF. 3a is CF2H. Thus, in one embodiment, R 1 is selected from OH, OCH3, OCH2CH3, OCF3, OCFH2, OCHF2, OCH2CF2H, and OCH2CF2H.

[0076] In one embodiment, R 1 is NR 5a R 6a and C 1~4 Alkylene NR 5a R 6a In one embodiment, R 1 is NR 5a R 6a and C 1~2 Alkylene NR 5a R 6a In one embodiment, R 5a and R 6a are independently H and C 1~4 In one embodiment, R 5a and R 6a are each independently selected from H, CH, and CF. In some embodiments, R 5a and R 6a One of R is H and the other is CH. In some embodiments, R 6a and R 5a are both CH3. In one embodiment, R 5a and R 6a are both H.

[0077] In one embodiment, R 5a and R 6a and are bonded together with the nitrogen atom therebetween to form a 3- to 7-membered saturated or unsaturated ring, and are N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and halo and C 1~6 In one embodiment, R 5a and R 6a together with the nitrogen atom therebetween, form a 3- to 7-membered heterocycle selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), morpholinyl, and azepanyl, and also halo and C 1~6 In one embodiment, R 5a and R 6a and are bonded together with the nitrogen atom between them, halo and C 1~6 In one embodiment, R 5a and R 6a and are bonded together with the nitrogen atom between them, halo and C 1~6 This forms aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl, optionally substituted with one or more of alkyl.

[0078] 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 CR 2 and X 3 is N. In one embodiment, X 2 and X 3Both CR 2 is.

[0079] In some embodiments, each R 2 H, halo and C 1~4 In one embodiment, each R 2 are H, F, Cl and C 1~4 In one embodiment, each R 2 are independently selected from H, F, Cl, CH, CF, CHF, and CHF. In certain embodiments, R 2 is selected from CF2H, CH3, and CF3. In certain embodiments, each R 2 are independently selected from H, F, Cl, CH, and CF. In certain embodiments, each R 2 is selected from H and F.

[0080] In one embodiment, X 2 and X 3 One of X is N and the other is CH. 2 is CH, and X 3 is N. In one embodiment, X 2 is CH, and X 3 is CF or CCl. In some embodiments, X 2 and X 3 and X are both CF. In one embodiment, X 2 is selected from CH, CF, CCl, CCH3 and CCF3, and X 3 is CH. In one embodiment, X 2 and X 3 are both CH.

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

[0082] In one embodiment, X 4 and X 5 One of X is N and the other is CH. 4 is N, and X 5 is CH. In an embodiment, X 4 is CH, and X 5 is N.

[0083] In one embodiment, Q is C 1~3 Alkylene, including O, S, S(O), SO, and NR 3 and / or one or more R 4 C optionally replaced by 1~3 It is alkylene.

[0084] In certain embodiments, Q is O, S, S(O), SO, and NR 3 C optionally interrupted with a hetero moiety selected from 1~3 In some embodiments, Q is O, SO, and NR 3 C optionally interrupted with a hetero moiety selected from 1~3 In some embodiments, Q is O or NR 3Optionally interrupted C 1~3 In some embodiments, Q is C 2~3 Alkylene, O or NR 3 optionally interrupted, and / or one or more R 4 C optionally replaced by 2~3 In some embodiments, Q is C 2~3 Alkylene optionally interrupted by O and / or one or two R 4 C optionally replaced by 2~3 In some embodiments, Q is an alkylene group optionally interrupted by hetero moieties selected from O and SO. 1~3 In some embodiments, Q is an alkylene. 1~3 In some embodiments, Q is an alkylene. 1~2 In some embodiments, Q is an alkylene. In some embodiments, Q is an alkylene optionally interrupted by SO. 1~2 In certain embodiments, Q is alkylene.

[0085] In one embodiment, R 3 is H and C 1~4 In one embodiment, R 3 is selected from H, CH3, and CH2CH3. In some embodiments, R 3 is selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In some embodiments, R 3 is selected from CF2H, CH3, and CF3. In some embodiments, R 3 is selected from H, CH, CHCH, and CF. In some embodiments, R 3is selected from CH3 and CF3. In some embodiments, R 3 is H.

[0086] In one embodiment, Q is C 1~3 alkylene and 1 to 3 R 4 In one embodiment, Q is CH or CHCH and one or two R 4 In some embodiments, Q is C alkylene and one or two R 4 In some embodiments, Q is optionally substituted by: In some embodiments, Q is CH. In some embodiments, Q is CHCH.

[0087] In some embodiments, each R 4 =O, F, Cl, C 1~4 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 5 R 6 , and C 1~6 Alkylene NR 5 R 6 In one embodiment, each R 4 =O, F, Cl, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~6 Heterocycloalkyl, OH, OC 1~4 Alkyl, NR 5 R 6 In one embodiment, R 4 One of them is =O.

[0088] In some embodiments, each R 4 are F, Cl, OH, C 1~4 Alkyl OC 1~4 Alkyl and NR 5 R 6 In one embodiment, each R 4 are F, Cl, OH, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, OCH3, OCH2CH3, OCF3, OCF2H, OCH(CH3)2 and NR 5 R 6 In one embodiment, each R 4 are F, Cl, OH, CH3, CF2H, CF3, CFH2, OCH3, OCF3, OCF2H and NR 5 R 6 In one embodiment, one to three R 4 are F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H and NR 5 R 6 In one embodiment, one to three R 4 are independently selected from F, Cl, CH, CFH, CF, OCH, OCF, and OCFH. In some embodiments, one to four R 4 are independently selected from F, CH3, and OCH3.

[0089] In some embodiments, each R 4 are F, Cl and C 1~4 In one embodiment, each R 4 is independently selected from F, Cl, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCHF. In certain embodiments, each R 4 are independently selected from F, Cl, CH, CFH, CF, and CHCFH. In certain embodiments, R 4 is selected from F, Cl, CH3, and CF3. In some embodiments, R 4 is selected from F, CH, and CF. In certain embodiments, each R 4is independently selected from F, CH, and CF. In certain embodiments, each R 4 are independently selected from F and CH. In some embodiments, R 4 At least one of at least one of R is F. In some embodiments, at least one of at least one of R 4 is F. In some embodiments, one or more, one to four, one to three, one or two, or one R 4 is CH3.

[0090] In some embodiments, one or two R 4 is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl and C 1~4 Alkylene C 3~6 In some embodiments, one or two R 4 is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~2 Alkylene C 3~6 Cycloalkyl and C 1~2 Alkylene C 3~6 In one embodiment, R 4 wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 4 wherein said cycloalkyl is selected from cyclopropyl and cyclobutyl.

[0091] In one embodiment, R 4wherein the heterocycloalkyl is selected from aziridinyl, oxiranyl, thiiranyl, oxaxylidinyl, dioxiranyl, azetidinyl, oxetanyl, thieitanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl. In certain embodiments, R 4 wherein said heterocycloalkyl is selected from azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl and pyrazolidinyl.

[0092] In some embodiments, each R 4 OH and OC 1~4 In one embodiment, each R 4 OH and OC 1~4 In some embodiments, one or two R 4 are independently selected from OH, OCH, OCHCH, OCF, OCFH, and OCH(CH). In some embodiments, one R 4 is selected from OH, OCH3, OCF3, and OCF2H.

[0093] In one embodiment, R 4 One of them is NR 5 R 6 or C 1~4 Alkylene NR 5 R 6 In one embodiment, R 4 One of them is NR 5 R 6 or C 1~2 Alkylene NR 5 R6 In one embodiment, R 4 One of them is NR 5 R 6 In one embodiment, one R 4 is C 1~2 Alkylene NR 5 R 6 In one embodiment, R 4 NR 5 R 6 or C 1~2 Alkylene NR 5 R 6 R in 5 and R 6 are both CH or both H. In some embodiments, one R 4 is NR 5 R 6 and R 4 R in 5 and R 6 are both H. In one embodiment, R 5 and R 6 are independently H and C 1~4 In one embodiment, R 5 and R 6 are each independently selected from H, CH, and CF. In some embodiments, R 5 and R 6 One of R is H and the other is CH. 5 and R 6 Both are CH3.

[0094] In one embodiment, R 5 and R 6 and are bonded together with the nitrogen atom therebetween to form a 3- to 7-membered saturated or unsaturated ring, and are N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 In one embodiment, R 5 and R 6together with the nitrogen atom therebetween, form a 3- to 7-membered heterocycle, 1~6 In some embodiments, R forms a ring selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), morpholinyl, and azepanyl, optionally substituted with one or more alkyl. 5 and R 6 and are bonded together with the nitrogen atom between them, halo and C 1~6 In one embodiment, R 5 and R 6 and are bonded together with the nitrogen atom between them, halo and C 1~6 This forms aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl, optionally substituted by one or more of alkyl.

[0095] In one embodiment, Q is C 1~3 In some embodiments, Q is C 1~3 alkylene, and one or two R 4 In some embodiments, Q is unsubstituted. In some embodiments, Q is substituted with one or two R 4 In one embodiment, Q is substituted by C 1~3 alkylene, and one or two R 4 and one R 4 is C 1~4 In one embodiment, Q is C 1~3 alkylene, and one or two R 4 and one or more R 4 is selected from F, CH3, and CF3. In some embodiments, Q is C 1~3 alkylene, and one or two R 4 and R4 In some embodiments, Q is unsubstituted. In some embodiments, Q is selected from one or two R 4 In certain embodiments, Q is substituted with one or two R 4 and at least one R 4 is C 1~4 In certain embodiments, Q is one or two R 4 and R 4 is selected from F, CH3, and CF3. In certain embodiments, Q is selected from one or two R 4 and R 4 is CH3. In some embodiments, Q is C 1~3 alkylene and 1 to 4 R 4 and each R 4 is independently selected from F, Cl, CH, CF, H, CF, OCH, OCF, and OCF. 1~3 alkylene and 1 to 4 R 4 and each R 4 are independently selected from F, CH3 and OCH3.

[0096] In one embodiment, Q is C 1~3 alkylene, and R 4a and R 4b In some embodiments, Q is C alkylene or C alkylene, and R 4a and R 4b In one embodiment, Q is optionally disubstituted on one carbon atom by CR 4a R 4b is.

[0097] In one embodiment, R 4a and R 4b and together with the carbon atoms between them form a 3- to 6-membered saturated or unsaturated ring, which may be N, NH, or NC 1~6Optionally containing one hetero moiety selected from alkyl, O, S, S(O), and SO2, and halo and C 1~4 The alkyl groups form a ring that is optionally substituted by one or more alkyls.

[0098] In one embodiment, R 4a and R 4b and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 4a and R 4b and, together with the carbon atoms therebetween, form a 3- to 6-membered cycloalkyl, including halo and C 1~4 In one embodiment, R forms a cycloalkyl ring selected from a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, and a cyclohexyl ring, optionally substituted with one or more alkyl rings. 4a and R 4b and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 4a and R 4 and together with the carbon atom between them form a 3- to 6-membered cycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 4a and R 4b and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 4a and R 4b and halo and C are bonded together with the carbon atoms between them. 1~4In one embodiment, R 4a and R 4b and bonded together with the atoms between them, halo and C 1~4 In one embodiment, R 4a and R 4b and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 4a and R 4b and together with the carbon atom between them form a cyclopropyl or cyclobutyl ring. 4a and R 4b are bonded together with the atoms between them to form a cyclopropyl ring.

[0099] In one embodiment, R 4a and R 4b and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 4a and R 4band, together with the carbon atoms therebetween, form a 3- to 6-membered heterocycloalkyl ring selected from aziridinyl, oxiranyl, thiiranyl, oxaxylidinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl. In certain embodiments, R 4a and R 4b and are linked together with the carbon atoms therebetween to form a 3- to 5-membered heterocycloalkyl ring. 4a and R 4b and, together with the carbon atoms therebetween, form a 3- to 5-membered heterocycloalkyl ring selected from oxiranyl, oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydrothiophenyl. 4a and R 4b and together with the atoms between them form an oxetanyl or azetidinyl. 4a and R 4b and together with the carbon atom between them form an oxetanyl. 4a and R 4b and bond together with the atoms between them. [ka] where "●" represents the point of covalent attachment to Q.

[0100] In certain embodiments, Q is one or two R 4cC optionally replaced by 2~4 In certain embodiments, Q is an alkenylene. In certain embodiments, Q is one or two R 4c C=C optionally substituted by

[0101] In certain embodiments, Q is optionally selected from C=N and N=C, and R 4c In certain embodiments, Q is C=N or N=C.

[0102] In some embodiments, each R 4c are F, Cl, C 1~4 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 5 R 6 , and C 1~6 Alkylene NR 5 R 6 In one embodiment, each R 4c are F, Cl, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~6 Heterocycloalkyl, OH, OC 1~4 Alkyl, NR 5 R 6 , and C 1~4 Alkylene NR 5 R 6 are independently selected from

[0103] In some embodiments, each R 4c are F, Cl, OH, C 1~4 Alkyl, OC 1~4Alkyl, C 1~2 Alkylene NR 5 R 6 and NR 5 R 6 In one embodiment, each R 4c is F, Cl, OH, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, OCH3, OCH2CH3, OCF3, OCF2H, OCH(CH3)2, C 1~2 Alkylene NR 5 R 6 and NR 5 R 6 In one embodiment, each R 4c is F, Cl, OH, CH3, CF2H, CF3, CFH2, OCH3, OCF3, OCF2H, C 1~2 Alkylene NR 5 R 6 and NR 9 R 10 In some embodiments, one or two R 4c is F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H, C 1~2 Alkylene NR 5 R 6 and NR 5 R 6 In some embodiments, one or two R 4c is F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H, C 1~2 Alkylene NR 5 R 6 and NR 5 R 6 are independently selected from

[0104] In some embodiments, each R 4c F and C 1~4 In one embodiment, each R 4c is independently selected from F, Cl, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCHF. In certain embodiments, each R 4cis independently selected from F, Cl, CH, CFH, CF, and CHCFH. In certain embodiments, each R 4c are independently selected from F, Cl, CH, and CF. In certain embodiments, R 4c is selected from F, CH3, and CF3. In some embodiments, R 4c is selected from F and CH. In some embodiments, R 4c At least one of R is F. In some embodiments, one or more, one to four, one to three, one or two, or one R 4c is CH3. In one embodiment, two R 4c One of them is CH3.

[0105] In some embodiments, each R 4c is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl and C 1~4 Alkylene C 3~6 In one embodiment, one R is independently selected from the group consisting of cycloalkyl, cyclohexane, cyclohexane-1, cyclohexane-2, cyclohexane-3, cyclohexane-4, cyclohexane-5, cyclohexane-6, cyclohexane-7, cyclohexane-8, cyclohexane-9, cyclohexane-10, cyclohexane-11, cyclohexane-12, cyclohexane-13, cyclohexane-14, cyclohexane-15, cyclohexane-16, cyclo 4c is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~2 Alkylene C 3~6 Cycloalkyl and C 1~2 Alkylene C 3~6 In one embodiment, R 4c wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 4c In one embodiment, R 4cwherein the heterocycloalkyl is selected from aziridinyl, oxiranyl, thiiranyl, oxaxylidinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, and dioxanyl and dithianyl. 4c wherein said heterocycloalkyl is selected from azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl and pyrazolidinyl.

[0106] In some embodiments, each R 4c OH and OC 1~4 In one embodiment, each R 4c OH and OC 1~4 In one embodiment, each R 4c is selected from OH, OCH, OCF, OCFH, OCHCH, and OCH(CH). In some embodiments, one R 4c is selected from OH, OCH3, OCF3, and OCF2H.

[0107] In some embodiments, one or two R 4c is NR 5 R 6 and C 1~4 Alkylene NR 5 R 6 In some embodiments, one or two R 4c are independently C 1~4 Alkylene NR 5 R 6 In one embodiment, R 4cOne of them is C 1~2 Alkylene NR 5 R 6 In one embodiment, R 4c One of them is NR 5 R 6 In one embodiment, R 4 The above NR 5 R 6 or C 1~2 Alkylene NR 5 R 6 R in 5 and R 6 are both CH3 or both H. In some embodiments, one R 4 is NR 5 R 6 or C 1~4 Alkylene NR 5 R 6 and R 4 R in 5 and R 6 are both H.

[0108] In one embodiment, R 4c R in 5 and R 6 are independently H and C 1~4 In one embodiment, R 4c R in 5 and R 6 are each independently selected from H, CH, and CF. In some embodiments, R 4c R in 5 and R 6 One of R is H and the other is CH. In some embodiments, R 4c R in 5 and R 6 Both are CH3.

[0109] In one embodiment, R 4c R in 5 and R 6 and together with the nitrogen atom therebetween form a 3- to 7-membered saturated or unsaturated ring, which is N, NH, NC 1~6Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 In one embodiment, R 4c R in 5 and R 6 together with the nitrogen atom therebetween, form a 3- to 7-membered heterocycle selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), morpholinyl, and azepanyl, and is selected from halo and C 1~6 In one embodiment, R 4c R in 5 and R 6 and halo and C, together with the nitrogen atom between them. 1~6 In one embodiment, R 4c R in 5 and R 6 and halo and C, together with the nitrogen atom between them. 1~6 This forms aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl, optionally substituted with one or more of alkyl.

[0110] In one embodiment, Q is NR 3 Optionally interrupted C 1~3 In one embodiment, R 3 is H and C 1~4 In one embodiment, R 3 is selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In some embodiments, R 3is selected from H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3.

[0111] In certain embodiments, Q is C alkylene or C alkylene, and R 4a and R 4b and R 4a and R 4b and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, Q forms a 3- to 5-membered cycloalkyl ring optionally substituted with one or more alkyls. 4a R 4b In R 4a and R 4b and halo and C are bonded together with the carbon atoms between them. 1~4 The ring forms a cyclopropyl or cyclobutyl ring, optionally substituted with one or more alkyls.

[0112] In certain embodiments, Q is one or two R 4c C optionally replaced by 2~4 alkenylene, and R 4c are F, Cl, C 1~4 Alkyl and OC 1~4 In certain embodiments, Q is independently selected from one or two R 4c and each R 4c are F, Cl, C 1~4 Alkyl and OC 1~4 In certain embodiments, Q is independently selected from one or two R 4c and each R 4c is independently selected from F, Cl, CH3, and OCH3OCF3, and OCF2H. In certain embodiments, Q is selected from one or two R 4cand each R 4c is F and C 1~4 In one embodiment, R 4c is selected from F and CH3. In certain embodiments, Q is C=C substituted by F. In certain embodiments, Q is C=C substituted by Cl. In certain embodiments, Q is C=C substituted by OCH3. In certain embodiments, Q is C=C substituted by CH3. In certain embodiments, Q is C=C substituted by F and CH3.

[0113] In certain embodiments, Q is selected from C=N and N=C, and one or two R 4c and each R 4c are F, Cl, C 1~4 Alkyl, OC 1~4 Alkyl, NR 5 R 6 In some embodiments, Q is selected from C=N and N=C, and one or two R 4c and each R 4c are F, Cl, CH3, OCH3, OCF3OCF2H, NR 5 R 6 In some embodiments, Q is selected from C=N and N=C, and one or two R 4c is optionally replaced by 、 Also, each R 4c is independently selected from F, Cl, CH, OCH, OCF, and OCFH. In some embodiments, Q is selected from C=N and N=C, and R 4c is optionally replaced by 、 and R 4c is selected from F and CH. In some embodiments, Q is selected from C=N or N=C, and R 4cand R 4c is selected from cyclopropyl and cyclobutyl. In certain embodiments, Q is C alkylene or C alkylene, and R 5a and R 5b In some embodiments, Q is selected from C=N or N=C and is optionally disubstituted on one carbon atom by one or two R 4c and one R 4c is C 1~2 Alkylene NR 5 R 6 and NR 5 R 6 is selected from.

[0114] In certain embodiments, Q is unsubstituted. In certain embodiments, Q is selected from one or two R 4 In certain embodiments, Q is substituted with one or two R 4 and R 4 is C 1~4 It is alkyl.

[0115] In one embodiment, Cy 1 is unsubstituted or substituted with one or more R 7 C is replaced by 6~10 In one embodiment, Cy is aryl. 1 is unsubstituted or substituted with one or more R 7 In one embodiment, Cy is phenyl substituted with 1 is unsubstituted phenyl. 1 is one or two R 7 is phenyl substituted by

[0116] In one embodiment, Cy 1 is unsubstituted or substituted with one or more R 7 C is replaced by 5~10 In one embodiment, Cy is heteroaryl.1 is unsubstituted or substituted with one or more R 7 In one embodiment, Cy is a pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, or pyridinyl substituted by 1 is unsubstituted or substituted with one or more R 7 is pyridine or pyrazolyl substituted by:

[0117] In one embodiment, Cy 1 is unsubstituted. In one embodiment, Cy 1 is 1 to 4 R 7 In one embodiment, Cy is substituted by 1 is 1 to 3 R 7 In one embodiment, Cy is substituted by 1 is one or two R 7 In one embodiment, Cy is substituted by 1 is one R 7 has been replaced by

[0118] In some embodiments, each R 7 Ha, Halo, C 1~4 Alkyl, NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 、 C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkylene C 3~7 Cycloalkyl and C 1~4 Alkylene C 3~7 heterocycloalkyl, and the last four groups are independently selected from 1 to 3 R 10 In one embodiment, each R 7 are F, Cl, C 1~4 Alkyl, NR 8 R 9 , C 1~4 Alkylene NR 8 R 9 , C 3~7 Cycloalkyl, C3~7 Heterocycloalkyl, C 1~4 Alkylene C 3~7 Cycloalkyl and C 1~4 Alkylene C 3~7 heterocycloalkyl, and the last four groups are independently selected from 1 to 3 R 10 is optionally replaced by

[0119] In some embodiments, one to three R 7 are F, Cl and C 1~4 alkyl. In one embodiment, one to three R 7 are independently selected from F, Cl, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, CH2CH2CH2CH3, CF2H, CF3, CFH2, CH2CH2F, CH2CF2H, CH2CF3CH2CH2F2H, CH2CH2CH2F2H, and CH(CH3)2. In some embodiments, one to three R 7 is independently selected from F, Cl, CH3, CH2CH3, CH(CH3)2, CF2H, CF3, CFH2, CH2CH2F, CH2CF2H, CH2CF3, CH2CH2F2H, and CH2CH2CH2F2H. In certain embodiments, each R 7 is independently selected from F, Cl, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCFH. In certain embodiments, each R 7 is independently selected from F, Cl, CH, CHCH, and CF. In certain embodiments, each R 7 is independently F, CH, or CF. In some embodiments, R 7 is CH3 or CF3. In some embodiments, one or more, one to four, one to three, one or two, or one R 7 is CF. In certain embodiments, one or more R 7 is F. In some embodiments, one to three R 7 are independently selected from F, Cl, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In some embodiments, one to three R7 are independently selected from F, Cl, CH3, CH2CH3, and CF3. In some embodiments, one to three R 7 are independently F, CH, or CF. In some embodiments, one to three R 7 are independently CH3 or CF3. In some embodiments, one to three R 7 is F. In some embodiments, one to three R 7 is CF3.

[0120] In one embodiment, Cy 1 is one or two R 7 and one or more R 7 is F.

[0121] In some embodiments, one or two R 7 is NR 8 R 9 and C 1~4 Alkylene NR 8 R 9 In one embodiment, one R 7 is NR 8 R 9 and C 1~3 Alkylene NR 8 R 9 is selected from.

[0122] In one embodiment, R 7 One of them is NR 8 R 9 and R 8 and R 9 are independently H and C 1~4 In one embodiment, R 7 is NR 8 R 9 and R 8 and R 9 are each independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 7 One of them is NR 8 R 9and R 8 and R 9 are each independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 7 One of them is NR 8 R 9 and R 8 and R 9 are independently selected from H, CF, CH, and CHCH. Thus, in some embodiments, R 7 One of R is selected from NH, N(CH), NH(CH), N(CH)(CHCH), NH(CHCH), and N(CHCH). 7 one of which is selected from NH2, N(CH3)2 and NH(CH3).

[0123] In one embodiment, R 7 One of them is C 1~4 Alkylene NR 8 R 9 and R 8 and R 9 are independently H and C 1~4 In one embodiment, R 7 One of them is C 1~4 Alkylene NR 8 R 9 and R 8 and R 9 are each independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 7 One of them is C 1~4 Alkylene NR 8 R 9 and R 8 and R 9 are each independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 7 One of them is C 1~4 Alkylene NR 8 R 9 and R8 and R 9 are each independently selected from H, CF, CH, and CHCH. Thus, in one embodiment, R 7 and one of R is selected from CHN(CHCH), C(CH)NH, CHN(CH), CHCHN(CH) and CHN(CH). 7 In one embodiment, one of R 7 One of them is C 1~4 Alkylene NR 8 R 9 and R 8 and R 9 are each independently selected from H and CH. In some embodiments, R 7 One of them is C 1~3 Alkylene 4 Alkylene NR 8 R 9 and R 8 and R 9 are either both H or both CH3.

[0124] In one embodiment, R 8 and R 9 are independently H and C 1~4 In one embodiment, R 8 and R 9 are independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 8 and R 9 are independently selected from H, CF3, and CH3. In certain embodiments, R 8 and R 9 are independently selected from H and CH3.

[0125] In one embodiment, Cy 1 is one or two R 7 and R 7 At least one of them is C 1~4 Alkylene NR 8R 9 In one embodiment, Cy 1 is one or two R 7 and R 7 At least one of them is C 1~2 Alkylene NR 8 R 9 In one embodiment, Cy 1 is one or two R 7 and R 7 At least one of the 8 R 9 is.

[0126] In one embodiment, R 7 There is exactly one and R 7 is NR 8 R 9 and R 8 and R 9 are independently H and C 1~4 In one embodiment, R 7 There is exactly one and R 7 is C 1~4 Alkylene NR 8 R 9 and R 8 and R 9 are independently H and C 1~4 alkyl.

[0127] In some embodiments, one or two R 7 is C 3~7 Cycloalkyl and C 3~7 Heterocycloalkyl, C 1~4 Alkylene C 3~7 Cycloalkyl and C 1~4 Alkylene C 3~7 heterocycloalkyl; and one to three R 10 In one embodiment, one R 7 is C 1~3 Alkylene C 3~7 Cycloalkyl and C 3~7cycloalkyl; and one or two R 10 In one embodiment, R 7 The above C 1~3 Alkylene C 3~7 Cycloalkyl and C 3~7 C in cycloalkyl 3~7 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hexanyl, and bicyclo[2.2.1]heptanyl; and one or two R 10 is optionally replaced by

[0128] In some embodiments, one or two R 7 is C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 heterocycloalkyl; and one to three R 10 In one embodiment, R 7 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl is a group consisting of one to three R 10In certain embodiments, R is selected from azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidin-2-onyl, azabicyclohexanyl, azabicycloheptanyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, thiepanyl, azabicyclohexanyl, azabicycloheptanyl, oxabicyclohexanyl, and oxabicycloheptanyl, optionally substituted by 7 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl is diazepanyl. In one embodiment, one R 7 is C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 heterocycloalkyl, and R 7 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidin-2-onyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, and dioxanyl; and one to three R 10 In one embodiment, R 7 The above C4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidin-2-onyl, thiazolidinyl, and isothiazolidinyl; one to three R 10 In one embodiment, R 7 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, pyrrolidin-2-onyl, and isothiazolidinyl, and one to three R 10 is optionally replaced by

[0129] In some embodiments, one or two R 7 is C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 heterocycloalkyl; and one to three R 10 In one embodiment, R 7 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl is a group consisting of one to three R 10In certain embodiments, one R is selected from azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, thiepanyl, azabicyclohexanyl, azabicycloheptanyl, oxabicyclohexanyl, and oxabicycloheptanyl, optionally substituted by 7 is C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 heterocycloalkyl, and R 7 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, and dioxanyl; and one to three R 10 In one embodiment, R 7 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, and isothiazolidinyl, and one to three R 10In one embodiment, R 7 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, and isothiazolidinyl, and has one to three R 10 In one embodiment, R 7 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is a heterocyclic group consisting of one or two R 10 and pyrrolidinyl optionally substituted by:

[0130] In one embodiment, R 7 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 A heterocycloalkyl contains at least one N atom. In certain embodiments, R 7 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl may each have one or two R 10 In one embodiment, one R is selected from azetidinyl, pyrrolidinyl, pyrrolidin-2-onyl, azabicyclohexanyl, azabicycloheptanyl, piperidinyl, piperazinyl, and morpholinyl, optionally substituted by 7 is one or two R 10 C optionally replaced by 4~6 heterocycloalkyl, and 4~6Heterocycloalkyl is pyrrolidinyl. In one embodiment, one R 7 is C 4~6 heterocycloalkyl, and 4~6 Heterocycloalkyl is R 10 optionally replaced by [ka] wherein R is a pyrrolidine selected from one or two of 10a is H and R 10 is selected from, and [ka] Cy 1 In one embodiment, the pyrrolidinyl represents a point of covalent attachment to one or two R 10 is optionally replaced by [ka] is selected from, where R 10a is H and R 10 is selected from, and [ka] Cy 1 In one embodiment, R 10a is H. In one embodiment, R 10a is R 10 is.

[0131] In one embodiment, R 7 One of them is 1 to 4 R 10 C, optionally replaced by 1~6 Alkylene C 3~7 heterocycloalkyl, wherein C 1~6 Alkylene C 3~7C in heterocycloalkyl 3~7 Heterocycloalkyl is selected from azetidinyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, piperazinyl, and morpholinyl. 7 One of them is 1 to 4 R 10 C, optionally replaced by 1~3 Alkylene C 4~7 heterocycloalkyl, and 1~6 Alkylene C 3~7 C in heterocycloalkyl 4~7 Heterocycloalkyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Thus, in one embodiment, R 7 One of them is 1 to 4 R 10 C, optionally replaced by 1~3 Alkyleneazetidinyl, C 1~3 Alkylenepyrrolidinyl, C 1~3 Alkylenepiperidinyl, C 1~3 Alkylenepiperazinyl and C 1~3 In one embodiment, R is selected from alkylenemorpholinyl. 7 One of them is 1 to 4 R 10 In one embodiment, R is selected from CH azetidinyl, CH pyrrolidinyl, CH piperidinyl, CH piperazinyl, and CH morpholinyl, optionally substituted by 11 One of them has one or two R 10 is optionally replaced by [ka] is selected from, where R 10d is H and R 10 is selected from, and [ka] Cy1 represents the point of covalent attachment to

[0132] In some embodiments, one R 7 is one or two R 10 C, optionally replaced by 1~6 Alkylene C 3~7 heterocycloalkyl, and 1~6 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl is pyrrolidinyl. In one embodiment, one R 7 is 1 to 3 R 10 C optionally replaced by 1~4 In one embodiment, one R is alkylenepyrrolidinyl. 7 is C 1~4 Alkylene C 4~6 heterocycloalkyl, and 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is a group consisting of one to three R 10 pyrrolidinyl optionally substituted by 10 is F.

[0133] In some embodiments, each R 10 are F, Cl, CN, and C 1~4 Alkyl and NR 11 R 11a In one embodiment, each R 10 is F, C 1~4 Alkyl and NR 11 R 11a In one embodiment, each R 10 F and C 1~4 In one embodiment, each R 10 is independently selected from F and CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In certain embodiments, R 10At least one of R 10 One of them is NR 11 R 11a is.

