8-Aminoisoquinoline compounds and their use

Abstract

3-carbonylamino-8-aminoisoquinoline compounds of formula (I); modifications thereof, and their use as HPK1 (hematopoietic progenitor kinase 1) inhibitors are described. The compounds are useful for treating HPK1-dependent disorders and enhancing immune responses. Methods for inhibiting HPK1, treating HPK1-dependent disorders, enhancing immune responses, and preparing the 3-carbonylamino-8-aminoisoquinoline compounds are also described. TIFF2022504080000984.tif39170

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Application No. 62 / 740,894, filed on October 3, 2018, and U.S. Provisional Application No. 62 / 870,529, filed on July 3, 2019, the contents of which are hereby incorporated by reference in their entirety.

Background Art

[0002] The main treatment modalities used by oncologists to treat cancer are surgical resection, radiation therapy, and classical chemotherapeutic agents. Unfortunately, surgical resection is not a viable option for many cancer tumors or morphologies. Furthermore, radiation therapy and chemotherapeutic agents do not target only the diseased cells and thus damage healthy cells. Therapeutic agents that more specifically target tumor cells have been developed by taking advantage of tumor - specific expression of antigens, or inappropriate expression or activation of specific proteins, within tumor cells. However, tumor cells are prone to mutation and can become resistant to agents that specifically target tumor cells.

[0003] A new cancer treatment paradigm has emerged that utilizes the patient's own immune system to overcome the immune - invasive methods utilized by many cancers and enhance anti - tumor immunity. One such method typically involves inhibiting negative regulators of the immune response that function to maintain peripheral tolerance, thereby allowing tumor antigens to be recognized as non - self elements.

[0004] Hematopoietic progenitor kinase 1 (HPK1) is an example of a negative regulator of dendritic cell activation and T and B cell responses that can be targeted to enhance anti-tumor immunity. HPK1 is mainly expressed by hematopoietic cells including early progenitors. In T cells, HPK1 negatively regulates T cell activation by phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, thereby reducing the persistence of microcluster signaling, which results in the recruitment of 14-3-3 proteins that bind to phosphorylated SLP76 and Gads and the release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters (Lasserre et al. (2011) J Cell Biol 195(5):839-853). HPK1 can also be activated in response to prostaglandin E2, which is often secreted by tumors and contributes to the escape of tumor cells from the immune system.

[0005] [Means for Solving the Problems] Disclosed are 3-carbonylamino-8-aminoisoquinoline compounds that are inhibitors of HPK1, compositions containing these compounds, and methods for enhancing an immune response and treating HPK1-dependent disorders such as cancer.

[0006] In one aspect, provided is a compound of formula (I), or any variant thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof) as detailed herein. Also provided is a pharmaceutical composition comprising a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or additive.

[0007] In another aspect, provided is a method of inhibiting HPK1, comprising contacting HPK1 in a subject with an effective amount of a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof. Also provided is a method of enhancing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof.

[0008] Further provided is a method of treating an HPK1-dependent disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is human. In some embodiments, the HPK1-dependent disorder is cancer, such as colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma. In some embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0009] Also provided is a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof, for use in a method of inhibiting HPK1, a method of enhancing an immune response, or a method of treating an HPK1-dependent disorder such as cancer.

[0010] Also provided is the use of a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof, in a method detailed herein (e.g., treating an HPK1-dependent disorder such as cancer).

[0011] Also provided is the use of a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof, for manufacturing a medicament for use in a method detailed herein (e.g., treating an HPK1-dependent disorder such as cancer).

[0012] A kit for treating HPK1-dependent disorders, comprising a pharmaceutical composition comprising a compound of formula (I), or any variant thereof detailed herein, or a pharmaceutically acceptable salt thereof; and instructions for use. A kit is also provided.

[0013] In another aspect, a method for preparing a compound of formula (I), or any variant thereof, is provided. Also provided are compound intermediates useful in the synthesis of a compound of formula (I), or any variant thereof.

Mode for Carrying Out the Invention

[0014] Disclosed herein are compounds of formula (I), or variants thereof such as formulae (IA), (IB), and (Ic), and pharmaceutical compositions thereof, which are inhibitors or regulators of HPK1 (hematopoietic progenitor kinase 1). To that end, the compounds and compositions are useful for treating diseases and disorders mediated by HPK1. An example of a treatment method is in the case of a subject suffering from cancer. The compounds can be used not only to fight cancer, but also advantageously to enhance the immune response in subjects in need of enhanced immune response.

[0015] The subject matter disclosed herein is described here more fully below. However, many modifications and other embodiments of the subject matter disclosed herein will come to mind to those of ordinary skill in the art having the benefit of the teachings presented in the foregoing description. Accordingly, the subject matter disclosed herein should not be limited to the specific embodiments disclosed, but rather modifications and other embodiments are intended to be included within the scope of the appended claims. That is, the subject matter described herein covers any alternatives, modifications, and equivalents. If one or more of the incorporated documents, patents, and the like differ from or conflict with this application (including, but not limited to, defined terms, term usage, described techniques, etc.), this application prevails. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Definitions

[0016] As used herein, "alkyl" means a saturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain having the specified number of carbon atoms, or combinations thereof (i.e., C1- 10 means 1 to 10 carbon atoms). Specific alkyl groups include those having 1 to 20 carbon atoms ("C1- 20 alkyl"), those having 1 to 8 carbon atoms ("C1-8 alkyl"), those having 1 to 6 carbon atoms ("C1-6 alkyl"), those having 2 to 6 carbon atoms ("C2-6 alkyl"), or those having 1 to 4 carbon atoms ("C 1-4 alkyl"). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; groups such as homologs and isomers such as, for example, n-pentyl group, n-hexyl, n-heptyl, n-octyl, etc., but are not limited thereto.

[0017] As used herein, "alkenyl" means an unsaturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain having at least one olefinically unsaturated site (i.e., having at least one moiety of the formula C═C), and having the specified number of carbon atoms, or a combination thereof (i.e., C 2-10 means from 2 to 10 carbon atoms). The alkenyl group can be in the "cis" or "trans" configuration, or in the "E" or "Z" configuration. Specific alkenyl groups are those having from 2 to 20 carbon atoms ("C2- 20 alkenyl"), those having from 2 to 8 carbon atoms ("C 2-8 alkenyl"), those having from 2 to 6 carbon atoms ("C 2-6 alkenyl"), or those having from 2 to 4 carbon atoms ("C 2-4 alkenyl"). Examples of alkenyl groups include, for example, ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, but-1,3-dienyl, 2-methylbut-1,3-dienyl, and groups such as homologues and isomers thereof, but are not limited thereto.

[0018] As used herein, "alkynyl" means an unsaturated straight-chain (i.e., unbranched) or branched monovalent hydrocarbon chain having at least one acetylenically unsaturated site (i.e., having at least one moiety of the formula C≡C) and having the specified number of carbon atoms, or a combination thereof (i.e., C 2-10 means from 2 to 10 carbon atoms). Specific alkynyl groups are those having from 2 to 20 carbon atoms ("C 2-20 alkynyl"), those having from 2 to 8 carbon atoms ("C 2-8 alkynyl"), those having from 2 to 6 carbon atoms ("C 2-6 alkynyl"), those having from 2 to 4 carbon atoms ("C 2-4is "alkynyl"). Examples of alkynyl groups include, for example, ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, groups such as homologs and isomers thereof, but are not limited thereto.

[0019] As used herein, "alkylene" is the same as alkyl but means a divalent residue. Specific alkylene groups have 1 to 6 carbon atoms ("C 1-6 alkylene"), those having 1 to 5 carbon atoms ("C 1-5 alkylene"), 1 to 4 carbon atoms ("C 1-4 alkylene"), or those having 1 to 3 carbon atoms ("C 1-3 alkylene"). Examples of alkylene include, for example, groups such as methylene (-CH2-), ethylene (-CH2-CH2-), 1,3-propylene (-CH2-CH2-CH2-), 1,2-propylene (-CH(CH3)-CH2-), 1,4-butylene (-CH2-CH2-CH2-CH2-), but are not limited thereto.

[0020] As used herein, "alkylidene" is the same residue as alkyl but is divalent at the point of attachment and is attached to the parent structure via a double bond. Specific alkylidene groups have 1 to 6 carbon atoms ("C 1-6 alkylidene), those having 1 to 5 carbon atoms ("C 1-5 alkylidene"), 1 to 4 carbon atoms ("C 1-4 alkylidene"), or those having 1 to 3 carbon atoms ("C 1-3 alkylidene"). Examples of alkylidene include, for example, groups such as methylidene (=CH2), ethylidene (=CH-CH2-), 1-propylidene (=CH-CH2-CH3), 2-propylidene (=C(CH3)2), 1-butylidene (=CH2-CH2-CH2-CH3), but are not limited thereto.

[0021] As used herein, "cycloalkyl" means a non-aromatic saturated or unsaturated cyclic monovalent hydrocarbon structure having the specified number of carbon atoms (i.e., C3- 10 means 3 to 10 carbon atoms). Cycloalkyl can be composed of one ring such as cyclohexyl, or multiple rings such as adamantyl, but excludes aryl groups. Cycloalkyl containing more than one ring can be fused, spiro, or bridged, or a combination thereof. Specific cycloalkyl groups have 3 to 12 cyclic carbon atoms. Preferred cycloalkyls are those having 3 to 8 cyclic carbon atoms ("C 3-8 cycloalkyl"), or cyclic hydrocarbons having 3 to 6 carbon atoms ("C 3-6 alkynyl"). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, etc.

[0022] As used herein, "aryl" means an unsaturated aromatic carbocyclic group having one ring (e.g., phenyl), or multiple fused rings (e.g., naphthyl or anthryl) where the fused rings may or may not be aromatic. Specific aryl groups have 6 to 14 cyclic (i.e., ring) carbon atoms ("C 6-14 aryl"). An aryl group having more than one ring with at least one non-aromatic ring can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, an aryl group having two or more rings with at least one non-aromatic ring is attached to the parent structure at an aromatic ring position.

[0023] As used herein, "heteroaryl" means an unsaturated aromatic cyclic group having from 1 to 14 cyclic (i.e., ring) carbon atoms and at least 1 cyclic heteroatom including, but not limited to, heteroatoms such as nitrogen, phosphorus, oxygen, and sulfur. A heteroaryl group can have one ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl), whether or not the fused rings are aromatic. Specific heteroaryl groups include 5- to 14-membered rings having from 1 to 12 cyclic (i.e., ring) carbon atoms and from 1 to 6 cyclic (i.e., ring) heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 5- to 10-membered rings having from 1 to 8 cyclic carbon atoms and from 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; and 5-, 6-, or 7-membered rings having from 1 to 5 cyclic carbon atoms and from 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, heteroaryl includes monocyclic aromatic 5-, 6-, or 7-membered rings having from 1 to 6 cyclic carbon atoms and from 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heteroaryl includes polycyclic aromatic rings having from 1 to 12 cyclic carbon atoms and from 1 to 6 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. A heteroaryl group having two or more rings in which at least one ring is non-aromatic can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, a heteroaryl group having two or more rings in which at least one ring is non-aromatic is attached to the parent structure at an aromatic ring position.

[0024] As used herein, "heterocyclic ring", "heterocyclic", or "heterocyclyl" means a saturated or unsaturated non-aromatic cyclic group having one ring or a plurality of fused rings, and having 1 to 14 cyclic (i.e., ring) carbon atoms and 1 to 6 cyclic (i.e., ring) heteroatoms such as nitrogen, phosphorus, sulfur, or oxygen. A heterocyclic ring containing two or more rings can be fused, spiro, or bridged, or any combination thereof. In a fused ring system, one or more of the fused rings can be cycloalkyl. Specific heterocyclyl groups include a 3- to 14-membered ring having 1 to 13 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; a 3- to 12-membered ring having 1 to 11 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; a 3- to 10-membered ring having 1 to 9 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; a 3- to 8-membered ring having 1 to 7 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; and a 3- to 6-membered ring having 1 to 5 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. In one variation, heterocyclyl includes monocyclic 3-, 4-, 5-, 6-, or 7-membered rings having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 cyclic carbon atoms and 1 to 2, 1 to 3, or 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. In another variation, heterocyclyl includes polycyclic non-aromatic rings having 1 to 12 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur.

[0025] "Halo" or "halogen" means fluoro, chloro, bromo, and / or iodo. "Haloalkyl" means an alkyl group substituted with one or more halogens which may be the same or different. When the residue is substituted with two or more halogens, the compound can be referred to using a prefix corresponding to the number of attached halogen moieties. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. mean aryl and alkyl substituted with two ("di") or three ("tri") halo groups which may be the same halo but need not necessarily be the same. Thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is substituted with a halo group is also called "perhaloalkyl". A preferred perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, "perhaloalkoxy" means an alkoxy group in which halogen occurs at each H in the hydrocarbon to create the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0026] "Carbonyl" means the group C=O.

[0027] "Oxo" means the moiety =O.

[0028] "Geminal" means the relationship of two moieties bonded to the same atom. For example, in the residue -CH2-CR x R y -, R x and R y are geminal, and R x is sometimes called a geminal R group with respect to R y .

[0029] "Vicinal" means the relationship of two moieties bonded to adjacent atoms. For example, in the residue -CHR x -CHR y -, R x and R y are vicinal, and R x is, with respect to R yIt may be referred to as a vicinal R group relative to

[0030] Unless otherwise specified, "optionally substituted" means that a group may be unsubstituted or may be substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents listed for that group, which substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1-2, 1-3, 1-4, or 1-5 substituents.

[0031] As used herein, the term "inhibitor" is intended to mean a molecule that inhibits the activity of HPK1. As used herein, "inhibit" means to reduce the activity of a target enzyme as compared to the activity of that enzyme in the absence of the inhibitor. In some embodiments, the term "inhibit" means a reduction in HPK1 activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In another embodiment, "inhibit" means a reduction in HPK1 activity of about 5% - about 25%, about 25% - about 50%, about 50% - about 75%, or about 75% - 100%. In some embodiments, "inhibit" means a reduction in HPK1 activity of about 95% - 100%, e.g., a 95%, 96%, 97%, 98%, 99%, or 100% reduction in activity. Such reduction can be measured using a variety of techniques recognizable to those of skill in the art, including in vitro kinase assays.

[0032] As used herein, an "HPK1 antagonist" or "HPK1 inhibitor" is a molecule that reduces, inhibits, or otherwise decreases one or more of the biological activities of HPK1 (e.g., serine / threonine kinase activity, recruitment to the TCR complex upon TCR activation, interaction with protein binding partners such as SLP76). Antagonism with an HPK1 antagonist does not necessarily represent complete removal of HPK1 activity. Instead, the activity can be decreased by a statistically significant amount, e.g., at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100% decrease in the activity of HPK1 compared to an appropriate control. In some embodiments, the HPK1 antagonist reduces, inhibits, or otherwise decreases the serine / threonine kinase activity of HPK1. In some of these embodiments, the HPK1 antagonist reduces, inhibits, or otherwise decreases HPK1-mediated phosphorylation of SLP76 and / or Gads. The compounds disclosed herein bind directly to HPK1 and inhibit its kinase activity.

[0033] A "specific antagonist" is intended to mean an agent that reduces, inhibits, or otherwise decreases the activity of a defined target more than the activity of an unrelated target. For example, an HPK1-specific antagonist decreases the activity of at least one biological activity of HPK1 by a statistically significant amount more than the inhibitory effect of an antagonist of any other protein (e.g., another serine / threonine kinase). In some embodiments, the IC 50 of the antagonist for the target is 50is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%, 0.001% or less. The compounds disclosed herein may or may not be specific HPK1 antagonists. A specific HPK1 antagonist reduces the biological activity of HPK1 by a statistically significant amount relative to the inhibitory effect of an antagonist of any other protein (e.g., another serine / threonine kinase). In certain embodiments, the HPK1 antagonist specifically inhibits the serine / threonine kinase activity of HPK1. In some of these embodiments, the IC 50 of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the IC 50 of the HPK1 antagonist for another serine / threonine kinase or another type of kinase (e.g., tyrosine kinase).