[0134] In one embodiment, R 11 and R 11a is H and C 1~4 In one embodiment, R 11 and R 11a are independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 11 and R 11a are independently selected from H, CF3, and CH3. In certain embodiments, R 11 and R 11a are independently selected from H and CH3.

[0135] In some embodiments, one R 7 is 1 to 3 R 10 C, optionally replaced by 1~4 alkylenepyrrolidinyl, wherein at least one R 10 is F. In one embodiment, R 7 In the above C 4~6 Heterocycloalkyl is [ka] where [ka] Cy 1 represents the point of covalent attachment to

[0136] In some embodiments, one R 7 is unsubstituted, C 3~7 Cycloalkyl, C 3~7 Heterocycloalkyl, C 1~4 Alkylene C 3~7 Cycloalkyl and C1~4 Alkylene C 3~7 In one embodiment, R 7 In the above C 3~7 Heterocycloalkyl is as defined above and is unsubstituted. In some embodiments, R 7 In the above C 3~7 Heterocycloalkyl is unsubstituted and is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, and isothiazolidinyl. In some embodiments, R 7 In the above C 3~7 The heterocycloalkyl is pyrrolidine.

[0137] In some embodiments, one R 7 is unsubstituted pyrrolidinyl. In one embodiment, one R 7 teeth, [ka] wherein: [ka] Cy 1 In one embodiment, one R 7 teeth [ka] is selected from, where: [ka] Cy 1 represents the point of covalent attachment to

[0138] In one embodiment, Cy 1 is 1 to 3 R 7 and R is phenyl, pyrrole, or pyridinyl substituted by 7One of them is one or more R 10 In one embodiment, Cy is pyrrolidinyl optionally substituted by 1 is 1 to 3 R 7 and one R 7 is one or more R 10 and pyrrolidinyl optionally substituted by:

[0139] In one embodiment, Cy 1 is 1 to 3 R 7 and one R 7 is one or two R 10 C optionally replaced by 1~4 In one embodiment, Cy is alkyl. 1 is 1 to 3 R 7 and one R 7 is one or two R 10 C optionally replaced by 1~4 It is alkyl alkylene pyrrolidinyl.

[0140] In one embodiment, Cy 1 is 1 to 3 R 7 and one or two R 7 is NR 8 R 9 and C 1~4 Alkylene NR 8 R 9 , C 3~7 Heterocycloalkyl, and C 1~4 Alkylene C 3~7 heterocycloalkyl, and the last two groups are selected from 1 to 4 R 10 In one embodiment, Cy 1 is 1 to 3 R 7 , one or two R7 NR 8 R 9 In one embodiment, Cy is phenyl or pyridinyl substituted by 1 is 1 to 3 R 7 and one or two R 7 is C 1~4 Alkylene NR 8 R 9 In one embodiment, Cy 1 is 1 to 3 R 7 and one or two R 7 are independently selected from CHN(CHCH), C(CH)NH, CHN(CH), CHCHN(CH) and CHN(CH). 1 is 1 to 3 R 7 and one R 7 is CHN(CH). In one embodiment, Cy 1 is 1 to 3 R 7 and one or two R 7 is 1 to 4 R 10 C optionally replaced by 1~2 Alkylene C 3~7 heterocycloalkyl.

[0141] In one embodiment, Cy 2 is one or more R 12 Monocyclic C substituted by 3~7 In one embodiment, Cy is heterocycloalkyl. 2 is 1 to 3 R 12In one embodiment, Cy is substituted with azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, or thiepanyl. 2 is 1 to 3 R 12 In one embodiment, Cy is selected from the group consisting of diaxepanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. 2 is 1 to 3 R 12 and tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, substituted by:

[0142] In one embodiment, Cy 2 is one or more R 12 Monocyclic C substituted by 3~7 In one embodiment, Cy is heterocycloalkyl. 2 is 1 to 3 R 12 In one embodiment, Cy is substituted with azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, or thiepanyl. 2 is 1 to 3 R12 diaxepanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each of which is substituted by Cy 2 is 1 to 3 R 12 In one embodiment, Cy is tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each substituted by 2 is 1 to 3 R 12 In one embodiment, Cy is a pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl substituted by 2 is selected from piperidinyl, piperazinyl, and morpholinyl, and Cy 2 is one or two R 12 In one embodiment, Cy is substituted by 2 is piperazinyl, and Cy 2 is one or two R 12 In one embodiment, Cy is substituted by 2 is 1 to 3 R 12 In certain embodiments, Cy is selected from tetrahydrofuranyl, dihydropyranyl, morpholinyl, and tetrahydropyranyl, each substituted by 2 is 1 to 3 R 12 and tetrahydropyranyl substituted by:

[0143] In one embodiment, Cy 2 is 1 to 3 R 12 In one embodiment, Cy is a bicyclic heterocycle substituted by 2 is 1 to 3 R 12 In one embodiment, Cy is a bridged, fused, or spiro-fused bicyclic heterocycle substituted by 2 is 1 to 3 R 12In one embodiment, Cy is a bridged bicyclic heterocycle substituted by 2 ~Three R's 12 In one embodiment, Cy is a fused bicyclic heterocycle substituted by 2 is a ring in which one or two of the ring carbon atoms are N, NH, or NR depending on the valency requirements of N. 12a is replaced by one to three R 12 C6-C 10 saturated bicyclic ring, where R 12a is H or R 12 In one embodiment, Cy 2 is 1 to 3 R 12 In one embodiment, Cy is a bridged azabicyclohexanyl, a bridged diazabicycloheptanyl, or a bridged diazabicyclooctanyl substituted by 2 is 1 to 3 R 12 is selected from the following structures, each of which is substituted by: [ka] , where [ka] Cy 1 represents the point of covalent attachment to, and R 12a is H or R 12 is selected from.

[0144] In one embodiment, Cy 2 is 1 to 3 R 12 is selected from the following structures, each of which is substituted by [ka] where [ka] Cy 1represents the point of covalent attachment to, and R 12a is H or R 12 is selected from.

[0145] In one embodiment, Cy 2 is selected from tetrahydrofuropyrrolyl, hexapyrazinooxazinyl, hexahydropyrrolopyrazinyl, and hexahydropyrrolodiazepinyl, and Cy 2 is one or more R 12 In one embodiment, Cy is substituted by 2 teeth,

[0146] One or more R 12 is replaced by [ka] is selected from, and where [ka] Cy 1 represents the point of covalent attachment to

[0147] In one embodiment, Cy 2 is an unsubstituted bicyclic heterocycle.

[0148] In some embodiments, each R 12 Halo, OH, =O, C 1~4 Alkyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkylene C 3~10 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylene OR 13 , C 1~4 Alkylene NR 13 R 14 , O.C. 1~4 Alkylene OR 13 , O.C. 1~4 Alkylene NR13 R 14 , C(O)R 13 , C(O)C 1~4 Alkylene OR 13 , C(O)C 1~4 Alkylene NR 13 R 14 , C(O)C 1~4 Alkylene OC 1~4 Alkylene NR 13 R 14 , C(O)NR 13 R 14 , CO2R 13 , CO2C 1~4 Alkylene OR 13 , CO2C 1~4 Alkylene OC 1~4 Alkylene NR 13 R 14 , N.R. 13 R 14 , N.R. 15 SO2R 13 , SO2R 13 and SO2NR 13 R 14 are independently selected from

[0149] In one embodiment, R 13 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl and C 1~4 Alkylene C 3~6 In one embodiment, R 13 H, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H and CH2CF3, C 1~4 Alkylene C 3~6 Cycloalkyl and C 1~4 Alkylene C 3~6 heterocycloalkyl.

[0150] In one embodiment, R 14 is H and C 1~4 In one embodiment, R 14is selected from H, CH, and CHCH; in some embodiments, R 14 is selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In some embodiments, R 3 is selected from CF2H, CH3, and CF3. In some embodiments, R 14 is selected from H, CH, CHCH, and CF. In some embodiments, R 14 is selected from CH3 and CF3. In some embodiments, R 14 is H.

[0151] In one embodiment, R 13 and R 14 and bond together with the nitrogen atom between them, N, NR 16 , O, S, S(O), and SO. 13 and R 14 and, together with the nitrogen atom therebetween, form a 4- to 6-membered heterocycle selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), and morpholinyl. 13 and R 14 and are bonded together with the nitrogen atom therebetween to form aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0152] In some embodiments, one R 12 is CO2R 13 In one embodiment, R 13 is H, C 1~4 alkyl. Thus, in one embodiment, one R 12 is CO2C 1~6 In one embodiment, R 13is selected from H, CH, CHCH, CH(CH), CF, CFH, CHCFH, and CHCF. Thus, in one embodiment, one R 12 is selected from CO2CCH3, CO2CH2CH3, CO2CF2H, CO2CF3, CO2CFH2, CO2CH2CF2H, CO2CH2CF3, CO2CH2CH2F2H, CO2CH2CH2CH2F2H, CO2CH(CH3)2, and CO2CH2CH(CH3)2. 12 is CO2CCH3.

[0153] In some embodiments, one R 12 is C(O)R 13 In one embodiment, R 13 is H, C 1~4 alkyl. Thus, in one embodiment, one R 12 is C(O)C 1~6 In one embodiment, R 13 is selected from H, CH, CHCH, CH(CH), CF, CFH, CHCFH, and CHCF. Thus, in one embodiment, one R 12 is selected from COCCH3, COCH2CH3, COCF2H, COCF3, COCFH2, COCH2CF2H, COCH2CF3, COCH2CH2F2H, COCH2CH2CH2F2H, COCH(CH3)2, and COCH2CH(CH3)2. 12 is COCH3.

[0154] In some embodiments, each R 12 are independently selected from the substituents listed below: [ka]

[0155] In some embodiments, each R 12 are independently selected from the substituents listed below: [ka] .

[0156] In some embodiments, one or two R 12 is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl and C 1~4 Alkylene C 3~6 In one embodiment, one R is independently selected from the group consisting of cycloalkyl, cyclohexane, cyclohexane-1, cyclohexane-2, cyclohexane-3, cyclohexane-4, cyclohexane-5, cyclohexane-6, cyclohexane-7, cyclohexane-8, cyclohexane-9, cyclohexane-10, cyclohexane-11, cyclohexane-12, cyclohexane-13, cyclohexane-14, cyclohexane-15, cyclohexane-16, cyclo 12 is C 3~5 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~5 Cycloalkyl and C 1~4 Alkylene C 3~5 heterocycloalkyl.

[0157] In some embodiments, one R 12 is selected from cyclopropyl, cyclobutyl, and cyclopentyl. 12 is independently selected from cyclopropyl and cyclobutyl.

[0158] In some embodiments, one R 12 is C 1~4 Alkylenecyclopropyl, C 1~4 Alkylenecyclobutyl and C 1~4 C selected from alkylenecyclopentyl 1~4 Alkylene C 3~5 In one embodiment, one R 12 is C 1~4 Alkylenecyclopropyl, C 1~4 Alkylene C3 cyclobutyl and C 1~4 In one embodiment, one R is selected from alkylene, C3 cyclopentyl, and 12 is C 1~3 In one embodiment, one R is alkylenecyclopropyl. 12 teeth, [ka] C selected from 1~3 It is alkylenecyclopropyl.

[0159] In some embodiments, one R 12 is selected from CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CH2CF2H, CH2CH2CH2CF2H, and CH2CF3. In one embodiment, one R 12 is selected from CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In certain embodiments, one R 12 is selected from CH3, CH2CH3, and CH(CH3)2. In certain embodiments, one R21 is selected from CH2CH3 and CH(CH3)2. In certain embodiments, one R 12 is selected from CH2CH3 and CH(CH3)2. In some embodiments, one R 12 is selected from CF2H, CH2CF2H, CH2CH2CF2H, and CH2CH2CH2CF2H. In certain embodiments, each R 12 is independently selected from CH, CHCH, CH(CH), CFH, CF, CFH, CHCFH, and CHCF. 12 are independently selected from optionally fluoro-substituted CH2CH3 and CH(CH3)2.

[0160] In some embodiments, one R 12 is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl. 12 is C 1~3 Alkyleneoxetanyl, C 1~3 Alkylenetetrahydrofuranyl and C 1~3 alkylenetetrahydropyranyl.

[0161] In some embodiments, each R 12 are independently selected from the substituents listed below: [ka]

[0162] In one embodiment, Cy 2 is 1 to 3 R 12 In one embodiment, Cy is substituted by 2 is one or two R 12 In one embodiment, Cy is substituted by 2 is one R 12 has been replaced by

[0163] In one embodiment, Cy 2 is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and R 12 is CH3, CH2CH3, or CH(CH3)2. In one embodiment, Cy 2 is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and R 12 is selected from CH3, CH2CH3 or CH(CH3)2.

[0164] In one embodiment, Cy 2 is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and R 12 is C 1~3 It is alkylenecyclopropyl.

[0165] In one embodiment, R 15 and R 16 is H and C 1~4 In one embodiment, R 15 and R 16 are independently selected from H, CH3, CH2CH3, and CH(CH3).

[0166] In certain embodiments, the compound of Formula (I) is a compound of Formula (IA), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, Q and X 1 , X 2 , X 3 , X 4 , R 1 , R 7 and Cy 2 is as defined in formula (I); and n is an integer selected from 0 to 4.

[0167] In certain embodiments, the compound of Formula (I) is a compound of Formula (IB), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] where X 1 , X 2 , X 3 , X 4 , X 5 , R 4c , R 7 and Cy 2 is as defined in formula (I); n is an integer selected from 0 to 4; and o is an integer selected from 0 to 2.

[0168] In certain embodiments, the compound of Formula (I) is a compound of Formula (IC) or (ID), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] where X 1 , X 2 , X 3 , X 4 , X 5 , R 4c , R 7 and Cy 2 is as defined in formula (I); p is an integer selected from 0 and 1; and n is an integer selected from 0 to 4.

[0169] In certain embodiments, each R in the compound of formula IB 7 is independently selected from F, Cl, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF2. In certain embodiments, each R in the compound of formula IB 7 is independently selected from F, Cl, CH3, CH2CH3, and CF3. In certain embodiments, each R in the compound of formula IB 7 is independently F, CH3, or CF3. In certain embodiments, at least one R in a compound of formula IB 7 is CH3 or CF3. In one embodiment, R in the compound of formula IB 7 is F.

[0170] In certain embodiments, one R in the compound of formula IB 7 is one or two R 10 C, optionally replaced by 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 In one embodiment, R 7 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is a heterocyclic group consisting of one or two R 10 In one embodiment, one R 10 is NR 11 R 11a is.

[0171] In one embodiment, n is an integer selected from 0-2.

[0172] In certain embodiments, the compound of Formula (I) is a compound of Formula (IE), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, Q and X 1 , X 2 , X 3 , and Cy 2 is as defined in formula (I); Each R 7 is NR 8 R 9 , C 1~6 Alkylene NR 8 R 9 , C 3~7 Heterocycloalkyl, and C 1~6 Alkylene C 3~7 heterocycloalkyl, and the latter two groups are independently selected from one or more R 10 optionally replaced by; q is an integer selected from 1 to 4; wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

[0173] In certain embodiments, the compound of Formula I is selected from the compounds listed in Table 1 or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [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] i) a compound of formula (II)

[0174] This application describes a new class of substituted aminopyridine HPK1 inhibitors.

[0175] The present application also encompasses compounds of formula (II) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof: [ka] where X 6 N and CR 17 Selected from; X 7 and X 8 are independently N and CR 18 Selected from; X 9 and X 10 are each independently selected from N and CH, with the proviso that X 9 and X 10 at least one of is N; Q' is C 1~4 Alkylene is O, S, S(O), SO and NR 19 and / or one or more R 20 and / or on one carbon R 21 and R 21a C optionally disubstituted by 1~4alkylene, with the proviso that when Q contains said hetero moiety, said hetero moiety is separated from the ring amide NH by other than methylene; or Q' is one or more R 22 C optionally replaced by 2~4 is alkenylene; or Q' is R 22 C=N or N=C optionally substituted by R 17 is H, halo, OR 23 , N.R. 24 R 25 , C 1~6 Alkylene NR 24 R 25 and C 1~6 alkyl; R 18 H, halo and C 1~6 alkyl; R 19 is H and C 1~6 alkyl; Each R 20 =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 26 R 27 and C 1~6 Alkylene NR 26 R 27 are independently selected from; R 21 and R 21a and together with the carbon atoms between them form a 3- to 6-membered saturated or unsaturated ring, which may be N, NH, NC 1~6 Optionally containing one hetero moiety selected from alkyl, O, S, S(O), and SO2, and halo and C 1~6forming a ring optionally substituted with one or more alkyl; Each R 22 Ha, 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 26 R 27 and C 1~6 Alkylene NR 26 R 27 are independently selected from; R 24 , R 25 , R 26 and R 27 are independently H and C 1~6 alkyl, or R 24 and R 25 , or R 26 and R 27 means, when bonded together with the atoms between them, a 3- to 7-membered saturated or unsaturated ring, which is N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Cy 3 is one or two R 28 and one to three R 29 C optionally further replaced by 6~10 Aryl or C 5~10 is heteroaryl; Each R 28 is NR 30 R 31 , C 1~6 Alkylene NR 30 R 31 、 C 3~7Heterocycloalkyl and C 1~6 Alkylene C 3~7 heterocycloalkyl, and the latter two groups are independently selected from one or more R 32 optionally replaced by; Each R 29 Ha, Halo, C 1~6 Alkyl, C 3~7 Cycloalkyl, and C 1~6 Alkylene C 3~7 cycloalkyl, and the latter two groups are independently selected from one or more R 32 optionally replaced by; R 30 and R 31 are independently H and C 1~6 alkyl; Each R 32 Ha, Halo, C 1~6 Alkyl, CN and NR 33 R 34 are independently selected from; R 33 and R 34 are independently H and C 1~6 alkyl; Cy 4 is C 3~14 Heterocycloalkyl, and Cy 4 is unsubstituted or substituted with one or more R 35 has been replaced by; Each R 35 Halo, =O, CN, OH, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkylene C 3~10 Cycloalkyl, C 1~6 Alkylene C 3~10 Heterocycloalkyl, C 1~6 Alkylene OR 36 , C 1~6 Alkylene NR 36 R 37 , O.C.1~6 Alkylene OR 36 , O.C. 1~6 Alkylene NR 36 R 37 , S.R. 36 , C(O)R 36 C(O)C 1~6 Alkylene OR 36 , C(O)C 1~6 Alkylene NR 36 R 37 , C(O)C 1~6 Alkylene OC 1~6 Alkylene NR 36 R 37 , C(O)NR 36 R 37 , CO2R 36 , CO2C 1~6 Alkylene OR 36 , CO2C 1~6 Alkylene OC 1~6 Alkylene NR 36 R 37 , N.R. 36 R 37 , N.R. 38 SO2R 36 , S(O)R 36 , SO2R 36 , SO2NR 36 R 37 and S(O)(NR 38 )R 36 are independently selected from; R 36 is H, C 1~6 Alkyl, C 1~6 Alkylene OR 14 , C 3~10 Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~6 Alkylene C 3~10 Cycloalkyl and C 1~6 Alkylene C 3~10 heterocycloalkyl; R 37 is H and C 1~6 alkyl; or R 36 and R 37 and bond together with the nitrogen atom between them, N, NR 39, forming a 4- to 6-membered saturated or unsaturated ring, optionally containing one additional hetero moiety selected from O, S, SO, and SO; and R 38 and R 39 is H and C 1~6 independently selected from alkyl; wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

[0176] In all of the following embodiments, it should be understood that all available hydrogen atoms are optionally replaced with fluorine atoms. This is not repeated throughout. Thus, in each embodiment where a group containing available hydrogen atoms is listed, all such atoms are optionally replaced with fluorine atoms, e.g., C 1~6 Unless otherwise specified, each description of alkyl is C 1~6 It should be understood that this also describes fluoroalkyl.

[0177] In one embodiment, X 6 is N. In one embodiment, X 6 is CR 17 is.

[0178] In one embodiment, R 17 are H, F, Cl, OR 23 , N.R. 24 R 25 , C 1~4 Alkylene NR 24 R 25 , and C 1~4 alkyl.

[0179] In one embodiment, R 17 are H, F, Cl and C 1~4 In one embodiment, R 17 is selected from H, F, Cl, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In some embodiments, R17 is selected from H, F, CF, CFH, CHCFH, and CH. In some embodiments, R 17 is selected from H, F, CF, CFH, and CHCFH. In some embodiments, R 17 is selected from H, F, CF3, and CH3. In some embodiments, R 17 is selected from H and F. In some embodiments, R 17 is H.

[0180] In one embodiment, R 17 is OR 23 In one embodiment, R 23 is selected from H, CH, CHCH, CF, CFH, CFH, CHCFH, and CHCFH. In certain embodiments, R 23 is H and C 1~4 In one embodiment, R 23 is selected from H, CH3, and CH2CH3. In some embodiments, R 23 is selected from H, CH, CHCH, CF, CFH, CHCFH, and CHCHF. In certain embodiments, R 23 is CF2H. Thus, in one embodiment, R 17 is selected from OH, OCH3, OCH2CH3, OCF3, OCFH2, OCHF2, OCH2CF2H, and OCH2CF2H.

[0181] In one embodiment, R 17 is NR 24 R 25 , and C 1~4 Alkylene NR 24 R 25 In one embodiment, R 17 is NR 24 R 25 and C 1~2 Alkylene NR 24 R 25 is selected from.

[0182] In one embodiment, R 24 and R 25are independently H and C 1~4 In one embodiment, R 24 and R 25 are each independently selected from H, CH, and CF. In some embodiments, R 24 and R 25 One of R is H and the other is CH. In some embodiments, R 24 and R 25 are both CH3. In one embodiment, R 24 and R 25 are both H.

[0183] In one embodiment, R 24 and R 25 and together with the atoms between them form a 3- to 7-membered saturated or unsaturated ring, and are N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 In one embodiment, R 24 and R 25 together with the nitrogen atom therebetween to form a 3- to 7-membered heterocycle selected from an azetidinyl ring, a diazetidinyl ring, a pyrrolidinyl ring, an imidazolidinyl ring, a pyrazolidinyl ring, a thiazolidinyl ring, an isothiozolidinyl ring, a piperidinyl ring, a diazinanyl (e.g., piperazinyl) ring, a morpholinyl ring, and an azepanyl ring; 1~6 In one embodiment, R 24 and R 25 and are bonded together with the atoms therebetween to form a 4- to 6-membered saturated ring, and halo and C 1~6 In one embodiment, R 24 and R 25and are bonded together with the atoms therebetween to form aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl, and halo and C 1~6 Optionally substituted with one or more alkyl.

[0184] In one embodiment, X 7 and X 8 One of them is N and the other is CR 18 In one embodiment, X 7 is CR 18 and X 8 is N. In one embodiment, X 7 and X 8 Both are independently CR 18 is.

[0185] In some embodiments, each R 18 H, halo and C 1~4 In one embodiment, each R 18 are H, F, Cl and C 1~4 In one embodiment, each R 18 are independently selected from H, F, Cl, CH, CF, CHF, and CHF. In certain embodiments, R 18 is selected from CF2H, CH3, and CF3. In certain embodiments, each R 18 are independently selected from H, F, Cl, CH, and CF. In certain embodiments, each R 18 is selected from H and F.

[0186] In one embodiment, X 7 and X 8 One of X is N and the other is CH. 7 is CH, and X 8 is N. In one embodiment, X 7 is CH, and X 8 is CF or CCl. In some embodiments, X 7 and X 8 and X are both CF. In one embodiment, X7 is selected from CH, CF, CCl, CCH3 and CCF3, and X 8 is CH. In one embodiment, X 7 and X 8 and X are both CH. In one embodiment, X 7 and X 8 are both N.

[0187] In one embodiment, X 6 is CR 17 and X 7 and X 8 Both are CR 18 In one embodiment, X 6 is N, and X 5 and X 6 is independently CR 18 In one embodiment, X 6 is N, and X 7 and X 8 and X are both CH. In one embodiment, X 6 is CR 17 and X 7 and X 8 One of them is N and the other is CR 18 In one embodiment, X 6 is CR 17 and X 7 and X 8 One of them is N and the other is CH.

[0188] In one embodiment, X 9 and X 10 One of X is N and the other is CH. 9 is N, and X 10 is CH. In an embodiment, X 9 is CH, and X 10 is N.

[0189] In one embodiment, Q′ is C 1~3 Alkylene, including O, S, S(O), SO, and NR 19and / or one or more R 20 C optionally replaced by 1~3 It is alkylene.

[0190] In certain embodiments, Q′ is O, S, S(O), SO 2 , and NR 19 C optionally interrupted with a hetero moiety selected from 1~3 In some embodiments, Q' is O, SO, and NR 19 C optionally interrupted with a hetero moiety selected from 1~3 In some embodiments, Q' is O and NR 19 C optionally interrupted with a hetero moiety selected from 1~3 In some embodiments, Q′ is an alkylene group optionally interrupted by hetero moieties selected from O and SO. 1~3 In some embodiments, Q′ is C optionally interrupted by O. 1~3 In some embodiments, Q′ is an alkylene group optionally interrupted by SO 1~2 In some embodiments, Q′ is an alkylene group optionally interrupted by SO 1~2 In certain embodiments, Q' is C=C optionally interrupted by SO2.

[0191] In one embodiment, R 19 is H and C 1~4 In one embodiment, R 19 is selected from H, CH, and CHCH; in some embodiments, R 19is selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 19 is selected from CF2H, CH3, and CF3. In some embodiments, R 19 is selected from H, CH, CHCH, and CF. In some embodiments, R 19 is selected from CH3 and CF3. In some embodiments, R 19 is H.

[0192] In one embodiment, Q′ is C 1~3 alkylene and 1 to 3 R 20 In some embodiments, Q' is CH2 or CH2CH2 and one or two R 20 In some embodiments, Q' is C alkylene and is optionally substituted with one or two R 20 In some embodiments, Q' is CH2. In some embodiments, Q' is CH2CH2.

[0193] In some embodiments, each R 20 =O, F, Cl, C 1~4 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 26 R 27 , and C 1~6 Alkylene NR 26 R 27 In one embodiment, each R 20 =O, F, Cl, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C3~6 Cycloalkyl, C 1~4 Alkylene C 3~6 Heterocycloalkyl, OH, OC 1~4 Alkyl, NR 26 R 27 , and C 1~4 Alkylene NR 26 R 27 In one embodiment, R 20 One of them is =O.

[0194] In some embodiments, each R 20 are F, Cl, OH, C 1~4 Alkyl OC 1~4 Alkyl and NR 26 R 27 In one embodiment, each R 20 are F, Cl, OH, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, OCH3, OCH2CH3, OCF3, OCF2H, OCH(CH3)2 and NR 26 R 27 In one embodiment, each R 20 are F, Cl, OH, CH3, CF2H, CF3, CFH2, OCH3, OCF3, OCF2H and NR 27 R 28 In one embodiment, one to three R 20 are F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H and NR 26 R 27 In one embodiment, one to three R 20 are independently selected from F, Cl, CH, CFH, CF, OCH, OCF, and OCFH. In some embodiments, one to four R 20 are independently selected from F, CH3, and OCH3.

[0195] In some embodiments, each R 20 are F, Cl and C 1~4 In one embodiment, each R 20is independently selected from F, Cl, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCHF. In certain embodiments, each R 20 is independently selected from F, Cl, CH3, CF2H, CF3, and CH2CF2H. In certain embodiments, each R20 is independently selected from F, Cl, CH3, and CF3. In certain embodiments, each R20 is independently selected from F, CH3, and CF3. In certain embodiments, each R 20 is independently selected from F, CH, and CF. In certain embodiments, each R 20 are independently selected from F and CH. In certain embodiments, one or two R 20 is F. In some embodiments, one or more, one to four, one to three, one or two, or one R 20 is CH3.

[0196] In some embodiments, one or two R 20 is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl and C 1~4 Alkylene C 3~6 In some embodiments, one or two R 4 is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~2 Alkylene C 3~6 Cycloalkyl and C 1~2 Alkylene C 3~6 In one embodiment, R 20 wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 20 wherein said cycloalkyl is selected from cyclopropyl and cyclobutyl.

[0197] In one embodiment, R 20wherein the heterocycloalkyl is selected from aziridinyl, oxiranyl, thiiranyl, oxaxylidinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl; and in certain embodiments, R 20 wherein said heterocycloalkyl is selected from azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl and pyrazolidinyl.

[0198] In some embodiments, each R 20 OH and OC 1~4 In one embodiment, each R 20 OH and OC 1~4 In some embodiments, one or two R 20 is selected from OH, OCH, OCF, OCFH, OCHCH, and OCH(CH). In some embodiments, one R 20 is selected from OH, OCH3, OCF3, and OCF2H.

[0199] In one embodiment, R 20 One of them is NR 26 R 27 or C 1~4 Alkylene NR 26 R 27 In one embodiment, R 20 One of them is NR 26 R 27 or C 1~2 Alkylene NR 27 R 28In one embodiment, R 20 One of them is NR 26 R 27 In one embodiment, one R 20 is C 1~2 Alkylene NR 26 R 27 In one embodiment, R 20 The above NR 26 R 27 or C 1~2 Alkylene NR 26 R 27 R in 27 and R 28 are both CH3 or both H. In some embodiments, one R 20 is NR 27 R 28 and R 20 R in 27 and R 28 are both H.

[0200] In one embodiment, R 26 and R 27 is H and C 1~4 In one embodiment, R 26 and R 27 are each independently selected from H, CH, and CF. In some embodiments, R 26 and R 27 One of R is H and the other is CH. In some embodiments, R 26 and R 27 Both are CH3.

[0201] In one embodiment, R 26 and R 27 and together with the atoms between them form a 3- to 7-membered saturated or unsaturated ring, and are N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 In one embodiment, R 26and R 27 together with the nitrogen atom therebetween, form a 3- to 7-membered heterocycle, 1~6 In some embodiments, R forms a ring selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), morpholinyl, and azepanyl, optionally substituted with one or more alkyl. 26 and R 27 and bonded together with the atoms between them, halo and C 1~6 In one embodiment, R 26 and R 27 and bonded together with the atoms between them, halo and C 1~6 This forms aziridinyl, azetidinyl, pyrrolidinyl or piperidinyl optionally substituted by one or more of alkyl.

[0202] In one embodiment, Q′ is C 1~3 In some embodiments, Q' is C 1~3 alkylene, and one or two R 20 In one embodiment, Q' is substituted by C 1~3 alkylene, and one or two R 20 and one R 20 is C 1~4 In one embodiment, Q' is C 1~3 alkylene, and one or two R 20 and one or R 20 is selected from F, CH3, and CF3. In some embodiments, Q' is C 1~3 alkylene, and one or two R 20 and R 20 In one embodiment, Q' is C 1~3alkylene and 1 to 4 R 20 and each R 20 is independently selected from F, Cl, CH3, CF2H, CF3, OCH3, OCF3, and OCF2H. In some embodiments, Q' is C 1~3 alkylene and 1 to 4 R 20 and each R 20 are independently selected from F, CH3 and OCH3.

[0203] In one embodiment, Q′ is C 1~3 alkylene, and R 21 and R 21a In some embodiments, Q' is C1 alkylene or C2 alkylene, and R 21 and R 21a In one embodiment, Q' is optionally disubstituted on one carbon atom by CR 21 R 21a is.

[0204] In one embodiment, R 21 and R 21a and are bonded together with the carbon atoms therebetween to form a 3- to 6-membered saturated or unsaturated ring, 1~4 N, NH, NC optionally substituted by one or more of alkyl 1~6 Forms a ring optionally containing one hetero moiety selected from alkyl, O, S, S(O), and SO2.

[0205] In one embodiment, R 21 and R 21a and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 21 and R 21aand, together with the carbon atoms therebetween, form a 3- to 6-membered cycloalkyl, including halo and C 1~4 In one embodiment, R forms a cycloalkyl ring selected from a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring, and a cyclohexyl ring, optionally substituted with one or more alkyl rings. 21 and R 21a and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 21 and R 21a and R are bonded together with the carbon atoms therebetween to form a cyclopropyl, cyclobutyl, or cyclopentyl ring optionally substituted with one or more of 21 and R 21a and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 21 and R 21a and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 21 and R 21a and together with the carbon atom between them form a cyclopropyl or cyclobutyl ring. 21 and R 21a are bonded together with the carbon atom between them to form a cyclopropyl ring.

[0206] In one embodiment, R 21 and R 21a and halo and C are bonded together with the carbon atoms between them. 1~4In one embodiment, R 21 and R 21a and are joined together with the carbon atoms therebetween to form a 3- to 6-membered heterocycloalkyl ring selected from aziridinyl, oxiranyl, thiiranyl, oxaxylidinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl. 21 and R 21a and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 21 and R 21a and together with the carbon atoms therebetween form a 3- to 5-membered heterocycloalkyl ring, 1~4 In some embodiments, R 1 forms a ring selected from oxiranyl, oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, and tetrahydrothiophenyl, optionally substituted with one or more alkyl. 21 and R 21a and halo and C are bonded together with the carbon atoms between them. 1~4 In one embodiment, R 21 and R 21aand together with the carbon atom between them form an oxetanyl. 21 and R 21a and bond together with the carbon atoms between them. [ka] where "●" represents the point of attachment to Q.

[0207] In certain embodiments, Q′ is one or two R 23 C optionally replaced by 2~4 In certain embodiments, Q′ is one or two R 23 C=C optionally substituted by

[0208] In some embodiments, Q' is selected from C=N or N=C, and R 22 In some embodiments, Q' is C=N or N=C.

[0209] In some embodiments, each R 22 are F, Cl, C 1~4 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 26 R 27 , and C 1~ 6 alkylene NR 26 R 27 In one embodiment, each R 22 are F, Cl, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl, C1~4 Alkylene C 3~6 Heterocycloalkyl, OH, OC 1~4 Alkyl, NR 26 R 27 , and C 1~4 Alkylene NR 26 R 27 are independently selected from

[0210] In some embodiments, each R 22 are F, Cl, OH, C 1~4 Alkyl, OC 1~4 Alkyl, C 1~2 Alkylene NR 26 R 27 and NR 26 R 27 In one embodiment, each R 22 is F, Cl, OH, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, OCH3, OCH2CH3, OCF3, OCF2H, OCH(CH3)2, C 1~2 Alkylene NR 26 R 27 and NR 26 R 27 In one embodiment, each R 22 is F, Cl, OH, CH3, CF2H, CF3, CFH2, OCH3, OCF3, OCF2H, C 1~2 Alkylene NR 26 R 27 and NR 26 R 27 In some embodiments, one or two R 22 is F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H, C 1~2 Alkylene NR 26 R 27 and NR 26 R 27 In some embodiments, one or two R 22 is F, Cl, CH3, CF2H, CF3, OCH3, OCF3, OCF2H, C 1~2 Alkylene NR 26 R 27 and NR 26 R27 are independently selected from

[0211] In some embodiments, each R 22 F and C 1~4 In one embodiment, each R 22 is independently selected from F, Cl, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCHF. In certain embodiments, each R 22 is independently selected from F, Cl, CH, CFH, CF, and CHCFH. In certain embodiments, each R 22 is independently selected from F, Cl, CH, and CF. In certain embodiments, each R 22 is independently selected from F, CH, and CF. In certain embodiments, each R 22 is independently selected from F and CH. In some embodiments, R 22 In some embodiments, one of R is F. In some embodiments, one or more, one to four, one to three, one to two, or one R 22 is CH3. In one embodiment, two R 22 One of them is CH3.

[0212] In some embodiments, one or two R 22 is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl and C 1~4 Alkylene C 3~6 In one embodiment, one R is independently selected from the group consisting of cycloalkyl, cyclohexane, cyclohexane-1, cyclohexane-2, cyclohexane-3, cyclohexane-4, cyclohexane-5, cyclohexane-6, cyclohexane-7, cyclohexane-8, cyclohexane-9, cyclohexane-10, cyclohexane-11, cyclohexane-12, cyclohexane-13, cyclohexane-14, cyclohexane-15, cyclohexane-16, cyclo 22 is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~2 Alkylene C 3~6 Cycloalkyl and C 1~2 Alkylene C 3~6 In one embodiment, R 22wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 22 wherein said cycloalkyl is selected from cyclopropyl and cyclobutyl.

[0213] In one embodiment, R 22 wherein the heterocycloalkyl is selected from aziridinyl, oxiranyl, thiiranyl, oxaxylidinyl, dioxiranyl, azetidinyl, oxetanyl, thietanyl, diazetidinyl, dioxetanyl, dithietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isoxthiolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, piperidinyl, triazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dioxazolyl, dithiazolyl, tetrazolyl, oxatetrazolyl, tetrahydropyranyl, diazinanyl (e.g., piperazinyl), morpholinyl, thiomorpholinyl, dioxanyl, and dithianyl. In certain embodiments, R 23 wherein said heterocycloalkyl is selected from azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl and pyrazolidinyl.

[0214] In some embodiments, each R 22 OH and OC 1~4 In one embodiment, each R 22 OH and OC 1~4 In one embodiment, each R 22 are independently selected from OH, OCH, OCF, OCFH, OCHCH, and OCH(CH). In some embodiments, one R 22 is selected from OH, OCH3, OCF3, and OCF2H.

[0215] In some embodiments, one or two R 22 is NR 26 R27 and C 1~4 Alkylene NR 26 R 27 In some embodiments, one or two R 22 is C 1~4 Alkylene NR 26 R 27 In one embodiment, R 22 One of them is C 1~2 Alkylene NR 26 R 27 In one embodiment, R 22 One of them is NR 26 R 27 In one embodiment, R 22 The above NR 26 R 27 or C 1~2 Alkylene NR 26 R 27 R in 26 and R 27 are both CH3 or both H. In some embodiments, one R 22 is NR 27 R 28 or C 1~4 Alkylene NR 26 R 27 and R 22 R in 26 and R 27 are both H.

[0216] In one embodiment, R 22 R in 26 and R 27 are each independently H and C 1~4 In one embodiment, R 22 R in 26 and R 27 are each independently selected from H, CH, and CF. In some embodiments, R 22 R in 26 and R 27 One of R is H and the other is CH. In some embodiments, R 22 R in 26 and R 27Both are CH3.

[0217] In one embodiment, R 22 R in 26 and R 27 and together with the atoms between them form a 3- to 7-membered saturated or unsaturated ring, and are N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 In one embodiment, R 22 R in 26 and R 27 together with the nitrogen atom therebetween, form a 3- to 7-membered heterocycle, 1~6 In one embodiment, R forms an azetidinyl ring, a diazetidinyl ring, a pyrrolidinyl ring, an imidazolidinyl ring, a pyrazolidinyl ring, a thiazolidinyl ring, an isothiozolidinyl ring, a piperidinyl ring, a diazinanyl (e.g., piperazinyl) ring, a morpholinyl ring, and an azepanyl ring, optionally substituted with one or more of alkyl. 22 R in 26 and R 27 and bonded together with the atoms between them, halo and C 1~6 In one embodiment, R 22 R in 26 and R 27 and bonded together with the atoms between them, halo and C 1~6 This forms aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl, optionally substituted with one or more of alkyl.

[0218] In one embodiment, Q is NR 19 Optionally interrupted C 1~3 In some embodiments, R 19is H and C 1~4 In one embodiment, R 19 is selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In some embodiments, R 19 is selected from H, CH3, CH2CH3 and CH(CH3)2.

[0219] In certain embodiments, Q is C alkylene or C alkylene, and R 21 and R 21a and is disubstituted on one carbon atom by R 21 and R 21a and halo and C are bonded together with the carbon atoms between them. 1~4 In some embodiments, Q is C alkylene or C alkylene, and R 21 and R 21a In one embodiment, Q is disubstituted on one carbon atom by CR 21 R 21a In one embodiment, R 21 and R 21a and C are bonded together with the carbon atom therebetween to form a cyclopropyl ring or a cyclobutyl ring, and halo and C 1~4 Optionally substituted with one or more alkyl.

[0220] In certain embodiments, Q is one or two R 22 C optionally replaced by 2~4 alkenylene, and each R 22 are F, Cl, C 1~4 Alkyl and OC 1~4 In certain embodiments, Q is independently selected from one or two R 22 and each R 22 are F, Cl, C 1~4 Alkyl and OC1~4 In certain embodiments, Q is independently selected from one or two R 22 and each R 22 is independently selected from F, Cl, CH, and OCHOCF, and OCFH. In certain embodiments, Q is selected from one or two R 22 and each R 22 is F and C 1~4 In one embodiment, R 22 is selected from F and CH3. In certain embodiments, Q is C=C substituted by F. In certain embodiments, Q is C=C substituted by Cl. In certain embodiments, Q is C=C substituted by OCH3. In certain embodiments, Q is C=C substituted by CH3. In certain embodiments, Q is C=C substituted by F and CH3.

[0221] In certain embodiments, Q is selected from C=N and N=C, and one or two R 22 and each R 22 are F, Cl, C 1~4 Alkyl, OC 1~4 Alkyl, NR 26 R 27 In some embodiments, Q is selected from C=N and N=C, and one or two R 22 and each R 22 are F, Cl, CH3, OCH3, OCF3OCF2H, NR 26 R 27 In some embodiments, Q is selected from C=N and N=C, and one or two R 22 and each R 22is independently selected from F, Cl, CH, OCH, OCF, and OCFH. In some embodiments, Q is selected from C=N and N=C, and R 22 and R 22 is selected from F and CH. In some embodiments, Q is selected from C=N or N=C, and R 22 and R 22 is selected from cyclopropyl and cyclobutyl. In some embodiments, Q is selected from C=N or N=C, and R 22 and R 22 is F and C 1~4 In some embodiments, Q is selected from C=N or N=C, and one or two R 22 and one R 22 is C 1~2 Alkylene NR 26 R 27 and NR 26 R 27 is selected from.

[0222] In some embodiments, Q is unsubstituted. In some embodiments, Q is one or two R 20 In certain embodiments, Q is substituted with one or two R 20 and R 20 is C 1~4 It is alkyl.

[0223] In one embodiment, Cy 3 is one or two R 28 and one to three R 29 C optionally further replaced by 6~10 In one embodiment, Cy is aryl. 3 is one or two R 28 and one to three R 29In some embodiments, Cy is phenyl optionally further substituted by 3 is one R 28 and one to three R 29 is phenyl optionally further substituted by

[0224] In one embodiment, Cy 3 is one or two R 28 and one to three R 29 C optionally further replaced by 5~10 In one embodiment, Cy is heteroaryl. 3 In the above C 5~10 Heteroaryl is a heteroaryl group consisting of one or two R 28 and one to three R 29 In one embodiment, Cy is selected from pyrrolyl, imidazolyl, oxazolyl, pyrazolyl, or pyridinyl, optionally further substituted by 3 In the above C 5~10 Heteroaryl is a heteroaryl group consisting of one or two R 28 and one to three R 29 is pyridine or pyrazolyl optionally further substituted by

[0225] In one embodiment, Cy 3 is one R 28 and one to three R 29 In one embodiment, Cy 3 is one R 28 and one or two R 29 is optionally further substituted by

[0226] In some embodiments, each R 28 is NR 30 R31 , C 1~4 Alkylene NR 30 R 31 、 C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 heterocycloalkyl, and the latter two groups are independently selected from one or more R 32 is optionally replaced by

[0227] In some embodiments, one R 28 is NR 30 R 31 and R 30 and R 31 are independently H and C 1~4 In one embodiment, R 28 is NR 30 R 31 and R 30 and R 31 , and R 30 and R 31 are each independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 28 is NR 30 R 31 and R 30 and R 31 are each independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 28 is NR 30 R 31 and R 30 and R 31 are independently selected from H, CF, CH, and CHCH. Thus, in some embodiments, R 28 In some embodiments, one of R is selected from NH, N(CH), NH(CH), N(CH)(CHCH), NH(CHCH), and N(CHCH). 28 is selected from NH2, N(CH3)2 and NH(CH3).

[0228] In one embodiment, R 28 One of them is C 1~4 Alkylene NR 30 R 31 and R 30 and R 31 are independently H and C 1~4 In one embodiment, R 28 One of them is C 1~4 Alkylene NR 30 R 31 and R 30 and R 31 are each independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 28 One of them is C 1~4 Alkylene NR 30 R 31 and R 30 and R 31 are each independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 28 One of them is C 1~4 Alkylene NR 30 R 31 and R 30 and R 31 are each independently selected from H, CF, CH, and CHCH. Thus, in one embodiment, R 28 One of R is CHN(CHCH), C(CH)NH, CHN(CH), CHCHN(CH) and CHN(CH). 28 One of the groups is selected from CH2N(CH3)2.

[0229] In one embodiment, R 28 One of them is C 1~4 Alkylene NR 30 R 31 and R 30 and R 31are each independently selected from H and CH. In some embodiments, R 28 One of them is C 1~3 Alkylene 4 Alkylene NR 30 R 31 and R 30 and R 31 are either both H or both CH3.

[0230] In one embodiment, R 30 and R 31 are independently H and C 1~4 In one embodiment, R 30 and R 31 are independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 30 and R 31 are independently selected from H, CF3, and CH3. In certain embodiments, R 30 and R 31 are independently selected from H and CH3.

[0231] In some embodiments, one R 28 is C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 heterocycloalkyl, and one to three R 32 In one embodiment, R 28 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl is a group consisting of one to three R 32In certain embodiments, R is selected from azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidin-2-onyl, azabicyclohexanyl, azabicycloheptanyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, thiepanyl, azabicyclohexanyl, azabicycloheptanyl, oxabicyclohexanyl, and oxabicycloheptanyl, optionally substituted by 28 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl is diazepanyl. In one embodiment, one R 28 is C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 heterocycloalkyl, and R 28 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidin-2-onyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, and dioxanyl; and one to three R 10 In one embodiment, R 28 The above C4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolidin-2-onyl, thiazolidinyl, and isothiazolidinyl; one to three R 32 In one embodiment, R 28 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl is selected from pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, pyrrolidin-2-onyl, and isothiazolidinyl, and one to three R 10 is optionally replaced by

[0232] In one embodiment, R 28 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 A heterocycloalkyl contains at least one N atom. In certain embodiments, R 28 The above C 3~7 Heterocycloalkyl and C 1~4 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl may each have one or two R 32 In one embodiment, R is selected from azetidinyl, pyrrolidinyl, pyrrolidin-2-onyl, azabicyclohexanyl, azabicycloheptanyl, piperidinyl, piperazinyl, and morpholinyl, optionally substituted by 28 The above C 4~6 Heterocycloalkyl and C 1~4 Alkylene C 4~6 C in heterocycloalkyl4~6 Heterocycloalkyl is a heterocyclic group consisting of one or two R 32 and pyrrolidinyl optionally substituted by:

[0233] In some embodiments, one R 28 is one or two R 32 C optionally replaced by 4~6 heterocycloalkyl, and 4~6 Heterocycloalkyl is pyrrolidinyl. In one embodiment, one R 28 is C 4~6 heterocycloalkyl, and 4~6 Heterocycloalkyl is a heterocyclic group consisting of one or two R 32 is optionally replaced by [ka] wherein R is a pyrrolidine selected from 32a is H and R 32 is selected from, and [ka] Cy 1 In one embodiment, the pyrrolidinyl represents a point of covalent attachment to one or two R 32 is optionally replaced by [ka] is selected from, where R 32a is H and R 32 is selected from, and [ka] Cy 1 In one embodiment, R 32a is H. In one embodiment, R32a is R 32 is.

[0234] In one embodiment, R 28 One of them is 1 to 4 R 32 C optionally replaced by 1~6 Alkylene C 3~7 heterocycloalkyl, and 1~6 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl is selected from azetidinyl, pyrrolidinyl, pyrrolidin-2-onyl, piperidinyl, piperazinyl, and morpholinyl. 28 One of them is 1 to 4 R 32 C optionally replaced by 1~3 Alkylene C 4~7 heterocycloalkyl, and 1~6 Alkylene C 3~7 C in heterocycloalkyl 4~7 Heterocycloalkyl is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. Thus, in one embodiment, R 28 One of them is 1 to 4 R 32 C, optionally replaced by 1~3 Alkyleneazetidinyl, C 1~3 Alkylenepyrrolidinyl, C 1~3 Alkylenepiperidinyl, C 1~3 Alkylenepiperazinyl and C 1~3 In one embodiment, R is selected from alkylenemorpholinyl. 28 One of them is 1 to 4 R 32 In one embodiment, R is selected from CH azetidinyl, CH pyrrolidinyl, CH piperidinyl, CH piperazinyl, and CH morpholinyl, optionally substituted by 28 One of them has one or two R 32is optionally replaced by [ka] is selected from, where R 32d is H and R 32 is selected from, and [ka] Cy 1 represents the point of covalent attachment to

[0235] In some embodiments, one R 28 is one or two R 32 C optionally replaced by 1~6 Alkylene C 3~7 heterocycloalkyl, and 1~6 Alkylene C 3~7 C in heterocycloalkyl 3~7 Heterocycloalkyl is pyrrolidinyl. In one embodiment, one R 28 is 1 to 3 R 32 C optionally replaced by 1~4 In one embodiment, one R is alkylenepyrrolidinyl. 28 is C 1~4 Alkylene C 4~6 heterocycloalkyl, and 1~4 Alkylene C 4~6 C in heterocycloalkyl 4~6 Heterocycloalkyl has one to three R 32 and pyrrolidinyl optionally substituted by:

[0236] In some embodiments, one R 28 is 1 to 3 R 32 C optionally replaced by 1~4 alkylenepyrrolidinyl, and wherein at least one R 32is F. In one embodiment, R 28 In the above C 4~6 Heterocycloalkyl is [ka] where [ka] Cy 1 represents the point of covalent attachment to

[0237] In some embodiments, one R 28 is unsubstituted pyrrolidinyl. In one embodiment, one R 28 teeth, [ka] is a pyrrolidinyl selected from [ka] Cy 1 In one embodiment, one R 28 teeth [ka] is selected from, where: [ka] Cy 1 represents the point of covalent attachment to

[0238] In some embodiments, one to three R 29 Ha, Halo, C 1~4 Alkyl, C 3~7 Cycloalkyl, and C 1~4 Alkylene C 3~7 cycloalkyl, and the last four groups are independently selected from 1 to 3 R 32is optionally replaced by

[0239] In some embodiments, one to three R 29 Halo and C 1~4 alkyl. In one embodiment, one to three R 29 are independently selected from F, Cl, CH3, CH2CH3, CH(CH3)2, CH2CH2CH3, CH2CH2CH2CH3, CF2H, CF3, CFH2, CH2CH2F, CH2CF2H, CH2CF3CH2CH2F2H, CH2CH2CH2F2H, and CH(CH3)2. In some embodiments, one to three R 29 are independently selected from F, Cl, CH3, CH2CH3, CH(CH3)2, CF2H, CF3, CFH2, CH2CH2F, CH2CF2H, CH2CF3, CH2CH2F2H, and CH2CH2CH2F2H. In some embodiments, one to three R 29 are independently selected from F, Cl, CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In some embodiments, one to three R 29 are independently selected from F, Cl, CH3, CH2CH3, and CF3. In some embodiments, one to three R 29 are independently F, CH3, or CF3. In some embodiments, one to three R 29 are independently CH3 or CF3. In some embodiments, one to three R 29 is F. In some embodiments, 1 to 3, 1 or 2, or 1 R 29 is CF3.

[0240] In some embodiments, one to three R 29 is C 3~7 Cycloalkyl and C 1~4 Alkylene C 3~7 cycloalkyl; and one to three R 32 In one embodiment, one R 29 is C 1~3 Alkylene C 3~7Cycloalkyl and C 3~7 cycloalkyl; and one or two R 29 In one embodiment, R 29 The above C 1~3 Alkylene C 3~7 Cycloalkyl and C 3~7 C in cycloalkyl 3~7 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]hexanyl, and bicyclo[2.2.1]heptanyl; and one or two R 32 is optionally replaced by

[0241] In one embodiment, Cy 3 is one R 28 and one to three R 29 and R is phenyl or pyridinyl optionally further substituted by 28 is C 1~4 Alkylene NR 30 R 31 In one embodiment, Cy 3 is one R 28 and one to three R 29 and R is phenyl or pyridinyl optionally further substituted by 28 is C 1~2 Alkylene NR 30 R 31 In one embodiment, Cy 3 is one R 28 and one to three R 29 phenyl or pyridinyl optionally further substituted by 28 is CH2NR 30 R 31 In one embodiment, Cy 3 is one R 28 and is substituted by one to three R 29and R 28 is C 1~4 Alkylene NR 30 R 31 In one embodiment, Cy 3 is one R 28 and one to three R 29 and R 28 is C 1~2 Alkylene NR 30 R 31 In one embodiment, Cy 3 is one R 28 and one to three R 29 and R 28 is CH2NR 30 R 31 is.

[0242] In one embodiment, Cy 3 is one R 28 and one to three R 29 and R 28 is one or more R 32 C, optionally replaced by 3~7 Heterocycloalkyl or C 1~4 Alkylene C 3~7 In one embodiment, Cy is heterocycloalkyl. 3 is one R 28 and one to three R 29 and R 28 is one or more R 32 C optionally replaced by 3~7 Heterocycloalkyl or C 1~2 Alkylene C 3~7It is heterocycloalkyl.

[0243] In some embodiments, each R 32 are F, Cl, CN, and C 1~4 Alkyl and NR 33 R 34 In one embodiment, each R 32 is F, C 1~4 Alkyl and NR 33 R 34 In one embodiment, each R 32 F and C 1~4 In one embodiment, each R 32 is independently selected from F and CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In certain embodiments, R 10 At least one of R 32 One of them is NR 33 R 34 is.

[0244] In one embodiment, R 33 and R 34 is H and C 1~4 In one embodiment, R 33 and R 34 are independently selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. 33 and R 34 are independently selected from H, CF3, and CH3. In certain embodiments, R 33 and R 34 are independently selected from H and CH3.

[0245] In one embodiment, Cy 4 is unsubstituted or substituted with one or more R 35 Monocyclic C substituted by 3~7 In one embodiment, Cy is heterocycloalkyl. 4 is 1 to 3 R 12In one embodiment, Cy is substituted with azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, thianyl, piperidinyl, piperazinyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, morpholinyl, dioxanyl, azepanyl, diazepanyl, oxepanyl, or thiepanyl. 4 is 1 to 3 R 35 In one embodiment, Cy is selected from the group consisting of diaxepanyl, 5,6-dihydro-1,2,4-triazinyl, 3,4,5,6-tetrahydro-1,2,4-triazinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl. 4 is 1 to 3 R 35 In one embodiment, Cy is tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, substituted by 4 is 1 to 3 R 35 In one embodiment, Cy is a pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl substituted by 4 is selected from piperidinyl, piperazinyl, and morpholinyl, and Cy 4 is unsubstituted or contains one or two R 35 In one embodiment, Cy is substituted by 4 is piperazinyl, and Cy 4 is unsubstituted or contains one or two R 35 In one embodiment, Cy is substituted by 4 is 1 to 3 R 35 In certain embodiments, R is selected from tetrahydrofuranyl, dihydropyranyl, morpholinyl, and tetrahydropyranyl, each substituted by 35 is 1 to 3 R35 and tetrahydropyranyl substituted by:

[0246] In one embodiment, Cy 4 is an unsubstituted monocyclic C 3~7 It is heterocycloalkyl.

[0247] In one embodiment, Cy 4 is unsubstituted or substituted with one or more R 35 In one embodiment, Cy is a bicyclic heterocycle substituted by 4 is 1 to 3 R 35 In one embodiment, Cy is a bridged, fused, or spiro-fused bicyclic heterocycle substituted by 4 is unsubstituted or contains 1 to 3 R 35 In one embodiment, Cy is a fused bicyclic heterocycle substituted by 4 is a ring in which one or two of the ring carbon atoms are N, NH, or NR depending on the valency requirements of N. 35a is replaced by one to three R 35 C6-C substituted by 10 In one embodiment, Cy is a saturated bicyclic ring. 4 is 1 to 3 R 35 In one embodiment, Cy is a bridged azabicyclohexanyl, a bridged diazabicycloheptanyl, or a bridged diazabicyclooctanyl substituted by 4 is 1 to 3 R 35 is selected from the following structures substituted by: [ka] , where [ka] Cy 3 represents the point of covalent attachment to, and R 35a is H or R 35 is selected from.

[0248] In one embodiment, Cy 4 is 1 to 3 R 35 is selected from the following structures substituted by [ka] where [ka] Cy 3 represents the point of covalent attachment to, and R 35a is H or R 35 is selected from.

[0249] In one embodiment, Cy 4 is selected from tetrahydrofuropyrrolyl, hexapyrazinooxazinyl, hexahydropyrrolopyrazinyl, and hexahydropyrrolodiazepinyl, and Cy 4 is unsubstituted or substituted with one or more R 35 In one embodiment, Cy is substituted by 4 is unsubstituted or substituted with one or more R 35 is replaced by [ka] , is selected from; and where [ka] Cy 1 represents the point of covalent attachment to

[0250] In one embodiment, Cy 4 is an unsubstituted bicyclic heterocycle.

[0251] In some embodiments, each R 35 Halo, =O, OH, C 1~4 Alkyl, C 3~10Cycloalkyl, C 3~10 Heterocycloalkyl, C 1~4 Alkylene C 3~10 Cycloalkyl, C 1~4 Alkylene C 3~10 Heterocycloalkyl, C 1~4 Alkylene OR 36 , C 1~4 Alkylene NR 36 R 37 , O.C. 1~4 Alkylene OR 36 , O.C. 1~4 Alkylene NR 36 R 37 , C(O)R 36 , C(O)C 1~4 Alkylene OR 36 , C(O)C 1~4 Alkylene NR 36 R 37 , C(O)C 1~4 Alkylene OC 1~4 Alkylene NR 36 R 37 , C(O)NR 36 R 37 , CO2R 36 , CO2C 1~4 Alkylene OR 36 , CO2C 1~4 Alkylene OC 1~4 Alkylene NR 36 R 37 , N.R. 36 R 37 , N.R. 38 SO2R 37 , SO2R 36 and SO2NR 36 R 37 are independently selected from

[0252] In one embodiment, R 36 is H, C 1~4 Alkyl, C 3~6 Cycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl and C 1~4 Alkylene C 3~6 In one embodiment, R36 is H, CH3, CH2CH3, CH(CH3)2, CF3, CFH2, CH2CF2H, CH2CF3, C 1~4 Alkylene C 3~6 Cycloalkyl and C 1~4 Alkylene C 3~6 heterocycloalkyl.

[0253] In one embodiment, R 37 is H and C 1~4 In one embodiment, R 37 is selected from H, CH, and CHCH; in some embodiments, R 37 is selected from H, CH, CHCH, CFH, CF, CFH, CHCFH, and CHCF. In some embodiments, R 37 is selected from CF2H, CH3, and CF3. In some embodiments, R 37 is selected from H, CH, CHCH, and CF. In some embodiments, R 37 is selected from CH3 and CF3. In some embodiments, R 37 is H.

[0254] In one embodiment, R 36 and R 37 and bond together with the atoms between them, N, NR 16 , O, S, S(O), and SO. 36 and R 37 and, together with the atoms therebetween, form a 4- to 6-membered heterocycle selected from azetidinyl, diazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, isothiozolidinyl, piperidinyl, diazinanyl (e.g., piperazinyl), and morpholinyl. 36 and R 37 and are bonded together with the atom between them to form aziridinyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0255] In some embodiments, one R 35 is CO2R 36 In one embodiment, R 35 is H, C 1~4 alkyl. Thus, in one embodiment, one R 35 is CO2R 36 and R 36 is H, C 1~4 alkyl. Thus, in one embodiment, one R 35 is CO2C 1~6 In one embodiment, R 13 is selected from H, CH, CHCH, CH(CH), CF, CFH, CHCFH, and CHCF. Thus, in one embodiment, one R 35 is selected from CO2CCH3, CO2CH2CH3, CO2CF2H, CO2CF3, CO2CFH2, CO2CH2CF2H, CO2CH2CF3, CO2CH2CH2F2H, CO2CH2CH2CH2F2H, CO2CH(CH3)2, and CO2CH2CH(CH3)2. 35 is CO2CCH3.

[0256] In some embodiments, one R 35 is C(O)R 36 In one embodiment, R 35 is H, C 1~4 alkyl. Thus, in one embodiment, one R 35 is C(O)C 1~6 In one embodiment, R 35 is selected from H, CH, CHCH, CH(CH), CF, CFH, CHCFH, and CHCF. Thus, in one embodiment, one R 35 is selected from COCCH3, COCH2CH3, COCF2H, COCF3, COCFH2, COCH2CF2H, COCH2CF3, COCH2CH2F2H, COCH2CH2CH2F2H, COCH(CH3)2, and COCH2CH(CH3)2. 35is COCH3.

[0257] In some embodiments, each R 35 are independently selected from the substituents listed below: [ka]

[0258] In some embodiments, one or two R 35 is C 3~6 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~6 Cycloalkyl and C 1~4 Alkylene C 3~6 In one embodiment, one R is independently selected from the group consisting of cycloalkyl, cyclohexane, cyclohexane-1, cyclohexane-2, cyclohexane-3, cyclohexane-4, cyclohexane-5, cyclohexane-6, cyclohexane-7, cyclohexane-8, cyclohexane-9, cyclohexane-10, cyclohexane-11, cyclohexane-12, cyclohexane-13, cyclohexane-14, cyclohexane-15, cyclohexane-16, cyclo 35 is C 3~5 Cycloalkyl, C 3~6 Heterocycloalkyl, C 1~4 Alkylene C 3~5 Cycloalkyl and C 1~4 Alkylene C 3~5 heterocycloalkyl.

[0259] In one embodiment, R 35 In the above C 3~6 Cycloalkyl is selected from cyclopropyl and cyclobutyl.

[0260] In some embodiments, one R 35 is selected from cyclopropyl, cyclobutyl, and cyclopentyl. 35 is independently selected from cyclopropyl and cyclobutyl.

[0261] In some embodiments, one R 35 is C 1~4 Alkylenecyclopropyl, C 1~4 C selected from alkylenecyclobutyl 1~4 Alkylene C 3~5 In one embodiment, one R35 is C 1~4 Alkylenecyclopropyl and C 1~4 In one embodiment, one R is selected from alkylene, C3 cyclobutyl. 35 is C 1~3 In one embodiment, one R is alkylenecyclopropyl. 12 teeth, [ka] C selected from 1~3 It is alkylenecyclopropyl.