[0034] As used herein, "treatment" or "treating" is an approach for obtaining a beneficial or desired result, including clinical results. Reduction of one or more symptoms attributable to a disease, diminution of the extent of the disease, stabilization of the disease (e.g., preventing or delaying worsening of the disease), preventing or delaying spread of the disease (e.g., metastasis), delaying or slowing the progression of the disease, restoration of the diseased state, providing remission of the disease (whether partial or complete), decreasing the dosage of one or more drugs required for treatment of the disease, enhancing the effect of another medicament, delaying the progression of the disease, increasing quality of life, and / or extending survival. "Treatment" also encompasses reduction of the pathological consequences of cancer. The methods of the invention contemplate any one or more of these aspects of treatment.

[0035] As used herein, "delaying" cancer progression means delaying, interfering with, slowing down, preventing, stabilizing, and / or postponing the progression of the disease. This delay can vary in length depending on the medical history being treated and / or the subject. As will be apparent to those skilled in the art, a sufficient or significant delay can effectively encompass prevention in that the subject does not develop the disease. A method of "delaying" cancer progression is a method that reduces the likelihood of disease progression and / or reduces the extent of the disease within a given time frame as compared to not using the method. Such comparisons are typically based on clinical studies using a statistically significant number of subjects. Cancer progression can be detected using standard methods such as routine physical examinations, mammograms, imaging, or biopsies. Progression can also mean the progression of a disease that may not be initially detectable and includes occurrences, recurrences, and onset.

[0036] As used herein, a "subject at risk" is a subject at risk of cancer progression. A "subject at risk" may or may not have a detectable disease and may or may not exhibit a detectable disease prior to the treatment methods described herein. "At risk" means that the subject has one or more so-called risk factors, which are measurable parameters that correlate with cancer progression and are described herein. A subject having one or more of these risk factors is more likely to have cancer progression than a subject not having these risk factors.

[0037] As used herein, "combination therapy" means a therapy that includes two or more different compounds. Thus, in one aspect, a combination therapy is provided that includes a compound detailed herein and another compound. In some variations, the combination therapy optionally includes one or more pharmaceutically acceptable carriers or additives, non-pharmaceutically active compounds, and / or inert substances.

[0038] As used herein, the term "effective amount" is intended to mean such an amount of a compound of the invention as would be effective in a given treatment modality in combination with parameters of effectiveness and toxicity. As understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administration of one or more therapeutic agents, and a single agent may be considered to be administered in an effective amount if, in combination with one or more other agents, a desired or beneficial result can be achieved or, if achieved, is achieved. The preferred dosage of any of the compounds to be co-administered may optionally be lowered due to the combined action (e.g., additive or synergistic effect) of the compounds. In various embodiments, an effective amount of a composition or treatment method: (i) reduces the number of cancer cells; (ii) reduces the major size; (iii) inhibits, impedes, delays, preferably stops, the invasion of cancer cells into peripheral organs to some extent; (iv) inhibits tumor metastasis (e.g., delays to some extent, preferably stops); (v) inhibits tumor growth; (vi) prevents or delays major occurrence and / or recurrence; and / or (vii) can reduce one or more symptoms associated with cancer to some degree. In various embodiments, the amount is sufficient to alleviate, reduce, mitigate, and / or delay one or more of the symptoms of cancer.

[0039] As understood in the art, an "effective amount" can be one or more doses, i.e., a single dose or multiple doses may be required to achieve the desired treatment endpoint. An effective amount may be considered in the context of administration of one or more therapeutic agents, and a compound, or a pharmaceutically acceptable salt thereof, and in combination with one or more other agents, a desired or beneficial result can be achieved or, if achieved, is achieved, and is considered to be administered in an effective amount.

[0040] "An effective amount for treatment" means an amount of a compound or a salt thereof that is sufficient to produce a desired therapeutic outcome (e.g., a decrease in the severity or duration of cancer, stabilization of the severity of cancer, or elimination of one or more symptoms of cancer). For therapeutic use, beneficial or desirable results include, for example, a decrease in one or more (biochemical, histological, and / or behavioral) symptoms caused by the disease, including complications and intermediate pathological phenotypes that appear during the progression of the disease, an increase in the quality of life of a subject suffering from the disease, a decrease in the dosage of other medications required for the treatment of the disease, a potentiating effect of another medication, a delay in the progression of the disease, and / or an extension of the survival of the patient.

[0041] "A prophylactically effective amount" means an amount of a compound, or a pharmaceutically acceptable salt thereof, that is sufficient to prevent or reduce the severity of one or more future symptoms of cancer when administered to a subject who is susceptible to developing cancer and / or a subject who is at risk of cancer progression. For prophylactic use, beneficial or desirable results include, for example, the removal or reduction of risk, a decrease in the severity of a future disease, or a delay in the onset of the disease (e.g., a delay in the biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that present during the future progression of the disease).

[0042] An effective amount of a compound or a pharmaceutically acceptable salt thereof, including a prophylactically effective amount, is understood to be administrable to a subject in an adjuvant setting, which means a clinical setting in which the subject has a history of cancer and is generally (but not necessarily) responsive to treatment modalities including, but not limited to, surgery (e.g., surgical resection), radiation therapy, and chemotherapy. However, due to their cancer history, these subjects are considered to be at risk of cancer progression. Treatment or administration in an "adjuvant setting" means a subsequent mode of treatment.

[0043] As used herein, the term "unit dosage form" means a physically discrete unit containing a predetermined amount of an active ingredient that is suitable as a unit dosage and is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier or additive. The unit dosage form may contain a single or combination therapy.

[0044] As used herein, the term "controlled release" means a pharmaceutical formulation or fraction thereof that does not result in an immediate release of the drug, i.e., it includes "controlled release" formulations and administration does not result in an immediate release of the drug into the absorption pool. This term encompasses depot formulations designed to gradually release the drug compound over an extended period. Controlled release formulations generally involve mixing the drug compound with a carrier, polymer, or other compound having desired release characteristics (e.g., pH-dependent or non-pH-dependent solubility, different degrees of water solubility, etc.) and formulating the mixture according to the desired delivery route (e.g., coated capsules, implanted reservoirs, injection solutions containing biodegradable capsules, etc.), and can include a wide variety of drug delivery systems.

[0045] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means a material that is not biologically or otherwise undesirable, e.g., a material that can be incorporated into a pharmaceutical composition for administration to a patient without causing any undesirable biological effects or interacting in a harmful manner with any of the other components of the composition in which it is contained. The pharmaceutically acceptable carrier or additive preferably meets the criteria required in toxicity and manufacturing tests and / or is included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0046] In some embodiments, the salts of the compounds of the present invention are pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" are those salts that retain at least the biological activity of the free (non-salt) compound and are administrable to a subject as a medicament or pharmaceutical. Such salts include, for example: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed with organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; (2) salts formed when the acidic proton present in the parent compound is either replaced by a metal ion, such as an alkali metal, alkaline earth ion, or aluminum ion, or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Pharmaceutically acceptable salts can be prepared by reacting in situ during the manufacturing process, or by separately reacting the purified compound of the present invention in free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salts so formed during subsequent purification.

[0047] As used herein, the term "additive" means an inert or inactive substance that can be used in the manufacture of drugs or pharmaceuticals, for example, a tablet containing the compound of the present invention as an active ingredient. The term "additive" can encompass various substances, including, but not limited to, binders, disintegrants, coating agents, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable tablets, sweeteners or flavors, suspension / gelling agents, or any substance used as a wet granulating agent. Examples of binders include carbomers, povidone, xanthan gum, etc.; examples of coating materials include cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; examples of compression / encapsulation materials include calcium carbonate, glucose, fructose dc (dc - "directly compressible"), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; examples of disintegrants include croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; examples of creams or lotions include maltodextrin, carrageenan, etc.; examples of lubricants include magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; examples of materials for chewable tablets include dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; examples of suspension / gelling agents include carrageenan, sodium starch glycolate, xanthan gum, etc.; examples of sweeteners include dextrose, fructose dc, sorbitol, sucrose dc, etc.; examples of wet granulating agents include calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the terms "additive" and "carrier" are used interchangeably.

[0048] The terms "subject" or "patient" mean animals such as mammals including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human or a human patient.

[0049] The terms "abnormal cell growth", "uncontrolled cell growth", and "hyperproliferative disease" are used interchangeably in this application. As used herein, "abnormal cell growth" means cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition), unless otherwise specified.

[0050] The term "cancer" means a condition in a subject characterized by uncontrolled cell growth, and cancerous cells are capable of local invasion and / or metastasis to non-adjacent sites. As used herein, "cancer cell", "cancerous cell", or "tumor cell" means a cell characterized by this uncontrolled cell growth and invasiveness. The term "cancer" encompasses all types of cancer, including but not limited to all forms of carcinoma, melanoma, blastoma, sarcoma, lymphoma, and leukemia, and includes, but is not limited to, bladder cancer, carcinoma of the urinary bladder, brain tumor, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrial cancer, hepatocellular carcinoma, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, and thyroid cancer, acute lymphoblastic leukemia, acute myeloid leukemia, ependymoma, Ewing sarcoma, glioblastoma, medulloblastoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, rodent cancer, and Wilms tumor (nephroblastoma).

[0051] A "chemotherapeutic agent" is a chemical compound or biological preparation useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carbocone, meturedopa, and uredopa; ethyleneimines and methylamelamines such as altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (particularly bratasin and bratasinone); δ-9-tetrahydrocannabinol (dronabinol, MARINOL®); β-lapachone; lapachol; colchicine; betulinic acid; camptothecin (synthetic analogs topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; pemetrexed; calistatin; CC-1065 (including its adozelesin, carzelesin, and bizelesin synthetic analogs); podophyllotoxin; podophyllinic acid; teniposide; cryptophycin (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (synthetic analogs such as KW-2189 and CB1-TM1); erythrobins; pancratistatin; TLK-286; the oral α-4 integrin inhibitor CDP323; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chloronaphazine, colophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobenbitin, phenesterine, prednimustine, trofosfamide, and uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine; enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin γ1I and calicheamicin ωI1 (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33:183-186 (1994)) and other antibiotics; dynemicin A including dynemicin;esperamicin, neocarzinostatin chromophore and related chromoprotein engyin antibiotic chromophores, actinomycin, actinomycin, anthramycin, azaserine, bleomycin, cactinomycin, carabicin, calminomycin, cardinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin hydrochloride liposome injection (DOXIL®) and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, keramycin, rhodrubicin, streptozocin, streptozocin, tubercidin, ubenimex, dinostatin, zorubicin; methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilone, and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiampurine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; antiadrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid supplements such as folic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatrexate; defofamine; demeclocycline; diaziquone; eflornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet;Pirarubicin; Losoxantrone; 2-Ethylhydrazide; Procarbazine; PSK (registered trademark) polysaccharide complex (JHS Natural Products, Eugene, OR); Razoxane; Rizoxin; Schizophyllan; Spirogermanium; Tenuazonic acid; Triaziquone; 2,2’,2’’-Trichlorotriethylamine; Trichothecene (especially T-2 toxin, Verruculin A, Loridine A and Anguizine); Urethane; Vinblastine (ELDISINE (registered trademark), FILDESIN (registered trademark)); Dacarbazine; Mannomustine; Mitobronitol; Mitolactol; Pipobroman; Gacitabine; Arabinoside (“Ara-C”); Thiotepa; Taxoid, such as Paclitaxel (TAXOL (registered trademark)), albumin-recombinant nanoparticle formulation of Paclitaxel (ABRAXANE (trademark)), and Docetaxel (TAXOTERE (registered trademark)); Chlorambucil; 6-Thioguanine; Mercaptopurine; Methotrexate; Platinum analogs such as Cisplatin and Carboplatin; Vinblastine (VELBAN (registered trademark)); Platinum; Etoposide (VP-16); Ifosfamide; Mitoxantrone; Vincristine (ONCOVIN (registered trademark)); Oxaliplatin; Folic acid; Vinorelbine (NAVELBINE (registered trademark)); Novantrone; Edatrexate; Daunomycin; Aminopterin; Ibandronate; Topoisomerase inhibitor RFS 2000; Difluoromethylornithine (DMFO); Retinoids such as Retinoic acid; and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (abbreviation for combination therapy of Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone), and FOLFOX (abbreviation for treatment regimen with Oxaliplatin (ELOXATIN{(trademark)}) in combination with 5-FU and Folic acid).;

[0052] As further examples of chemotherapeutic agents, there are "anti-hormonal agents" which act to control, reduce, block, or inhibit the effectiveness of hormones that can promote cancer growth and are often in the form of systemic or whole-body treatment. They may themselves be hormones. For example, anti-estrogens and selective estrogen receptor modulators (SERMs) are included, such as tamoxifen (including NOLVADEX® tamoxifen), raloxifene (EVISTA®), droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON®); anti-progesterone; estrogen receptor downregulators (ERD); estrogen receptor antagonists such as fulvestrant (FASLODEX®); agents that function to suppress or close the ovaries, such as leuprolide acetate (LUPRON® and ELIGARD®), goserelin acetate, buserelin acetate, and luteinizing hormone-releasing hormone (LHRH) agonists such as triptorelin; anti-androgen agents such as flutamide, nilutamide, and bicalutamide; and aromatase inhibitors that inhibit the enzyme aromatase, which controls estrogen production in the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, megestrol acetate (MEGASE®), exemestane (AROMASIN®), formestane, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), anastrozole (ARIMIDEX®).Furthermore, examples of chemotherapeutic agents having such a definition include clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); and troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways suggested by adherent cell growth, such as PKC-α, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); THERATOPE® vaccine, and gene therapy vaccines, such as ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitors (e.g., LURTOTECAN®); anti-estrogen agents such as fulvestrant; EGFR inhibitors such as erlotinib or cetuximab; anti-VEGF inhibitors such as bevacizumab; irinotecan; rmRH (e.g., ABARELIX®); 17AAG (a geldanamycin derivative that is a heat shock protein (Hsp) 90 poison), and pharmaceutically acceptable salts, acids, or derivatives of any of the above are included.

[0053] The definition of "chemotherapeutic agent" also includes the following: (i) antihormonal agents that act to regulate or inhibit the hormonal action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including tamoxifen (NOLVADEX (registered trademark); including tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and FARESTON (registered trademark) (toremifene citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase that regulates estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, MEGASE (registered trademark) (megestrol acetate), AROMASIN (registered trademark) (exemestane; Pfizer), formestane, fadrozole, RIVISOR (registered trademark) (vorozole), FEMARA (registered trademark) (letrozole; Novartis), and ARIMIDEX (registered trademark) (anastrozole; AstraZeneca); (iii) antiandrogenic drugs, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabine (1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways involved in abnormal cell proliferation, such as PKC-alpha, Ralf, and H-Ras; (vii) ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME (registered trademark)) and HER2 expression inhibitors; (viii) gene therapy vaccines, such as ALLOVECTIN (registered trademark), LEUVECTIN (registered trademark), and VAXID (registered trademark) vaccines; PROLEUKIN (registered trademark) rIL-2; topoisomerase 1 inhibitors such as LURTOTECAN (registered trademark); ABARELIX (registered trademark) rmRH; (ix) antiangiogenic agents such as bevacizumab (AVASTIN (registered trademark), Genentech); and (x) pharmaceutically acceptable salts, acids, and derivatives of any of the above.

[0054] In some embodiments, the chemotherapeutic agent is an immunotherapeutic agent. As used herein, an "immunotherapeutic agent" is a compound that enhances the immune system to assist in the fight against cancer, either specifically or non-specifically. Immunotherapeutic agents include cytokines, interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-21), interferons (e.g., IFN-α, IFN-β, IFN-γ), GM-CSF, thalidomide (THALOMID®, Celgene), lenalidomide (REVLIMID®, Celgene), pomalidomide (POMALYST®, Celgene), imiquimod (ZYCLARA®, Valeant), and other monoclonal antibodies and non-specific immunotherapies that boost the immune system. Non-limiting examples of monoclonal antibodies useful as chemotherapeutic agents include trastuzumab (HERCEPTIN®, Genentech), bevacizumab (AVASTIN®, Genentech), cetuximab (ERBITUX®, Bristol-Myers Squibb), panitumumab (VECTIBIX®, Amgen), ipilimumab (YERVOY®, Bristol-Myers Squibb), rituximab (RITUXAN®, Genentech), alemtuzumab (CAMPATH®, Genzyme), ofatumumab (ARZERRA®, Genmab), gemtuzumab ozogamicin (MYLOTARG®, Wyeth), brentuximab vedotin (ADCETRIS®, Seattle Genetics), 90 Y-labeled ibritumomab tiuxetan (ZEVALIN®, Biogen Idec), 131I-labeled tositumomab (BEXXAR®, GlaxoSmithKline), ado-trastuzumab emtansine (KADCYLA®, Genentech), blinatumomab (BLINCYTO®, Amgen), pertuzumab (PERJETA®, Genentech), obinutuzumab (GAZYVA®, Genentech), nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck), pidilizumab (CureTech), MPDL3280A (described in International Publication No. 2010 / 077634, the entire disclosure of which is incorporated herein by reference), MDX-1105 (described in International Publication No. 2007 / 005874, the entire disclosure of which is incorporated herein by reference), and MEDI4736 (described in International Publication No. 2011 / 066389 and U.S. Patent Application Publication No. 2013 / 034559, the entire disclosures of which are incorporated herein by reference) are included. Another useful immunotherapeutic agent is AMP-224 (described in International Publication Nos. 2010 / 027827 and 2011 / 066342, the entire disclosures of which are incorporated herein). Compound

[0055] The compounds disclosed herein are 3-carbonylamino-8-aminoisoquinoline compounds of formula (I), or salts thereof (e.g., pharmaceutically acceptable salts), solvates (e.g., hydrates), prodrugs, metabolites, or derivatives. These compounds are useful as inhibitors of HPK1.

[0056] In one aspect, formula (I): TIFF0007698575000001.tif39170(wherein, R 15 is -OR 16 , -SR 16 or -NR 17 R 18 ; Each R 16 is independently hydrogen, C 1-6 alkyl, C 3-10is cycloalkyl, 7- to 14-membered heteroaryl, or 3- to 14-membered heterocyclyl; R 16 of C 1-6 alkyl, C 3-10 cycloalkyl, 7- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; R 17 is hydrogen or C 1-6 alkyl; R 18 is C 1-6 alkyl, C 3-10 cycloalkyl, or 3- to 14-membered heterocyclyl; R 18 of C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 14-membered heterocyclyl may each be independently substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; or, R 17 and R 18 together with the nitrogen atom to which they are attached may form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; R 3 is hydrogen, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 14-membered heterocyclyl, or -OR 7 ; R 3 of C 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 14-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; R 4 is 5- to 14-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; R 5 is hydrogen, halogen, cyano, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, -C(O)R 6 , -C(O)OR 7 , -C(O)NR 8a R 8b , -OR 7 , -OC(O)R 6 , -OC(O)NR 8a R 8b , -SR 7 , -S(O)R 9 , -S(O)2R 9 , -S(O)2NR 8a R 8b , -P(O)R 9a R 9b , -NR 8a R 8b , -N(R 8 )C(O)R 6 , -N(R 8 )C(O)OR 7 , -N(R 8 )C(O)NR 8a R 8b , -N(R 8 )S(O)2R 9 , or -N(R 8 )S(O)2NR 8a R 8b ; R 5 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; each R 6 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10Aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; R 6 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; each R 7 is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; R 7 's C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; each R 8 is independently hydrogen or C 1-6 alkyl; each R 8a and R 8b are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; R 8a and R 8b 's C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; or, R 8a and R 8b together with the nitrogen atom to which they are attached, R10 optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of; forming a 4- to 12-membered heterocyclyl; each R 9 is independently C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; R 9 's C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of R 10 ; each R 9a and R 9b are independently C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclyl, or -O-C 1-6 alkyl; R 9a and R 9b 's C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of R 10 ; or, R 9a and R 9b together with the phosphorus atom to which they are attached, optionally form a 4- to 12-membered heterocyclyl substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of R 10 ; each R 10 is independently oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, -C(O)R a , -C(O)OR b , -C(O)NR c R d , -OR b , -OC(O)R a , -OC(O)NR c R d , -SR b , -S(O)R e , -S(O)2R e , -S(O)(=NH)R e , -S(O)2NR c R d , -NR c R d , -N(R f )C(O)R a , -N(R f )C(O)OR b , -N(R f )C(O)NR c R d , -N(R f )S(O)2R e , -N(R f )S(O)2NR c R d , or -P(O)R g R h ; R 10 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl may be substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ; each R a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; R a 's C 1-6Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from 11 ; each R b is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C b of R 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from 11 ; each R c and R d are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C c of R d and R 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from 11 ; alternatively, R c and R d together with the nitrogen atom to which they are attached may form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from 11 ; each R e is independently C 1-6 alkyl, C 3-8Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; R e Of C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ; Each R f Is independently hydrogen or C 1-6 Alkyl; Each R g And R h Are independently C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or -O-C 1-6 Alkyl; R g And R h Of C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ; Or, R g And R h Together with the phosphorus atom to which they are attached, may form a 4- to 12-membered heterocyclyl substituted with 1, 2, 3, or 4 substituents independently selected from R 11 ; Each R 11 Is independently oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano, -C(O)R a1 ,-C(O)OR b1 ,-C(O)NR c1R d1 、 -OR b1 、 -OC(O)R a1 、 -OC(O)NR c1 R d1 、 -SR b1 、 -S(O)R e1 、 -S(O)2R e1 、 -S(O)2NR c1 R d1 、 -NR c1 R d1 、 -N(R f1 )C(O)R a1 、 -N(R f1 )C(O)OR b1 、 -N(R f1 )C(O)NR c1 R d1 、 -N(R f1 )S(O)2R e1 、 -N(R f1 )S(O)2NR c1 R d1 、 or -P(O)R g1 R h1 ; R is; R 11 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-14 aryl, 5 - to 14 - membered heteroaryl, and 3 - to 14 - membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ; Each R a1 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 - to 10 - membered heteroaryl, or 3 - to 8 - membered heterocyclyl; R a1 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 - to 10 - membered heteroaryl, and 3 - to 8 - membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R12 optionally substituted with 1, 2, 3, or 4 substituents independently selected from; each R b1 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; R b1 's C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl may each be optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ; each R c1 and R d1 are independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; R c1 and R d1 's C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl may each be optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ; or, R c1 and R d1 together with the nitrogen atom to which they are attached, form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ; each R e1 is independently C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; R e1 's C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ; each R f1 is independently hydrogen or C 1-6 alkyl; each R g1 and R h1 are independently C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or -O-C 1-6 alkyl; R g1 and R h1 's C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ; or, R g1 and R h1 together with the phosphorus atom to which they are attached, may form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 ; each R 12 is independently oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, halogen, cyano, -C(O)R a2 , -C(O)OR b2 , -C(O)NR c2 R d2 , -OR b2 , -OC(O)R a2 , -OC(O)NR c2 R d2 , -S(O)2R e2 , -S(O)2NR c2 R d2 , -NR c2 R d2 、-N(Rf2 )C(O)R a2 、 -N(R f2 )C(O)OR b2 、 -N(R f2 )C(O)NR c2 R d2 、 -N(R f2 )S(O)2R e2 、 -N(R f2 )S(O)2NR c2 R d2 、 or -P(O)R g2 R h2 ; R 12 's C 1-6 alkyl, C 3-6 cycloalkyl, C6 aryl, 5 - to 6 - membered heteroaryl, and 3 - to 6 - membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 13 ; Each R a2 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C6 aryl, 5 - to 6 - membered heteroaryl, or 3 - to 6 - membered heterocyclyl; R a2 's C 1-6 alkyl, C 3-6 cycloalkyl, C6 aryl, 5 - to 6 - membered heteroaryl, and 3 - to 6 - membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 13 ; Each R b2 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 3 - to 6 - membered heterocyclyl; R b2 's C 1-6 alkyl, C 3-6 cycloalkyl, and 3 - to 6 - membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 13 ; Each R c2 and R d2 are independently hydrogen, C 1-6 alkyl, C 3-6is cycloalkyl or a 3- to 8-membered heterocyclyl; R c2 and R d2 of C 1-6 alkyl, C 3-6 cycloalkyl, and the 3- to 8-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 13 ; or, R c2 and R d2 together with the nitrogen atom to which they are attached, form a 4- to 6-membered heterocyclyl which may be substituted with 1, 2, 3, or 4 substituents independently selected from R 13 ; each R e2 is independently C 1-6 alkyl, C 3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; the C e2 alkyl, C 1-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R 3-6 may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 13 ; each R f2 is independently hydrogen or C 1-6 alkyl; each R g2 and R h2 are independently C 1-6 alkyl, C 3-6 cycloalkyl, 3- to 8-membered heterocyclyl, or -O-C 1-6 alkyl; the C g2 alkyl, C h2 cycloalkyl, and 3- to 8-membered heterocyclyl of R 1-6 and R 3-6 may each be substituted with 1, 2, 3, or 4 substituents independently selected from R 13 ; or, R g2 and R h2 together with the phosphorus atom to which they are attached, R 13and forming a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 13 are independently oxo, halogen, hydroxyl, -O(C 1-6 Alkyl), Cyano, C 1-6 Alkyl, or C 1-6 haloalkyl) or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., a hydrate), prodrug, metabolite, or derivative thereof.

[0057] In some embodiments, the compound is a compound of Formula (I), or a salt (e.g., a pharma- ceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof, wherein R 15 -OR 16 , -SR 16 or -NR 17 R 18 It is.

[0058] In some embodiments, R 15 -OR 16 , or -SR 16 where each R 16 is independently 1-6 Alkyl, C 3-10 cycloalkyl, 7-14 membered heteroaryl, or 3-14 membered heterocyclyl; R 16 C 1-6 Alkyl, C 3-10 The cycloalkyl, 7- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R. In some of these embodiments, R 15 -OR 16 In some of these embodiments, R 15 -SR 16 It is.

[0059] In one embodiment, the compound of formula (IA) or (IC): TIFF0007698575000002.tif65170(wherein, each R 16 is independently C 1-6 alkyl, C 3-10 cycloalkyl, 7- to 14-membered heteroaryl, or 3- to 14-membered heterocyclyl; and R 16 's C 1-6 alkyl, C 3-10 cycloalkyl, 7- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; and R 3 , R 4 , R 5 and R 10 are as defined by formula (I) or are variants detailed herein). Provided are compounds of or salts thereof (e.g., pharmaceutically acceptable salts).

[0060] In some embodiments, the compound is a compound of formula (I), (IA) or (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite or derivative thereof, wherein R 16 is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 alkyl; optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 1-6 cycloalkyl; optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 7- to 14-membered heteroaryl; or optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 3-10 3- to 14-membered heterocyclyl. In some embodiments, R 10 is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 alkyl; R 16 is 10 optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 1-6 alkyl; R 10C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 3-10 cycloalkyl; or R 10 is a 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from

[0061] In some embodiments, R 16 is a 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 10 R. In some of these embodiments, R 16 has 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, and R 10 is a 4- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 16 R. In some of these embodiments, R 10 has 1 or 2 heteroatoms independently selected from the group consisting of N, O and S, and R 16 is a 4- to 7-membered monocyclic heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 10 R. In some of these embodiments, R

[0062] In some embodiments, R 16 is optionally substituted C 10 cycloalkylalkyl independently selected from 1, 2, 3, 4 or 5 substituents. In some embodiments, R 3-10 is optionally substituted C 16 cycloalkylalkyl independently selected from 1, 2, 3, 4 or 5 substituents. 10 is optionally substituted C 3-8 cycloalkylalkyl independently selected from 1, 2, 3, 4 or 5 substituents.

[0063] In some embodiments, R 16 is a 7- to 14-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 . In some embodiments, R 16 is a fused 7- to 14-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 , the heteroaryl includes a partially saturated ring, and the point of attachment is on the partially saturated ring. In one variation, R 16 is 5H-pyrrolo[1,2-a]imidazol-6-yl.

[0064] In one variation, R 16 is C 10 alkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 1-6 . In some of these embodiments, R 16 is C 1-6 alkyl or C 1-6 haloalkyl. In some of these embodiments, R 16 is C 1-6 alkyl (e.g., isopropyl or neopentyl). In some of these embodiments, R 16 is C 10 cycloalkyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 1-6 . In one variation, R 16 is C 1-6 alkyl (e.g., 2,2,2-trifluoroethyl).

[0065] In some of these embodiments, R 16 is -C( 1-6 alkylene)-R 19 , where R 19 is C 3-10 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, cyano, -OR 7 , -NR 8aR 8b 、 or -S(O)2R 9 ; R 19 's C 3-10 Cycloalkyl, C 6-14 Aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents selected independently from R 10 . In one variation, R 19 is a 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3 or 4 substituents selected independently from R 10 ; or R 10 is a 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents selected independently from R 19 . In one variation, R 10 is a C 3-10 Cycloalkyl optionally substituted with 1, 2, 3 or 4 substituents selected independently from R 10 ; or R 19 is phenyl optionally substituted with 1, 2, 3 or 4 substituents selected independently from R 7 8a . In another variation, RR 8b is cyano, -OR 9 . In another variation, R 19 is -OCH3, -NH2, or -S(O)2CH3.

[0066] In some of these embodiments, R 16 is TIFF0007698575000003.tif239170TIFF0007698575000004.tif125170(wherein the wavy line indicates the point of attachment) selected from the group consisting of.

[0067] In some embodiments, R 16 is TIFF0007698575000005.tif249170TIFF0007698575000006.tif57170 (where the wavy line indicates the bonding point) is selected from the group consisting of.

[0068] In some of these embodiments, R 16 is selected from the group consisting of TIFF0007698575000007.tif21170, and each is independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 , and the wavy line represents the bonding point. In some embodiments, each is independently optionally substituted with 1 substituent independently selected from R 10 . In some of these embodiments, R 10 is independently C 1-6 alkyl (e.g., methyl) or cyano. In some of these embodiments, R 10 is independently C 1-6 alkyl (e.g., methyl).

[0069] In some embodiments, R 15 is -NR 17 R 18 , where R 17 is hydrogen or C 1-6 alkyl; R 18 is a 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ; C 10 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 3-10 , or C 10 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 1-6 ; or R 17 and R 18 , together with the nitrogen atom to which they are attached, are R 10is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from, and forms a 4- to 12-membered heterocyclyl.

[0070] In one embodiment, formula (IB): TIFF0007698575000008.tif31170(wherein, R 17 is hydrogen or C 1-6 alkyl; R 18 is C 1-6 alkyl, C 3-10 cycloalkyl, or a 3- to 14-membered heterocyclyl; R 18 's C 1-6 alkyl, C 3-10 cycloalkyl, and 3- to 14-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; or, R 17 and R 18 together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 ; R 3 , R 4 , R 5 and R 10 are as defined in formula (I) or are variants detailed herein) of the compound, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0071] In some embodiments, the compound is of formula (I) or formula (IB), or a salt thereof (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite or derivative, and R 17 is hydrogen, or C 1-6 alkyl. In some of these embodiments, R 17 is hydrogen.

[0072] In some embodiments, the compound is of formula (I) or (IB), or a salt thereof (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite or derivative thereof, wherein R 18 is, independently, a 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ; a C 10 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 3-10 ; or a C 10 alkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 1-6 .

[0073] In some embodiments, R 18 is a 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 . In some of these embodiments, R 18 is TIFF0007698575000009.tif230170 (wherein the wavy line indicates the point of attachment) selected from the group consisting of.

[0074] In some embodiments, R 18 is TIFF0007698575000010.tif217170 (wherein the wavy line indicates the point of attachment) selected from the group consisting of.

[0075] In some embodiments, R 18 is a C 10 cycloalkyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 3-10 . In some of these embodiments, R 18 is TIFF0007698575000011.tif45170 (wherein the wavy line indicates the point of attachment) selected from the group consisting of.

[0076] In some embodiments, R 18 is TIFF0007698575000012.tif85170 (wherein the wavy line indicates a bonding point) selected from the group consisting of.