[0262] In some embodiments, one R 35 is selected from oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl. 35 is C 1~3 Alkyleneoxetanyl, C 1~3 Alkylenetetrahydrofuranyl and C 1~3 alkylenetetrahydropyranyl.

[0263] In some embodiments, one R 35 is selected from CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, CH2CH2CF2H, CH2CH2CH2CF2H, and CH2CF3. In one embodiment, one R 35 is selected from CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In certain embodiments, one R 35 is selected from CH3, CH2CH3, and CH(CH3)2. In certain embodiments, one R21 is selected from CH2CH3 and CH(CH3)2. In certain embodiments, one R 35 is selected from CH2CH3 and CH(CH3)2. In some embodiments, one R 35 is selected from CF2H, CH2CF2H, CH2CH2CF2H, and CH2CH2CH2CF2H. I.

[0264] In some embodiments, each R 35are independently selected from the substituents listed below: [ka]

[0265] In one embodiment, Cy 4 is 1 to 3 R 35 In one embodiment, Cy is substituted by 4 is one or two R 35 In one embodiment, Cy is substituted by 4 is one R 35 has been replaced by

[0266] In one embodiment, Cy 4 is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and R 35 is CH3, CH2CH3, CF2H, CF3, CFH2, CH2CF2H, and CH2CF3. In one embodiment, Cy 4 is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and R 12 is CH2CH3 or CH(CH3)2.

[0267] In one embodiment, Cy 4 is pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, and R 35 is C 1~3 It is alkylenecyclopropyl.

[0268] In one embodiment, R 38 and R 39 is H and C 1~4 In one embodiment, R 38 and R 39 are independently selected from H, CH3, CH2CH3, and CH(CH3)2.

[0269] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-A), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] Here, Q' and X 5 , X 6 , X 7 , X 8 , X 9 , R 28 , R 29 and Cy 3 is as defined in formula (II); and r is an integer selected from 0 to 3; and s is an integer selected from 1 and 2; wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

[0270] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-B), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] where X 4 , X 5 , X 6 , R 4c , R 22 , Cy 3 and Cy 4 is as defined in formula (II); and t is an integer selected from 0 to 2, wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

[0271] In certain embodiments, the compound of Formula (II) is a compound of Formula (II-C) or (II-D), or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [ka] where X4 , X 5 , X 6 , R 22 , Cy 3 and Cy 4 is as defined in formula (II); and u is an integer selected from 0 and 1; wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

[0272] In one embodiment, Cy 4 is an unsubstituted monocyclic C 3~7 and the compound of formula (II) is a compound of formula II-(E) or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof, [ka] where X 4 , X 5 , X 6 , R 22 and Cy 3 is as defined in formula (II); and Cy 4 is an unsubstituted monocyclic C 3~7 is heterocycloalkyl; wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

[0273] Thus, the present application further encompasses compounds of formula (II) or pharmaceutically acceptable salts, solvates, and / or prodrugs thereof, [ka] where: X 4 N and CR 17 Selected from; X 5 and X 6 are independently N and CR 18Selected from; Q' is C 1~4 Alkylene is O, S, S(O), SO and NR 19 and / or one or more R 20 and / or on one carbon R 21 and R 21a optionally disubstituted by C 1~4 alkylene, with the proviso that when Q contains said hetero moiety, said hetero moiety is separated from the ring amide NH by other than methylene; or Q' is one or more R 22 C optionally replaced by 2~4 is alkenylene; or Q' is R 22 C=N or N=C optionally substituted by R 17 is H, halo, OR 23 , N.R. 24 R 25 , C 1~6 Alkylene NR 24 R 25 and C 1~6 alkyl; R 18 H, halo and C 1~6 alkyl; R 19 is H and C 1~6 alkyl; Each R 20 =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 26 R 27 and C 1~6Alkylene NR 26 R 27 are independently selected from; R 21 and R 21a and together with the carbon atoms between them form a 3- to 6-membered saturated or unsaturated ring, which may be N, NH, NC 1~6 Optionally containing one hetero moiety selected from alkyl, O, S, S(O), and SO2, and halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Each R 22 Ha, 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 26 R 27 and C 1~6 Alkylene NR 26 R 27 are independently selected from; R 24 , R 25 , R 26 and R 27 are independently H and C 1~6 alkyl, or R 24 and R 25 , or R 26 and R 27 means, when bonded together with the atoms between them, a 3- to 7-membered saturated or unsaturated ring, which is N, NH, NC 1~6 Optionally containing one additional hetero moiety selected from alkyl, O, S, S(O), and SO2, and also halo and C 1~6 forming a ring optionally substituted with one or more alkyl; Cy 3 is one or two R 28 and is substituted by one to three R29 C optionally further replaced by 6~10 Aryl or C 5~10 is heteroaryl; Each R 28 is NR 30 R 31 , C 1~6 Alkylene NR 30 R 31 、 C 3~7 Heterocycloalkyl and C 1~6 Alkylene C 3~7 heterocycloalkyl, and the latter two groups are independently selected from one or more R 32 optionally replaced by; Each R 29 Ha, Halo, C 1~6 Alkyl, C 3~7 Cycloalkyl, and C 1~6 Alkylene C 3~7 cycloalkyl, and the latter two groups are independently selected from one or more R 32 optionally replaced by; R 30 and R 31 are independently H and C 1~6 alkyl; Each R 32 Ha, Halo, C 1~6 Alkyl, CN and NR 33 R 34 are independently selected from; R 33 and R 34 are independently H and C 1~6 alkyl; Cy 4 is an unsubstituted monocyclic C 3~7 is heterocycloalkyl; and wherein all available hydrogen atoms are optionally replaced by fluorine atoms.

[0274] In certain embodiments, the compound of Formula I is selected from the compounds listed in Table 1-A or a pharmaceutically acceptable salt, solvate, and / or prodrug thereof: [Table 1-10] [Table 1-11]

[0275] In certain embodiments of the present application, the compounds described herein may have at least one asymmetric center. When a compound has two or more asymmetric centers, the compound may exist as diastereomers. It should be understood that all such isomers and mixtures thereof in any ratio are encompassed within the scope of the present application. While the stereochemistry of a compound may be as shown in a given compound listed in the present disclosure, it should be further understood that the compound may contain a certain amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of the same compound of the present application having an alternative stereochemistry. Any optical isomer as an isolated, pure, or partially purified optical isomer, or a racemic mixture thereof, is intended to be encompassed within the scope of the present application.

[0276] The compounds of the present application may exist in different tautomeric forms, and it is intended that any tautomers that the compounds form, as well as mixtures thereof, are included within the scope of the present application.

[0277] The compounds of the present application may exist in different tautomeric forms, and any tautomeric forms that the compounds form, or mixtures thereof, are intended to be included within the scope of the present application.

[0278] In one embodiment, the pharmaceutically acceptable salt is an acid addition salt or a base addition salt, and the selection of an appropriate salt is within the skill of the art (see, e.g., SM Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19).

[0279] Acid addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic acid addition salts of any basic compound. Basic compounds that form acid addition salts include, for example, 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 acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. 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- or di-acid salts are formed, and such salts may exist in hydrated, solvated, or substantially anhydrous form. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents and generally exhibit higher melting points than their free base forms. Criteria for selecting an appropriate salt will be known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as, but not limited to, oxalates, may be used, for example, in the isolation of compounds of the present application for experimental use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0280] Base addition salts suitable for or compatible with the treatment of a subject include any non-toxic organic or inorganic base addition salts of any acidic compound. Acidic compounds that form base addition salts include, for example, 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, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.For example, if there is an ester functional group in another part of the compound, it may be useful to select an appropriate salt to prevent the ester functional group from being hydrolyzed.The criteria for selecting an appropriate salt will be known to those skilled in the art.

[0281] Solvates of the compounds of the present application include, for example, those formed with pharmaceutically acceptable solvents, such as water (the resulting solvates are called hydrates), ethanol, and the like.

[0282] Prodrugs of the compounds of the present application may be, for example, conventional esters formed with available hydroxy, thiol, amino, or carboxyl groups. Some common esters that have been utilized as prodrugs are phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates, and amino acid esters.

[0283] The compounds of the present application include compounds with alternative isotopes, including radioactive and non-radioactive isotopes, of any of the atoms. For example, in some embodiments, the compounds of the present application include compounds in which one or more available hydrogen atoms are replaced with deuterium. In some embodiments, the compounds of the present application include compounds in which one or more available carbon atoms are replaced with deuterium. 13 C-substituted compounds are also included.

[0284] The compounds of the present application are suitably formulated into compositions using one or more carriers in a conventional manner.Therefore, the present application also encompasses compositions comprising one or more compounds of the present application and a carrier.The compounds of the present application are suitably formulated into pharmaceutical compositions for administration to a subject in a biologically compatible form suitable for in vivo administration.Therefore, the present application also encompasses pharmaceutical compositions comprising one or more compounds of the present application and a pharmaceutically acceptable carrier.

[0285] Although the compounds of the present application, including their salts and / or solvates, are suitably used alone, they will generally be administered in the form of a composition comprising one or more compounds of the present application (active ingredients) in association with an acceptable carrier. Depending on the mode of administration, the composition will contain from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight, of the active ingredient, and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of an acceptable carrier. All weight percentages are based on the total composition.

[0286] The compounds of the present application may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. For example, the compounds of the present application may be administered, for example, orally, parenterally, bucally, sublingually, nasally, rectally, by patch, pump, or transdermal administration, and the pharmaceutical composition may be formulated accordingly. Administration may also be via a pump for periodic or continuous delivery. Conventional procedures and ingredients for the selection and preparation of appropriate compositions are described, for example, in Remington's Pharmaceutical Sciences (2000 - 20th edition) and The United States Pharmacopeia: The National Formulary, published in 1999 (USP 24 NF19).

[0287] Parenteral administration includes intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) modes of administration. Parenteral administration may also be by continuous infusion over a selected period of time.

[0288] Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.

[0289] The compounds of the present application may be administered orally, for example, with an inert diluent or an assimilable edible carrier, or enclosed in hard or soft shell gelatin capsules, or compressed into tablets, or incorporated directly with food in the diet. For oral therapeutic administration, the compounds may be incorporated with a formulation excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, caplets, pellets, granules, lozenges, chewing gum, powders, syrups, elixirs, wafers, aqueous solutions, aqueous suspensions, etc. In the case of tablets, carriers used include lactose, corn starch, sodium citrate, and salts of phosphoric acid. Pharmaceutically acceptable formulation additives include binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); 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 by methods well known in the art. For tablets, capsules, caplets, pellets, or granules for oral administration, a pH-sensitive enteric coating, such as Eudragits®, designed to control the release of the active ingredient, is 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- or timed-release, controlled-release (CR), or continuous-release (CR or Contin) formulations, such as coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., agglomerates of molecular sieve-type particles), or bundles of fine hollow permeable fibers, or chopped hollow permeable fibers assembled or held together in a fibrous packet. Timed-release compositions may also be formulated, for example, as liposomes or formulations in which the active compound is protected by a differentially degradable coating (e.g., by microencapsulation, multilayer coating, etc.). Liposomal 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, useful carriers or diluents include lactose and dried cornstarch.

[0290] Liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or may be conveniently presented as a dry product for constitution with water or other suitable vehicle before use. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present application are suitably suspended or dissolved in an oily phase combined with an emulsifying and / or suspending agent. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Such liquid preparations for oral administration are prepared in a conventional manner using pharmaceutically acceptable additives. Pharmaceutically acceptable additives include, for example, suspending agents (e.g., sorbitol syrup, methylcellulose, or edible hydrogenated fats); emulsifiers (e.g., lecithin or acacia); non-aqueous 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 glycols.

[0291] For example, for the preparation of injectable products, the compounds of the present application can be lyophilized and the resulting lyophilizates used.

[0292] The compounds of the present application may be administered parenterally. Solutions of the compounds of the present application in water, suitably mixed with a surfactant, such as hydroxypropylcellulose, can be prepared. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof (with or without alcohol), and in oils. Under ordinary storage and use conditions, these preparations contain a preservative to prevent the growth of microorganisms. Those skilled in the art know how to prepare suitable formulations. For parenteral administration, sterile solutions of the compounds of the present application are usually prepared, and the pH of the solution is suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled so that the preparation is isotonic. For ocular administration, ointments or instillable liquids may be delivered using ocular delivery systems known in the art, such as applicators or droppers. Such compositions may contain mucosal mimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropylmethylcellulose, or polyvinyl alcohol, preservatives such as sorbic acid, EDTA, or benzyl chromium chloride, as well as conventional amounts of diluents or carriers. For pulmonary administration, the diluent or carrier will be selected to be suitable to allow the formation of an aerosol.

[0293] The compounds of the present application may be formulated for parenteral administration by injection, including conventional catheterization techniques or infusion. Formulations for injection may be presented, for example, in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as sterile suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. In all cases, the form must be sterile and fluid to the extent that easy syringability exists. Alternatively, the compounds of the present application are preferably in sterile powder form for reconstitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

[0294] Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels, and powders.

[0295] For intranasal or inhalation administration, the compounds are conveniently delivered in the form of a solution, dry powder formulation, or suspension from a pump spray container that is squeezed or pumped by the patient, or as an aerosol spray from a pressurized container or nebulizer. Aerosol formulations typically contain a solution or fine suspension of the active compound in a physiologically acceptable aqueous or non-aqueous solvent, and are usually provided as single-dose or multi-dose formulations in a sterile form in a sealed container. The container may take the form of a cartridge or refill for use with an atomizing 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. When the dosage 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 fluorochlorohydrocarbon. Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkanes, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit is suitably determined by providing a valve to dispense a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing, for example, a powder mix of the compound of the present application and a suitable powder base, such as lactose or starch. The aerosol dosage form may also take the form of a pump-atomizer.

[0296] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastilles, wherein 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.

[0297] The compounds of the present application in suppository form are useful for vaginal, urethral, ​​and rectal administration. Such suppositories are generally composed of a mixture of materials that are solid at room temperature (RT) but melt at body temperature. Materials commonly used to make such vehicles include, but are not limited to, cocoa butter (also known as cacao butter), glycerinated gelatin, other glycerides, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol. For further description of suppository dosage forms, see, for example, Remington's Pharmaceutical Sciences, 16th Ed., Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0298] The compounds of the present application may be conjugated with soluble polymers as targetable drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropylmethacrylamide-phenol, polyhydroxy-ethylaspartamide-phenol, or polyethylene oxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds of the present application may be conjugated to biodegradable polymers useful for achieving controlled drug release, such as polylactic acid, polyglycolic acid, copolymers of polylactic acid and polyglycolic acid, poly-ε-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.

[0299] In some embodiments, the compounds of the present application may be coupled with viral, non-viral, or other vectors. Viral vectors can include retroviruses, lentiviruses, adenoviruses, herpes viruses, poxviruses, alphaviruses, vaccinia viruses, or adeno-associated viruses. Non-viral vectors can include nanoparticles, cationic lipids, cationic polymers, metal nanoparticles, nanorods, liposomes, micelles, microbubbles, cell-penetrating peptides, or lipospheres. Nanoparticles can include silica, lipids, carbohydrates, or other pharmaceutically acceptable polymers.

[0300] In certain embodiments, depending on the mode of administration, the pharmaceutical composition comprises from about 0.05% to about 99% by weight, or from about 0.10% to about 70% by weight of the active ingredient (one or more compounds of the present application), and from about 1% to about 99.95% by weight, or from about 30% to about 99.90% by weight of one or more pharmaceutically acceptable carriers, all weight percentages being based on the total composition.

[0301] In some embodiments, the compounds of the present application are administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or together in a single unit dosage form. Thus, the present application provides a single unit dosage form comprising one or more compounds of the present application (e.g., a compound of Formula (I)), an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0302] For clarity, in the above, the term "compound" also encompasses embodiments in which one or more compounds are referred to.

[0303] III. Methods and Uses of the Present Application The compounds of the present application have been shown to be capable of inhibiting HPK1 activity. In one embodiment, the HPK1 is human HPK1 (see, e.g., Hu, MC et al.; Genes Dev. 10 (1): 2251-2264, 1996).

[0304] Accordingly, the present application also includes a method for inhibiting HPK1 in a cell in a biological sample or in a patient, comprising administering to the cell an effective amount of one or more compounds of the present application. The present application also includes the use of one or more compounds of the present application for inhibiting HPK1 in a cell, as well as the use of one or more compounds of the present application for the preparation of a medicament for inhibiting HPK1 in a cell. The present application further includes one or more compounds of the present application for use in inhibiting HPK1.

[0305] Because the compounds of the present application have been shown to be capable of inhibiting HPK1, the compounds of the present application are useful for treating diseases, disorders, or conditions by inhibiting HPK1. Accordingly, the compounds of the present application are useful as pharmaceuticals. Accordingly, the present application encompasses the compounds of the present application for use as pharmaceuticals.

[0306] The present application also includes methods for treating a disease, disorder, or condition treatable by inhibiting HPK1, comprising administering to a subject in need of treatment a therapeutically effective amount of one or more compounds of the present application.

[0307] The present application also encompasses the use of one or more compounds of the present application for the treatment of a disease, disorder, or condition treatable by inhibiting HPK1, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of a disease, disorder, or condition treatable by inhibiting HPK1. The present application further encompasses one or more compounds of the present application for use in the treatment of a disease, disorder, or condition treatable by inhibiting HPK1.

[0308] In one embodiment, the disease, disorder, or condition treatable by inhibiting HPK1 is a neoplastic disorder. Accordingly, the present application also encompasses a method for treating a neoplastic disorder, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need of treatment. The present application also encompasses the use of one or more compounds of the present application for treating a neoplastic disorder, as well as the use of one or more compounds of the present application for preparing a medicament for treating a neoplastic disorder. The present application further encompasses one or more compounds of the present application for use in treating a neoplastic disorder. In one embodiment, the treatment is in an amount effective to alleviate at least one symptom of the neoplastic disorder, particularly, for example, reducing cell proliferation or reducing tumor burden, in a subject in need of such treatment.

[0309] The compounds of the present application have been demonstrated to inhibit HPK1, and thus inhibit cytokine release in immune-derived cells (e.g., Jurkat T cells). Accordingly, in certain other embodiments of the present application, the disease, disorder, or condition treatable by inhibiting HPK1 is cancer. Accordingly, the present application also encompasses a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application. The present application also encompasses the use of one or more compounds of the present application for the treatment of cancer, as well as the use of one or more compounds of the present application for the preparation of a medicament for the treatment of cancer. The application further encompasses one or more compounds of the present application for use in treating cancer. In certain embodiments, the compound is administered for the prevention of cancer in a subject predisposed to cancer, e.g., a mammal predisposed to cancer.

[0310] In one embodiment, the cancer is selected from hematological cancer, breast cancer, ovarian cancer, lung cancer, melanoma, colon cancer, and glioblastoma.

[0311] In some embodiments, the disease, disorder, or condition treatable by inhibiting HPK1 is a disease, disorder, or condition associated with unregulated and / or abnormal cellular activity that is directly or indirectly affected by inhibiting HPK1. In certain other embodiments, the unregulated and / or abnormal cellular activity that is directly or indirectly affected by inhibiting HPK1 is proliferative activity in a cell. Accordingly, the present application also encompasses a method of inhibiting proliferative activity in a cell, comprising administering to a cell an effective amount of one or more compounds of the present application. The present application also encompasses the use of one or more compounds of the present application for inhibiting proliferative activity in a cell, as well as the use of one or more compounds of the present application for the preparation of a medicament for inhibiting proliferative activity in a cell. The present application further encompasses one or more compounds of the present application for use in inhibiting proliferative activity in a cell by boosting immune cell function through HPK1 inhibition.

[0312] The present application also includes a method for inhibiting unregulated and / or abnormal cellular activity that is affected directly or indirectly by inhibiting HPK1 in a cell in a biological sample or in a subject, comprising administering to the cell an effective amount of one or more compounds of the present application. The present application also includes the use of one or more compounds of the present application for inhibiting unregulated and / or abnormal cellular activity that is affected directly or indirectly by inhibiting HPK1 in a cell, as well as the use of one or more compounds of the present application for the preparation of a medicament for inhibiting unregulated and / or abnormal cellular activity that is affected directly or indirectly by inhibiting HPK1 in a cell. The present application further includes one or more compounds of the present application for use in inhibiting unregulated and / or abnormal cellular activity that is affected directly or indirectly by inhibiting HPK1 in a cell.

[0313] The present 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 a therapeutically effective amount of one or more compounds of the present application in combination with other known agents useful for treating a disease, disorder, or condition treatable by inhibiting HPK1. The present application also includes the use of one or more compounds of the present 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, as well as the use of one or more compounds of the present 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 present application further includes one or more compounds of the present 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 treatable by inhibiting HPK1 is cancer.

[0314] 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, hi certain other embodiments, the additional cancer therapies are selected from radiation therapy, chemotherapy, targeted therapies such as antibody therapy, and small molecule tyrosine kinase inhibitor therapy, immunotherapy, hormonal therapy, and anti-angiogenic therapy, etc.

[0315] When used in combination with other agents or therapies useful for treating a disease, disorder, or condition by inhibiting HPK1, it is one embodiment for the compounds of the present application to be administered contemporaneously with those agents or therapies. In the present disclosure, "concurrent administration" of two substances or therapies to a subject means providing each of the two substances or therapies so that they are active in the individual at the same time. The exact details of administration will depend on the pharmacokinetics of the two substances or therapies in the presence of each other, but may include administering the two substances or therapies within a few hours of each other, or even administering one substance or treatment within 24 hours of the other, provided the pharmacokinetics are suitable. Designing an appropriate dosing regimen is routine for those skilled in the art. In certain embodiments, the two substances or therapies are administered substantially simultaneously, i.e., within minutes of each other, or, in the case of administration of two substances, in a single composition. It is a further embodiment of the present application that a combination of agents or therapies is administered non-concurrently.

[0316] In some embodiments, the subject is a mammal, hi some embodiments, the subject is a human.

[0317] In the context of treating a disease, disorder, or condition treatable by inhibiting HPK1, an effective amount is, for example, an amount that inhibits HPK1 compared to the inhibition occurring when one or more compounds are not administered. An effective amount can vary depending on factors such as the disease state, age, sex, and / or weight of the subject. The amount of a given compound that corresponds to an effective amount 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 subject being treated, but can nevertheless be routinely determined by one of ordinary skill in the art. An effective amount is one that, after treatment with that amount, is manifested as an improvement or reduction in disease symptoms. When the disease is cancer, an effective amount can cause a reduction in the number, growth rate, size, and / or distribution of tumors.

[0318] The dosage of the compounds of the present application will vary depending on many factors, including, for example, the pharmacokinetic properties of the compound, the mode of administration, the recipient's age, health, and weight, the nature and severity of symptoms, the frequency of treatment, and the type of concurrent treatment (if any), as well as the rate of clearance of the compound in the treated subject. One of skill in the art will be able to determine appropriate dosages based on the above factors. The compounds of the present application may be initially administered at an appropriate dosage, which may be adjusted as necessary depending on clinical response. Dosages are generally selected to maintain serum levels of the compounds of the present application between about 0.01 μg / cc and about 1000 μg / cc, or between about 0.1 μg / cc and about 100 μg / cc. Typically, the oral dosage of one or more compounds of the present application for an adult ranges from about 1 mg to about 1000 mg per day, preferably from about 1 mg to about 500 mg per day, and more preferably from about 1 mg to about 200 mg per day. For parenteral administration, typical dosages are about 0.001 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. For oral administration, typical dosages are about 0.001 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, about 0.01 mg / kg to about 1 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. When administered in suppository form, a typical amount is about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg. In some embodiments of the present application, the composition is formulated for oral administration, and the compound is suitably 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 active ingredient per tablet.The compounds of the present application may be administered in a once-daily, once-weekly, or once-monthly dose, or the total daily dose may be divided into two, three, or four doses per day.

[0319] In some embodiments, the compound is administered at least once a week. However, in other embodiments, the compound is administered to a subject about once every two weeks, about once every three weeks, or about once a month. In other embodiments, the compound is administered about once a week to about once a day. In other embodiments, the compound is administered once, twice, three times, four times, five times, 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, and / or a combination thereof. It will also be understood that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment regimen. Modifications in dosage may occur and be evident using standard diagnostic assays known in the art. In some cases, chronic administration may be necessary. For example, the compound is administered to a subject in an amount and for a period of time sufficient to treat the subject.

[0320] IV. Methods of Preparing the Compounds of the Present Application The compounds of the present application can be prepared by a variety of synthetic processes. The selection of certain structural features and / or substituents may influence the selection of one process over another. Selecting a particular process for preparing a given compound of Formula (I) is within the scope of one of ordinary skill in the art. Some starting materials for preparing the compounds of the present application are available from commercial chemical suppliers. Other starting materials, such as those described below, are 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 the present application, all variables are as defined in Formula (I) unless otherwise specified.

[0321] Compounds of formula (I) can generally be prepared by the processes depicted in the following schemes. In the structural formulas depicted below, unless otherwise noted, the variables are as defined in formula (I). Those skilled in the art will recognize that many of the reactions depicted in the schemes below are oxygen and water sensitive and will know to conduct the reactions under an anhydrous, inert atmosphere, if necessary. Reaction temperatures and reaction times are given for illustrative purposes only and may be varied to optimize yields, as will be understood by those skilled in the art.

[0322] Thus, in certain embodiments, compounds of formula (I) are prepared as shown in Schemes 1-6.

[0323] In one embodiment, as shown in Scheme 1, a compound of Formula (I) is prepared by coupling a boronic acid or boronic ester of a compound of Formula (A) with a dihalogenated compound of Formula (B) to form a monohalogenated intermediate compound of Formula (C). The intermediate compound of Formula (C) can then be coupled with a boronic acid or boronic ester intermediate compound of Formula (D) to form a compound of Formula (I). In one embodiment, Hal 1 and Hal 2 are different halogens selected to have different reactivities in coupling reactions as known to those skilled in the art. In certain embodiments, Hal 1 and Hal 2 are Cl and Br, respectively. In another embodiment, Hal 1 and Hal 2 are Cl and I, respectively. In some embodiments, R a , R b , R c and R d are all H. In one embodiment, R a and R b together or R c and R d together form a cycloalkyl ring. 1 、 X 2 , X3 , X 4 , X 5 , Cy 1 and Cy 2 is as defined in Formula (I). In certain 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]

[0324] In a further embodiment, as shown in Scheme 2, a compound of Formula (I) is synthesized by first coupling a boronic acid or boronic ester intermediate compound of Formula (D) with a dihalogenated intermediate compound of Formula (B) using a coupling reaction to form a monohalogenated intermediate compound of Formula (E). The intermediate compound of Formula (E) can then be reacted with an appropriate boronic acid or boronic ester intermediate compound of Formula (A), thereby forming a compound of Formula (I). In certain embodiments, Hal 1 and Hal 2 are different halogens selected to have different reactivities in coupling reactions as known to those skilled in the art. In certain embodiments, Hal 1 and Hal 2 are Cl and Br, respectively. In another embodiment, Hal 1 and Hal 2 are Cl and I, respectively. In some embodiments, R a , R b , R c and R d are all H. In one embodiment, R a and R b together or R c and R d together form a cycloalkyl ring. 1 , X 2 , X 3 , X 4 , X 5, Cy 1 and Cy 2 is as defined in Formula I. In certain 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]

[0325] In one embodiment shown in Scheme 3, X 2 or X 3 is N or CR 2 and X 4 、 X 5 , R 2 is as defined in formula I. Compounds of formula (I) can be prepared by reacting a boronic acid or boronic ester intermediate (H) with Hal 3 The boronic acid or ester compound of formula (H) can then be synthesized by coupling reaction with the boronic acid or ester compound of formula (H). 4 is treated with a compound of formula (G) where is halo to form a tricyclic intermediate compound of formula (J). The intermediate compound of formula (J) is then halogenated under standard conditions to form the tricyclic intermediate compound of formula (J). 2 is halo, which can be reacted with an intermediate compound of formula (D), thereby forming a compound of formula (I). 2 , Hal 3 and Hal 4 Each R is a halogen selected to work under specific coupling conditions that would be known to one of skill in the art. c , R d , R e and R f are all H. In one embodiment, R c and R d together or R e and R f together form a cycloalkyl ring.1 , X 2 , X 3 , X 4 , X 5 , Cy 1 and Cy 2 is as defined in Formula I. In certain embodiments, the coupling reaction is 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 certain embodiments, the halogenation conditions include a halogenating reagent, such as N-bromosuccinamide. [ka]

[0326] In one embodiment, as shown in Scheme 4, the intermediate compound of formula (E) in Scheme 2 is synthesized by borylation of an intermediate compound of formula (B) to give an intermediate compound of formula (K), which is subsequently reacted with a halogenated intermediate compound of formula (L) in a coupling reaction to form the intermediate compound of formula (E). 1 and Hal 2 are different halogens selected to have different reactivities in coupling reactions as known to those skilled in the art. In certain embodiments, Hal 1 and Hal 2 are Cl and Br, respectively. 1 and Hal 2 are Cl and I, respectively. In some embodiments, Hal 5 is any suitable halogen. In some embodiments, R g and R h are both H. In one embodiment, R g and R h together form a cycloalkyl ring, 4 , X 5 , Cy 1 and Cy 2is as defined in Formula I. In certain embodiments, the coupling reaction is 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 borylation comprises a borylation agent in the presence of a catalyst, such as a palladium catalyst in an inert solvent. [ka]

[0327] In one embodiment, Cy 1 is phenyl and R 7 but [ka] where R 10a is H and R as defined in formula (I) 10 A compound of formula (I) selected from is prepared by coupling a boronic acid or boronic ester compound of formula (M) with a halogenated compound of formula (N) under suitable conditions, such as Suzuki coupling conditions, to form a compound of formula (I). In one embodiment, R 10a is an amino protecting group, e.g., tert-butyloxycarbonyl (Boc), which can be removed under appropriate conditions, e.g., with a strong acid such as trifluoroacetic acid, to give R 10a is H. In one embodiment, Hal 6 is Br. In one embodiment, R i and R j are both H. In one embodiment, R i and R j together form a cycloalkyl ring. 1 , X 2 , X 3 , Cy 1 and Cy 2 is as defined in Formula I. In certain embodiments, the compound of Formula I is an S-enantiomer, and R7 is the S-enantiomer. [ka] [ka]

[0328] In one embodiment, as shown in Scheme 6, the intermediate compound of formula (N) in Scheme 5 is synthesized by coupling a dihalogenated ester compound of formula (O) with a halogenated compound of formula (P) under suitable coupling conditions, such as in the presence of zinc, to form a halogenated ester compound of formula (Q). This halogenated ester compound of formula (Q) is then reduced under suitable reducing conditions, such as in the presence of lithium aluminum hydride, to form a hydroxy compound of formula (R), which is then oxidized under suitable oxidizing conditions, such as in the presence of manganese dioxide (MnO), to provide the halogenated aldehyde compound of formula (S). This compound of formula (S) is then coupled with tert-butanesulfonamide (compound of formula (T)) to form an aldimine compound of formula (U), which is further coupled with (1,3-dioxan-2-ylethyl)(1,3-dioxan-2-ylethyl)manganese bromide (compound of formula (V)) under suitable Grignard reaction conditions to provide an intermediate compound of formula (W), which is cyclized under suitable cyclization conditions, such as in the presence of trifluoric acid (TFA) and triethylsilane (EtSiH), to form a compound of formula (N). In certain embodiments, the tert-butanesulfinamide (compound of formula T) is S-tert-butanesulfinamide, and the subsequent compounds of formula (U), (W), and (N) are S-enantiomers. In certain embodiments, Hal 6 , Hal 7 and Hal 8 Each is a halogen selected to work under specific coupling conditions that would be known to one of skill in the art. In certain embodiments, Hal 6 and Hal7 are Br and I, respectively. 8 is any suitable halogen. In some embodiments, Hal 8 is I. The fluctuation factor Cy 1 and Cy 2 is as defined in formula I. [ka]

[0329] The above schemes are provided for illustrative purposes, and it will be understood by those skilled in the art that the most appropriate reagents to use may vary depending on the intermediate compounds of formula (A)-(W), and that the most appropriate route will also depend on the intermediates and the target compound of formula (I).

[0330] Intermediates of formula (A)-(W) are commercially available or may be prepared using methods known in the art.

[0331] It will be appreciated by those skilled in the art that compounds of formula (II) may be prepared according to the processes and schemes described above for compounds of formula (I).

[0332] Generally, the above reactions are carried out in a suitable inert organic solvent at a temperature and for a time period that optimizes 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 the like.

[0333] Salts of the compounds of the present application are generally formed by dissolving the neutral compound in an inert organic compound, adding either the desired acid or base, and isolating the resulting salt by filtration or other known means.

[0334] The formation of solvates of the compounds of the present application will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in an appropriate solvent and isolating the solvate by cooling or by using an anti-solvent. The solvate is typically dried or azeotroped under ambient conditions. The selection of appropriate conditions for forming a particular solvate can be achieved by one of ordinary skill in the art. Examples of suitable solvents include ethanol, water, etc. When water is the solvent, the molecule is referred to as a "hydrate."

[0335] Prodrugs of the compounds of the present application may be, for example, conventional esters formed between available hydroxy, thiol, amino, or carboxyl groups. For example, available hydroxy or amino groups may be acylated with an activated acid in the presence of a base, and optionally in an inert solvent (e.g., an acid chloride in pyridine). Some common esters that have been utilized as prodrugs include phenyl esters, aliphatic (C1-C24) esters, acyloxymethyl esters, carbamates, and amino acid esters.

[0336] It should be understood that throughout the processes described in this disclosure, suitable protecting groups are added to, and subsequently removed from, various reactants and intermediates, where appropriate, in a manner that would be readily understood by one of ordinary skill in the art. Conventional techniques for using such protecting groups, and examples of suitable protecting groups, are described, for example, in "Protective Groups in Organic Synthesis," T.W. Green, P.G.M. Wuts, Wiley-Interscience, New York (1999). It should also be understood that, on intermediates along a synthetic route to a final product or on the final product, groups or substituents can be converted to other groups or substituents by chemical manipulation, with the scope of the possible transformations being limited only by the inherent incompatibility of other functionality possessed by the molecule at that stage with the conditions or reagents used in the transformation. Such inherent incompatibilities, and how to circumvent them by carrying out appropriate transformations and synthetic steps in the appropriate order, will be readily apparent to one of ordinary skill in the art. While examples of transformations are given in this disclosure, it should also be understood that the described transformations are not limited to only the generic groups or substituents for which the transformations are exemplified. References and descriptions of other suitable transformations are provided in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" by R.C. Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions can be found in organic chemistry textbooks, such as "Advanced Organic Chemistry", March, 4th ed., McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purification of intermediates and final products include, for example, normal and reverse phase chromatography on columns or spinning plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, and will be readily apparent to those skilled in the art. [Example]

[0337] The following non-limiting examples are illustrative of the present application. A. Preparation of Exemplary Compounds of the Present Application i. Preparation of Exemplary Compounds of Formula I Example 1: 6-(3-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-1) [ka] Step 1: 3-chloro-5-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-amine [ka]

[0338] A vial was charged with 2-amino-5-bromo-3-chloropyrazine (100 mg, 0.480 mmol), CsCO (469 mg, 1.44 mmol), 4-(4-methylpiperazin-1-yl)phenylboronic acid, pinacol ester (145 mg, 0.480 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (PdCldppf) (35.1 mg, 0.048 mmol) suspended in HO (2 mL) and (dimethyl ether) DME (4 mL). The reaction was degassed by evacuating and backfilling with Ar, then sealed and heated at 90 °C for 2 h under microwave irradiation. The reaction mixture was concentrated under reduced pressure, deposited onto Celite®, and purified by flash chromatography (25 g SiO2 InnoFlash® cartridge, using methanol (MeOH) in dichloromethane (CH2Cl2), eluting with 9% MeOH) to give the product as a pale yellow solid (162 mg, quantitative). LCMS: [M + H]+ = 304.12. Step 2: 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0339] To a degassed suspension of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (3 g, 13.3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (5.07 g, 20 mmol), and KOAc (3.92 g, 40 mmol) in 1,4-dioxane (30 mL) was added Pd(dppf)Cl. CHCl (1.08 g, 1.3 mmol). The reaction mixture was heated to 85 °C for 16 h under an argon atmosphere and cooled to room temperature. The reaction mixture was filtered through a Celite bed, which was washed with ethyl acetate (EtOAc) (100 mL). The combined filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (silica gel 100-200 mesh) using 50-70% EtOAc in petroleum ether as the eluent to give the product (3 g, 82%) as a pale yellow solid. TLC (70% EtOAc: petroleum ether; Rf = 0.6). Step 3: 6-(3-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0340] A mixture of 3-chloro-5-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-amine (47 mg, 0.147 mmol) and reagent grade >= 98% tribasic potassium phosphate (KPO) (109 mg, 0.513 mmol), XPhos Pd G2 (11.54 mg, 0.015 mmol) was placed under N2. 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (42.6 mg, 0.156 mmol) in 1,4-dioxane (1.5 mL), HO (2 mL), and CH3CN ("ACN") (3 mL) was added. The mixture was degassed with N2 and then heated to 100 °C in a microwave reactor for 2 h. The reaction mixture was concentrated under reduced pressure, loaded onto Celite®, and purified by flash chromatography (12 g SiO InnoFlash® cartridge, using MeOH in CH2Cl2, eluting with 75% MeOH, pooled fractions: 13-23). ​​These fractions were concentrated under reduced pressure, loaded onto Celite®, and purified by preparative HPLC (30 g Biotage® SNAP KP-C 18 -HS, eluted with 37% MeOH in (H2O+0.05% TFA), fractions pooled: 26-30) to give the TFA salt of the compound described in the title as an orange solid (47 mg, 50%). 1 H NMR (500 MHz, CD3OD) δ 8.37 (br s, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.92 (br d, J = 8.7 Hz, 2H), 7.80 (br d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.12 (br d, J = LCMS: [M+H] + = 415.48. Example 2: 5-(3-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,3-dimethylisoindolin-1-one (I-2) [ka] Step 1: 3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one [ka]

[0341] 5-Bromo-3,3-dimethyl-2,3-dihydro-1H-isoindol-1-one (50 mg, 0.208 mmol), B2pin2 (58.2 mg, 0.229 mmol), KOAc (61.3 mg, 0.625 mmol), and PdCl2dppf (7.62 mg, 10.41 μmol) were placed under an atmosphere of Ar, and then anhydrous 1,4-dioxane (7 mL) was added. The mixture was degassed with Ar and then heated in a microwave reactor at 100 °C for 2 h. LCMS: [M + H] + = 288.10. Step 2: 5-(3-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,3-dimethylisoindolin-1-one [ka]

[0342] In a procedure similar to Step 3 of Example 1, using 3-chloro-5-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-amine (52 mg, 0.164 mmol), KPO (105 mg, 0.493 mmol), XPhos Pd G (12.93 mg, 0.016 mmol), and 3,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one (61 mg, 2.05 mL in 1,4-dioxane, 0.214 mmol), the compound described in the heading (64 mg, 59%) was obtained as a pale yellow solid. 1 H NMR (500 MHz, CD3OD) δ = 8.34 (br s, 1H), 7.97 (s, 1H), 7.93 - 7.88 (m, 4H), 7.11 (br d, J = 7.9 Hz, 2H), 3.95 (br d, J = 13.2 Hz, 2H), 3.63 (br d, J = LCMS: [M + H] + = 429.33. Example 3: 6-(3-amino-6-(4-(4-isopropylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-3) [ka] Step 1: 3-chloro-5-(4-(4-isopropylpiperazin-1-yl)phenyl)pyrazin-2-amine [ka]

[0343] The intermediate was prepared in a procedure similar to that described in Step 1 of Example 1 using 2-amino-5-bromo-3-chloropyrazine (80 mg, 0.384 mmol), CsCO (375 mg, 1.151 mmol), 4-(4-isopropylpiperazinyl)phenylboronic acid, pinacol ester (127 mg, 0.384 mmol), PdCldppf (28.1 mg, 0.038 mmol), HO (2 mL), and DME (4 mL) by heating under microwave irradiation at 90 °C for 2 h. Purification by flash chromatography (12 g SiO InnoFlash® cartridge, using MeOH in CHCl eluting with 7% MeOH) afforded the product as a tan solid (61 mg, 40% based on 84% purity). LCMS: [M + H] + = 332.19. Step 2: 6-(3-amino-6-(4-(4-isopropylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0344] In a manner similar to Step 3 of Example 1, the compound described in the heading was prepared using 3-chloro-5-(4-(4-isopropylpiperazin-1-yl)phenyl)pyrazin-2-amine (61 mg, 0.154 mmol), 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (54.8 mg, 0.201 mmol), XPhos Pd G2 (12.15 mg, 0.015 mmol), HO (2 mL), and MeCN (3 mL); this was done by heating in a microwave reactor at 100 °C for 3 h. Flash chromatography (25 g SiO2 InnoFlash® cartridge, using MeOH in CHCl2, eluting with 4% MeOH) followed by preparative HPLC (30 g Biotage® SNAP KP-C 18-HS, MeOH in (H2O + 0.05% TFA), eluting with 35% MeOH) to give the compound described in the title as a light tan solid (42 mg, 40% based on 98% purity). 1 H NMR (500 MHz, CD3OD) δ 8.32 (s, 1H), 8.10 (d, J = 7.9 Hz, 1H), 7.91 (br d, J = 8.6 Hz, 2H), 7.79 (br d, J = 7.9 Hz, 1H), 7.74 (s, 1H), 7.11 (br d, J = 8.4 Hz, 2H), 4.06 - 3.93 (m, 2H), 3.66 - 3.53 (m, 5H), 3.29 - 3.25 (m, 2H), 3.16 - 3.05 (m, 4H), 1.43 (d, J = 6.6 Hz, 6H). The 2H peak at approximately 3.3 ppm (2H) is partially obscured by solvent. LCMS: [M + H] + = 443.40. Example 4: 6-(3-amino-6-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-4) [ka] Step 1: 3-chloro-5-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-amine [ka]

[0345] The intermediate was prepared in a manner similar to Step 1 of Example 1 using 2-amino-5-bromo-3-chloropyrazine (100 mg, 0.480 mmol), CsCO (469 mg, 1.439 mmol), 3-fluoro-4-(4-methyl-1-piperazinyl)benzeneboronic acid pinacol ester (154 mg, 0.480 mmol), PdCl dppf (35.1 mg, 0.048 mmol), HO (2 mL), and DME (4 mL) as follows: heated at 90 °C for 3 h under microwave irradiation. Purification by flash chromatography (25 g SiO InnoFlash® cartridge, eluting with 0-100% EtOAc in CHCl, then MeOH in CHCl, 10% MeOH) afforded the product as a yellow solid (91 mg, 59%). LCMS: [M + H] + = 322.24. Step 2: 6-(3-amino-6-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0346] A procedure analogous to that described in Step 3 of Example 1 using 3-chloro-5-(3-fluoro-4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-amine (61 mg, 0.190 mmol), 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (57.0 mg, 0.209 mmol), and XPhos Pd G2 (14.92 mg, 0.019 mmol) gave the compound described in the title (17 mg, 14%) as a yellow solid. 1H NMR (500 MHz, CD3OD) δ 8.44 (br s, 1H), 8.09 (br d, J = 7.9 Hz, 1H), 7.81 - 7.72 (m, 4H), 7.16 (br t, J = 8.6 Hz, 1H), 3.72 - 3.54 (m, 6H), 3.42 - 3.33 (m, 2H), 3.20 - 3.04 (m, 4H), 2.99 (s, 3H); LCMS: [M + H] + = 433.24. Example 5: 6-(3-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-5) [ka] Step 1: 8-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0347] A sealed, degassed mixture of 6-bromo-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one (125 mg, 0.51 mmol), B2pin2 (143 mg, 0.56 mmol), KOAc (151 mg, 1.54 mmol), and PdCl2dppf (18.74 mg, 0.026 mmol) in anhydrous 1,4-dioxane (6 mL) was heated in a microwave reactor at 100 °C for 2 h. The reaction was worked up using standard methods, and the resulting crude product was used in the next step without purification. LCMS: [M + H] + = 292.00. Step 2: 6-(3-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-8-fluoro-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0348] Following a procedure analogous to Step 3 of Example 1, the compound described in the heading was prepared using 3-chloro-5-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-amine (62.7 mg, 0.206 mmol) (prepared as described in Step 1 of Example 1), KPO (131 mg, 0.619 mmol), XPhos Pd G (16.2 mg, 0.021 mmol), 8-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (66.1 mg, 0.23 mmol in 1,4-dioxane (2.67 mL); crude product from Step 1) in HO (4 mL) and MeCN (6 mL); this was done as follows: It was sealed and heated in a microwave reactor at 100 °C for 3 h. Flash chromatography (25 g SiO Biotage® cartridge, MeOH in CH Cl) followed by preparative HPLC (30 g Biotage® SNAP KP-C 18 Purification with HCl, MeOH in (H2O+0.05% TFA) gave the TFA salt of the compound described in the title (43 mg, 31% based on 98% purity). 1 H NMR (500 MHz, CD3OD) δ 8.40 (br s, 1H), 7.91 (m, J = 8.8 Hz, 2H), 7.60 (s, 1H), 7.53 (br d, J = 12.0 Hz, 1H), 7.11 (m, J = 8.9 Hz, 2H), 3.89 - 4.02 LCMS: [M + H] + = 433.33. Example 6: 6-(3-amino-6-(4-(4-hydroxypiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-6) [ka] Step 1: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol [ka]

[0349] To 1-(4-bromophenyl)piperidin-4-ol (250 mg, 0.976 mmol), B2pin2 (273 mg, 1.074 mmol), KOAc (287 mg, 2.93 mmol), and PdCl2dppf (35.7 mg, 0.049 mmol) was added 1,4-dioxane (6 mL). The mixture was degassed with N2 and then heated in an oil bath at 100 °C for 7 h. The resulting product was used in the next step as a crude 1,4-dioxane mixture. LCMS: [M + H] + = 304.10. Step 2: 1-(4-(5-amino-6-chloropyrazin-2-yl)phenyl)piperidin-4-ol [ka]

[0350] The intermediate was prepared in a procedure similar to Step 1 of Example 1 by using 2-amino-5-bromo-3-chloropyrazine (76 mg, 0.363 mmol), CsCO (237 mg, 0.726 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidin-4-ol (108 mg, 0.242 mmol) in 1,4-dioxane (3.65 mL) with PdCldppf (8.9 mg, 0.012 mmol), HO (2 mL), and DME (1.25 mL) and heating at 90 °C for 1 hour by microwave irradiation. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (25 g SiO2Biotage® cartridge, using MeOH in CH2Cl2, eluting with 5% MeOH) to give the product as a yellow solid (70 mg, 74% based on 78% purity). LCMS: [M + H] + = 305.23. Step 3: 6-(3-amino-6-(4-(4-hydroxypiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0351] The compound described in the title was prepared analogously to Step 3 of Example 1 using 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (73.4 mg, 0.269 mmol), KPO (114 mg, 0.537 mmol), 1-(4-(5-amino-6-chloropyrazin-2-yl)phenyl)piperidin-4-ol (70 mg, 0.179 mmol), XPhos Pd G (14.10 mg, 0.018 mmol), MeCN (9 mL), and HO (6 mL) to give the compound described in the title (6 mg, 6%) as a yellow film. 1H NMR (500 MHz, CD3OD) δ 8.54 (s, 1H), 8.20 (m, J = 8.7 Hz, 2H), 8.11 (d, J = 8.0 Hz, 1H), 7.83 (br d, J = 8.1 Hz, 1H), 7.78 (s,1H), 7.67 (m, J = 8.7 Hz, 2H), 4.10 (br s, 1H), 3.88 (br t, J = 8.0 Hz, 2H), 3.59 (br t, J = 6.6 Hz, 4H), 3.12 (t, J = 6.6 Hz, 2H), 2.16 - 2.31 (m, 2H), 1.98 - 2.08 (m, 2H); LCMS: [M+H] + = 416.26. Example 7: (R)-6-(3-amino-6-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-7) [ka] Step 1: (R)-4-(4-chlorophenyl)-2-isopropylmorpholine [ka]

[0352] 1-Chloro-4-iodobenzene (0.500 g, 2.097 mmol), (R)-2-isopropylmorpholine (0.298 g, 2.31 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.058 g, 0.063 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.109 g, 0.189 mmol), and CsCO (2.050 g, 6.29 mmol) were placed in a 30 mL vial. The vial was sealed with a cap and septum, and the reaction vessel was then evacuated and backfilled with nitrogen. Toluene (7 mL) was added, and the reaction vessel was evacuated and backfilled with nitrogen again. The reaction was heated at 100° C. for 18 hours, then cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with additional EtOAc (×2). The organic layer was concentrated and the residue was loaded onto Celite and purified by flash chromatography (eluting with 1-15% EtOAc / hexanes) to give the product (398 mg, 79%). LCMS: [M + H] + = 240.11. Step 2: (R)-2-Isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine [ka]

[0353] A 30 mL vial was charged with (R)-4-(4-chlorophenyl)-2-isopropylmorpholine (0.397 g, 1.656 mmol), bis(pinacolato)diboron (0.526 g, 2.070 mmol), KOAc (0.325 g, 3.31 mmol), and XPhos Pd G2 (0.098 g, 0.124 mmol). The vial was evacuated and backfilled with nitrogen, and 1,4-dioxane (5 mL) was added. The vial was then evacuated and backfilled again. The reaction mixture was then heated to 90 °C on an aluminum block for 18 h. The reaction mixture was concentrated onto Celite and purified by flash chromatography (1-15% EtOAc / hexanes) to give the product (451 mg, 82%). LCMS: [M + H] + = 332.08. Step 3: (R)-3-chloro-5-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-amine [ka]

[0354] A 30 mL vial was charged with 2-amino-5-bromo-3-chloropyrazine (0.076 g, 0.362 mmol), (R)-2-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.100 g, 0.302 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.022 g, 0.030 mmol), and CsCO (0.246 g, 0.755 mmol). After sealing the vial with a cap and septum, the reaction vessel was evacuated and backfilled with nitrogen. 1,4-Dioxane (2 mL) and H2O (1 mL) were added via syringe, and the vessel was evacuated and backfilled. The reaction was heated to 80 °C for 3 h, then stirred at room temperature overnight and concentrated onto Celite. Purification by flash chromatography (0.5-10% MeOH / CH2Cl2 + 0.5% NH4OH) gave the product (71 mg, 71%). LCMS: [M + H] + = 333.21. Step 4: (R)-6-(3-amino-6-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0355] In a 30 mL vial equipped with a magnetic stir bar, (R)-3-chloro-5-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-amine (0.025 g, 0.075 mmol), 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (0.025 g, 0.090 mmol, prepared as described in Step 3 of Example 1), and XPhos Pd G2 (5.91 mg, 7.51 μmol) were placed. The vial was sealed with a cap and septum, and the reaction vessel was evacuated and backfilled with nitrogen. 1,4-Dioxane (1.0 mL) and aqueous K3PO4 (0.144 mL, 0.188 mmol) were added, and the reaction vessel was evacuated and backfilled with nitrogen again. The reaction mixture was heated on an aluminum block at 90° C. for 18 hours, concentrated onto Celite, and purified by flash chromatography (eluting with 0.5-10% MeOH / CH2Cl2 + 0.5% NH4OH) to give the compound described in the title (16 mg, 48%). 1 H NMR (500 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.9-8.0 (m, 2H), 7.86 (d, J = 9.0 Hz, 2H), 7.75 (dd, J = 8.0, 1.7 Hz, 1H), 7.71 (s, 1H), 7.03 (d, J = 9.0 Hz, 2H), 6.24 (s, 2H), 3.97 (dd, J = 11.3, 2.3 Hz, 1H), 3.5-3.7 (m, 4H), 3.43 (dt, J = 6.5, 2.8 Hz, 3H), 3.25 (ddd, J = 10.4, 6.4, 2.1 Hz, 1H), 3.00 (t, J = 6.5 Hz, 2H), 2.69 (dt, 11.8, 3.5 Hz, 1H), 1.74 (qd, J = 13.4, 6.8 Hz, 1H), 0.96 (dd, J = 6.8, 3.1 Hz, 6H); LCMS: [M + H] + = 444.4. Example 8: (S)-6-(3-amino-6-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-8) [ka] Step 1: (S)-4-(4-chlorophenyl)-2-isopropylmorpholine [ka]

[0356] The procedure followed was analogous to Step 1 of Example 7, using 1-chloro-4-iodobenzene (0.500 g, 2.097 mmol), (S)-2-isopropylmorpholine (0.298 g, 2.31 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.058 g, 0.063 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.109 g, 0.189 mmol), and CsCO (2.05 g, 6.29 mmol). Workup and purification afforded the product (404 mg, 80%). LCMS: [M + H] + = 240.03. Step 2: (S)-2-Isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine [ka]

[0357] Analogous to Step 2 of Example 7, using (S)-4-(4-chlorophenyl)-2-isopropylmorpholine (0.404 g, 1.685 mmol), bis(pinacolato)diboron (0.535 g, 2.106 mmol), KOAc (0.331 g, 3.37 mmol), and XPhos Pd G2 (0.099 g, 0.126 mmol), the product (1.43 mmol, 85%) was obtained. LCMS: [M + H] = 332.08. Step 3: (S)-3-chloro-5-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-amine [ka]

[0358] A procedure analogous to Step 3 of Example 7 was performed using 2-amino-5-bromo-3-chloropyrazine (0.076 g, 0.362 mmol), (S)-2-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.100 g, 0.302 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.022 g, 0.030 mmol), and CsCO (0.246 g, 0.755 mmol) to give the product (53 mg, 53%). LCMS: [M + H] + = 333.29. Step 4: (S)-6-(3-amino-6-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0359] A procedure analogous to Step 4 of Example 7 was performed using (S)-3-chloro-5-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-amine (0.025 g, 0.075 mmol), 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (0.025 g, 0.090 mmol), and XPhos Pd G2 (5.91 mg, 7.51 μmol) to give the compound described in the title (6 mg, 12%). 1H NMR (500 MHz, CD3OD) δ 8.22 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 7.8 Hz, 1H), 7.77 (s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.69 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.56 (s, 2H), 4.03 (dd, J = 11.4, 2.0 Hz, 1H), 3.76 (dt, J = 11.5, 2.6 Hz, 1H), 3.62 (br d, J = 11.7 Hz, 1H), 3.51 (br d, J = LCMS: [M + H] + = 429.4. Example 9: (R)—N-(1-(4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide (I-9) [ka] Step 1: (R)—N-(1-(4-chlorophenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide [ka]

[0360] A procedure analogous to Step 1 of Example 7 was performed using 1-chloro-4-iodobenzene (0.250 g, 1.05 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.031 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.055 g, 0.094 mmol), and CsCO (1.025 g, 3.15 mmol) to give the product (149 mg, 49%). LCMS: [M + H] + = 289.14. Step 2: (R)-N-methyl-N-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methanesulfonamide [ka]

[0361] In a procedure analogous to Step 2 of Example 7, (R)—N-(1-(4-chlorophenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide (0.149 g, 0.516 mmol), bis(pinacolato)diboron (0.197 g, 0.774 mmol), KOAc (0.101 g, 1.03 mmol), and XPhos Pd G2 (0.030 g, 0.039 mmol) were used to give the product (119 mg, 61%). LCMS: [M + H] + = 381.28 Step 3: (R)—N-(1-(4-(5-amino-6-chloropyrazin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide) [ka]

[0362] A procedure analogous to Step 3 of Example 7 was performed using 2-amino-5-bromo-3-chloropyrazine (0.033 g, 0.158 mmol), (R)-N-methyl-N-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methanesulfonamide (0.050 g, 0.131 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (9.62 mg, 0.013 mmol), and CsCO (0.107 g, 0.329 mmol) to give the product (37 mg, 74%). LCMS: [M + H] + = 382.25 Step 4: (R)—N-(1-(4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide (I-9) [ka]

[0363] A procedure analogous to Step 4 of Example 7 was performed using (R)—N-(1-(4-(5-amino-6-chloropyrazin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide (0.037 g, 0.097 mmol), 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (0.032 g, 0.116 mmol), and XPhos Pd G2 (7.62 mg, 9.69 μmol) to give, after work-up and purification, the compound described under the heading (12 mg, 35%). 1H NMR (500 MHz, DMSO-d6) δ 8.24 (d, J = 2.3 Hz, 1H), 7.9-8.0 (m, 2H), 7.58 (br d, J = 2.1 Hz, 1H), 7.5-7.5 (m, 4H), 6.68 (br d, J = 8.8 Hz, 2H), 5.72 (br d, J = 8.8 Hz, 2H), s, 2H), 4.10 (quin, J = 7.1 Hz, 1H), 3.62 (br d, J = 6.7 Hz, 2H), 3.4-3.5 (m, 5H), 3.06 (s, 3H), 2.96 (br t, J = 6.4 Hz, 2H), 2.39 (q, J = 7.1 Hz, 2H); LCMS: [M+H] + = 463.2. Example 10: (S)—N-(1-(4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide (I-10) [ka] Step 1: (S)—N-(1-(4-chlorophenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide [ka]

[0364] In a procedure similar to that described in Step 1 of Example 7, using 1-chloro-4-iodobenzene (0.250 g, 1.048 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.029 g, 0.031 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.055 g, 0.094 mmol), and CsCO (1.025 g, 3.15 mmol), the product (149 mg, 55%) was obtained. LCMS: [M + H] + = 288.91. Step 2: (S)—N-methyl-N-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methanesulfonamide [ka]

[0365] Following a procedure analogous to that described in Step 2 of Example 7, using (S)—N-(1-(4-chlorophenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide (0.166 g, 0.575 mmol), bis(pinacolato)diboron (0.219 g, 0.862 mmol), KOAc (0.113 g, 1.15 mmol), and XPhos Pd G2 (0.034 g, 0.043 mmol), the product (168 mg, 77%) was obtained. LCMS: [M + H]+ = 381.05. Step 3: S)—N-(1-(4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide [ka]

[0366] A procedure analogous to Step 3 of Example 7 was performed using 2-amino-5-bromo-3-chloropyrazine (0.057 g, 0.275 mmol), (S)—N-methyl-N-(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-yl)methanesulfonamide (0.087 g, 0.229 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.017 g, 0.023 mmol), and CsCO (0.186 g, 0.572 mmol) to give the product (66 mg, 76%). LCMS: [M + H] + = 382.25. Step 4: S)—N-(1-(4-(5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide [ka]

[0367] A procedure analogous to Step 4 of Example 7 was performed using (S)—N-(1-(4-(5-amino-6-chloropyrazin-2-yl)phenyl)pyrrolidin-3-yl)-N-methylmethanesulfonamide (0.066 g, 0.173 mmol), 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (0.057 g, 0.207 mmol), and XPhos Pd G2 (0.014 g, 0.017 mmol) to give the compound described in the title (9 mg, 24%). 1 H NMR (500 MHz, DMSO-d6) δ 8.25 (d, J = 2.3 Hz, 1H), 7.9-8.0 (m, 2H), 7.58 (br d, J = 2.2 Hz, 1H), 7.5-7.5 (m, 4H), 6.69 (br d, J = 8.7 Hz, 2H), 5.69 (br LCMS: [M + H] + = 463.3. Example 11: (R)-6-(3-amino-6-(4-(3-methylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-11) [ka] Step 2: (R)-4-(4-chlorophenyl)-3-methylmorpholine [ka]

[0368] A procedure analogous to Step 1 of Example 7 was performed using 1-chloro-4-iodobenzene (0.500 g, 2.097 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.058 g, 0.063 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.109 g, 0.189 mmol), and CsCO (2.05 g, 6.29 mmol) to give the product (150 mg, 34%). LCMS: [M + H] + = 212.29. Step 2: (R)-3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine [ka]

[0369] Following an analogous procedure to Step 2 of Example 7, (R)-4-(4-chlorophenyl)-3-methylmorpholine (0.120 g, 0.567 mmol), bis(pinacolato)diboron (0.180 g, 0.709 mmol), KOAc (0.111 g, 1.13 mmol), and XPhos Pd G2 (0.033 g, 0.043 mmol) gave the product (127 mg, 74%). LCMS: [M + H] + = 304.41. Step 3: (R)-3-chloro-5-(4-(3-methylmorpholino)phenyl)pyrazin-2-amine [ka]

[0370] A procedure analogous to Step 3 of Example 7 was used with 2-amino-5-bromo-3-chloropyrazine (0.103 g, 0.495 mmol), (R)-3-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.125 g, 0.412 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.030 g, 0.041 mmol), and CsCO (0.336 g, 1.031 mmol) to give the product (89 mg, 71%). LCMS [M + H] + = 305.31. Step 4: (R)-6-(3-amino-6-(4-(3-methylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0371] A procedure analogous to Step 4 of Example 7 was performed using (R)-3-chloro-5-(4-(3-methylmorpholino)phenyl)pyrazin-2-amine (0.044 g, 0.144 mmol), 3,4-dihydro-1(2H)-isoquinolinone-6-boronic acid pinacol ester (0.047 g, 0.173 mmol), and XPhos Pd G2 (0.011 g, 0.014 mmol) to give the compound described in the title (15 mg, 25%). 1H NMR (500 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.9-8.0 (m, 2H), 7.86 (d, J = 8.9 Hz, 2H), 7.75 (dd, J = 8.0, 1.7 Hz, 1H), 7.71 (s, 1H), 6.96 (d, J = 8.9 Hz, 2H), 6.22 (s, 2H), 3.93 (br d, J = 7.1 Hz, 2H), 3.7-3.8 (m, 2H), 3.57 (dt, J = 11.3, 3.0 Hz, 1H), 3.43 (dt, J = 6.6, 2.6 Hz, 2H), 3.2-3.3 (m, 1H), 3.0-3.1 (m, 3H), 1.02 (d, J = 6.5 Hz, 3H); LCMS: [M + H] + = 416.5. Example 12: 6-(3-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-12) [ka] Step 1: 6-Bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0372] NaN3 (114 mg, 1.746 mmol, 2 equiv.) was added portionwise to a solution of 5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (200 mg, 0.873 mmol, 1 equiv.) in 0.4 mL of a mixture of methanesulfonic acid and CHCl2 (1:1) at 0 °C. The resulting mixture was stirred at room temperature for 8 h. The reaction mixture was cooled to 0 °C in an ice bath, neutralized with 5% aqueous NaOH, and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with H2O and brine, dried over MgSO4, and filtered. The filtrate was concentrated under vacuum and purified by silica gel flash column chromatography using CHCl2-MeOH to give the product as a white solid (150 mg, 71%). LCMS: [M + H] + = 246.20 Step 2: 8-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroiso-quinolin-1(2H)-one [ka]