[0077] In some embodiments, R 18 is 1-6 alkyl, C 1-6 haloalkyl, or -(C 1-6 alkylene)-R 19 wherein R 19 is 3-10 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, cyano, -OR 7 , -NR 8a R 8b or -S(O)2R 9 wherein; the C 19 of R 3-10 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 In some of these embodiments, R 19 is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 and is 3- to 14-membered heteroaryl. In some of these embodiments, R 19 is optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 and is C 3-10 cycloalkyl. In one variant, R 19 is optionally substituted pyrazolyl (e.g., 1-methylpyrazol-4-yl), cyclopropyl, or cyano.

[0078] In some embodiments, R 18 is TIFF0007698575000013.tif99170 (where the wavy line indicates the junction point) is selected from the group consisting of.

[0079] In some embodiments, the compound is of formula (I) or (IB), or a salt thereof (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite or derivative, and R 17 and R 18 together with the nitrogen atom to which they are attached, may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 to form a 4- to 12-membered heterocyclyl which may be substituted. In one variation, R 17 and R 18 together with the nitrogen atom to which they are attached, may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 to form a 5- or 6-membered heterocyclyl which may be substituted. In one variation, R 17 and R 18 together with the nitrogen atom to which they are attached, form a 5- or 6-membered heterocyclyl (e.g., pyrrolidin-1-yl or piperidin-1-yl).

[0080] In some embodiments, the compound is of formula (I), or, where applicable, variations thereof such as formula (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), and R 4 is a 5- to 14-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 . In some embodiments, R 4 is a 5- to 10-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 . In some embodiments, R 4 is a monocyclic 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 . In some embodiments, R 4is a 5-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 . In some embodiments, R 4 is a 6-membered heteroaryl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 .

[0081] In some embodiments, R 4 is TIFF0007698575000014.tif28170 (wherein the wavy line indicates the point of attachment, R 4a , R 4b , and R 4c are each independently hydrogen or R 10 , or two vicinal R 4(a-c) together with the atoms to which they are attached form a fused 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 , or a fused 5- or 6-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 ). ).

[0082] In some embodiments, R 4 is TIFF0007698575000015.tif24170 (wherein the wavy line represents the point of attachment, and R 4a , R 4b , and R 4c are each independently hydrogen or R 10 , or two vicinal R 4(a-c) together with the atoms to which they are attached form a fused 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 10 or a fused 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from condensed C 5-8 cycloalkyl, or R 10optionally substituted with 1, 2, 3, or 4 substituents independently selected from, to form a fused 5- or 10-membered heterocyclyl) is.

[0083] In some of these embodiments, R 4 is TIFF0007698575000016.tif27170 (where the wavy line indicates the point of attachment) selected from the group consisting of.

[0084] In some embodiments, R 4 is TIFF0007698575000017.tif23170 (where the wavy line indicates the point of attachment; R 4a is halogen, C 1-6 alkyl or C 3-6 cycloalkyl; and R 4b and R 4C together with the atoms to which they are attached, are optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, halogen, and cyano, a fused 5- to 10-membered heterocyclyl, or C 1-6 alkyl, hydroxyl, halogen, and cyano, a fused C 5-8 cycloalkyl to form) is.

[0085] In some embodiments, R 4 is TIFF0007698575000018.tif25170 (where the wavy line indicates the point of attachment; R 4a is C 1-6 alkyl (e.g., methyl or ethyl), and R 4b and R 4C together with the atoms to which they are attached, form a fused 5- to 10-membered heterocyclyl) is.

[0086] In some of these embodiments, R 4 is TIFF0007698575000019.tif118170 (where the wavy line indicates the junction point) selected from the group consisting of

[0087] In some of these embodiments, R 4 is TIFF0007698575000020.tif30170 (where the wavy line indicates the junction point) selected from the group consisting of

[0088] In some of these embodiments, R 4 is R 10 substituted with one substituent selected from TIFF0007698575000021.tif26170, where the wavy line indicates the junction point. In some of these embodiments, R 10 is independently C 1-6 alkyl (e.g., methyl or ethyl). In some of these embodiments, R 4 is TIFF0007698575000022.tif25170

[0089] Each and every variation of R described by formula (I), or a variation thereof such as formula (IA), (IB), or (Ic), is intended and understood to be combinable with each and every variation of R described by formula (I), (IA), (IB), or (Ic), as if every combination were specifically and individually described. For example, in some embodiments, R 15 is (a), (b), or (c): 4 is 15 (a) - OR (a) - OR 16 (wherein R 16 is (i), (ii), (iii), (iv), or (v): (i) having one or two heteroatoms independently selected from the group consisting of N, O and S, and R 10 a 4- to 10-membered heterocyclyl which may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from (ii) R 10 C which may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from 3-10 cycloalkyl; (iii) C 1-6 alkyl, (iv) C 1-6 haloalkyl, or (v) (C 1-6 alkylene)-R 19 wherein R 19 is a 5- or 6-membered heteroaryl which may be substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ; a 3- to 10-membered heterocyclyl which may be substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ; a C 10 cycloalkyl which may be substituted with 1, 2, 3 or 4 substituents independently selected from R 3-10 ; a phenyl which may be substituted with 1, 2, 3 or 4 substituents independently selected from R 10 ; cyano, -OR 7 , -NR 8a R 8b , or -S(O)2R 9 ); (b) -NR 17 R 18 (wherein R 17 is hydrogen and R 18 is a 3- to 14-membered heterocyclyl which may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ; a C 10 cycloalkyl which may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 3~10 ; C 1~6 haloalkyl, or -(C 1-6 alkylene)-R 19 (wherein R19 is pyrazolyl (e.g., 1-methylpyrazol-4-yl), cyclopropyl, or cyano, which may be substituted; or (c)-SR 16 ; R 4 is TIFF0007698575000023.tif28170 (where the wavy line indicates the bonding point) selected from the group consisting of. In some of these embodiments, R 4 is TIFF0007698575000024.tif26170.

[0090] In some embodiments, the compound is a compound of formula (I), or a modification thereof such as a compound of formula (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), where R 3 is hydrogen, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, a 3- to 14-membered heterocyclyl, or -OR 7 ; and the C 3 alkyl, C 1-6 cycloalkyl, and 3- to 14-membered heterocyclyl of R 3-8 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 . In some embodiments, R 3 is hydrogen, fluoro, chloro, cyano, hydroxyl, C 3-4 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), or -O(C 1-6 haloalkyl). In one modification, R 3 is hydrogen, fluoro, cyano, or C 1-6 alkyl (e.g., methyl). In another modification, R 3 is hydrogen or fluoro. In another modification, R 3 is hydrogen.

[0091] In some embodiments, the compound is of formula (I), or of formula (IA), (IB), and (Ic), their variants, or a salt thereof (e.g., a pharmaceutically acceptable salt), where R 5 is hydrogen, halogen, cyano, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-14 aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, halogen, cyano, -C(O)R 6 , -C(O)OR 7 , -C(O)NR 8a R 8b , -OR 7 , -OC(O)R 6 , -OC(O)NR 8a R 8b , -SR 7 , -S(O)R 9 , -S(O)2R 9 , -S(O)2NR 8a R 8b , -P(O)R 9a R 9b , -NR 8a R 8b , N(R 8 )C(O)R 6 , -N(R 8 )C(O)OR 7 , -N(R 8 )C(O)NR 8a R 8b , -N(R 8 )S(O)2R 9 , or -N(R 8 )S(O)2NR 8a R 8b ; and the C 5 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 cycloalkyl, C 3-8 aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 6-14 . In some embodiments, R 10 ​5 is hydrogen, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, a 3- to 14-membered heterocyclyl, -OR 7 , -NR 8a R 8b , or -N(R 8 )C(O)R 6 ; R 5 's C 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 . In some embodiments, R 5 is hydrogen, fluoro, chloro, cyano, hydroxyl, C 3-4 cycloalkyl, C 1-6 alkyl, C 1-6 haloalkyl, -O(C 1-6 alkyl), or -O(C 1-6 haloalkyl). In one variation, R 5 is hydrogen, fluoro, cyano, or C 1-6 alkyl. In another variation, R 5 is hydrogen, fluoro, or cyano. In another variation, R 5 is hydrogen. In another variation, R 5 is fluoro.

[0092] For each and all variations or combinations thereof of R 15 and R 4 described for formula (I), (IA), (IB) or (Ic), each and all combinations are intended and understood to be combinable with each and all variations of R 3 and R 5 described for formula (I), or formula (IA), (IB) or (IC), as if each and all combinations were specifically and individually described. For example, in some embodiments, R 3 is hydrogen, R 5 is fluoro, R 4is a variant of formula (I), or formula (IA), (IB), (Ic), etc., as detailed in this specification. In some embodiments of the compound of formula (I), or a salt thereof (e.g., a pharmaceutically acceptable salt), R 15 is, as detailed above, (a), (b), or (c); R 3 is hydrogen; R 5 is fluoro; and R 4 is TIFF0007698575000025.tif28170 (where the wavy line indicates the bonding point) is selected from the group consisting of

[0093] In some embodiments of the compound of formula (I), or, where applicable, their variants such as formula (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), each R 6 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C 6 of 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 In one variant, R 6 is C 1-6 alkyl, C 3-8 cycloalkyl, or 3- to 12-membered heterocyclyl; the C 6 of 1-6 alkyl, C 3-8 cycloalkyl, and 3- to 12-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 In one variant, R6 is C 1-6 alkyl (e.g., methyl). In one variation, R 6 is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 and is a 3- to 12-membered heterocyclyl.

[0094] In some embodiments of the compound of formula (I), or, where applicable, its variants such as formula (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), each R 7 is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; and the C 7 alkyl, C 1-6 cycloalkyl, C 3-8 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl of R 6-10 are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 In one variation, R 7 is hydrogen, C 10 alkyl optionally substituted with R 1-6 In one variation, R 7 is C 1-6 alkyl. In one variation, R 7 is a 3- to 12-membered heterocyclyl.

[0095] In some embodiments of the compound of formula (I), or, where applicable, its variants such as formula (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), each R 8 is independently hydrogen or C 1-6 alkyl; and each R 8a and R 8b are independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10Aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; R 8a and R 8b of C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 or, R 8a and R 8b together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10 . In one variation, R 8 is hydrogen or C 1-6 alkyl (e.g., methyl). In one variation, each R 8a and R 8b is independently hydrogen or C 1-6 alkyl. In one variation, each R 8a and R 8b is hydrogen. In one variation, R 8a and R 8b together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclyl optionally substituted with R 10 .

[0096] In some embodiments of the compound of formula (I) or, where applicable, its variants such as formula (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), each R 9 is independently C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; R 9 of C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 10It is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected therefrom. In one variation, R 9 is C 10 alkyl optionally substituted with R 1-6 , or C 10 aryl optionally substituted with R 6-10 . In one variation, R 9 is C 1-6 alkyl (such as methyl).

[0097] In some embodiments of the compound of formula (I), or, where applicable, its variations such as formula (IA), (IB), and (IC), or a salt thereof (such as a pharmaceutically acceptable salt), each R 10 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, -C(O)R a , -C(O)OR b , -C(O)NR c R d , -OR b , -OC(O)R a , -OC(O)NR c R d , -SR b , -S(O)R e , -S(O)2R e , -S(O)(=NH)R e , -S(O)2NR c R d , -NR c R d , -N(R f )C(O)R a , -N(R f )C(O)OR b , -N(R f )C(O)NR c R d , -N(R f )S(O)2R e , or -N(R f )S(O)2NR c Rd and; R 10 of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 and is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R

[0098] In one variation, R 10 is independently oxo, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, -C(O)R a -C(O)NR c R d -OR b -S(O)2R e -S(O)2NR c R d -NR C R d and; R 10 of C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3 or 4 substituents independently selected from R 11 and is optionally substituted with 1, 2, 3 or 4 substituents independently selected from R

[0099] In one variation, R 10 is independently oxo; C 11 alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1-6 and; R 11 5- to 10-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b halogen, -OR e -S(O)(=NH)R c -NR d Rf )C(O)R a 、 or -N(R f )S(O)2NR c R d is.

[0100] In one variation, R 10 is independently oxo, halogen, cyano, C 11 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1-6 alkyl, or -OR b is.

[0101] In one variation, R 10 is independently -NR c R d , -N(R f )C(O)R a , -N(R f )C(O)OR b , -N(R f )C(O)NR c R d , -N(R f )S(O)2R e , or -N(R f )S(O)2NR c R d is.

[0102] In one variation, R 10 is independently oxo, -OR b , -OC(O)R a , -OC(O)NR c R d , -SR b , -S(O)R e , -S(O)2R e , -S(O)(=NH)R e , or -S(O)2NR c R d is.

[0103] In one variation, each R 10 is independently C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8Cycloalkyl, C 6-10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, -C(O)R a , -C(O)OR b , -C(O)NR c R d ; R 10 's C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, C 6-10 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 .

[0104] In one variation, each R 10 is independently optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 and is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl.

[0105] In one variation, R 10 is C 11 Alkyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 1-6 . In one variation, R 10 is 3- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 .

[0106] In one variation, R 10 is halogen, cyano, -NR c R d , -C(O)NR c R d , -OR b , -S(O)2R e , C 1-6 Haloalkyl, -(C 1-6 Alkylene)-OH, or -(C 1-6is (alkylene)-OH.

[0107] In one variation, R 10 is hydroxyl, cyano, halogen, -CHF2, -CF3, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -O(C 1-6 alkyl), -SO2(C 1-6 alkyl), -S(O)2NR c R d , -C(O)NR c R d , or -N(R f )C(O)R a is.

[0108] In one variation, R 10 is independently C 1-6 alkyl (such as methyl) or cyano. In one variation, R 10 is independently C 1-6 alkyl (such as methyl).

[0109] In some embodiments, each R a is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C a of R 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 . In one variation, R a is independently hydrogen or C 1-6 alkyl. In one variation, R a is hydrogen. In one variation, R a is C1-6 is alkyl (e.g., methyl).

[0110] In some embodiments, each R b is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C b alkyl, C 1-6 cycloalkyl, C 3-8 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of each R 6-10 is each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 . In one variation, each R b is independently hydrogen or C 1-6 alkyl. In one variation, each R b is hydrogen. In one variation, each R b is C 1-6 alkyl (e.g., methyl).

[0111] In some embodiments, each R c and each R d is independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C c alkyl, C d cycloalkyl, C 1-6 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of each R 3-8 and each R 6-10 is each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 , or R c and R d together with the nitrogen atom to which they are attached form a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 . In one variation, each Rc and R d is independently hydrogen or C 1-6 alkyl. In one variation, R c and R d one of which is hydrogen and R cおよび R d the other of which is C 1-6 alkyl. In one variation, each R c and R d is hydrogen. In one variation, each R c and R d is independently C 1-6 alkyl.

[0112] In some embodiments, each R e is independently C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; R e 's C 1-6 alkyl, C 3-8 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 11 . In one variation, R e is independently C 1-6 alkyl (e.g., methyl).

[0113] In some embodiments, each R f is independently hydrogen or C 1-6 alkyl. In one variation, R f is hydrogen.

[0114] In some embodiments, each R 11 is independently oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10Aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano, -C(O)R a1 , -C(O)OR b1 , -C(O)NR c1 R d1 , -OR b1 , -OC(O)R a1 , -OC(O)NR c1 R d1 , -SR b1 , -S(O)R e1 , -S(O)2R e1 , -S(O)2NR c1 R d1 , -NR c1 R d1 , -N(R f1 )C(O)R a1 , -N(R f1 )C(O)OR b1 , -N(R f1 )C(O)NR c1 R d1 , -N(R f1 )S(O)2R e1 , or -N(R f1 )S(O)2NR c1 R d1 ; where R 11 's C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 alkyl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 .

[0115] In one variation, R 11 is independently oxo, C 12 alkyl, or -OR 1-6 optionally substituted with 1, 2, 3, or 4 substituents independently selected from R b1 .

[0116] In one variation, each R 11 is independently oxo, C 1-6 alkyl, C3-6 Cycloalkyl, 3- to 8-membered heterocyclyl, halogen, cyano, or -OR b1 wherein; R 11 of C 1-6 alkyl, C 3-6 cycloalkyl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 .

[0117] In one variation, R 11 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 C 1-6 alkyl. In one variation, R 11 is 3- to 8-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 .

[0118] In one variation, R 11 is halogen, cyano, -NR c1 R d1 , -C(O)NR c1 R d1 , -OR b1 , -S(O)2R e1 , C 1-6 haloalkyl, -(C 1-6 alkylene)-OH, or -(C 1-6 alkylene)-OH.

[0119] In one variation, R 11 is hydroxyl, cyano, halogen, -CHF2, -CF3, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2, -O(C 1-6 alkyl), -SO2(C 1-6 alkyl), -S(O)2NR c1 R d1 , -C(O)NR c1 R d1 , or -N(R f1 )C(O)R a1 .

[0120] In one variation, R 11 is halogen, cyano, -O(C 1-6 alkyl), -O(C 1-6 alkylene)-NH2, or -(C 1-6 alkylene)-OH.

[0121] In some embodiments, each R a1 is independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and the C a1 alkyl, C 1-6 alkenyl, C 2-6 alkynyl, C 2-6 cycloalkyl, C 3-6 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R 6-10 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 . In one variation, R a1 is independently hydrogen or C 1-6 alkyl (e.g., methyl).

[0122] In some embodiments, each R b1 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and the C b1 alkyl, C 1-6 cycloalkyl, C 3-6 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R 6-10 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 . In one variation, R b1 is independently hydrogen or C 1-6is alkyl. In one variation, R B1 is hydrogen. In one variation, R b1 is C 1-6 alkyl (e.g., methyl).

[0123] In some embodiments, each R c1 and R d1 are independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; the C c1 of R d1 alkyl, C 1-6 cycloalkyl, C 3-6 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 6-10 ; or R 12 and R c1 and R d1 together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 . In one variation, each R c1 and R d1 are independently hydrogen or C 1-6 alkyl.

[0124] In some embodiments, each R e1 is independently C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; the C e1 of R 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 . In one variation, R e1is independently C 1-6 alkyl.

[0125] In some embodiments, each R f1 is independently hydrogen or C 1-6 alkyl. In one variation, R f1 is hydrogen.

[0126] In some embodiments, each R 12 is independently oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, halogen, cyano, -C(O)R a2 , -C(O)OR b2 , -C(O)NR c2 R d2 , -OR b2 , -OC(O)R a2 , -OC(O)NR c2 R d2 , -S(O)2R e2 , -S(O)2NR c2 R d2 , -NR c2 R d2 , -N(R f2 )C(O)R a2 , -N(R f2 )C(O)OR b2 , -N(R f2 )C(O)NR c2 R d2 , -N(R f2 )S(O)2R e2 , or -N(R f2 )S(O)2NR c2 R d2 ; and the C 12 alkyl, C 1-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R 3-6 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 13 .

[0127] In one variation, each R 12is independently oxo, halogen, cyano, -OR b2 , or C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 13 R 1-6 alkyl. In one variation, each R 12 is independently oxo, halogen, cyano, or hydroxyl.

[0128] In one variation, R 12 is C optionally substituted with 1, 2, 3, or 4 substituents independently selected from 13 R 1-6 alkyl.

[0129] In one variation, R 12 is oxo, hydroxyl, C 1-6 alkyl, or -O(C 1-6 alkyl).

[0130] In some embodiments, each R a2 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; and the C a2 alkyl, C 1-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R 3-6 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 13 . In one variation, R a2 is independently hydrogen or C 1-6 alkyl.

[0131] In some embodiments, each R b2 is independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 6-membered heterocyclyl; and the C b2 alkyl, C 1-6 cycloalkyl, and 3- to 6-membered heterocyclyl of R 3-6 are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from13 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from. In one variation, R B2 is hydrogen.

[0132] In some embodiments, each R c2 and R d2 are independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or 3- to 8-membered heterocyclyl; the C c2 of R d2 alkyl, C 1-6 cycloalkyl, and 3- to 8-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3-6 , or R 13 and R c2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R d2 . In one variation, each R 13 and R c2 are independently hydrogen or C d2 alkyl. 1-6 alkyl.

[0133] In some embodiments, each R e2 is independently C 1-6 alkyl, C 3-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; the C e2 alkyl, C 1-6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3-6 . In one variation, R 13 is independently C e2 alkyl. 1-6 alkyl.

[0134] In some embodiments, each R f2is independently hydrogen or C 1-6 alkyl. In one variation, R f2 is hydrogen.

[0135] In some embodiments, each R 13 is independently oxo, halogen, hydroxyl, -O(C 1-6 alkyl), cyano, C 1-6 alkyl, or C 1-6 haloalkyl.

[0136] In one variation, each R 13 is independently halogen, hydroxyl, -O(C 1-6 alkyl), cyano, or C 1-6 alkyl.

[0137] In one variation, R 13 is oxo, hydroxyl, C 1-6 alkyl, or -O(C 1-6 alkyl).

[0138] Also provided is a compound of formula (IA): TIFF0007698575000026.tif31170(wherein R 3 , R 4 , R 5 and R 16 are, as detailed herein, of formula (I) or an applicable variation thereof) or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0139] In some embodiments, also provided is a compound of formula (IA-1): TIFF0007698575000027.tif31170(wherein R 4 and R 16 are, as detailed herein, of formula (IA) or an applicable variation thereof) or a salt thereof.

[0140] In some embodiments, also provided is a compound of formula (IA-2): TIFF0007698575000028.tif38170(wherein, R 4a is C 1-6 alkyl; R 4b and R 4C are independently hydrogen or R 10 or R 4b and R 4C together with the atom to which they are attached, are optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, halogen and cyano, a fused 5- to 10-membered heterocyclyl, or C 1-6 alkyl, hydroxyl, halogen and cyano, a fused C 5-8 cycloalkyl; and R 10 and R 16 are, as detailed herein, of formula (IA) or an applicable variant thereof) a compound of, or a salt thereof (e.g., a pharmaceutically acceptable salt). In one variant, R 16 has 1 or 2 heteroatoms independently selected from the group consisting of N, O and S and is a 5- or 6-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R 10 ; R 4a is C 1-6 alkyl (e.g., methyl); R 4b and R 4C together with the atom to which they are attached, form a fused 6-membered heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, halogen and cyano.

[0141] Further provided is a compound of formula (IB): TIFF0007698575000029.tif30170(wherein, R 3 , R 4 , R 5 , R 17 and R18 is a compound of formula (I) or an applicable variation thereof, as detailed herein or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0142] In some embodiments, further provided is a compound of formula (IB-1): TIFF0007698575000030.tif29170 (wherein R 3 , R 4 , R 5 and R 18 are a compound of formula (IB) or an applicable variation thereof, as detailed herein or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0143] In some embodiments, further provided is a compound of formula (IB-2): TIFF0007698575000031.tif38170 (wherein R 4a is C 1-6 alkyl; R 4b and R 4C are independently hydrogen or R 10 , or R 4b and R 4C together with the atom to which they are attached, may be substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, halogen, and cyano-substituted condensed 5- to 10-membered heterocyclyl, or C 1-6 alkyl, hydroxyl, halogen, and cyano-substituted condensed C 5-8 cycloalkyl; and R 10 and R 18 are a compound of formula (IB) or an applicable variation thereof, as detailed herein or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0144] Further provided is a compound of formula (Ic): TIFF0007698575000032.tif30170(wherein, R 3 , R 4 , R 5 and R 16 are, as detailed herein, of formula (I) or an applicable variation thereof) is a compound of, or a salt (e.g., a pharmaceutically acceptable salt) thereof.

[0145] In some embodiments, further provided is formula (IC-1): TIFF0007698575000033.tif26170(wherein, R 4 and R 16 are, as detailed herein, of formula (Ic) or an applicable variation thereof) is a compound of, or a salt thereof.

[0146] In some embodiments, further provided is formula (IC-2): TIFF0007698575000034.tif40170(wherein, R 4a is C 1-6 alkyl; R 4b and R 4C are independently hydrogen or R 10 , or R 4b and R 4C together with the atoms to which they are attached, are optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of C 1-6 alkyl, hydroxyl, halogen, and cyano-substituted fused 5- to 10-membered heterocyclyl, or C 1-6 alkyl, hydroxyl, halogen, and cyano-substituted fused C 5-8 cycloalkyl; and R 10 and R 16 are, as detailed herein, of formula (Ic) or an applicable variation thereof) is a compound of, or a salt (e.g., a pharmaceutically acceptable salt) thereof. In some embodiments, R 16has one or two heteroatoms independently selected from the group consisting of N, O and S, and R 10 is a 4- to 10-membered heterocyclyl optionally substituted with one, two, three, four or five substituents independently selected from R 16 is a 5- or 6-membered heterocyclyl (e.g., tetrahydro-2H-pyran-4-yl); R 4a is C 1-6 alkyl (e.g., methyl); R 4b and R 4C together with the atoms to which they are attached form a fused 6-membered heterocyclyl.

[0147] Representative compounds are listed in Table 1. The individual enantiomers and diastereomers are included in the table "Compound Number and Compound Name" below, and it is understood that their corresponding structures can be readily measured therefrom. In some cases, the enantiomers and diastereomers are distinguished by their respective properties, e.g., retention time on chiral HPLC, or biological activity, and the absolute configuration of the chiral centers is arbitrarily assigned. [Table 1] TIFF0007698575000035.tif244170TIFF0007698575000036.tif228170TIFF0007698575000037.tif223170TIFF0007698575000038.tif225170TIFF0007698575000039.tif244170TIFF0007698575000040.tif241170TIFF0007698575000041.tif209170TIFF0007698575000042.tif224170TIFF0007698575000043.tif248170TIFF0007698575000044.tif234170TIFF0007698575000045.tif235170TIFF0007698575000046.tif204170TIFF0007698575000047.tif221170TIFF0007698575000048.tif224170TIFF0007698575000049.tif236170TIFF0007698575000050.tif231170TIFF0007698575000051.tif226170TIFF0007698575000052.tif208170TIFF0007698575000053.tif238170TIFF0007698575000054.tif240170TIFF0007698575000055.tif235170TIFF0007698575000056.tif245170TIFF0007698575000057.tif203170TIFF0007698575000058.tif245170TIFF0007698575000059.tif217170TIFF0007698575000060.tif182170TIFF0007698575000061.tif236170TIFF0007698575000062.tif239170TIFF0007698575000063.tif245170TIFF0007698575000064.tif235170TIFF0007698575000065.tif248170TIFF0007698575000066.tif220170TIFF0007698575000067.tif203170TIFF0007698575000068.tif236170TIFF0007698575000069.tif239170TIFF0007698575000070.tif236170TIFF0007698575000071.tif235170TIFF0007698575000072.tif236170TIFF0007698575000073.tif224170TIFF0007698575000074.tif190170TIFF0007698575000075.tif247170TIFF0007698575000076.tif225170TIFF0007698575000077.tif201170TIFF0007698575000078.tif227170TIFF0007698575000079.tif214170TIFF0007698575000080.tif214170TIFF0007698575000081.tif239170TIFF0007698575000082.tif180170TIFF0007698575000083.tif245170TIFF0007698575000084.tif211170TIFF0007698575000085.tif192170TIFF0007698575000086.tif239170TIFF0007698575000087.tif221170TIFF0007698575000088.tif215170TIFF0007698575000089.tif249170TIFF0007698575000090.tif236170TIFF0007698575000091.tif247170TIFF0007698575000092.tif181170TIFF0007698575000093.tif241170TIFF0007698575000094.tif209170TIFF0007698575000095.tif243170TIFF0007698575000096.tif212170TIFF0007698575000097.tif235170TIFF0007698575000098.tif245170TIFF0007698575000099.tif244170TIFF0007698575000100.tif231170TIFF0007698575000101.tif209170TIFF0007698575000102.tif188170TIFF0007698575000103.tif211170TIFF0007698575000104.tif224170TIFF0007698575000105.tif187170TIFF0007698575000106.tif196170TIFF0007698575000107.tif119170TIFF0007698575000108.tif201170TIFF0007698575000109.tif231170TIFF0007698575000110.tif149170TIFF0007698575000111.tif218170TIFF0007698575000112.tif222170TIFF0007698575000113.tif243170TIFF0007698575000114.tif249170TIFF0007698575000115.tif241170TIFF0007698575000116.tif154170TIFF0007698575000117.tif216170TIFF0007698575000118.tif238170TIFF0007698575000119.tif243170TIFF0007698575000120.tif195170TIFF0007698575000121.tif205170TIFF0007698575000122.tif232170TIFF0007698575000123.tif249170TIFF0007698575000124.tif188170TIFF0007698575000125.tif221170TIFF0007698575000126.tif175170TIFF0007698575000127.tif204170TIFF0007698575000128.tif230170TIFF0007698575000129.tif244170TIFF0007698575000130.tif221170TIFF0007698575000131.tif244170TIFF0007698575000132.tif224170TIFF0007698575000133.tif247170TIFF0007698575000134.tif238170TIFF0007698575000135.tif245170TIFF0007698575000136.tif234170TIFF0007698575000137.tif231170TIFF0007698575000138.tif211170.

[0148] In some embodiments, provided is a compound selected from compound numbers 401 - 584, 601, and 701 - 756 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, compound numbers 401, 402, 403, 403a, 403b, 404, 405, 405a, 405b, 406, 407, 408, 408a, 408b, 409, 409a, 409b, 410, 410a, 410b, 411, 411a, 411b, 412, 412a, 412b, 413, 414, 414a, 414b, 415, 415a, 415b, 416, 416a, 416b, 417, 418, 418a, 418b, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 432a, 432b, 433, 433a, 433b, 434, 435, 436, 437, 437a, 437b, 438, 439, 439a, 439b, 440, 440a, 440b, 441, 441a, 441b, 441c, 441d, 442, 442a, 442b, 442c, 442d, 443, 444, 444a, 444b, 445, 445a, 445b, 445c, 445d, 446, 447, 447a, 447b, 448, 449, 450, 451, 451a, 451b, 452, 452a, 452b, 452c, 452d, 453, 454, 455, 456, 457, 458, 459, 460, 461, 461a, 461b, 462, 463, 464, 465, 466, 467, 467a, 467b, 467c, 467d, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 477a, 477b, 477c, 477d, 478, 478a, 478b, 479, 479a, 479b, 480, 480a, 480b, 481, 481a, 481b, 482, 482a, 482b, 482c, 482d, 483, 483a, 483b, 484, 484a, 484b, 485, 485a, 485b, 486, 486a, 486b, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 499a, 499b, 500, 501, 502, 502a, 502b, 503, 504, 504a, 504b, 505, 506, 506a, 506b, 507, 507a,507b, 508, 509, 510, 510a, 510b, 510c, 510d, 511, 511a, 511b, 512, 512a, 512b, 513, 513a, 513b, 514, 514a, 514b, 515, 515a, 515b, 515c, 515d, 516, 516a, 516b, 516c, 516d, 517, 517a, 517b, 518, 518a, 518b, 518c, 518d, 519, 519a, 519b, 520, 520a, 520b, 521, 522, 522a, 522b, 523, 523a, 523b, 524, 525, 525a, 525b, 526, 526a, 526b, 526c, 526d, 527, 527a, 527b, 528, 528a, 528b, 529, 529a, 529b, 530, 530a, 530b, 531, 531a, 531b, 531c, 531d, 532, 533, 533a, 533b, 533c, 533d, 534, 534a, 534b, 535, 535a, 535b, 535c, 535d, 536, 536a, 536b, 537, 537a, 537b, 538, 538a, 538b, 538c, 538d, 539, 539a, 539b, 540, 541, 541a, 541b, 542, 542a, 542b, 542c, 542d, 543, 543a, 543b, 544, 544a, 544b, 544c, 544d, 545, 545a, 545b, 545c, 545d, 546, 546a, 546b, 546c, 546d, 547, 547a, 547b, 548, 548a, 548b, 548c, 548d, 549, 549a, 549b, 550, 550a, 550b, 551, 551a, 551b, 552, 553, 553a, 553b, 554, 554a, 554b, 555, 555a, 555b, 555c, 555d, 556, 556a, 556b, 556c, 556d, 557, 557a, 557b, 558, 558a, 558b, 558c, 558d, 559, 559a, 559b, 559c, 559d, 560, 560a, 560b, 560c, 560d, 561, 561a, 561b, 561c, 561d, 562, 562a, 562b, 562c, 562d, 563, 563a, 563b, 563c, 563d, 566, 566a, 566b, 566c, 566d, 567, 567a, 567b, 567c, 567d, 567e, 567fCompounds selected from 567g, 567h, 568, 568a, 568b, 568c, 568d, 569, 569a, 569b, 569c, 569d, 570, 570a, 570b, 570c, 570d, 571, 571a, 571b, 572, 572a, 572b, 573, 573a, 573b, 573c, 573d, 574, 574a, 574b, 575, 575a, 575b, 576, 576a, 576b, 577, 577a, 577b, 578, 578a, 578b, 579, 580, 581, 581a, 581b, 581c, 581d, 582, 582a, 582b, 582c, 582d, 583, 583a, 583b, 583c, 583d, 584, 584a, 584b, 584c, 584d, 601, 701, 702, 703, 703a, 703b, 703c, 704, 705, 706, 707, 708, 709, 710, 710a, 710b, 711, 711a, 711b, 712, 712a, 712b, 712c, 712d, 713, 713a, 713b, 714, 715, 716, 717, 718, 719, 719a, 719b, 720, 721, 722, 722a, 722b, 723, 723a, 723b, 723c, 723d, 724, 724a, 724b, 725, 726, 726a, 726b, 726c, 726d, 727, 727a, 727b, 727c, 727d, 728, 728a, 728b, 728c, 728d, 729, 729a, 729b, 729c, 729d, 730, 730a, 730b, 730c, 730d, 731, 732, 732a, 732b, 733, 733a, 733b, 734, 734a, 734b, 735, 736, 736a, 736b, 736c, 736d, 737, 738, 739, 740, 740a, 740b, 741, 742, 743, 744, 745, 746, 747, 747a, 747b, 747c, 747d, 748, 748a, 748b, 749, 750, 750a, 750b, 750c, 750d, 751, 752, 753, 754, 755, and 756, or salts thereof (e.g., pharmaceutically acceptable salts).