[0373] To 6-bromo-5-fluoro-3,4-dihydroisoquinolin-1(2H)-one (50 mg, 0.205 mmol, 1 equiv.) was added bis(pinacolato)diboron (58.2 mg, 0.229 mmol, 1.1 equiv.), KOAc (61.3 mg, 0.625 mmol, 3 equiv.), and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7.62 mg, 10.41 μmol, 0.05 equiv.) in 1,4-dioxane (2.5 mL) under Ar. The mixture was heated at 100° C. for 2 hours in a microwave oven. LCMS showed less than 10% starting material. The reaction mixture was used in the next step without purification. LCMS: [M + H] + = 292.0 Step 3: 6-(3-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one, formate [ka]

[0374] XPhos Pd G2 (14.74 mg, 0.019 mmol, 0.1 equiv.), reagent grade tribasic K3PO4 (119 mg, 0.562 mmol, 3 equiv.), and 3-bromo-5-(4-(4-methylpiperazin-1-yl)phenyl)pyrazin-2-amine (65.2 mg, 0.187 mmol, 1 equiv.) were dissolved in a mixture of HO (4 mL) and ACN (6 mL) in a microwave vial. The reaction was degassed with N2. 7-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (60 mg, 0.206 mmol, 1.1 equiv.) in dioxane (4 mL) was added, and the mixture was degassed again. The vial was sealed and heated overnight at 100° C. The resulting mixture was dried over Celite and purified by reverse-phase flash chromatography (water / ACN) to give the formate salt of the title compound as a dark yellow solid (10 mg, 11%). 1 H NMR (500 MHz, CDCl3) δ 8.41 (s, 1H), 7.84 (d, J = 10.3 Hz, 1H), 7.78 (d, J = 7.9 Hz, 2H), 7.47 - 7.40 (m, 1H), 6.92 (d, J = 8.2 Hz, 2H), 5.96 - 5.89 LCMS: [M + H] + = 433.41. Example 13: (R)-6-(3-amino-6-(2-fluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-13) [ka] Step 1: (R)-4-(4-chloro-3-fluorophenyl)-2-isopropylmorpholine [ka]

[0375] A 30 mL vial was charged with 4-bromo-1-chloro-2-fluorobenzene (0.15 g, 0.72 mmol), (R)-2-isopropylmorpholine (0.10 g, 0.79 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.020 g, 0.021 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.037 g, 0.064 mmol), and CsCO (0.70 g, 2.1 mmol). The vial was sealed with a cap and septum, and the reaction vial was then evacuated and backfilled with nitrogen. Toluene (2.5 mL) was added, and the reaction vial was evacuated and backfilled with nitrogen again. The reaction was heated conventionally at 100° C. for 18 hours. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with additional EtOAc (×2). The combined organic extracts were dried and concentrated onto Celite. Flash chromatography (1-15% EtOAc / hexanes) afforded the product (0.18 g, 99%). LCMS: [M + H] + = 258.2. Step 2: (R)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine [ka]

[0376] A 30 mL vial was charged with (R)-4-(4-chloro-3-fluorophenyl)-2-isopropylmorpholine (0.67 g, 2.6 mmol), bis(pinacolato)diboron (0.83 g, 3.3 mmol), KOAc (0.51 g, 5.2 mmol), and XPhos Pd G2 (0.15 g, 0.20 mmol). The vial was sealed with a cap and septum, and the reaction vial was then evacuated and backfilled with N2. 1,4-Dioxane (8 mL) was added, and the reaction vial was evacuated and backfilled with nitrogen. The reaction was heated to 90 °C for 18 h. After cooling to room temperature, the reaction mixture was concentrated directly onto Celite and purified by flash chromatography (1-15% EtOAc / hexanes) to give the product (0.92 g, quantitative yield). LCMS: [M + H] + = 350.2. Step 3: (R)-6-(3-amino-6-(2-fluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0377] A 30 mL vial was charged with (R)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine (0.033 g, 0.094 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.025 g, 0.078 mmol), and XPhos Pd G2 (0.014 g, 0.018 mmol). The vial was sealed with a cap and septum, and the reaction vial was evacuated and backfilled with nitrogen. 1,4-Dioxane (1 mL) and 1.3 M aqueous KPO (0.20 mL, 0.26 mmol) were added, and the reaction vial was evacuated and backfilled with nitrogen. The reaction was conventionally heated at 100 °C for 18 h. After cooling to room temperature, the reaction mixture was concentrated directly onto Celite and purified by flash chromatography [0.5-5.0% MeOH / CHCl + 0.5% NHOH] to give the compound described in the title (19 mg, 53%). 1 H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J = 2.4 Hz, 1H), 7.98 (br s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.78 (t, J = 9.2 Hz, 1H), 7.73 (dd, J = 8.0, 1.7 Hz, 1H), 7.69 (s, 1H), 6.8-6.9 (m, 2H), 6.37 (s, 2H), 3.97 (dd, J = 10.8, 2.9 Hz, 1H), 3.6-3.7 (m, 4H), 3.42 (dt, J = 6.6, 2.8 Hz, 3H), 3.23 (ddd, J = 10.4, 6.2, 2.4 Hz, 1H), 2.99 (br t, J = 6.5 Hz, 2H), 2.7-2.8 (m, 1H), 1.73 (qd, J = 13.4, 6.7 Hz, 1H), 0.96 (d, J = 6.7 Hz, 6H); LCMS: [M + H] + = 462.4. Example 14: (S)-6-(3-amino-6-(2-fluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-14) Step 1: 1-(4-bromophenyl)-3-chloropropan-1-one (2): [ka]

[0378] To a stirred solution of AlCl (47 g, 352.5 mmol) in CHCl (500 mL) was added bromobenzene (33.3 mL, 320.5 mmol) and 3-chloropropanoyl chloride (31.30 mL, 320.5 mmol) in CHCl (400 mL) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with ice H0 (500 mL) and extracted with CHCl (3 × 300 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product (75 g, 95%) as a pale yellow semi-solid. TLC: 20% EA in petroleum ether; R f = 0.4. Step 2: 5-Bromo-2,3-dihydro-1H-inden-1-one [ka]

[0379] To a stirred room temperature solution of 1-(4-bromophenyl)-3-chloropropan-1-one (70 g, 71.6 mmol) in H2SO4 (700 mL). The mixture was stirred at 100 °C for 4 h and then cooled to room temperature. The reaction mixture was diluted with ice H2O and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product (40 g crude) as a brown solid. This material was used in the next step without further purification. TLC: 20% EA in petroleum ether; Rf = 0.5. Step 3: 6-Bromo-3,4-dihydroisoquinolin-1(2H)-one: [ka]

[0380] To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (30 g, 142.8 mmol) in CHCl (240 mL) was added MsOH (120 mL) at 0 °C. NaN (32.5 g, 500 mmol) was then added portionwise. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was basified with 20% NaOH solution and extracted with CHCl (2 × 500 mL). The combined organic layers were dried over NaSO and concentrated to give the crude product, which was purified by column chromatography (100-200 silica gel) using 0-7% MeOH in CHCl as the eluent to give the product (11.5 g, 35%) as a pale yellow solid. LCMS: [M + H] + = 225.96. Step 4: 3,5-Dibromopyrazin-2-amine [ka]

[0381] To a stirred solution of pyrazin-2-amine (10 g, 105.2 mmol) in DMSO (100 mL) was added NBS (37.4 g, 210.5 mmol) at room temperature. The reaction mixture was then stirred at room temperature for 4 hours, diluted with HO (200 mL), and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine solution (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (100-200 mesh, silica gel) using 0-40% EtOAc in petroleum ether as the eluent to give the product (12 g, 46%) as a pale orange solid. TLC: 50% EtOAc in petroleum ether; R f = 0.5. Step 5: 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0382] To a stirred solution of 6-bromo-3,4-dihydroisoquinolin-1(2H)-one (1.7 g, 7.5 mmol) and 3,5-dibromopyrazin-2-amine (2.8 g, 11.3 mmol) in DMF:HO (20:1, 20 mL) was added KCO (2 g, 15.1 mmol), and argon was bubbled through for 15 min at room temperature. PdCl(PPh) (0.053 g, 0.075 mmol) was then added, and the reaction mixture was heated at 90 °C for 16 h, diluted with HO (100 mL), and extracted with EtOAc (3 × 200 mL). The combined organic layers were washed with brine (200 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give the crude compound. Purification by column chromatography (100-200 mesh silica gel) using 0-10% MeOH in CH2Cl2 as the eluent gave the product (0.7 g, 35.0%) as a brick-red solid. 1H NMR (400 MHz, DMSO-d6): δ 8.11 (s, 1H), δ 8.01 (brs, 1H), δ 7.96 (d, J = 7.6 Hz, 1H), δ 7.63 (d, J = 7.6 Hz, 1H), δ 7.60 (s, 1H), δ 6.56 (brs, 2H), 3.42-3.33 (m, 2H), δ 2.97 (t, J = 6.4 Hz, 2H); LCMS: [M + H] + = 319.26 Step 6: (S)-4-(4-chloro-3-fluorophenyl)-2-isopropylmorpholine [ka]

[0383] A procedure analogous to Step 1 of Example 7 was carried out using (S)-2-isopropylmorpholine (0.339 g, 2.63 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.500 g, 2.387 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.066 g, 0.072 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.124 g, 0.215 mmol), and CsCO (2.33 g, 7.16 mmol) to give the product (782 mg, quantitative yield). LCMS: [M + H] + = 258.15. Step 7: (S)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine [ka]

[0384] In a procedure analogous to Step 2 of Example 7, (S)-4-(4-chloro-3-fluorophenyl)-2-isopropylmorpholine (0.782 g, 3.03 mmol), bis(pinacolato)diboron (0.963 g, 3.79 mmol), KOAc (0.596 g, 6.07 mmol), and XPhos Pd G2 (0.179 g, 0.228 mmol) were used to give the product (810 mg, 76%). LCMS: [M + H] + = 350.21. Step 8: (S)-6-(3-amino-6-(2-fluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0385] A 30 mL vial equipped with a magnetic stir bar was charged with (S)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine (0.033 g, 0.094 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.025 g, 0.078 mmol), and XPhos Pd G2 (0.014 g, 0.018 mmol). The vial was sealed with a cap and septum, and the reaction vessel was evacuated and backfilled with nitrogen. 1,4-Dioxane (1 mL) and aqueous KPO (0.196 mL of a 1.3 M solution, 0.255 mmol) were added, and the reaction vessel was evacuated and backfilled with nitrogen. The reaction mixture was heated at 100 °C on an aluminum block for 22 h, then concentrated onto Celite and purified by flash chromatography (0.5% to 5% MeOH / CHCl + 0.5% NHOH) to give the compound described in the title (20 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ 8.32 (d, J = 2.4 Hz, 1H), 7.98 (br s, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.78 (t, J = 9.1 Hz, 1H), 7.73 (dd, J = 8.0, 1.3 Hz, 1H), 7.69 (s, 1H), 6.8-6.9 (m, 2H), 6.37 (s, 2H), 3.97 (dd, J = 10.5, 3.1 Hz, 1H), 3.6-3.7 (m, 4H), 3.42 (dt, J = 6.5, 2.8 Hz, 3H), 3.2-3.3 (m, 1H), 2.99 (t, J = 6.5 Hz, 2H), 2.7-2.8 (m, 1H), 1.73 (qd, J = 13.4, 6.8 Hz, 1H), 0.96 (d, J = 6.7 Hz, 6H); LCMS: [M + H] + = 462.4. Example 15: (R)-6-(3-amino-6-(2,3-difluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-15) [ka] Step 1: (R)-4-(2,3-difluorophenyl)-2-isopropylmorpholine [ka]

[0386] A 30 mL vial was charged with 1-bromo-2,3-difluorobenzene (0.15 g, 0.78 mmol), (R)-2-isopropylmorpholine (0.11 g, 0.86 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.023 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.040 g, 0.070 mmol), and CsCO (0.76 g, 2.3 mmol). The vial was sealed with a cap and septum, and the reaction vial was then evacuated and backfilled with N. Toluene (2.5 mL) was added, and the reaction vial was evacuated and backfilled with nitrogen. The reaction was conventionally heated at 100 °C for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with additional EtOAc (×2). The combined organic extracts were dried and concentrated onto Celite. Flash chromatography (1-15% EtOAc / hexanes) afforded the product (0.11 g, 60%). LCMS: [M + H] + = 241.9. Step 2: (R)-4-(4-bromo-2,3-difluorophenyl)-2-isopropylmorpholine [ka]

[0387] N-Bromosuccinimide (0.091 g, 0.51 mmol) was added to a stirred 0 °C solution of (R)-4-(2,3-difluorophenyl)-2-isopropylmorpholine (0.11 g, 0.46 mmol) (2 mL) in CHCl. ​​The reaction was allowed to warm gradually to room temperature overnight. The reaction mixture was concentrated directly onto Celite and purified by flash chromatography (1-10% EtOAc / hexanes) to give the product (0.11 g, 77%). LCMS: [M + H] + = 320.1. Step 3: (R)-4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine [ka]

[0388] A 30 mL vial was charged with (R)-4-(4-bromo-2,3-difluorophenyl)-2-isopropylmorpholine (0.44 g, 1.4 mmol), bis(pinacolato)diboron (0.44 g, 1.7 mmol), KOAc (0.27 g, 2.7 mmol), and XPhos Pd G2 (0.08 g, 0.10 mmol). The vial was sealed with a cap and septum, and the reaction vial was then evacuated and backfilled with N2. 1,4-Dioxane (8 mL) was added, and the reaction vial was evacuated and backfilled with N2 again. The reaction was conventionally heated at 90 °C for 18 h. After cooling to room temperature, the reaction mixture was concentrated directly onto Celite and purified by flash chromatography (1-15% EtOAc / hexanes) to give the product (0.26 g, 51%). LCMS: [M + H] + = 368.2. Step 4: (R)-6-(3-amino-6-(2,3-difluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0389] A 30 mL vial was charged with (R)-4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine (0.035 g, 0.094 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.025 g, 0.078 mmol, prepared according to the procedure in Step 5 of Example 14), and XPhos Pd G2 (0.014 g, 0.018 mmol). The vial was sealed with a cap and septum, and the reaction vial was evacuated and backfilled with N2. 1,4-Dioxane (1 mL) and aqueous KPO (0.20 mL of a 1.3 M solution, 0.26 mmol) were added, and the reaction vial was evacuated and backfilled with N. The reaction was heated at 100 °C for 18 h. After cooling to room temperature, the reaction mixture was concentrated directly onto Celite and purified by flash chromatography (0.5-5.0% MeOH / CHCl + 0.5% NHOH) to give the title compound (240 mg, 64%). 1 H NMR (500 MHz, DMSO-d6) δ 8.34 (d, J = 2.6 Hz, 1H), 7.99 (br s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.73 (dd, J = 8.0 Hz, 1.7, 1H), 7.69 (s, 1H), 7.62 (dt, J = 8.6, 1.7 Hz, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.54 (s, 2H), 3.9-4.0 (m, 1H), 3.67 (dt, J = 11.4, 2.4 Hz, 1H), 3.42 (dt, J = 6.5, 2.8 Hz, 2H), 3.3-3.4 (m, 2H), 3.2-3.3 (m, 1H), 2.99 (t, J = 6.5 Hz, 2H), 2.83 (dt, J = 11.7, 3.2 Hz, 1H), 2.61 (dd, J = 11.4, 10.5 Hz, 1H), 1.71 (qd, J = 13.4, 6.7 Hz, 1H), 0.93 (dd, J = 16.0, 6.8 Hz, 6H); LCMS: [M + H] + = 480.4. Example 16: (S)-6-(3-amino-6-(2,3-difluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-16) [ka] Step 1: (S)-4-(2,3-difluorophenyl)-2-isopropylmorpholine [ka]

[0390] A 30 mL vial was charged with (S)-2-isopropylmorpholine (0.331 g, 2.56 mmol), 1-bromo-2,3-difluorobenzene (0.450 g, 2.332 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.064 g, 0.070 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.121 g, 0.210 mmol), and CsCO (2.279 g, 7.00 mmol). The vial was sealed with a cap and septum, and the reaction vessel was then evacuated and backfilled with nitrogen. Toluene (6 mL) was added, and the reaction vessel was evacuated and backfilled with nitrogen again. The reaction was heated at 100 °C for 18 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with additional EtOAc (×2). LCMS

[01] showed clean conversion to the desired product. After concentrating the combined extracts to dryness, the crude product was passed through a short plug of silica gel and eluted with 5% EtOAc / hexane to give the product (628 mg, quantitative yield) after removal of volatiles. LCMS: [M + H] + = 242.21 Step 2: (S)-4-(4-bromo-2,3-difluorophenyl)-2-isopropylmorpholine [ka]

[0391] NBS (0.519 g, 2.91 mmol) was added to a stirred room temperature solution of (S)-4-(2,3-difluorophenyl)-2-isopropylmorpholine in CH2Cl2 (6 mL), and the mixture was stirred for 14 h. Standard workup gave the product (747 mg, 71%). LCMS: [M + H] + = 320.2. Step 2: (S)-4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine [ka]

[0392] In a procedure similar to Step 2 of Example 7, (S)-4-(4-bromo-2,3-difluorophenyl)-2-isopropylmorpholine (0.528 g, 1.65 mmol), bis(pinacolato)diboron (0.523 g, 2.06 mmol), KOAC (0.324 g, 3.30 mmol), and XPhos Pd G2 (0.097 g, 0.124 mmol) were used to give the product (143 mg, 24%). LCMS: [M + H] + = 368.26 Step 4: (S)-6-(3-amino-6-(2,3-difluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0393] A procedure analogous to that used in Step 4 of Example 7 using (S)-4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine (0.035 g, 0.094 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.025 g, 0.078 mmol) and XPhos Pd G2 (0.014 g, 0.018 mmol) gave the compound described in the title (15 mg, 40%). 1 H NMR (500 MHz, DMSO-d6) δ 8.34 (d, J = 2.3 Hz, 1H), 7.99 (br s, 1H), 7.95 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 7.62 (br t, J = 8.4 Hz,1H), 6.98 (br t, J = 8.3 Hz, 1H), 6.54 (s, 2H), 3.9-4.0 (m, 1H), 3.67 (dt, J 11.3, 2.2 Hz, 1H), 3.42 (td, J = 6.5, 3.2 Hz, 3H), 3.36 (br d, J = 12.0 Hz, 2H), 3.27 (br d, J = 12.6 Hz, 1H), 2.99 (br t, J = 6.5 Hz, 2H), 2.83 (dt, J = 11.7, 3.0 Hz, 1H), 2.6-2.6 (m, 1H), 1.71 (qd, J = 13.4 Hz, 6.8, 1H), 0.93 (dd, J = 15.9, 6.7 Hz, 6H); LCMS: [M + H] + = 480.4. Example 17: (R)-6-(3-amino-6-(2-fluoro-4-(2-methylpiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-17) [ka] Step 1: (R)-1-(4-chloro-3-fluorophenyl)-2-methylpiperidine [ka]

[0394] Analogous to Step 1 of Example 7, using (R)-2-methylpiperidine (0.284 g, 2.86 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.500 g, 2.387 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.066 g, 0.072 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.124 g, 0.215 mmol), and CsCO (2.333 g, 7.16 mmol), the product (140 mg, 26%) was obtained. LCMS: [M + H] = 228.25 Step 2: (R)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpiperidine [ka]

[0395] The procedure used was similar to that described in Step 2 of Example 7, using (R)-1-(4-chloro-3-fluorophenyl)-2-methylpiperidine (0.140 g, 0.615 mmol), bis(pinacolato)diboron (0.195 g, 0.769 mmol), KOAc (0.121 g, 1.230 mmol), and XPhos Pd G2 (0.036 g, 0.046 mmol) to give the product (112 mg, 57%). LCMS: [M + H] + = 320.43. Step 3: (R)-6-(3-amino-6-(2-fluoro-4-(2-methylpiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0396] In a procedure similar to that described in Step 4 of Example 7, using (R)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpiperidine (0.036 g, 0.113 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.030 g, 0.094 mmol) and XPhos Pd G2 (0.011 g, 0.014 mmol), the compound described in the title (24 mg, 59%) was obtained as a yellow powder. 1 H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J = 2.3 Hz, 1H), 7.9-8.0 (m, 2H), 7.7-7.8 (m, 2H), 7.69 (s, 1H), 6.82 (dd, J = 9.0, 2.4 Hz, 1H), 6.73 (dd, J = 15.9, 2.3 Hz, 1H), 6.32 (s, 2H), 4.1-4.2 (m, 1H), 3.4-3.5 (m, 4H), 2.99 (t, J = 6.5 Hz, 2H), 2.87 (dt, J = 12.4 Hz, 3.1, 1H), 1.7-1.8 (m, 2H), 1.5-1.6 (m, 4H), 1.02 (d, J = 6.7 Hz, 3H); LCMS: [M + H] + = 432.4. Example 18: (S)-6-(3-amino-6-(2-fluoro-4-(2-methylpiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-18) [ka] Step 1: (S)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpiperidine [ka]

[0397] A procedure analogous to that described in Step 1 of Example 7 using (S)-(+)-2-methylpiperidine (0.284 g, 2.86 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.500 g, 2.387 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.066 g, 0.072 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.124 g, 0.215 mmol), and CsCO (2.33 g, 7.16 mmol) gave the product (180 mg, 33%) as an oil. LCMS: [M + H] + = 228.15. Step 2: (S)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpiperidine [ka]

[0398] The procedure followed was analogous to Step 2 of Example 7, using (S)-1-(4-chloro-3-fluorophenyl)-2-methylpiperidine (0.180 g, 0.790 mmol), bis(pinacolato)diboron (0.251 g, 0.988 mmol), KOAc (0.155 g, 1.58 mmol), and XPhos Pd G2 (0.047 g, 0.059 mmol). After workup, (137 mg, 54%) of the product was obtained. LCMS: [M + H] + = 320.20. Step 3: (S)-6-(3-amino-6-(2-fluoro-4-(2-methylpiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0399] A procedure similar to that described in Step 4 of Example 7 was carried out using (S)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpiperidine (0.036 g, 0.113 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.030 g, 0.094 mmol) and XPhos Pd G2 (0.011 g, 0.014 mmol) to give the compound described in the title (35 mg, 86%). 1 H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J = 2.4 Hz, 1H), 7.9-8.0 (m, 2H), 7.7-7.8 (m, 2H), 7.69 (s, 1H), 6.82 (dd, J = 9.0, 2.5 Hz, 1H), 6.73 (dd, J = 15.8, 2.4 Hz, 1H), 6.32 (s, 2H), 4.2-4.2 (m, 1H), 3.4-3.5 (m, 4H), 2.99 (t, J = 6.5 Hz, 2H), 2.87 (dt, J = 12.4, 3.1 Hz, 1H), 1.7-1.8 (m, 2H), 1.5-1.6 (m, 4H), 1.02 (d, J = 6.6 Hz, 3H); LCMS: [M + H] + = 432.5. Example 19: 6-(6-(4-(4-acetylpiperazin-1-yl)phenyl)-3-aminopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-19) [ka]

[0400] The compound described in the title was prepared in a manner similar to that described in Step 3 of Example 1 using 4-(4-acetyl-1-piperazinyl)phenylboronic acid (54.4 mg, 0.219 mmol), PdCl2dppf (16.05 mg, 0.022 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (70 mg, 0.219 mmol) and Cs2CO3 (214 mg, 0.658 mmol) to give the compound described in the title (55 mg, 57%) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.50 (s, 1H), 7.92 - 8.02 (m, 2H), 7.87 (m, J = 8.8 Hz, 2H), 7.73 - 7.76 (m, 1H), 7.70 (s, 1H), 7.03 (m, J = 8.8 Hz, 2H), 6.24 (s, 2H), 3.59 (br s, 4H), 3.39 - 3.46 (m, 2H), 3.19 - 3.25 (m, 2H), 3.12 - 3.19 (m, 2H), 3.00 (br t, J = 6.4 Hz, 2H), 2.05 (s, 3H); LCMS: [M+H] + = 443.57. Example 20: 6-(3-amino-6-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-20) [ka] Step 1: 1-(4-chloro-3-fluorophenyl)-N,N-dimethylpyrrolidin-3-amine [ka]

[0401] A procedure analogous to Step 1 of Example 7 was carried out using 3-(dimethylamino)pyrrolidine (0.234 mL, 1.43 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.139 mL, 1.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.033 g, 0.036 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.062 g, 0.107 mmol), and CsCO (1.17 g, 3.58 mmol) to give the product (286 mg, 99%). LCMS: [M + H] + = 243.19 Step 2: 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine [ka]

[0402] A procedure analogous to that described in Step 2 of Example 7, using 1-(4-chloro-3-fluorophenyl)-N,N-dimethylpyrrolidin-3-amine (0.286 g, 1.18 mmol), bis(pinacolato)diboron (0.374 g, 1.47 mmol), KOAc (0.231 g, 2.36 mmol), and XPhos Pd G2 (0.070 g, 0.088 mmol), afforded the product (234 mg, 42%), which was judged to be approximately 70% pure and was used in the next step without further purification. LCMS: [M + H] + = 335.24. Step 3: 6-(3-amino-6-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2-fluorophenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-20) [ka]

[0403] A procedure similar to Step 4 of Example 7 was carried out using 1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine (0.041 g, 0.122 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.030 g, 0.094 mmol) and XPhos Pd G2 (7.40 mg, 9.40 μmol) to give, after work-up and purification, the compound described in the title (25 mg, 60%). 1 H NMR (500 MHz, DMSO-d6) δ 8.28 (d, J = 2.2 Hz, 1H), 7.9-8.0 (m, 2H), 7.7-7.8 (m, 3H), 6.48 (dd, J = 8.8, 1.8 Hz, 1H), 6.4-6.4 (m, 1H), 6.27 (s, 2H), 3.5-3.5 (m, 2H), 3.4-3.4 (m, 4H), 3.2-3.3 (m, 1H), 3.06 (br t, J = 8.7 Hz, 1H), 2.99 (br t, J = 6.3 Hz, 2H), 2.8-2.8 (m, 1H), 2.1-2.2 (m, 9H), 1.8-1.9 (m, 1H); LCMS: [M+H] + = 447.8. Example 21: 6-(3-amino-6-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2,3-difluorophenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-21) [ka] Step 1: 1-(2,3-difluorophenyl)-N,N-dimethylpyrrolidin-3-amine [ka]

[0404] Following a procedure analogous to that described in Step 1 of Example 7, using 1-bromo-2,3-difluorobenzene (0.152 mL, 1.30 mmol), 3-(dimethylamino)pyrrolidine (0.254 mL, 1.55 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.036 g, 0.039 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.067 g, 0.117 mmol), and CsCO (1.27 g, 3.89 mmol), the product was obtained. LCMS: [M + H] = 227.32. Step 2: 1-(4-bromo-2,3-difluorophenyl)-N,N-dimethylpyrrolidin-3-amine [ka]

[0405] N-Bromosuccinimide (0.288 g, 1.62 mmol) was added to a stirred, room-temperature solution of 1-(2,3-difluorophenyl)-N,N-dimethylpyrrolidin-3-amine in CHCl (8 mL), and the mixture was stirred for 16 h. The mixture was concentrated onto Celite and purified by silica gel chromatography (eluting with 0.5-10% CHCl / MeOH + 0.5% NHOH) to give the product (261 mg, 66%). LCMS: [M + H] + = 305.42. Step 3: 1-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine [ka]

[0406] A procedure analogous to that described in Step 2 of Example 7, using 1-(4-bromo-2,3-difluorophenyl)-N,N-dimethylpyrrolidin-3-amine (0.261 g, 0.855 mmol), bis(pinacolato)diboron (0.271 g, 1.069 mmol), KOAc (0.168 g, 1.711 mmol), and XPhos Pd G2 (0.050 g, 0.064 mmol), afforded the product (74 mg, 17%), which was judged to be approximately 70% pure and was used in the next step without further purification. LCMS: [M + H] + = 353.44. Step 4: 6-(3-amino-6-(4-(3-(dimethylamino)pyrrolidin-1-yl)-2,3-difluorophenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0407] A procedure similar to Step 4 of Example 7 was carried out using 1-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-N,N-dimethylpyrrolidin-3-amine (0.024 g, 0.069 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.020 g, 0.063 mmol) and XPhos Pd G2 (4.93 mg, 6.27 μmol) to give the compound described in the title (11 mg, 38%) after workup and purification. 1H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J = 2.0 Hz, 1H), 7.9-8.0 (m, 2H), 7.7-7.8 (m, 2H), 7.52 (br t, J = 8.6 Hz, 1H), 6.63 (br t, J = 8.4 Hz, 1H), 6.41 (s, 2H), 3.4-3.6 (m, 10H), 3.25 (br d, 2H, J = 8.4 Hz), 2.99 (br t, J = 6.2 Hz, 2H), 2.78 (br d, J = 4.8 Hz, 2H), 2.21 (br s, 7H), 2.1-2.2 (m, 1H), 1.7-1.8 (m, 1H); LCMS: [M+H] + = 465.7. Example 22: (R)-6-(3-amino-6-(2-fluoro-4-(3-methylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-22) [ka] Step 1: (R)-4-(4-chloro-3-fluorophenyl)-3-methylmorpholine [ka]

[0408] An analogous procedure was performed in Step 1 of Example 7 using (R)-3-methylmorpholine (0.21 mL, 1.43 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.139 mL, 1.194 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.033 g, 0.036 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.062 g, 0.107 mmol), and CsCO (1.167 g, 3.58 mmol) to give the product (84 mg, 31%). LCMS: [M + H] + = 230.11. Step 2: (R)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylmorpholine [ka]

[0409] In a procedure analogous to that described in Step 2 of Example 7, (R)-4-(4-chloro-3-fluorophenyl)-3-methylmorpholine (0.084 g, 0.366 mmol), bis(pinacolato)diboron (0.116 g, 0.457 mmol), KOAc (0.072 g, 0.731 mmol), and XPhos Pd G2 (0.022 g, 0.027 mmol) were used to give the product (165 mg, 45%). LCMS: [M + H] + = 322.23. Step 3: (R)-6-(3-amino-6-(2-fluoro-4-(3-methylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0410] In a procedure similar to Step 4 of Example 7, using (R)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylmorpholine (0.022 g, 0.069 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.020 g, 0.063 mmol) and XPhos Pd G2 (4.93 mg, 6.27 μmol), the compound described in the title was obtained as a yellow powder (15 mg, 55%). 1H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J = 2.3 Hz, 1H), 7.9-8.0 (m, 2H), 7.78 (t, J = 9.2 Hz, 1H), 7.73 (dd, J = 8.0, 1.3 Hz, 1H), 7.69 (s, 1H), 6.82 (dd, J = 8.9, 2.2 Hz, 1H), 6.76 (br dd, J = 15.5, 2.0 Hz, 1H), 6.35 (s, 2H), 3.9-4.0 (m, 2H), 3.7-3.7 (m, 2H), 3.54 (dt, J = 11.5, 2.9 Hz, 1H), 3.4-3.5 (m, 3H), 3.0-3.1 (m, 3H), 1.06 (d, J = 6.6 Hz, 3H); LCMS: [M + H] + = 434.7. Example 23: (S)-6-(3-amino-6-(2-fluoro-4-(3-methylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-23) [ka] Step 1: (S)-4-(4-chloro-3-fluorophenyl)-3-methylmorpholine [ka]

[0411] A procedure analogous to Step 1 of Example 7 was carried out using (S)-3-methylmorpholine (0.21 mL, 1.43 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.139 mL, 1.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.033 g, 0.036 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.062 g, 0.107 mmol), and CsCO (1.17 g, 3.58 mmol) to give the product (114 mg, 42%). LCMS: [M + H] + = 232.29 Step 2: (S)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylmorpholine [ka]

[0412] In a procedure analogous to that described in Step 2 of Example 7, (S)-4-(4-chloro-3-fluorophenyl)-3-methylmorpholine (0.114 g, 0.496 mmol), bis(pinacolato)diboron (0.158 g, 0.620 mmol), KOAc (0.097 g, 0.993 mmol), and XPhos Pd G2 (0.029 g, 0.037 mmol) were used to give the product (41 mg, 26%). LCMS: [M + H] + = 322.23. Step 3: (S)-6-(3-amino-6-(2-fluoro-4-(3-methylmorpholino)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0413] In a procedure similar to Step 4 of Example 7, using (S)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-methylmorpholine (0.021 g, 0.066 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.020 g, 0.063 mmol) and XPhos Pd G2 (4.93 mg, 6.27 μmol), the compound described in the title (11 mg, 40%) was obtained as a yellow powder. 1H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J = 2.2 Hz,1H), 7.9-8.0 (m, 2H), 7.78 (t, J = 9.2 Hz, 1H), 7.73 (br d, J = 8.1 Hz, 1H), 7.69 (s, 1H), 6.82 (dd, J = 8.9, 2.1 Hz, 1H), 6.76 (dd, J = 15.5, 2.0 Hz, 1H), 6.35 (s, 2H), 3.9-4.0 (m, 2H), 3.7-3.7 (m, 2H), 3.54 (dt, J = 11.5, 2.9 Hz, 1H), 3.4-3.4 (m, 2H), 3.0-3.1 (m, 3H), 1.06 (d, J = 6.6 Hz, 3H); LCMS: [M + H] + 434.7. Example 24: 6-(3-amino-6-(4-(3-isopropylpiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-24) [ka] Step 1: (5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid [ka]

[0414] To a stirred solution of 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (1 g, 3.1 mmol, prepared as described in Example 19) in 1,4-dioxane (20 mL) was added B2Pin2 (3.97 g, 15.7 mmol) and KOAc (0.92 g, 98.6 mmol), argon was bubbled through at room temperature for 15 minutes, and Pd(dppf)Cl2 was added. .The reaction mixture was heated at 60° C. for 16 hours and filtered through a bed of Celite, washed with EtOAc, and concentrated under reduced pressure to give the crude compound, which was triturated with 70% EtOAc in hexanes to give the product (0.7 g, 78%) as a black solid. LCMS: [M + H] + = 285.37. Step 2: 6-(3-amino-6-(4-(3-isopropylpiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0415] In a procedure similar to Step 4 of Example 7, using 1-(4-chlorophenyl)-3-isopropylpiperidine (0.023 g, 0.097 mmol), (5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid (0.025 g, 0.088 mmol), and XPhos Pd G2 (6.92 mg, 8.80 μmol), the compound described in the title (3 mg, 8%) was obtained. 1 H NMR (500 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.9-8.0 (m, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.75 (br d, J = 8.1 Hz, 1H), 7.70 (s, 1H), 6.98 (br d, J = 8.9 Hz, 2H), 6.20 (s, 2H), 3.72 (br d, J = 12.0 Hz, 2H), 3.42 (br dd, J = 6.4, 2.4 Hz, 2H), 3.00 (br t, J = 6.4 Hz, 2H), 2.6-2.7 (m, 1H), 1.8-1.8 (m, 1H), 1.72 (br d, J = 13.2 Hz, 1H), 1.5-1.6 (m, 2H), 1.3-1.4 (m, 1H), 1.13 (dq, J = 12.2, 3.7 Hz, 1H), 0.93 (dd, J = 15.3, 6.8 Hz, 6H); LCMS: [M + H] += 442.6. Example 25: 6-(3-amino-6-(2-fluoro-4-(3-isopropylpiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-25) Step 1: 1-(4-chloro-3-fluorophenyl)-3-isopropylpiperidine [ka]

[0416] A procedure analogous to Step 1 of Example 7 was carried out using 3-(propan-2-yl)piperidine (0.182 g, 1.432 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.250 g, 1.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.033 g, 0.036 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.062 g, 0.107 mmol), and CsCO (1.17 g, 3.58 mmol) to give the product (214 mg, 70%). LCMS: [M + H] + = 256.12. Step 2: 6-(3-amino-6-(2-fluoro-4-(3-isopropylpiperidin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0417] A procedure analogous to Step 4 of Example 7 was carried out using 1-(4-chloro-3-fluorophenyl)-3-isopropylpiperidine (0.025 g, 0.097 mmol), (5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid (0.025 g, 0.088 mmol, from Example 24), and XPhos Pd G2 (6.92 mg, 8.80 μmol) to give the compound described in the title (7 mg, 17%). 1H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J = 2.2 Hz, 1H), 7.9-8.0 (m, 2H), 7.7-7.8 (m, 2H), 7.69 (s, 1H), 6.84 (dd, J = 8.9, 2.2 Hz, 1H), 6.76 (dd, J = 15.6, 2.0 Hz, 1H), 6.33 (s, 2H), 3.76 (br t, J = 11.9 Hz, 2H), 3.42 (br dd, J = 6.1, 4.0 Hz, 2H), 2.99 (br t, J = 6.4 Hz, 2H), 2.71 (dt, J = 12.4, 2.5 Hz, 1H), 2.54 (br s, 1H), 1.79 (br d, J = 12.2 Hz, 1H), 1.71 (br d, J = 13.1 Hz, 1H), 1.4-1.6 (m, 2H), 1.3-1.4 (m, 1H), 1.1-1.2 (m, 1H), 0.92 (dd, J = 17.0, 6.7 Hz, 6H); LCMS: [M + H] + = 460.6. Example 26: 6-(3-amino-6-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-26) [ka] Step 1: (1S,4S)-2-(4-chlorophenyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane [ka]

[0418] A mixture of (1S,4S)-2-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane hydrobromide (246 mg, 0.849 mmol) was filtered through a Waters PoraPak CX column (2 g), rinsed with MeOH, and eluted with 2 M NH in MeOH. The MeOH / NH fraction was concentrated under reduced pressure, and the residue was taken up in anhydrous THF (10 mL) and treated with 37 wt% formaldehyde solution in water (0.702 mL, 9.34 mmol). After stirring for 3 h at room temperature, NaBH(OAc) (234 mg, 1.10 mmol) in THF (10 mL) was treated with 37 wt% formaldehyde solution in water (0.702 mL, 9.34 mmol) at room temperature. After stirring for an additional 3 h at room temperature, another portion of NaBH(OAc) (234 mg, 1.104 mmol) was added and stirring was continued for 16 h. The mixture was concentrated under reduced pressure, loaded onto a Biotage® sample, and purified by flash chromatography (25 g SiO2 Biotage® cartridge, MeOH in CH2Cl2, eluting with 15% MeOH, pooled fractions 15–35) to give the product as a white solid (199 mg, quantitative yield). LCMS: [M + H] + = 223.26. Step 2: 6-(3-amino-6-(4-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-26) [ka]

[0419] The procedure used was similar to that described in Step 3 of Example 1, using XPhos Pd G2 (22.16 mg, 0.028 mmol), (1S,4S)-2-(4-chlorophenyl)-5-methyl-2,5-diazabicyclo[2.2.1]heptane (62.7 mg, 0.282 mmol), 5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid (80 mg, 0.282 mmol) (prepared as described in Example 24), and aqueous K3PO4 (0.650 mL of a 1.3 M solution, 0.845 mmol) to give the product (5.0 mg, 4% based on 98% purity) as a yellow solid. 1 H NMR (500 MHz, CD3OD) δ ppm 8.25 (s, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.68 - 7.75 (m, 3H), 7.66 (s, 1H), 6.61 (br d, J = 8.8 Hz, 2H), 4.32 (br s, 1H), 3.55 (br s, 1H), 3.47 (br t, J = 6.7 Hz, 2H), 3.39 - 3.43 (m, 1H), 3.27 (br d, J = 9.7 Hz, 1H), 2.97 - 3.04 (m, 2H), 2.72 - 2.85 (m, 2H), 2.35 (s, 3H), 1.97 (br d, J = 9.7 Hz, 1H), 1.82 - 1.92 (m, 1H); LCMS: [M + H] + = 427.49 Example 27: (R)-6-(3-amino-6-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-27) [ka] Step 1: 3-(3-bromo-4-fluorophenyl)propanoic acid [ka]

[0420] To a stirred solution of EtN (31 mL, 224.6 mmol), formic acid (22 mL, 561.6 mmol) was added portionwise, and the mixture was stirred for 15 min at room temperature. The mixture was then diluted with DMF (150 mL), and 3-bromo-4-fluorobenzaldehyde (38 g, 187.2 mmol) and Meldrum's acid (27 g, 187.2 mmol) were added. The mixture was then heated at 100 °C for 16 h and then cooled to room temperature. The reaction mixture was poured into ice-cold water (1.8 L) and concentrated HCl (100 mL). The mixture was extracted with CHCl (2 × 600 mL). The organic layer was washed with 1 N NaOH (2 × 500 mL). The aqueous layer was acidified with concentrated HCl and extracted with EtOAc (2 × 600 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the product (38 g, 46.7% purity by LCMS) as a brown liquid. This crude compound was taken on to the next step without further purification. LCMS: [M + H] + = 247.20 Step 2: 5-Bromo-6-fluoro-2,3-dihydro-1H-inden-1-one [ka]

[0421] To a stirred solution of 3-(3-bromo-4-fluorophenyl)propanoic acid (38 g, 46.7% pure by LCMS) (16 g, 65 mmol) in CHCl (100 mL) was added oxalyl chloride (22 mL, 260 mmol) and DMF (1 mL) at room temperature for 30 min. The solvent was concentrated under reduced pressure to give a crude residue. This residue was dissolved in CHCl (200 mL) and added dropwise to a stirred solution of AlCl (35 g, 260 mmol) in CHCl (1 lt). The mixture was stirred for 2 h at room temperature. The mixture was poured into ice-cold water (800 mL) and concentrated HCl (50 mL) and extracted with CHCl (2 × 600 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 230-400 mesh) using 0-10% EtOAc in petroleum ether as eluent to give the product (14 g, 94%) as an off-white solid. LCMS: [M+H] + = 229.24. Step 3: 6-Bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0422] To a stirred solution of 5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one (14.8 g, 65 mmol) in CHCl (120 mL) and methanesulfonic acid (60 mL) was added NaN (14.7 g, 227.2 mmol) portionwise at 0 °C for 1 h. The mixture was basified with 20% aqueous NaOH (300 mL) and extracted with CHCl (2 × 400 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure to give the crude product. The crude compound was purified by column chromatography (silica gel, 230-400 mesh) using 0-90% EtOAc in hexane as the eluent to give the product (8 g, 51%) as an off-white solid. TLC: 80% EtOAc:petroleum ether; R f = 0.3. Step 4: 7-Fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0423] To a stirred solution of 6-bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (8 g, 33 mmol) in 1,4-dioxane (100 mL) was added KOAc (9.7 g, 99 mmol) and 6-bromo-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (12.5 g, 49.3 mmol) at room temperature, and the mixture was then degassed with argon for 30 minutes. Pd(dppf)Cl .CHCl(0) (2.7 g, 3.3 mmol) was added, and the reaction mixture was heated at 85° C. for 16 h, then cooled to room temperature. The reaction mixture was filtered through a Celite bed and washed with EtOAc (700 mL), and the filtrate was concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (silica gel, 100-200 mesh) using 0-100% EtOAc in petroleum ether and 0-5% MeOH in CHCl as eluents to give the product (5.5 g, 57%) as a brown gummy liquid. LCMS: [M + H] + = 210.32. Step 5: 6-(3-amino-6-bromopyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0424] To a stirred solution of 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (7 g, 24 mmol) in DMF:water (70 mL:7 mL) was added KCO (6.6 g, 48 mmol) and 3,5-dibromopyrazin-2-amine (7.2 g, 28.8 mmol, prepared as described in Step 4 of Example 14) at room temperature, and the reaction mixture was then degassed with argon for 30 minutes. Trans-dichlorobis(triphenylphosphine)palladium(II) (845 mg, 1.2 mmol) was added, and the reaction mixture was heated at 90° C. for 16 hours, then cooled to room temperature. The mixture was filtered through a Celite bed and washed with EtOAc (500 mL), and the filtrate was washed with cold water (200 mL). The organic layer was separated, then dried over Na2SO4, and concentrated under reduced pressure to give the crude compound. The crude product was purified by column chromatography (silica gel, 230-400 mesh) using 0-100% EtOAc in petroleum ether as the eluent to give the product (2.4 g, 40%) as a light brown solid. LCMS: [M + H]+ = 337.21. Step 6: (R)-6-(3-amino-6-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0425] In a procedure similar to Step 4 of Example 7, using (R)-2-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.030 g, 0.091 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (0.031 g, 0.091 mmol) and XPhos Pd G2 (7.13 mg, 9.06 μmol), the compound described in the title (19 mg, 46%) was obtained as a yellow powder. 1 H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.14 (br s, 1H), 7.80 (br d, J = 8.3 Hz, 2H), 7.64 (br d, J = 10.1 Hz, 1H), 7.51 (br d, J = 6.7 Hz, 1H), 7.01 (br d, J = 6.7 Hz, 1H), d, J = 8.6 Hz, 2H), 6.18 (s, 2H), 3.97 (br d, J = 11.6 Hz, 1H), 3.5-3.7 (m, 4H), 3.42 (br s, 3H), 3.2-3.3 (m, 2H), 2.96 (br t, J = 6.0 Hz, 2H), 2.68 (dt, J = LCMS: [M + H] + = 462.4. Example 28: (S)-6-(3-amino-6-(4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-28) [ka]

[0426] In a procedure similar to Step 4 of Example 7, using (S)-2-isopropyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine (0.030 g, 0.091 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (0.031 g, 0.091 mmol) and XPhos Pd G2 (7.13 mg, 9.06 μmol), the compound described in the title (18 mg, 43%) was obtained as a yellow powder. 1 H NMR (500 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.14 (br s, 1H), 7.80 (br d, J = 8.8 Hz, 2H), 7.64 (d, J = 10.1 Hz, 1H), 7.51 (br d, J = 6.8 Hz, 1H), 7.01 (br d, J = 8.8 Hz, 2H), 6.18 (s, 2H), 3.9-4.0 (m, 1H), 3.5-3.6 (m, 5H), 3.42 (br d, J = 4.0 Hz, 3H), 3.2-3.3 (m, 3H), 2.96 (br t, J = 6.3 Hz, 2H), 2.6-2.7 (m, 1H), 2.4-2.5 (m, 2H), 1.73 (qd, J = 13.3, 6.4 Hz, 1H), 0.96 (dd, J = 6.6, 2.9 Hz, 6H); LCMS: [M + H] + = 462.4. Example 29: (R)-6-(3-amino-6-(2-fluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-29) [ka]

[0427] In a procedure similar to that described in Step 4 of Example 7, using (R)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine (0.030 g, 0.086 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (0.029 g, 0.086 mmol) and XPhos Pd G2 (6.76 mg, 8.59 μmol), the compound described in the title (14 mg, 34%) was obtained as a yellow powder. 1 H NMR (500 MHz, DMSO-d6) δ 8.35 (d, J = 1.7 Hz, 1H), 8.15 (br s, 1H), 7.70 (br t, J = 9.2 Hz, 1H), 7.64 (d, J = 10.1 Hz, 1H), 7.52 (br d, J = 6.8 Hz, 1H), 6.8-6.9 (m, 2H), 6.32 (s, 2H), 3.9-4.0 (m, 1H), 3.6-3.7 (m, 4H), 3.42 (br s, 3H), 3.2-3.3 (m, 1H), 2.95 (br t, J = 6.2 Hz, 2H), 2.7-2.8 (m, 1H), 1.73 (qd, J = 13.2, 6.6 Hz, 1H), 0.96 (br d, J = 6.7 Hz, 6H); LCMS: [M + H] + = 480.4. Example 30: (S)-6-(3-amino-6-(2-fluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-30) [ka]

[0428] In a procedure similar to that described in Step 4 of Example 7, using (S)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine (0.030 g, 0.086 mmol), 6-(3-amino-6-bromopyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (prepared as described in Step 5 of Example 27) (0.029 g, 0.086 mmol) and XPhos Pd G2 (6.76 mg, 8.59 μmol), the compound described in the title (13 mg, 32%) was obtained as a yellow powder. 1 H NMR (500 MHz, DMSO-d6) δ 8.35 (d, J = 2.2 Hz, 1H), 8.15 (br s, 1H), 7.70 (br t, J = 9.2 Hz, 1H), 7.64 (d, J = 10.1 Hz, 1H), 7.52 (d, J = 6.7 Hz, 1H), 6.8-6.9 (m, 2H), 6.32 (s, 2H), 3.97 (br dd, J = 11.1, 2.6 Hz, 1H), 3.6-3.7 (m, 3H), 3.4-3.5 (m, 3H), 3.2-3.3 (m, 1H), 2.95 (br t, J = 6.2 Hz, 2H), 2.71 (dt, J = LCMS: [M + H] + = 480.4. Example 31: (R)-6-(3-amino-6-(2,3-difluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-31) [ka]

[0429] A mixture of (R)-4-(2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine (60 mg, 0.163 mmol) (prepared as described in Step 3 of Example 15), 6-(3-amino-6-bromopyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (prepared as described in Step 5 of Example 27) (55.1 mg, 0.163 mmol), and XPhos Pd G2 (12.85 mg, 0.016 mmol) was added to a sealed, evacuated, and back-filled reaction vessel with N2. Tribasic KPO (87 mg, 0.408 mmol) in 1,4-dioxane (2 mL) and HO (0.4 mL) was added, and the reaction vessel was evacuated and backfilled with nitrogen. The reaction mixture was heated at 90 °C overnight, worked up, and the product purified in a manner similar to the previous example to give the compound described in the title (20 mg, 23%). 1 H NMR (500 MHz, DMSO-d6) δ 8.4-8.4 (m, 1H), 8.15 (br s, 1H), 7.64 (d, J = 10.1 Hz, 1H), 7.5-7.6 (m, 2H), 6.96 (br t, J = 8.1 Hz, 1H), 6.50 (s, 2H), 3.94 (br d, J = 11.0 Hz, 1H), 3.6-3.7 (m, 1H), 3.4-3.5 (m, 2H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 2H), 2.95 (br t, J = 6.1 Hz, 2H), 2.8-2.9 (m, 1H), 2.6-2.6 (m, 1H), 1.71 (qd, J = 13.4, 6.7 Hz, 1H), 0.95 (br d, J = 6.7 Hz, 3H), 0.91 (br d, J = 6.7 Hz, 3H); LCMS: [M + H] + = 498.3. Example 32: (S)-6-(3-amino-6-(2,3-difluoro-4-(2-isopropylmorpholino)phenyl)pyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (I-32) [ka]

[0430] (S)-4-(2,3-Difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropylmorpholine (40 mg, 0.109 mmol, 1 equiv.), 6-(3-amino-6-bromopyrazin-2-yl)-7-fluoro-3,4-dihydroisoquinolin-1(2H)-one (36.7 mg, 0.109 mmol, 1 equiv.), and XPhos Pd G2 (8.57 mg, 10.89 μmol, 0.1 equiv.) were placed in a reaction vial. 1,4-Dioxane (2 mL) and tribasic K3PO4 (57.8 mg, 0.272 mmol) in HO (0.4 mL) were added under a nitrogen atmosphere. The reaction mixture was bubbled with nitrogen and sealed. The reaction mixture was heated at 90 °C overnight, evaporated through Celite, and purified by reverse-phase flash chromatography (HO / ACN) followed by normal-phase flash chromatography (CHCl / ACN). Fractions containing the pure compound were collected and dried to give the compound described in the title as a yellow solid (10 mg, 18%). 1 H NMR (500 MHz, DMSO-d6) δ 8.39 (d, J = 2.3 Hz, 1H), 8.15 (br s, 1H), 7.64 (d, J =10.3 Hz, 1H), 7.5-7.6 (m, 2H), 6.96 (br t, J = 8.1 Hz, 1H), 6.50(s, 2H), 3.94 (br d, J = 10.1 Hz, 1H), 3.6-3.7 (m, 1H), 3.4-3.5 (m, 2H), 3.4-3.4 (m, 1H), 3.2-3.3 (m, 2H), 2.95 (br t, J = 6.3 Hz, 2H), 2.82 (dt, J = 11.6 Hz, 2.9, 1H), 2.5-2.6 (m, 1H), 1.71 (qd, J = 13.4, 6.7 Hz, 1H), 0.95 (br d, J = 6.7 Hz, 3H), 0.91 (br d, J = 6.8 Hz, 3H); LCMS: [M + H] + = 498.51. Example 33: 6-(3-amino-6-(4-(1-methyl-5,6-dihydro-1,2,4-triazin-4(1H)-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-33) [ka]

[0431] The compound described in the title was obtained according to a procedure analogous to that described in Step 3 of Example 1, using 5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid (224 mg, 0.787 mmol) (prepared as described in Step 1 of Example 24), Pd(amphos)Cl (13.93 mg, 0.020 mmol), 4-(4-bromophenyl)-1-methyl-1,4,5,6-tetrahydro-1,2,4-triazine (100 mg, 0.393 mmol) (prepared as described in Step 8 of Example 31), KPO (251 mg, 1.180 mmol), and HO (0.75 mL), yielding the compound described in the title as a yellow solid (16.0 mg, 10% based on 97% purity). 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.54 (s, 1H), 7.90 - 8.03 (m, 4H), 7.75 (br d, J = 8.0 Hz, 1H), 7.69 (br s, 1H), 7.42 - 7.49 (m, 1H), 7.21(br d, J = 8.8 LCMS: [M + H] + = 414.30. Example 34: 6-(3-amino-6-(4-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-34) [ka] Step 1: (1S,4S)-2-(4-chlorophenyl)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptane [ka]

[0432] (1S,4S)-(-)-2-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]heptane hydrobromide (70 mg, 0.242 mmol) was filtered through a Waters PoraPak CX column to produce the corresponding free base. A solution of this free base in THF (15 mL) in a round-bottom flask equipped with a reflux condenser was heated to 70 °C. Phenylsilane (0.060 mL, 0.483 mmol) was added to this, followed by TFA (0.032 mL, 0.423 mmol) at 70 °C. After stirring at 70 °C for 3 hours, another batch of TFA (1.75 equiv.) and phenylsilane (2 equiv.) were added at 70 °C. Finally, after stirring for an additional 2 hours at 70°C, a third batch of TFA (1.75 equiv.) and phenylsilane (2 equiv.) was added, and the reaction was stirred continuously overnight at 70°C. The reaction mixture was concentrated to dryness and adsorbed onto Celite. Silica gel chromatography (eluting with 0-8% EtOAc / hexane) afforded the product as a white solid (86 mg, 100% based on 82% purity). LCMS: [M + H] + = 291.32. Step 2: 6-(3-amino-6-(4-((1S,4S)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0433] (1S,4S)-2-(4-chlorophenyl)-5-(2,2,2-trifluoroethyl)-2,5-diazabicyclo[2.2.1]heptane (43 mg, 0.126 mmol), (5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid (prepared as described in Step 1 of Example 24) (42.9 mg, 0.151 mmol), XPhos Pd A microwave vial containing G2 (12.86 mg, 0.016 mmol), KPO (80 mg, 0.377 mmol), 1-butanol (4 mL), and water (0.8 mL) was flushed with argon. The reaction mixture was heated in a microwave reactor at 90 °C for 1.75 h. The reaction mixture was partitioned between brine and EtOAc. The layers were separated, and the aqueous layer was further extracted with a CHCl / IPA (4:1) solvent mixture (2 × 4 mL). The combined extracts were dried and concentrated onto Celite. Silica gel chromatography (eluting with 0–80% EtOAc / hexanes) followed by a second silica gel column (eluting with 0–2% MeOH / CHCl) and filtration through a Waters PoraPak CX column afforded the title compound as a pale yellow solid (13.5 mg, 20%). 1H NMR (500 MHz, DMSO-d6) δ 8.4-8.5 (m, 1H), 7.9-8.0 (m, 2H), 7.8-7.8 (m, 2H), 7.7-7.8 (m, 1H), 7.7-7.7 (m, 1H), 6.6-6.7 (m, 2H), 6.14 (s, 2H), 4.40 (br s, 1H), 3.7-3.7 (m, 1H), 3.4-3.5 (m, 4H), 3.3-3.3 (m, 1H), 3.2-3.3 (m, 1H), 3.0-3.1 (m, 3H), 2.6-2.7 (m, 1H), 1.8-1.9 (m, 2H). LCMS: [M+H] + = 495.55. Example 35: 6-(3-amino-6-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-35) [ka] Step 1: 1-(4-chlorophenyl)-4-(2,2,2-trifluoroethyl)piperazine [ka]

[0434] A slurry of 1-chloro-4-iodobenzene (250 mg, 1.05 mmol), 1-(2,2,2-trifluoroethyl)piperazine (176 mg, 1.05 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (54.6 mg, 0.094 mmol), tris(dibenzylideneacetone)dipalladium(0) (28.8 mg, 0.031 mmol), and potassium tert-butoxide (353 mg, 3.15 mmol) in toluene (5 mL) was flushed with argon. The slurry was heated in an oil bath at 110 °C for 3 h. The reaction was partitioned between EtOAc (10 mL) and water. The layers were separated, and the organic layer was washed twice with water. The organic layer was concentrated onto Celite. Silica gel chromatography (eluting with 0-2% EtOAc / hexanes) afforded the product as a white powder (166 mg, 57%). LCMS: [M + H] + = 279.47 Step 2: 6-(3-amino-6-(4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0435] In a procedure analogous to that of Step 2 of Example 34, 1-(4-chlorophenyl)-4-(2,2,2-trifluoroethyl)piperazine (25 mg, 0.090 mmol) was used with (5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid (prepared as described in Step 1 of Example 24) (30.6 mg, 0.0108 mmol) in a microwave reactor at 90 °C for 1.75 h. The reaction mixture was partitioned between brine and EtOAc. The layers were separated, and the aqueous layer was further extracted with CHCl. ​​The combined extracts were dried and concentrated onto Celite. Silica gel chromatography (eluted with EtOAc / hexane) and filtration through a Waters PoraPak CX column afforded the title compound as a pale yellow solid (7.5 mg, 16%). 1 H NMR (500 MHz, DMSO-d6) δ 8.55 - 8.41 (m, 1H), 7.96 (br d, J = 8.2 Hz, 2H), 7.85 (br d, J = 8.6 Hz, 2H), 7.79 - 7.73 (m, 1H), 7.72 - 7.68 LCMS: [M+H] + = 483.46. Example 36: 6-(3-amino-6-(4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-36) [ka] Step 1: Preparation of 4-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)piperidine [ka]

[0436] A procedure analogous to that described in Step 1 of Example 34 was used in which 4-(4-bromophenyl)piperidine (250 mg, 1.04 mmol) in THF (5 mL) was reacted with phenylsilane (0.257 mL, 2.08 mmol) and TFA (0.140 mL, 1.82 mmol) in a round-bottom flask equipped with a reflux condenser at 70° C. for 2 h. The reaction mixture was concentrated, and the residue was taken up in dichloromethane and washed with saturated aqueous NaHCO3 (×2). The organic solution was then dried and concentrated onto Celite. Silica gel chromatography (eluting with 0–60% EtOAc / hexane) afforded the product as a pale yellow oil (301 mg, 79% based on 89% purity). LCMS: [M + H] + = 322.41. Step 2: 6-(3-amino-6-(4-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0437] In a procedure analogous to that of Step 2 of Example 34, 4-(4-bromophenyl)-1-(2,2,2-trifluoroethyl)piperidine (25 mg, 0.078 mmol, 88.5% purity) was used with (5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid (prepared as described in Step 1 of Example 24) (26.5 mg, 0.093 mmol) in a microwave reactor at 90 °C for 1.75 h. The reaction mixture was partitioned between brine and EtOAc. The layers were separated, and the aqueous layer was further extracted with CHCl (×2). The combined extracts were dried and concentrated onto Celite. Silica gel chromatography (eluting with 0-3.5% MeOH / CH2Cl2) gave the compound described in the title as a pale yellow solid (9 mg, 23%). 1 H NMR (500 MHz, CDCl3) δ 8.51 - 8.42 (m, 1H), 8.25 - 8.19 (m, 1H), 7.94 - 7.87 (m, 2H), 7.83 (br d, J = 7.8 Hz, 1H), 7.71 (s, 1H),7.36 - 7.29 (m, 2H), 6.21 - 6.12 (m, 1H), 4.94 - 4.73 (m, 2H), 3.67 - 3.62 (m, 2H), 3.14 - 3.09 (m, 4H), 3.07 - 3.01 (m, 2H), 2.56 - 2.47 (m, 3H), 1.90 - 1.84 (m, 4H); LCMS: [M + H] + = 482.46 Example 37: 6-(3-amino-6-(4-((1R,5S)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-37) [ka] Step 1: (1R,5S)-1-(4-bromophenyl)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane [ka]

[0438] To a room temperature slurry of (1R,5S)-1-(4-bromophenyl)-3-azabicyclo[3.1.0]hexane (100 mg, 0.420 mmol) in DMF (2 mL) was added 2-fluoroethyl 4-methylbenzenesulfonate (183 mg, 0.840 mmol) and triethylamine (0.585 mL, 4.20 mmol), and the reaction mixture was heated overnight in an oil bath at 100 °C. The reaction mixture was partitioned between water (6 mL) and a CHCl3 / IPA (4:1) solvent mixture (6 mL). The layers were separated, and the aqueous layer was further extracted twice with a CHCl3 / IPA (4:1) solvent mixture. The combined extracts were dried and concentrated onto Celite. Silica gel chromatography of the residue (eluting with CH2Cl2 containing 0-2.5% MeOH and 0-0.25% NH4OH) gave the compound described in the title as a brown oil (84 mg, 62% based on 88% purity). LCMS: [M + H]+ = 484.36. Step 2: 6-(3-amino-6-(4-((1R,5S)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexan-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0439] A procedure analogous to that of Step 2 of Example 34 was carried out using (1R,5S)-1-(4-bromophenyl)-3-(2-fluoroethyl)-3-azabicyclo[3.1.0]hexane (42 mg, 0.129 mmol, 88% purity) and (5-amino-6-(1-oxo-1,2,3,4-tetrahydroisoquinolin-6-yl)pyrazin-2-yl)boronic acid (prepared as described in Step 1 of Example 24) (47.5 mg, 0.167 mmol) to give the compound described in the title as a pale yellow solid (10 mg, 23%). 1 H NMR (500 MHz, DMSO-d6) δ 8.61 - 8.49 (m, 1H), 8.02 - 7.95 (m, 2H), 7.93 - 7.87 (m, 2H), 7.77 - 7.73 (m, 1H), 7.72 - 7.69 (m, 1H), 7.25 - 7.18 (m, 2H), 6.45 - 6.30 (m, 2H), 4.63 - 4.56 (m, 1H), 4.53 - 4.47 (m, 1H), 3.45 - 3.43 (m, 4H), 3.15 - 3.10 (m, 1H), 3.03 - 2.98 (m, 2H), 2.82 - 2.76 (m, 1H), 2.73 - 2.66 (m, 1H), 2.56 (br s, 1H), 1.91 - 1.82 (m, 1H), 1.39 - 1.34 (m, 1H), 0.82 - 0.78 (m, 1H); LCMS: [M + H] + = 444.47. Example 38: (R)-6-(3-amino-6-(4-(3-isopropyl-4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one 19399 (I-38) [ka] Step 1: tert-Butyl (R)-3-isopropyl-4-methylpiperazine-1-carboxylate [ka]