[0149] In some embodiments, provided is a compound selected from compound numbers 401 - 456, 458 - 494, and 496 - 509, 601, 701 - 720, and 722 - 745 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, provided is a compound selected from compound numbers 401, 744, and 745 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0150] In some embodiments, provided is a compound selected from compound numbers 457, 495, 510 - 563, and 566 - 584 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0151] In some embodiments, provided are compounds selected from Compound Numbers 401 - 563, 566 - 584 in Table 1, or salts thereof (e.g., pharmaceutically acceptable salts). In some embodiments, Compound Numbers 401, 402, 403, 403a, 403b, 404, 405, 405a, 405b, 406, 407, 408, 408a, 408b, 409, 409a, 409b, 410, 410a, 410b, 411, 411a, 411b, 412, 412a, 412b, 413, 414, 414a, 414b, 415, 415a, 415b, 416, 416a, 416b, 417, 418, 418a, 418b, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 432a, 432b, 433, 433a, 433b, 434, 435, 436, 437, 437a, 437b, 438, 439, 439a, 439b, 440, 440a, 440b, 441, 441a, 441b, 441c, 441d, 442, 442a, 442b, 442c, 442d, 443, 444, 444a, 444b, 445, 445a, 445b, 445c, 445d, 446, 447, 447a, 447b, 448, 449, 450, 451, 451a, 451b, 452, 452a, 452b, 452c, 452d, 453, 454, 455, 456, 457, 458, 459, 460, 461, 461a, 461b, 462, 463, 464, 465, 466, 467, 467a, 467b, 467c, 467d, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 477a, 477b, 477c, 477d, 478, 478a, 478b, 479, 479a, 479b, 480, 480a, 480b, 481, 481a, 481b, 482, 482a, 482b, 482c, 482d, 483, 483a, 483b, 484, 484a, 484b, 485, 485a, 485b, 486, 486a, 486b, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 499a, 499b, 500, 501, 502, 502a, 502b, 503, 504, 504a, 504b, 505, 506, 506a, 506b, 507, 507a, 507b,508,509,510,510a,510b,510c,510d,511,511a,511b,512,512a,512b,513,513a,513b,514,514a,514b,515,515a,515b,515c,515d,516,516a,516b,516c,516d,517,517a,517b,518,518a,518b,518c,518d,519,519a,519b,520,520a,520b,521,522,522a,522b,523,523a,523b,524,525,525a,525b,526,526a,526b,526c,526d,527,527a,527b,528,528a,528b,529,529a,529b,530,530a,530b,531,531a,531b,531c,531d,532,533,533a,533b,533c,533d,534,534a,534b,535,535a,535b,535c,535d,536,536a,536b,537,537a,537b,538,538a,538b,538c,538d,539,539a,539b,540,541,541a,541b,542,542a,542b,542c,542d,543,543a,543b,544,544a,544b,544c,544d,545,545a,545b,545c,545d,546,546a,546b,546c,546d,547,547a,547b,548,548a,548b,548c,548d,549,549a,549b,550,550a,550b,551,551a,551b,552,553,553a,553b,554,554a,554b,555,555a,555b,555c,555d,556,556a,556b,556c,556d,557,557a,557b,558,558a,558b,558c,558d,559,559a,559b,559c,559d,560,560a,560b,560c,560d,561,561a,561b,561c,561d,562,562a,562b,562c,562d,563,563a,563b,563c,563d,566,566a,566b,566c,566d,567,567a,567b,567c,567d,567e,567f,567g,Provided is a compound selected from 567h, 568, 568a, 568b, 568c, 568d, 569, 569a, 569b, 569c, 569d, 570, 570a, 570b, 570c, 570d, 571, 571a, 571b, 572, 572a, 572b, 573, 573a, 573b, 573c, 573d, 574, 574a, 574b, 575, 575a, 575b, 576, 576a, 576b, 577, 577a, 577b, 578, 578a, 578b, 579, 580, 581, 581a, 581b, 581c, 581d, 582, 582a, 582b, 582c, 582d, 583, 583a, 583b, 583c, 583d, 584, 584a, 584b, 584c, and 584d, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0152] In some embodiments, provided is a compound selected from compound numbers 401-456, 458-494, and 496-509 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, provided is a compound selected from compound numbers 401, 402, 403, 403a, 403b, 404, 405, 405a, 405b, 406, 407, 408, 408a, 408b, 409, 409a, 409b, 410, 410a, 410b, 411, 411a, 411b, 412, 412a, 412b, 413, 414, 414a, 414b, 415, 415a, 415b, 416, 416a, 416b, 417, 418, 418a, 418b, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 432a, 432b, 433, 433a, 433b, 434, 435, 436, 437, 437a, 437b, 438, 439, 439a, 439b, 440, 440a, 440b, 441, 441a, 441b, 442, 442a, 442b, 442c, 442d, 443, 444, 444a, 444b, 445, 445a, 445b, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, and 509 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0153] In some embodiments, provided is a compound selected from compound numbers 457, 495, 510-563, and 566-584 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0154] In some embodiments, provided is a compound selected from compound numbers 701 to 756 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, provided is a compound selected from compound numbers 701, 702, 703, 703a, 703b, 703c, 704, 705, 706, 707, 708, 709, 710, 710a, 710b, 711, 711a, 711b, 712, 712a, 712b, 712c, 712d, 713, 713a, 713b, 714, 715, 716, 717, 718, 719, 719a, 719b, 720, 721, 722, 722a, 722b, 723, 723a, 723b, 723c, 723d, 724, 724a, 724b, 725, 726, 726a, 726b, 726c, 726d, 727, 727a, 727b, 727c, 727d, 728, 728a, 728b, 728c, 728d, 729, 729a, 729b, 729c, 729d, 730, 730a, 730b, 730c, 730d, 731, 732, 732a, 732b, 733, 733a, 733b, 734, 734a, 734b, 735, 736, 736a, 736b, 736c, 736d, 737, 738, 739, 740, 740a, 740b, 741, 742, 743, 744, 745, 746, 747, 747a, 747b, 747c, 747d, 748, 748a, 748b, 749, 750, 750a, 750b, 750c, 750d, 751, 752, 753, 754, 755, and 756 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0155] In some embodiments, provided are compounds selected from Compound Numbers 701 to 720, and 722 to 745 in Table 1, or salts thereof (e.g., pharmaceutically acceptable salts). In some embodiments, provided are compounds selected from Compound Numbers 701, 702, 703, 703a, 703B, 703c, 704, 705, 706, 707, 708, 709, 710, 710a, 710B, 711, 711a, 711B, 712, 712a, 712B, 712c, 713, 713a, 713B, 714, 715, 716, 717, 718, 719, 720, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744 and 745 in Table 1, or salts thereof (e.g., pharmaceutically acceptable salts).

[0156] In some embodiments, provided are compounds selected from Compound Numbers 721 and 746 to 756 in Table 1, or salts thereof (e.g., pharmaceutically acceptable salts).

[0157] In some embodiments, provided are compounds selected from Compound Number 601 in Table 1, or salts thereof (e.g., pharmaceutically acceptable salts).

[0158] The compounds of formula (I) described herein or salts thereof can exist as stereoisomers (e.g., containing one or more asymmetric carbon atoms). Individual stereoisomers (enantiomers and diastereomers), as well as mixtures thereof, are included within the scope of the subject matter disclosed herein. Similarly, the compounds or salts of formula (I) can exist in tautomeric forms other than those represented by the formula, and these are also understood to be included within the scope of the subject matter disclosed herein. The subject matter disclosed herein should be understood to include the specific combinations and subsets of groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers, as well as purified enantiomers, or enantiomerically / diastereomerically enriched mixtures. The subject matter disclosed herein should be understood to include the specific combinations and subsets of groups defined herein.

[0159] The subject matter disclosed herein also includes isotopically labeled forms of the compounds described herein with respect to the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds described herein, and their pharmaceutically acceptable salts, include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. For example, the compounds disclosed herein include forms in which one or more hydrogen atoms are replaced or enriched with deuterium.

[0160] The subject matter disclosed herein includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of the compounds of formula (I). Metabolites of the compounds of formula (I) include compounds prepared by a process that includes contacting the compounds of formula (I) with a mammal for a time sufficient to obtain its metabolites.

[0161] When the compound of formula (I) is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treating the free base with an inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.), or an organic acid (such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), etc.).

[0162] When the compound of formula (I) is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, etc. Examples of suitable salts include organic salts derived from amino acids (such as glycine and arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (such as piperidine, morpholine and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium, but are not limited thereto.

[0163] The compounds of formula (I) can be in the form of "prodrugs", which include compounds having moieties that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or by other mechanisms for the active agent. Examples of prodrugs and their use are well known in the art (see, e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19). Prodrugs can be prepared in situ during the final isolation and purification of the compound or by separately reacting the purified compound in its free acid form or hydroxyl with a suitable esterifying agent. Hydroxyl groups can be converted to esters by treatment with carboxylic acids. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate esters), lower alkenyl esters, di-lower alkylamino lower alkyl esters (e.g., dimethylaminoethyl esters), acylamino lower alkyl esters (e.g., acetyloxymethyl esters), acyloxy lower alkyl esters (e.g., pivaloyloxymethyl esters), aryl esters (phenyl esters), aryl lower alkyl esters (e.g., benzyl esters), substituted (e.g., by methyl, halo, or methoxy substituents) aryl and aryl lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides, and hydroxyamides. Also included are prodrugs that are converted to the active form by other in vivo mechanisms. In a plurality of embodiments, the compounds of the present invention are prodrugs having any of the formulas herein.

[0164] The compounds of formula (I) can be prepared by general synthetic methods and the precedents described in the examples as described herein, or by methods known in the art. Pharmaceutical Compositions and Formulations

[0165] The compounds disclosed in this specification can be formulated into pharmaceutical compositions together with pharmaceutically acceptable carriers or additives.

[0166] The compound of formula (I), or its variants such as formula (IA), (IB), and (IC), can be formulated according to standard pharmaceutical practices as a pharmaceutical composition. In accordance with this aspect, a pharmaceutical composition is provided that includes the compound of formula (I), or its variants such as formula (IA), (IB), and (IC), associated with a pharmaceutically acceptable additive, diluent, or carrier.

[0167] Typical formulations are prepared by mixing the compound of formula (I), or its variants such as formula (IA), (IB), and (IC), and a carrier, diluent, or additive. Suitable carriers, diluents, and additives are well known to those skilled in the art and include materials such as carbohydrates, waxes, water-soluble and / or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, and water. The specific carrier, diluent, or additive used depends on the means and purpose for which the compound of formula (I), or its variants such as formula (IA), (IB), and (IC), is applied. Solvents are generally selected based on solvents that are recognized by those skilled in the art as being safe (GRAS) for administration to mammals. Generally, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc., and mixtures thereof. The formulations may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifying agents, suspending agents, preservatives, antioxidants, opacifying agents, flow promoters, processing aids, coloring agents, sweetening agents, flavoring agents, fragrance agents, and other known additives to provide accurate presentation of the drug (i.e., the compound of formula (I), or its variants such as formula (IA), (IB), and (IC)) or to assist in the manufacture of pharmaceuticals (i.e., medicines).

[0168] The formulation may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., the compound of formula (I), or its variants such as those of formulae (IA), (IB), and (IC), or a stabilized form of the compound of formula (I), or its variants such as those of formulae (IA), (IB), and (IC) (e.g., complexed with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above additives. The compound of formula (I) is typically formulated into a pharmaceutical dosage form so as to provide an easily controllable drug dosage and enable patient compliance with a given regimen.

[0169] The pharmaceutical composition (or formulation) for administration may be packaged in a variety of ways depending on the method used to administer the drug. Generally, the dispensing article includes a container having the pharmaceutical formulation disposed therein in a suitable form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include an anti-tampering assembly to prevent inadvertent access to the contents of the package. In addition, the container has a label thereon that describes the contents of the container. The label may also include appropriate cautions.

[0170] Drug formulations can be prepared for various routes of administration and types. For example, the compound of formula (I) having the desired purity is optionally in the form of a lyophilized formulation, a ground powder, or an aqueous solution, with a pharmaceutically acceptable diluent, carrier, additive, or stabilizer (Remington’s Pharmaceutical Sciences (1980) 16 thIt may be mixed with (Osol, A. Ed.). The formulation may be carried out by mixing with a physiologically acceptable additive or carrier, i.e., an additive or carrier that is non-toxic to the recipient at the dosage and concentration used, at ambient temperature, at an appropriate pH, and at the desired degree of purity. The pH of the formulation may range from about 3 to about 8, although it mainly depends on the specific use and the concentration of the compound. A formulation in acetate buffer at pH 5 is a preferred embodiment.

[0171] The compound of formula (I) may be sterilized. In particular, formulations for in vivo administration must be sterilized. Such sterilization is easily achieved by filtration through a sterile filtration membrane.

[0172] The compound can usually be stored as a solid composition, a lyophilized formulation, or an aqueous solution.

[0173] The pharmaceutical composition containing the compound of formula (I) can be formulated, dosed, and administered in a manner consistent with good medical practice, i.e., in terms of amount, concentration, schedule, process, vehicle, and route of administration. Factors to be considered in this regard include the specific disease being treated, the specific mammal being treated, the clinical condition of the individual patient, the cause of the disease, the site of drug delivery, the method of administration, the dosing schedule, and other factors known to medical practitioners. The "therapeutically effective amount" of the compound administered is governed by such considerations and is the minimum amount necessary to prevent, ameliorate, or treat a coagulation factor-mediated disease. In some embodiments, the amount is below an amount that is toxic to the host or that makes the host more susceptible to bleeding.

[0174] Acceptable diluents, carriers, additives, and stabilizers are non-toxic to the recipient at the dosages and concentrations employed, and include buffers such as phosphoric acid, citric acid, and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (octadecyl dimethyl benzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol, etc.); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The active pharmaceutical ingredient may also be incorporated in, for example, microcapsules prepared by coacervation techniques or interfacial polymerization, such as hydroxy methyl cellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules respectively, in colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16 th edition, Osol, A. Ed., 1980.

[0175] Sustained-release formulations of the compounds of formula (I) can be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds of formula (I), which matrices are in the form of shaped articles such as, for example, films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and γ-ethyl-L-glutamate, non-degradable ethylene vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0176] Formulations include those suitable for the routes of administration detailed herein. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art. The techniques and formulations are generally found in Remington’s Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing the active ingredient into association with an additive or carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid additive or carrier, or a finely divided solid additive or carrier, or both, and then, if necessary, shaping the product.