[0440] To a solution of (R)-1-Boc-3-isopropyl-piperazine (1.0 g, 4.4 mmol) in 1:1 MeOH:THF (20 mL) was added aqueous formaldehyde (37%, 0.5 mL, 6.6 mmol), followed by sodium triacetoxyborohydride (1.4 g, 6.6 mmol). The reaction was stirred at room temperature for 18 hours. Volatiles were removed in vacuo, and the residue was partitioned between aqueous KOH (1 N) and CHCl. ​​The layers were separated, and the aqueous layer was extracted twice with additional CHCl. ​​The combined organic extracts were dried over MgSO and concentrated to dryness to give the product (1.1 g, quantitative yield). LCMS: [M + H] + = 243.3. Step 2: (R)-2-Isopropyl-1-methylpiperazine [ka]

[0441] TFA (2 mL, 26 mmol) was added to a room temperature solution of tert-butyl (R)-3-isopropyl-4-methylpiperazine-1-carboxylate (0.50 g, 2.06 mmol) in CHCl (10 mL). The reaction mixture was allowed to stir at room temperature for 18 hours. The volatiles were removed under a stream of compressed air, and the residue was dried under reduced pressure to give the trifluoroacetate salt of (R)-2-isopropyl-1-methylpiperazine (1.1 g, quantitative yield). LCMS: [M + H] + = 143.4. Step 3: (R)-4-(4-chlorophenyl)-2-isopropyl-1-methylpiperazine [ka]

[0442] A 30 mL vial was charged with the trifluoroacetate salt of (R)-2-isopropyl-1-methylpiperazine (0.50 g, 1.4 mmol), 1-chloro-4-iodobenzene (0.40 g, 1.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.037 g, 0.041 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.070 g, 0.12 mmol), and CsCO (2.6 g, 8.1 mmol). The vial was sealed with a cap and septum, and the reaction vial was then evacuated and backfilled with nitrogen. Toluene (6 mL) was added, and the reaction vial was evacuated and backfilled with nitrogen again. The reaction was conventionally heated at 100° C. for 18 h. After cooling to room temperature, the reaction mixture was concentrated directly onto Celite® and purified by flash chromatography (0.5-9.5% CH2Cl2 / MeOH + 0.5% NH4OH) to give the product (0.18 g, 51%). LCMS: [M + H] + = 253.3. Step 4: (R)-2-Isopropyl-1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine [ka]

[0443] A 30 mL vial was charged with (R)-4-(4-chlorophenyl)-2-isopropyl-1-methylpiperazine (0.18 g, 0.69 mmol), bis(pinacolato)diboron (0.26 g, 1.0 mmol), KOAc (0.14 g, 1.4 mmol), and XPhos® Pd G2 (0.041 g, 0.052 mmol). The vial was sealed with a cap and septum, and the reaction vial was then evacuated and backfilled with nitrogen. 1,4-Dioxane (6 mL) was added, and the reaction vial was evacuated and backfilled with nitrogen again. The reaction was heated conventionally at 110° C. for 18 hours. After cooling to room temperature, the reaction mixture was concentrated directly onto Celite and purified by flash chromatography (0.5-7.5% CH2Cl2 / MeOH+0.5% NH4OH) to give the product (0.20 g, 83%). LCMS: [M + H] + = 345.4. Step 5: (R)-6-(3-amino-6-(4-(3-isopropyl-4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0444] A 30 mL vial was charged with 6-(3-amino-6-bromopyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (0.055 g, 0.17 mmol), (R)-2-isopropyl-1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (0.065 g, 0.19 mmol), and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CHCl complex (0.014 g, 0.017 mmol). The vial was sealed with a cap and septum, and the reaction vessel was evacuated and backfilled with nitrogen. 1,4-Dioxane (2.0 mL) and 2 M aqueous Na2CO3 (0.26 mL, 0.52 mmol) were added, and the reaction vessel was evacuated and backfilled with nitrogen. The reaction mixture was heated on an aluminum block at 90 °C for 18 h. The reaction mixture was concentrated onto Celite® and purified by flash chromatography (0.5–9.5% CHCl2 / MeOH + 0.5% NH4OH). The product-containing fractions were concentrated and further purified by reverse-phase chromatography (Biotage SNAP C18; 5–60% MeCN / water + 0.1% formic acid). Isolation of the compound described in the title was achieved by a catch-and-release procedure using Biotage SCX2 silica gel to yield the compound described in the title (120 mg, 14%) as a beige solid. 1H NMR (500 MHz; DMSO-d6) δ 8.48 (s, 1H), 7.9-8.0 (m, 2H), 7.84 (d, J = 8.8 Hz; 2H), 7.75 (dd, J = 8.0, 1.5 Hz, 1H), 7.71 (s, 1H), 6.99 (d, J = 8.9 Hz, 2H), 6.22 (s, 2H), 3.60 (br d, J = 10.8 Hz, 1H), 3.52 (br d, J = 11.5 Hz, 1H), 3.43 (dt, J = 6.5, 2.6 Hz, 2H), 2.99 (t, J = 6.5 Hz, 2H), 2.8-2.9 (m, 1H), 2.74 (dt, J = 11.8, 2.9 Hz, 1H), 2.31 (dt, J = 11.6, 3.2 Hz, 1H), 2.20 (s, 3H), 2.13 (dt, J = 6.9, 4.3 Hz, 1H), 1.95 (td, J = 10.9, 3.3 Hz, 1H), 1.00 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); LCMS: [M + H] + = 457.3. Example 39: (R)-6-(3-amino-6-(2-fluoro-4-(3-isopropyl-4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-39) [ka] Step 1: tert-Butyl (R)-3-isopropyl-4-methylpiperazine-1-carboxylate [ka]

[0445] An analogous procedure to Step 1 of Example 38 using (R)-1-Boc-3-isopropyl-piperazine (1.0 g, 4.38 mmol), a 37% wt. solution of formaldehyde in water (0.489 mL, 6.57 mmol), and NaBH(OAc) (1.39 g, 6.57 mmol) in MeOH / THF (10 mL each) gave the product (1.06 g, 100%) as a clear oil. LCMS: [M + H] + = 243.34. Step 2: (R)-2-Isopropyl-1-methylpiperazine trifluoroacetate [ka]

[0446] An analogous procedure (1.97 ml, 25.8 mmol) was used in Step 2 of Example 38 using tert-butyl (R)-3-isopropyl-4-methylpiperazine-1-carboxylate (0.50 g, 2.06 mmol) to give the product (1.07 g, 140%). LCMS: [M + H] + = 143.35. Step 3: (R)-4-(4-chloro-3-fluorophenyl)-2-isopropyl-1-methylpiperazine [ka]

[0447] In a procedure analogous to Step 3 of Example 38, (R)-2-isopropyl-1-methylpiperazine, 2 TFA (0.500 g, 1.35 mmol), and 4-bromo-1-chloro-2-fluorobenzene (0.196 mL, 1.688 mmol) were used to give the product (167 mg, 46%). LCMS: [M + H] + = 271.09. Step 4: (R)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropyl-1-methylpiperazine) [ka]

[0448] An analogous procedure was performed in Step 4 of Example 38 using (R)-4-(4-chloro-3-fluorophenyl)-2-isopropyl-1-methylpiperazine (0.167 g, 0.617 mmol), bis(pinacolato)diboron (0.235 g, 0.925 mmol), KCO (0.121 g, 1.233 mmol), and XPhos Pd G (36 mg, 0.046 mmol) to give the product (263 mg, quantitative yield). LCMS: [M + H] + = 363.30. Step 5: (R)-6-(3-amino-6-(2-fluoro-4-(3-isopropyl-4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-39) [ka]

[0449] In a procedure similar to that described in Step 5 of Example 38, using 1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CHCl complex (0.014 g, 0.017 mmol) and (R)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropyl-1-methylpiperazine (0.069 g, 0.190 mmol), the compound described in the title (12 mg, 13%) was obtained. 1H NMR (500 MHz, DMSO-d6) δ 8.31 (d, J = 2.4 Hz, 1H), 7.9-8.0 (m, 2H), 7.7-7.8 (m, 2H), 7.69 (s, 1H), 6.87 (dd, J = 8.9, 2.4 Hz, 1H), 6.81 (dd, J = 15.3, 2.3 Hz, 1H), 6.35 (s, 2H), 3.65 (br d, J = 12.1 Hz, 1H), 3.53 (br d, J = 11.9 Hz, 1H), 3.42 (dt, J = 6.5, 2.7 Hz, 3H), 2.99 (t, J = 6.5 Hz, 2H), 2.8-2.9 (m, 1H), 2.78 (dt, J = 11.8, 2.9 Hz, 1H), 2.29 (dt, J = 11.5, 3.0 Hz, 2H), 2.19 (s, 3H), 2.12 (dt, J = 6.9, 4.2 Hz, 1H), 1.92 (td, J = 10.7, 3.5 Hz, 1H), 1.00 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.1 Hz, 3H); LCMS: [M + H] + = 475.3. Example 40: (S)-6-(3-amino-6-(4-(3-isopropyl-4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-40) [ka] Step 1: tert-Butyl (S)-3-isopropyl-4-methylpiperazine-1-carboxylate [ka]

[0450] An analogous procedure to Step 1 of Example 38 was performed using (S)-1-Boc-3-isopropyl-piperazine (1.0 g, 4.38 mmol), a 37 wt% solution of formaldehyde in water (0.49 mL, 6.57 mmol), followed by NaBH(OAc) (1.39 g, 6.57 mmol) to give the product (1.09 g, quantitative yield). LCMS: [M + H] + = 243.42. Step 2: (S)-4-(4-chlorophenyl)-2-isopropyl-1-methylpiperazine [ka]

[0451] An analogous procedure to Step 2 of Example 38 was performed using TFA (1.97 mL, 25.8 mmol), tert-butyl (S)-3-isopropyl-4-methylpiperazine-1-carboxylate (0.50 g, 2.063 mmol) in CH2Cl2 (10 mL) at room temperature to give the product (1.05 g, quantitative yield). LCMS: [M + H] + = 143.42. Step 3: (S)-4-(4-chlorophenyl)-2-isopropyl-1-methylpiperazine [ka]

[0452] (S)-2-Isopropyl-1-methylpiperazine was prepared by a procedure analogous to Step 3 of Example 38. . Using TFA (0.500 g, 1.35 mmol), 1-chloro-4-iodobenzene (0.402 g, 1.69 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.037 g, 0.041 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.070 g, 0.122 mmol), and CsCO (2.64 g, 8.10 mmol), the product (150 mg, 44%) was obtained. LCMS: [M + H] += 253.27. Step 4: (S)-2-Isopropyl-1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine [ka]

[0453] A procedure analogous to Step 4 of Example 38 was performed using (S)-4-(4-chlorophenyl)-2-isopropyl-1-methylpiperazine (0.150 g, 0.593 mmol), bis(pinacolato)diboron (0.226 g, 0.890 mmol), KOAc (0.116 g, 1.19 mmol), and XPhos Pd G2 (0.035 g, 0.045 mmol) to give the product (158 mg, 77%). LCMS: [M + H] + = 345.32. Step 5: (S)-6-(3-amino-6-(4-(3-isopropyl-4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one [ka]

[0454] A procedure analogous to Step 5 of Example 38 was performed using [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CHCl complex (0.017 g, 0.020 mmol), (S)-2-isopropyl-1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (0.077 g, 0.224 mmol), and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CHCl complex (0.017 g, 0.020 mmol) to give the compound described in the heading (13 mg, 13%) as a yellow powder. 1H NMR (500 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.9-8.0 (m, 2H), 7.84 (d, J = 8.9 Hz, 2H), 7.75 (dd, J = 8.0, 1.5 Hz, 1H), 7.71 (s, 1H), 6.99 (d, J = 8.9 Hz, 2H), 6.22 (s, 2H), 3.60 (br d, J = 11.6 Hz, 1H), 3.52 (br d, J = 12.0 Hz, 1H), 3.43 (dt, J = 6.5, 2.8 Hz, 2H), 2.99 (t, J = 6.5 Hz, 2H), 2.8-2.9 (m, 1H), 2.74 (dt, J = 11.8, 2.9 Hz, 1H), 2.31 (dt, J = 11.5, 3.1 Hz, 1H), 2.20 (s, 3H), 2.13 (qd, J = 11.1, 7.0 Hz, 1H), 1.95 (td, J = 10.7, 3.3 Hz, 1H), 1.00 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H); LCMS: [M + H] + = 457.3. Example 41: (S)-6-(3-amino-6-(2-fluoro-4-(3-isopropyl-4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one 19402 (I-40) [ka] Step 1: (S)-4-(4-chloro-3-fluorophenyl)-2-isopropyl-1-methylpiperazine [ka]

[0455] By a procedure similar to Step 3 of Example 38, (S)-2-isopropyl-1-methylpiperazine .Using TFA (prepared as described in Step 2 of Example 40) (0.500 g, 1.350 mmol), 4-bromo-1-chloro-2-fluorobenzene (0.196 mL, 1.69 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.037 g, 0.041 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.070 g, 0.122 mmol), and CsCO (2.64 g, 8.10 mmol), the product (178 mg, 49%) was obtained. LCMS: [M + H] + = 271.01. Step 2: (S)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropyl-1-methylpiperazine [ka]

[0456] A procedure similar to Step 4 of Example 38 was carried out using (S)-4-(4-chloro-3-fluorophenyl)-2-isopropyl-1-methylpiperazine (0.178 g, 0.657 mmol), bis(pinacolato)diboron (0.250 g, 0.986 mmol), KOAc (0.129 g, 1.32 mmol), and XPhos Pd G2 (0.039 g, 0.049 mmol) to give the product (252 mg, quantitative yield). LCMS: [M + H] + = 363.22. Step 3: (S)-6-(3-amino-6-(2-fluoro-4-(3-isopropyl-4-methylpiperazin-1-yl)phenyl)pyrazin-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-40) [ka]

[0457] A procedure analogous to Step 5 of Example 38 was performed using [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CHCl complex (0.013 g, 0.016 mmol), (S)-4-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-isopropyl-1-methylpiperazine (0.062 g, 0.172 mmol), and [1,12-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CHCl complex (0.013 g, 0.016 mmol) ...

Claims

1. Compounds of formula (I-A), or pharmaceutically acceptable salts and / or solvates thereof, 【Chemistry 1】 Here: X ２ and X ３ N and CR are independent of each other. ２ Selected from; X ４ and X ５ Each is independently selected from N and CH, except X ４ and X ５ At least one of them is N; Q is one or more Rs ４ C optionally substituted by １～４ alkylene; or Q is one or more R ４ｃ C is optionally substituted by ２～４ It is alkenylene; or Q is R ４ｃ C=N or N=C is optionally substituted by; R １ H, Haro, OR ３ａ , NR ５ａ R ６ａ , C １～６ Alkilen NR ５ａ R ６ａ and C １～６ Selected from alkyl groups; R ２ H, Halo and C １～６ Selected from alkyl groups; R ３ａ H and C １～４ Selected from alkyl groups; Each R ４ 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 ５ R ６ and C １～６ Alkilen NR ５ R ６ Selected independently from; Each R ４ｃ Hello, C １～６ Alkyl, C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl, C １～６ Alkilen C ３～６ Cycloalkyl and C １～６ Alkilen C ３～６ Heterocycloalkyl, OH, OC １～６ Alkyl, NR ５ R ６ , and C １～６ Alkilen NR ５ R ６ Selected independently from; R ５ , R ５ａ , R ６ and R ６ａ H and C are independent of each other. １～６ Selected from alkyl groups, or R ５ and R ６ , or R ５ａ and R ６ａ This refers to a 3- to 7-membered saturated or unsaturated ring, formed by bonding together with the nitrogen atoms between them, such as 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. １～６ Forming a ring optionally substituted by one or more alkyl groups; Each R ７ is, halo, =O, C １～６ Alkyl, NR ８ R ９ , and C １～６ Alkilen NR ８ R ９ , 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 rear four groups are one or more R groups. １０ It is optionally replaced by; R ８ and R ９ H and C are independent of each other. １～６ Selected from alkyl groups; Each R １０ Hello, C １～６ Alkyl, CN and NR １１ R １１ａ Selected independently from; R １１ and R １１ａ H and C are independent of each other. １～６ Selected from alkyl groups; Cy ２ is a monocyclic C １２ heterocycloalkyl substituted by one or more R ３～７ groups, or is an unsubstituted or bicyclic C １２ heterocycloalkyl substituted by one or more R ６～１２ groups; Each R １２ is halo, CN, =O, OH, C １～６ alkyl, C ２～６ alkenyl, C ２～６ alkynyl, C ３～１０ cycloalkyl, C ３～１０ heterocycloalkyl, C １～６ alkylene C ３～１０ cycloalkyl, C １～６ alkylene C ３～１０ heterocycloalkyl, C １～６ alkylene OR １３ , C １～６ alkylene NR １３ R １４ , OC １～６ alkylene OR １３ , OC １～６ alkylene NR １３ R １４ , SR １３ , C(O)R １３ , C(O)C １～６ alkylene OR １３ , C(O)C １～６ alkylene NR １３ R １４ , C(O)C １～６ alkylene OC １～６ alkylene NR １３ R １４ , C(O)NR １３ R １４ , CO ２ R １３ , CO ２ C １～６ alkylene OR １３ , CO ２ C １～６ alkylene OC １～６ alkylene NR １３ R １４ , NR １３ R １４ , NR １５ SO ２ R １３ , S(O)R １３ , SO ２ R １３ , SO ２ NR １３ R １４ and S(O)(NR １５ )R １３ Selected independently from; R １３ H, C １～６ Alkyl, C １～６ Alkilen OR １４ , 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 heterocycloalkyl groups, R １４ H and C １～６ Selected from alkyl groups; or R １３ and R １４ It is bonded to and together with the nitrogen atoms between them, forming a 4- to 6-membered saturated or unsaturated ring, N,NR １６ , O, S, S(O) and SO ２ Forming a ring which optionally includes one additional heteromorph selected from; R １５ and R １６ H and C １～６ Selected from alkyl; and n is an integer chosen from 0 to 4. Here, all available hydrogen atoms are optionally replaced by fluorine atoms. However, Cy ２ In the case where the adjacent phenyl is an unsubstituted phenyl, 【Chemistry 2】 Instead, here 【Transformation 3】 This represents a covalent bond point to an adjacent phenyl molecule. However, the compound is not 6-(3-amino-6-(4-(4-hydroxytetrahydro-2Hpyran-4-yl)phenyl)pyrazine-2-yl)-3,4-dihydroisoquinoline-1(2H)-one.

2. R １ is OR ３ａ , NR ５ａ R ６ａ , C １～４ Alkilen NR ５ａ R ６ａ 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 ４ C is optionally substituted by １～３ It is alkylene, and each R ４ 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 ５ R ６ , and C １～４ Alkilen NR ５ R ６ Either selected independently from, Q is one or two R ４ｃ C is optionally substituted by ２～４ It is an alkenylene, and each R ４ｃ 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 ５ R ６ , and C １～４ Alkilen NR ５ R ６ Either selected independently from, Q is selected from C=N and N=C, and R ４ｃ It is optionally substituted by and R ４ｃ 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 ５ R ６ , and C １～４ Alkilen NR ５ R ６ Selected from, 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 independently CR ２ And, Each R ２ These are H, F, Cl and C １～４ Independently selected from alkyl, and X ４ and X ５ One of them is N, and the other is CH. Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 1.

5. n is an integer selected from 0 to 2, Here, each R ７ Hello, C １～４ Alkyl, NR ８ R ９ , C １～４ Alkilen NR ８ R ９ 、 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, the rear four groups consist of 1 to 3 R groups. １０ It is optionally replaced by Each R １０ F, Cl, CN, C １～４ Alkyl and NR １１ R １１ａ Selected independently from, R １１ and R １１ａ H and C are independent of each other. １～４ Selected from alkyl groups, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 1.

6. Cy ２ This is one to three R's. １２ Monoring C replaced by ３～７ It is either heterocycloalkyl or, Cy ２ This is one to three R's. １２ It is a bicyclic heterocycle that is substituted by, Here, each R １２ H is a halo, = O, OH, C １～４ Alkyl, C ３～１０ 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 １３ , C １～４ Alkilen NR １３ R １４ , OC １～４ Alkilen OR １３ , OC １～４ Alkilen NR １３ R １４ , C(O)R １３ , C(O)C １～４ Alkilen OR １３ , C(O)C １～４ Alkilen NR １３ R １４ , C(O)C １～４ Alkilen OC １～４ Alkilen NR １３ R １４ , C(O)NR １３ R １４ CO ２ R １３ CO ２ C １～４ Alkilen OR １３ CO ２ C １～４ Alkilen OC １～４ Alkilen NR １３ R １４ , NR １３ R １４ , NR １５ SO ２ R １３ SO ２ R １３ and SO ２ NR １３ R １４ Selected independently from, R １３ H, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Alkilen C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl and C １～４ Alkilen C ３～６ Selected from heterocycloalkyl groups, or R １３ and R １４ It is bonded to a 5-membered or 6-membered saturated or unsaturated ring, N,NR １６ , O, S, S(O) and SO ２ A ring is formed which optionally includes one additional heteromorph selected from, R １５ and R １６ H and C １～４ Selected independently from alkyl, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 1.

7. The compound of formula (I-A) is shown 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 A compound according to claim 1, selected from the compounds listed in () or pharmaceutically acceptable salts and / or solvates thereof.

8. Compounds of formula (II-A), or pharmaceutically acceptable salts and / or solvates thereof, 【Transformation 8】 Here X ６ is N and CR １７ Selected from; X ７ and X ８ N and CR are independent of each other. １８ Selected from; X ９ and X １０ Each is independently selected from N and CH, except X ９ and X １０ At least one of them is N; Q' is one or more R ２０ C is optionally substituted by １～４ It is alkylene; or Q' is one or more R ２２ C is optionally substituted by ２～４ It is alkenylene; or Q' is R ２２ C=N or N=C is optionally substituted by; R １７ H, Haro, OR ２３ , NR ２４ R ２５ , C １～６ Alkilen NR ２４ R ２５ and C １～６ Selected from alkyl groups; R １８ H, Halo and C １～６ Selected from alkyl groups; Each R ２０ 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 ２６ R ２７ and C １～６ Alkilen NR ２６ R ２７ Selected independently from; Each R ２２ 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 ２６ R ２７ and C １～６ Alkilen NR ２６ R ２７ Selected independently from; R ２３ H and C １～４ Selected from alkyl groups; R ２４ , R ２５ , R ２６ and R ２７ H and C are independent of each other. １～６ Selected from alkyl groups, or R ２４ and R ２５ , or R ２６ and R ２７ This refers to a 3- to 7-membered saturated or unsaturated ring formed by bonding together with the atoms between them, such as 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. １～６ Forming a ring optionally substituted by one or more alkyl groups; Each R ２８ NR ３０ R ３１ , C １～６ Alkilen NR ３０ R ３１ 、 C ３～７ Heterocycloalkyl and C １～６ Alkilen C ３～７ Independently selected from heterocycloalkyl groups, the two rear groups are one or more R groups. ３２ It is optionally replaced by; Each R ２９ Hello, C １～６ Alkyl, C ３～７ Cycloalkyl, and C １～６ Alkilen C ３～７ Independently selected from cycloalkyl groups, the two rear groups are one or more R groups. ３２ It is optionally replaced by; R ３０ and R ３１ H and C are independent of each other. １～６ Selected from alkyl groups; Each R ３２ Hello, C １～６ Alkyl, CN and NR ３３ R ３４ Selected independently from; R ３３ and R ３４ H and C are independent of each other. １～６ Selected from alkyl groups; Cy ４ is C ３～１４ It is heterocycloalkyl, and Cy ４ is either unsubstituted or contains one or more R ３５ It is replaced by; Each R ３５ 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 １～６ Alkilen C ３～１０ Cycloalkyl, C １～６ Alkilen C ３～１０ Heterocycloalkyl, C １～６ Alkilen OR ３６ , C １～６ Alkilen NR ３６ R ３７ , OC １～６ Alkilen OR ３６ , OC １～６ Alkilen NR ３６ R ３７ , SR ３６ , C(O)R ３６ C(O)C １～６ Alkilen OR ３６ , C(O)C １～６ Alkilen NR ３６ R ３７ , C(O)C １～６ Alkilen OC １～６ Alkilen NR ３６ R ３７ , C(O)NR ３６ R ３７ CO ２ R ３６ CO ２ C １～６ Alkilen OR ３６ CO ２ C １～６ Alkilen OC １～６ Alkilen NR ３６ R ３７ , NR ３６ R ３７ , NR ３８ SO ２ R ３６ S(O)R ３６ SO ２ R ３６ SO ２ NR ３６ R ３７ and S(O)(NR ３８ ) R ３６ Selected independently from; R ３６ H, C １～６ Alkyl, C １～６ Alkilen OR 37, 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 heterocycloalkyl groups, R ３７ H and C １～６ Selected from alkyl groups; or R ３６ and R ３７ It is bonded to and together with the nitrogen atoms between them, forming a 4- to 6-membered saturated or unsaturated ring, N,NR ３９ O, S, SO and SO ２ Forming a ring which optionally includes one additional heteromorph selected from; R ３８ and R ３９ H and C １～６ Independently selected from alkyl; r is an integer chosen from 0 to 3; and s is an integer chosen from 1 and 2; Here, all available hydrogen atoms are optionally replaced by fluorine atoms.

9. X ６ Is it N, or X ６ CR １７ And R １７ is H, F, Cl, OR ２３ , NR ２４ R ２５ , C １～４ Alkilen NR ２４ R ２５ , and C １～４ Selected from alkyl groups, Here, R ２４ and R ２５ H and C are independent of each other. １～４ Selected from alkyl groups, or R ２４ and R ２５ It is bonded to and together with the atoms between them, forming a 3- to 7-membered saturated or unsaturated ring, such as N, NH, NC １～６ Alkyl, O, S, S(O), and SO ２ Optionally includes one additional heteromorph selected from, and halo and C １～６ A ring is formed which one or more alkyl groups are optionally substituted, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 8.

10. X ７ and X ８ One of them is N, and the other is CR １８ is or X ７ and X ８ Both are independently CR １８ And, Each R １８ H, halo, and C １～４ Selected independently from alkyl, X ９ is N, and X １０ is CH, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 8.

11. Q' is C １～３ It is alkylene and has 1 to 3 R ２０ It is optionally substituted by each R ２０ F, Cl, OH, C １～４ Alkyl, OC １～４ Alkyl and NR ２６ R ２７ Either selected independently from, Q' is C which is optionally substituted by one or two R22s. ２～４ It is either an alkenylene or Q' is selected from C=N or N=C, and R ２２ It is optionally replaced by Each R ２２ 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 ２６ R ２７ , and C １～ 6 Alkylene NR ２６ R ２７ Selected independently from, R ２６ and R ２７ These are H and C, respectively, independently. １～４ Selected from alkyl groups, or R ２６ and R ２７ It is bonded to a 3- to 7-membered 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. １～６ A ring is formed which one or more alkyl groups are optionally substituted, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 8.

12. R ２８ One of them is C １～４ Alkilen NR ３０ R ３１ And R ３０ and R ３１ H and C are independent of each other. １～４ Selected from alkyl groups, or R ２８ One of them is C ３～７ Heterocycloalkyl and C １～４ Alkilen C ３～７ Selected from heterocycloalkyl groups, with 1 to 3 R groups ３２ It is optionally replaced by The compound according to claim 8.

13. Cy ４ is either unsubstituted or contains one or more R ３５ Monoring C replaced by ３～７ It is heterocycloalkyl, or Cy ４ This is one to three R's. ３５ A bridging bicyclic heterocycle, a fused bicyclic heterocycle, or a spiro-fused bicyclic heterocycle that is substituted by, Each R ３５ H is a halo, = O, OH, C １～４ Alkyl, C ３～１０ 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 ３６ , C １～４ Alkilen NR ３６ R ３７ , OC １～４ Alkilen OR ３６ , OC １～４ Alkilen NR ３６ R ３７ , C(O)R ３６ , C(O)C １～４ Alkilen OR ３６ , C(O)C １～４ Alkilen NR ３６ R ３７ , C(O)C １～４ Alkilen OC １～４ Alkilen NR ３６ R ３７ , C(O)NR ３６ R ３７ CO ２ R ３６ CO ２ C １～４ Alkilen OR ３６ CO ２ C １～４ Alkilen OC １～４ Alkilen NR ３６ R ３７ , NR ３６ R ３７ , NR ３８ SO ２ R ３７ SO ２ R ３６ and SO ２ NR ３６ R ３７ Selected independently from, R ３６ H, C １～４ Alkyl, C ３～６ Cycloalkyl, C １～４ Alkilen C ３～６ Cycloalkyl, C ３～６ Heterocycloalkyl and C １～４ Alkilen C ３～６ Selected from heterocycloalkyls, and R ３７ H and C １～４ Selected from alkyl groups, or R ３６ and R ３７ It is bonded to and together with the nitrogen atoms between them, forming a 4- to 6-membered saturated or unsaturated ring, N,NR １６ , O, S, S(O) and SO ２ A ring is formed which optionally includes one additional heteromorph selected from, Here, all available hydrogen atoms are optionally replaced by fluorine atoms. The compound according to claim 8.

14. The compound of formula (II-A) is selected from the compounds listed in Table 1-A or their pharmaceutically acceptable salts and / or solvates, according to claim 8: Table 1-A Table 1-10 。

15. A pharmaceutical composition comprising one or more compounds described in any one of claims 1 to 7, or pharmaceutically acceptable salts and / or solvates thereof, and a pharmaceutically acceptable carrier and / or diluent.

16. An agent for use in the treatment of cancer, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt and / or solvate thereof.

17. An agent for use in inhibiting growth activity, comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt and / or solvate thereof.

18. A pharmaceutical composition comprising a compound according to any one of claims 8 to 14 or a pharmaceutically acceptable salt and / or solvate thereof, and a pharmaceutically acceptable carrier and / or diluent.

19. An agent for use in the treatment of cancer, comprising a compound according to any one of claims 8 to 14 or a pharmaceutically acceptable salt and / or solvate thereof.

20. An agent for use in inhibiting growth activity, comprising a compound according to any one of claims 8 to 14 or a pharmaceutically acceptable salt and / or solvate thereof.

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