[0177] Formulations of the compounds of formula (I) suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of the compound of formula (I).

[0178] Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in free-flowing form as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant, etc. Molded tablets can be made by molding a mixture of wetted powdered active ingredient and an inert liquid diluent in a suitable machine. The tablets may optionally be coated or grooved and are optionally formulated to provide a sustained or controlled release of the active ingredient therefrom.

[0179] Tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups, or elixirs can be prepared for oral use. Formulations of the compounds of formula (I) intended for oral use may be prepared according to any method known in the art of manufacture of pharmaceutical compositions, and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents, and preservatives to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable additives suitable for the manufacture of tablets are acceptable. These additives can be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binding agents such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc. Tablets may or may not be coated or may be coated by known techniques including microencapsulation to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, time-delay materials such as glyceryl monostearate or glyceryl distearate can be used alone or in combination with waxes.

[0180] For the treatment of the eye or other external tissues, such as the mouth and skin, the formulation is preferably applied as a topical ointment or cream containing the active ingredient in an amount of 0.075 to 20% w / w. When formulated in an ointment, the active ingredient can be used with either a paraffin-based or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base.

[0181] If desired, the aqueous phase of the cream base can contain a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups, such as propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol (including PEG400) and mixtures thereof. The topical formulation can optionally contain a compound that enhances the absorption or penetration of the active ingredient through the skin or other affected area. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues.

[0182] The oily phase of the emulsion can be composed of known components in a known manner. The phase can simply contain an emulsifier, but the phase can also contain at least one emulsifier and a mixture of fat and / or oil. A hydrophilic emulsifier contained with a lipophilic emulsifier can serve as a stabilizer. In summary, an emulsifier with or without a stabilizer constitutes a so-called emulsifying wax, and together with oils and fats, the wax constitutes a so-called emulsifying ointment base that forms the oily dispersed phase of the cream formulation. Suitable emulsifiers and emulsion stabilizers for use in the formulation include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulfate.

[0183] The aqueous suspension of the compound of formula (I) contains an active material mixed with additives suitable for the production of an aqueous suspension. Such additives include suspending agents such as sodium carboxymethyl cellulose, croscarmellose, povidone, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinyl pyrrolidone, tragacanth gum, and acacia gum, natural occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxy cetanol), and condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate), etc., dispersants or wetting agents. The aqueous suspension also contains one or more preservatives, e.g., ethyl or n-propyl p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweetening agents such as sucrose or saccharin.

[0184] The pharmaceutical compositions of the compound of formula (I), or variants such as formula (IA), (IB), and (Ic) can be in the form of a sterile injectable preparation, such as a sterile aqueous or oily suspension. This suspension can be formulated according to known techniques using these suitable dispersants or wetting agents and suspending agents described above. The sterile injectable formulation can further be a sterile injectable, parenterally acceptable, non-toxic diluent or solvent, e.g., a solution or suspension in 1,3-butanediol. The sterile injectable preparation can also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, a fixed oil for sterilization can be conventionally used as a solvent or suspending medium. For this purpose, any brand of fixed oil containing synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be used in the preparation of injectables.

[0185] The amount of active ingredient that can be combined with additives or carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. For example, a sustained release formulation intended for oral administration to humans may contain from about 1 to 1000 mg of active material, formulated with an appropriate and convenient amount of additive or carrier material, which can vary from about 5 to about 95% (weight:weight) of the total composition. The pharmaceutical composition can be prepared to provide an easily measurable amount for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of active ingredient per milliliter of solution so that a suitable volume of infusion occurs at a rate of about 30 mL / hour.

[0186] Formulations suitable for parenteral administration may include aqueous and non-aqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the recipient to which the formulation is targeted, as well as aqueous and non-aqueous sterile suspensions that may include suspending and thickening agents.

[0187] Formulations suitable for topical administration to the eye also include eye drops, in which the active ingredient is dissolved or suspended in a suitable additive or carrier, particularly an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations at a concentration of about 0.5 to 20% w / w, for example, about 0.5 to 10% w / w, for example about 1.5% w / w.

[0188] Formulations suitable for topical administration to the mouth include flavored bases, usually lozenges containing the active ingredient in sucrose and acacia or tragacanth, pastilles containing the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia, and mouthwashes containing the active ingredient in a suitable liquid additive or carrier.

[0189] Formulations for rectal administration may be presented as suppositories, for example, with a suitable base including cocoa butter or a salicylate.

[0190] Formulations suitable for pulmonary or nasal administration have a particle size in the range of, for example, 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in units of microns such as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation from the nostrils or by inhalation from the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents such as compounds previously used for the treatment or prevention of the diseases described below.

[0191] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, additives or carriers known in the art to be appropriate.

[0192] The formulations may be packaged in unit dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried state that requires only the addition of a sterile liquid additive or carrier, such as water, immediately prior to use for injection. Immediate injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred unit dose formulations contain the daily dose or daily unit sub-dose of the active ingredient as described hereinabove, or an appropriate fraction thereof.

[0193] The subject further provides veterinary compositions comprising at least one active ingredient as defined above together with a veterinary additive or carrier for the active ingredient. The veterinary additive or carrier is a substance useful for the purpose of administering the composition and can otherwise be a solid, liquid, or gaseous substance that is inert or acceptable in the art of veterinary medicine and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0194] In certain embodiments, a pharmaceutical composition comprising a compound disclosed herein further comprises a chemotherapeutic agent. In some of these embodiments, the chemotherapeutic agent is an immunotherapeutic agent. Method of Use

[0195] The compounds disclosed herein are found to be useful for inhibiting the activity of the enzyme HPK1. HPK1, also known as mitogen-activated protein kinase kinase kinase kinase kinase 1 or MAP4K1, is a member of the germinal center kinases subfamily of Ste20-related serine / threonine kinases. HPK1 functions as a MAP4K by phosphorylating and activating MAP3K proteins, including MEKK1, MLK3, and TAK1, resulting in the activation of the MAPK Jnk.

[0196] In one embodiment, the subject matter disclosed herein is a method of inhibiting HPK1, the method comprising contacting HPK1 with an effective amount of a compound of formula (I) described herein, or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutical composition.

[0197] In one embodiment, the subject matter disclosed herein is a method of enhancing an immune response in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I) described herein, or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutical composition. In certain aspects of this embodiment, the subject's T cells have at least one of improved priming, improved activation, improved migration, improved proliferation, improved survival, and improved cytolytic activity compared to prior to administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, activation of the T cells is characterized by an increase in the frequency of γ-IFN+CD8 T cells, an increase in the frequency of γ-IFN+CD4 T cells, or an increase in the production of IL-2 or granzyme B by the T cells, compared to prior to administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the number of T cells increases compared to prior to administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the T cells are antigen-specific CD8 T cells. In certain aspects of this embodiment, the T cells are antigen-specific CD4 T cells. In certain aspects of this embodiment, the subject's antigen-presenting cells have enhanced maturation and activation compared to prior to administration of the compound or pharmaceutical composition. In certain aspects of this embodiment, the antigen-presenting cells are dendritic cells. In certain aspects of this embodiment, maturation of the antigen-presenting cells is characterized by an increase in the frequency of CD83+ dendritic cells. In certain aspects of this embodiment, activation of the antigen-presenting cells is characterized by an increase in the expression of CD80 and CD86 in the dendritic cells. In some aspects, the compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutical composition thereof, provides general priming of an immune response (e.g., a vaccine) against a tumor or virus for additional immunization / anti-viral / tumor immunogenesis.

[0198] In the method described herein, the compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutical composition thereof, is administered to a subject having a cancer described elsewhere herein.

[0199] In one embodiment, the subject matter disclosed herein is a method of treating an HPK1-dependent disorder, the method comprising administering to a subject in need of treatment for an HPK1-dependent disorder an effective amount of a compound of formula (I) described herein, or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutical composition. In certain aspects of this embodiment, the HPK1-dependent disorder is cancer. In certain aspects of this embodiment, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma. In certain aspects of this embodiment, the cancer has an increased amount of T cell infiltration. In certain aspects of this embodiment, the cancer cells in the subject have a selectively increased expression of MHC class I antigen expression as compared to before administration of the compound or composition.

[0200] In the method described herein, the method can further comprise administering a chemotherapeutic agent to the subject. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject simultaneously with the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject prior to administration of the compound or composition. In certain aspects of this embodiment, the chemotherapeutic agent is administered to the subject after administration of the compound or the composition.

[0201] The polynucleotides and polypeptides of HPK1 are known in the art (Hu et al. (1996) Genes Dev 10:2251-2264, which is incorporated herein by reference in its entirety). Certain HPK1 polynucleotides and polypeptides containing the human HPK1 polynucleotide are accessible and the sequences are known, for example, nucleotides 141-2642 of GenBank accession number NM_007181.5, and the encoded human HPK1 polypeptide (accession number NP_009112.1); and nucleotides 141-2606 of GenBank accession number NM_001042600.2, and the encoded human HPK1 polypeptide (accession number NP_001036065.1).

[0202] The HPK1 polypeptide contains various conserved structural motifs. The HPK1 polypeptide contains an amino-terminal Ste20-like kinase domain that includes an ATP-binding site. Following the kinase domain are four proline-rich (PR) motifs that function as binding sites for SH3-containing proteins such as CrkL, Grb2, HIP-55, Gads, Nck, and Crk. HPK1 is phosphorylated and activated in response to TCR or BCR stimulation. Phosphorylation of the tyrosine residue located between PR1 and PR2 by induction of TCR and BCR mediates binding to SLP-76 in T cells or BLNK in B cells via the SLP-76 or BLNK SH2 domain, which is required for activation of the kinase. The citron homology domain found at the C-terminus of HPK1 can function as a regulatory domain and can be involved in macromolecular interactions.

[0203] The compounds disclosed herein bind directly to HPK1 and inhibit its kinase activity. In some embodiments, the compounds disclosed herein reduce, inhibit, or otherwise decrease HPK1-mediated phosphorylation of SLP76 and / or Gads.

[0204] The compounds disclosed herein may or may not be specific HPK1 antagonists. A specific HPK1 antagonist reduces the biological activity of HPK1 by a statistically significant amount relative to the inhibitory effect of an antagonist of any other protein (e.g., other serine / threonine kinases). In certain embodiments, the compounds disclosed herein specifically inhibit the serine / threonine kinase activity of HPK1. In some of these embodiments, the IC 50 of the HPK1 antagonist for HPK1 is about 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 0.1%, 0.01%, 0.001% or less of the IC 50 of the HPK1 antagonist for another serine / threonine kinase or another type of kinase (e.g., tyrosine kinase).

[0205] The compounds disclosed herein can be used in methods of inhibiting HPK1. Such methods include contacting HPK1 with an effective amount of a compound disclosed herein. "Contacting" is intended to bring the compound sufficiently close to an isolated HPK1 enzyme or a cell expressing HPK1 (e.g., a T cell, B cell, dendritic cell) such that the compound can bind and inhibit the activity of HPK1. The compound can be contacted with HPK1 in vitro or in vivo by administering the compound to a subject.

[0206] Whether HPK1 is inhibited can be measured using any method known in the art for measuring the kinase activity of HPK1, including in vitro kinase assays using antibodies specific for phosphorylation targets of HPK1 such as SLP76 and Gads, or measuring downstream biological effects of HPK1 kinase activity such as recruitment of 14-3-3 proteins to phosphorylated SLP7 and Gads, release of SLP76-Gads-14-3-3 from LAT-containing microclusters, or activation of T or B cells.

[0207] The compounds disclosed herein can be used to treat HPK1-dependent disorders. As used herein, "HPK1-dependent disorder" is a condition in which HPK1 activity is required for the development or continuation of the condition. In some embodiments, the HPK1-dependent disorder is cancer.

[0208] The compounds disclosed herein are also found to have utility in methods of enhancing an immune response in a subject in need thereof. Such methods include administering an effective amount of a compound disclosed herein (i.e., a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof).

[0209] As used herein, "enhancing an immune response" means improving any immunogenic response to an antigen. Non-limiting examples of improving the immunogenic response to an antigen include improved maturation or migration of dendritic cells, improved activation of T cells (e.g., CD4 T cells, CD8 T cells), improved proliferation of T cells (e.g., CD4 T cells, CD8 T cells), improved proliferation of B cells, increased survival of T cells and / or B cells, improved antigen presentation by antigen-presenting cells (e.g., dendritic cells), improved antigen clearance, increased production of cytokines by T cells (e.g., interleukin-2), increased resistance to prostaglandin E2-induced immunosuppression, and improved priming and / or cytolytic activity of CD8 T cells.

[0210] In some embodiments, the subject's CD8 T cells have an increase in priming, activation, proliferation, and / or cytolytic activity compared to before administration of a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, priming of CD8 T cells is characterized by an increase in CD44 expression and / or enhanced cytolytic activity in CD8 T cells. In some embodiments, activation of CD8 T cells is γ-IFN+ Characterized by an increase in the frequency of CD8 T cells. In some embodiments, the CD8 T cells are antigen-specific T cells.

[0211] In some embodiments, the CD4 T cells of a subject have an increase in priming, activation, proliferation, and / or cytolytic activity as compared to before administration of a compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, priming of CD4 T cells is characterized by an increase in CD44 expression in the CD4 T cells and / or enhancement of cytolytic activity. In some embodiments, activation of CD4 T cells is γ-IFN + Characterized by an increase in the frequency of CD4 T cells. In some embodiments, the CD4 T cells are antigen-specific T cells.

[0212] In some embodiments, the antigen-presenting cells of a subject have enhanced maturation and activation as compared to before administration of a compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the antigen-presenting cells are dendritic cells. In some embodiments, maturation of the antigen-presenting cells is CD83 + Characterized by an increase in the frequency of dendritic cells. In some embodiments, activation of the antigen-presenting cells is characterized by an increase in the expression of CD80 and CD86 in the dendritic cells.

[0213] In some embodiments, the serum concentrations of the cytokines IL-10 and / or the chemokine IL-8, the human homolog of mouse KC, in a subject are decreased as compared to before administration of a compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0214] The involvement of TCR leads to the activation of HPK1, which functions as a negative regulator of the AP-1 response pathway induced by TCR. By phosphorylating SLP76 at Ser376 (Di Bartolo et al. (2007) JEM 204:681-691) and Gads at Thr254, and by reducing the persistence of microcluster signaling, HPK1 negatively controls T cell activation, which results in the recruitment of 14-3-3 proteins that bind to phosphorylated SLP76 and Gads, and the release of the SLP76-Gads-14-3-3 complex from LAT-containing microclusters, thereby leading to T cell dysfunction, including anergy and exhaustion (Lasserre et al. (2011) J Cell Biol 195(5):839-853).

[0215] The term "dysfunction" in the context of immunodysfunction refers to a state of reduced responsiveness to antigenic stimulation. This term includes both common elements of exhaustion and / or anergy where antigen recognition can occur, but the subsequent immune response is ineffective in controlling the rate of infection or tumor growth.

[0216] As used herein, the term "dysfunctional" includes unresponsiveness or non-responsiveness to antigen recognition, specifically, impairment of the ability to translate antigen recognition into downstream T cell effector functions such as proliferation, cytokine production (e.g., IL-2, γ-IFN), and / or target cell killing.

[0217] The term "anergy" refers to a state of unresponsiveness to antigenic stimulation resulting from incomplete or insufficient signals delivered via the T cell receptor (e.g., an increase in intracellular Ca +2 in the absence of ras activation). T cell anergy can also occur upon stimulation with antigen in the absence of co-stimulation, and as a result, the cell becomes refractory to subsequent activation by the antigen even in the context of co-stimulation. The unresponsive state can often be abrogated by the presence of interleukin-2. Anergic T cells do not undergo clonal expansion and / or acquire effector functions.

[0218] The term "exhaustion" refers to T cell exhaustion as a state of T cell dysfunction resulting from persistent TCR signaling that occurs during many chronic infections and cancer development. This is distinguished from anergy in that it is due to persistent signaling rather than incomplete or insufficient signaling. It is defined by effector function defects that are distinct from functional effector or memory T cells, persistent expression of inhibitory receptors, and transcriptional states. Exhaustion impedes the optimal control of infections and tumors. Exhaustion can result from both exogenous negative regulatory pathways (e.g., immunosuppressive cytokines) and cell-intrinsic negative regulatory (costimulatory) pathways (such as PD-1, B7-H3, B7-H4).

[0219] In some embodiments, administration of a compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof, results in an improvement in T cell function. In some embodiments, administration of an HPK1 inhibitor described herein can enhance / renew / reactivate an immune response or activate a de novo immune response.

[0220] "Enhancing T cell function" means inducing, causing, or stimulating T cells to have a sustained or amplified biological function, or regenerating or reactivating exhausted or inactive T cells. Examples of improving T cell function include increased secretion of cytokines (such as γ-interferon, IL-2, IL-12, and TNFα), increased proliferation, increased antigen responsiveness (such as viral, pathogen, or tumor clearance) compared to levels prior to intervention, and increased effector granule production by CD8 T cells or CD4 T cells such as granzyme B. In one embodiment, the level of enhancement is at least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to those of skill in the art.

[0221] Thus, the compounds of formula (I) disclosed herein, or variants thereof such as formulae (IA), (IB), and (IC), or pharmaceutically acceptable salts, prodrugs, metabolites, or derivatives thereof, are useful for the treatment of T cell dysfunctional diseases. A "T cell dysfunctional disease" is a disease or condition of T cells characterized by a reduced responsiveness to antigenic stimulation. In certain embodiments, the T cell dysfunctional disease is a disease specifically associated with an increase in the kinase activity of HPK1. In another embodiment, the T cell dysfunctional disorder is a disorder in which T cells are anergic or have a reduced ability to secrete cytokines, proliferate, or execute cytolytic activity. In a specific aspect, the reduced responsiveness results in ineffective control of pathogens or tumors expressing immunogens. Examples of T cell dysfunctional diseases characterized by T cell dysfunction include unexplained acute infections, chronic infections, and tumor immunity.

[0222] Thus, the compounds disclosed herein can be used under treatment conditions where enhancement of immunogenicity, such as an increase in tumor immunogenicity for cancer treatment, is desired.

[0223] "Immunogenicity" refers to the ability of a particular substance to induce an immune response. Tumors are immunogenic, and enhancement of tumor immunogenicity aids in the clearance of tumor cells by the immune response. Viruses can also be immunogenic, and enhancement / activation of immunogenicity can assist in the clearance of virus particles by the immune response.

[0224] "Tumor immunity" refers to the process by which tumors avoid immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such avoidance is attenuated and the tumor is recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage, and tumor clearance.

[0225] In one aspect, provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In some embodiments, the subject has melanoma. The melanoma can be early or late stage. In some embodiments, the subject has colorectal cancer. The colorectal cancer can be early or late stage. In some embodiments, the subject has non-small cell lung cancer. The non-small cell lung cancer can be early or late stage. In some embodiments, the subject has pancreatic cancer. The pancreatic cancer can be in an early or advanced state. In some embodiments, the subject has a hematological malignancy. The hematological malignancy can be early or late stage. In some embodiments, the subject has ovarian cancer. The ovarian cancer can be early or late stage. In some embodiments, the subject has breast cancer. The breast cancer can be early or late stage. In some embodiments, the subject has renal cell carcinoma. The renal cell carcinoma can be early or late stage. In some embodiments, the cancer has an increased level of T cell infiltration.

[0226] In one aspect, provided herein is a method for treating a viral infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof. In one aspect, provided herein is a method for enhancing response or boosting immunity in a subject in need thereof for both a vaccine (cancer vaccine or personalized cancer vaccine (PCV)) or CAR-T cells, the method comprising administering to the subject an effective amount of a compound of formula (I), or a variant thereof such as formulae (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof.

[0227] The compounds disclosed herein may be administered by any suitable method known in the art. In some embodiments, the compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof is administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by transplantation, by inhalation, intrathecally, intraventricularly, intratumorally, or intranasally.

[0228] In some embodiments, the HPK1 antagonist is administered continuously. In other embodiments, the HPK1 antagonist is administered intermittently. Further, the treatment of a subject with an effective amount of an HPK1 antagonist can include a single treatment or can include a course of treatments.

[0229] It is understood that the appropriate dosage of the active compound will depend on a number of factors within the knowledge of a physician or veterinarian in the art. The dosage of the active compound will vary, for example, depending on the age, weight, general health, sex, and diet of the subject, the timing of administration, the route of administration, the rate of excretion, and any combination of drugs.

[0230] Furthermore, it will be understood that the effective dosage of the compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof used in the treatment may increase or decrease over the course of a particular treatment. The change in dosage will result and will become apparent from the results of diagnostic assays.

[0231] In some embodiments, the HPK1 antagonist is administered to a subject at a dose of about 0.001 μg / kg to about 1000 mg / kg, including but not limited to about 0.001 μg / kg, about 0.01 μg / kg, about 0.05 μg / kg, about 0.1 μg / kg, about 0.5 μg / kg, about 1 μg / kg, about 10 μg / kg, about 25 μg / kg, about 50 μg / kg, about 100 μg / kg, about 250 μg / kg, about 500 μg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, and about 200 mg / kg.

[0232] In some embodiments, provided is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt, prodrug, metabolite, or derivative thereof, and further comprising administering an additional treatment method. The additional treatment method can be radiotherapy, surgery (such as tumor resection and mastectomy), chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing. The additional treatment method can be in the form of adjuvant therapy or neoadjuvant therapy. In some embodiments, the additional treatment method is administering an anti-metastatic agent. In some embodiments, the additional treatment method is administering a side effect limiting agent (e.g., an agent intended to reduce the occurrence and / or severity of side effects of the treatment, such as an antiemetic agent, etc.). In some embodiments, the additional treatment method is radiotherapy. In some embodiments, the additional treatment method is surgery. In some embodiments, the additional treatment method is a combination of radiotherapy and surgery. In some embodiments, the additional treatment method is gamma irradiation. In some embodiments, the additional treatment method is a treatment method targeting the PI3K / AKT / mTOR pathway, an HSP90 inhibitor, a tubulin inhibitor, an apoptosis inhibitor, and / or a chemopreventive agent.

[0233] The additional treatment method can be one or more of chemotherapeutic agents. Therefore, the cancer treatment method can include administering the HPK1 antagonist disclosed herein together with at least one chemotherapeutic agent.

[0234] As used herein, "together with" means administering one treatment modality together with another treatment modality. Therefore, "together with" refers to the administration of another treatment method before, during, or after the administration of one treatment method to a subject.

[0235] For example, the HPK1 antagonist and the chemotherapeutic agent can be administered sequentially (at different times) or simultaneously (at the same time). The HPK1 antagonist and the chemotherapeutic agent can be administered by the same route of administration or by different routes of administration.

[0236] In certain embodiments, the HPK1 antagonist is administered in combination with another immunotherapy. For example, the HPK1 antagonist can be combined with a chemotherapeutic agent or a biological agent that targets the PD-L1 / PD-1 pathway. Known inhibitory checkpoint pathways involve signaling through the PD-1 receptor. The programmed cell death 1 (PD-1) receptor, and its ligands PD-L1 and PD-L2, are part of the same family as the co-inhibitory molecule CTLA-4. - For details, see http: / / www.onclive.com / web-exclusives / the-role-of-anti-pd-l1-immunotherapy-in-cancer / 2#sthash.cGfYa1T1.dpuf. Chemotherapeutic agents or biological agents that block the binding of PD-L1 to PD-1 and CD80 can prevent the PD-L1-mediated inhibition / suppression of T cell activation. Programmed cell death ligand 1 (PD-L1) is widely expressed in antigen-presenting cells (APCs) and other immune cells. This is upregulated in tumor cells derived from a wide range of human cancers, suggesting inhibition of anti-tumor T cell immunity. PD-L1 is a cell surface protein that binds to the receptors PD-1 and CD80 on activated T cells, B cells, and other myeloid cells. The binding of PD-L1 to PD-1 on activated T cells has been found to interfere with T cell proliferation and inhibit the immune response. Overexpression of PD-L1 on cancer cells can enable these cells to avoid immune detection and elimination. High levels of PD-L1 expression on tumor cells are associated with increased tumor aggressiveness and poor prognosis. Chemotherapeutic agents or biological agents that block the binding of PD-L1 to PD-1 include, among others, anti-PD-L1 antibodies such as durvalumab, nivolumab, pidilizumab, MPDL3280A, MK-3475, BMS-936559. In some embodiments, the HPK1 antagonist is administered with a PD-1 antagonist such as an anti-PD-1 antibody, a PD-L1 antagonist such as an anti-PD-L1 antibody, and / or a PD-L2 antagonist such as a PD-L2 antibody.Examples of anti-PD-L1 antibodies include, but are not limited to, avelumab, atezolizumab (also known as MPDL3280A), pembrolizumab (also known as MK-3475), LY3300054 (Eli Lilly), STI-A1014 (Sorrento), KN035 (Suzhou Alphamab), and BMS-936559 (Bristol Myers Squibb). Examples of anti-PD-1 antibodies include, but are not limited to, nivolumab, pidilizumab, PDR001 (Novartis), REGN2810 (Regeneron), BGB-108 (BeiGene), BGB-A317 (BeiGene), JS-001 (Shanghai Junshi), STI-A1110 (Sorrento), INCSHR-1210 (Incyte), PF-06801591 (Pfizer), TSR-042 (also known as ANB011; Tesaro / AnaptysBio), AM0001 (ARMO Biosciences), and ENUM 244C8 (Enumeral Biomedical Holdings).

[0237] In another example, an HPK1 antagonist can be combined with a chemotherapeutic agent or a biological agent that targets OX40 and its ligand OX40L, which are members of the TNF superfamily. OX40 is expressed on activated CD4(+) and CD8(+) T cells, as well as on other lymphoid and non-lymphoid cells. The co-stimulatory signal from OX40 to conventional T cells promotes proliferation and survival, and increases the clonal expansion of effector and memory populations when an antigen is being generated. OX40 further suppresses the differentiation and activity of regulatory T cells and further amplifies this process. OX40 and OX40L also control cytokine production from T cells, antigen-presenting cells, natural killer cells, and natural killer T cells, and regulate cytokine receptor signaling. Stimulatory OX40 has been shown to be a target for therapeutic immunization methods against cancer as one of the most prominent co-stimulatory molecules known to control T cells. Some examples of OX40 agonists include those disclosed in GBR 830, and Linch, et al., Frontiers in Oncology, v.5, pp. 1-10 (2015) (which is hereby incorporated by reference in its entirety).

[0238] In another example, the HPK1 antagonist can be combined with a chemotherapeutic agent or a biological agent that targets CD28, OX40, GITR, CD137, CD27, CD40, ICOS, HVEM, NKG2D, MICA, 2B4, IL-2, IL-12, IFNγ, IFNα, TNFα, IL-1, CDN, HMGB1, TLR, the PD-L1 axis, CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7H4, CD96, CD226, prostaglandin, VEGF, endothelin B, IDO, arginase, MICA / MICB, TIM-3, IL-10, IL-4, IL-13, TIGIT, or TGFβ. In another example, the HPK1 antagonist can be combined with an antagonist of the PD-L1 axis, CTLA-4, TIM-3, BTLA, VISTA, LAG-3, B7H4, CD96, TIGIT, CD226, prostaglandin, VEGF, endothelin B, IDO, arginase, MICA / MICB, TIM-3, IL-10, IL-4, or IL-13. In another example, the HPK1 antagonist can be combined with an immunotherapy comprising an agonist of CD28, OX40, GITR, CD137, CD27, CD40, ICOS, HVEM, NKG2D, MICA, 2B4, IL-2, IL-12, IFNγ, IFNα, TNFα, IL-1, CDN, HMGB1, or TLR.

[0239] In another example, the HPK1 antagonist can be combined with PCV. In another example, the HPK1 antagonist can be combined with adoptive T cell therapy.

[0240] A method for inhibiting HPK1, comprising contacting HPK1 in a subject with an effective amount of a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof.

[0241] A method for enhancing an immune response in a subject in need thereof, comprising administering to the subject an effective amount of a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the subject has cancer.

[0243] A method for treating an HPK1-dependent disorder, comprising administering to a subject in need of treatment for an HPK1-dependent disorder an effective amount of a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the HPK1-dependent disorder is cancer.

[0245] In some embodiments, the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma.

[0246] In some embodiments, the method further comprises administering a chemotherapeutic agent to the subject.

[0247] In some embodiments, the present invention also provides a compound of formula (I) as described herein, or a variant thereof such as formula (IA), (IB), and (IC), or a pharmaceutical composition as described herein for use in the method for inhibiting HPK1 described herein, in the method for enhancing an immune response in a subject in need of enhancing an immune response as described herein, and / or in the method for treating an HPK1-dependent disorder as described herein.

[0248] In some embodiments, the present invention also provides a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic) as described herein, or a pharmaceutical composition as described herein for use in a method of inhibiting HPK1 as described herein.

[0249] In some embodiments, the present invention also provides a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic) as described herein, or a pharmaceutical composition as described herein for use in a method of enhancing an immune response in a subject in need of enhancing the immune response as described herein.

[0250] In some embodiments, the present invention also provides a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic) as described herein, or a pharmaceutical composition as described herein for use in a method of treating an HPK1-dependent disorder as described herein.

[0251] In some embodiments, the present invention also provides the use of a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic) as described herein, or a pharmaceutical composition as described herein for the manufacture of a medicament for inhibiting HPK1, a medicament for enhancing an immune response in a subject in need of enhancing the immune response, and / or a medicament for treating an HPK1-dependent disorder.

[0252] In some embodiments, the present invention also provides the use of a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic) as described herein, or a pharmaceutical composition as described herein for the manufacture of a medicament for inhibiting HPK1.

[0253] In some embodiments, the present invention also provides the use of a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic), or a pharmaceutical composition as described herein, for the manufacture of a medicament for enhancing an immune response in a subject in need of such enhancement of the immune response.

[0254] In some embodiments, the present invention also provides the use of a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic), or a pharmaceutical composition as described herein, for the manufacture of a medicament for treating an HPK1-dependent disorder.

[0255] In some embodiments, the present invention also provides the use of a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic), or a pharmaceutical composition as described herein, in the method for inhibiting HPK1 as described herein, in the method for enhancing an immune response in a subject in need of such enhancement of the immune response as described herein, and / or in the method for treating an HPK1-dependent disorder as described herein.

[0256] In some embodiments, the present invention also provides the use of a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic), or a pharmaceutical composition as described herein, in the method for inhibiting HPK1 as described herein.

[0257] In some embodiments, the present invention also provides the use of a compound of formula (I) as described herein, or variants such as formula (IA), (IB), and (Ic), or a pharmaceutical composition as described herein, in the method for enhancing an immune response in a subject in need of such enhancement of the immune response as described herein.

[0258] In some embodiments, the present invention also provides the use of a compound of formula (I), or variants such as formula (IA), (IB), and (Ic), or a pharmaceutical composition described herein, in the methods of treating HPK1-dependent disorders described herein.

[0259] In some embodiments, the treatment results in a sustained response in the subject after a treatment hiatus. "Sustained response" refers to the continued effect on the reduction of tumor growth after discontinuation of treatment. For example, the tumor size remains the same or becomes smaller compared to the size at the start of the dosing period. In some embodiments, the sustained response has a duration that is at least the same as the treatment period, at least 1.5-fold, 2.0-fold, 2.5-fold, or 3.0-fold the treatment period.

[0260] The treatment methods disclosed herein can result in partial or complete response. As used herein, "complete response" or "CR" means the disappearance of all target lesions, and "partial remission" or "PR" means a reduction of at least 30% in the sum of the longest diameters (SLD) of the target lesions, with reference to the baseline SLD. "Stable disease" or "SD" means that, starting from the initiation of treatment, with reference to the smallest SLD, there is neither sufficient shrinkage of the target lesions to be considered a PR nor sufficient increase in the target lesions to be considered a PD. As used herein, "overall response rate" (ORR) means the sum of the complete response (CR) rate and the partial response (PR) rate.

[0261] The treatment methods disclosed herein can result in an increase in the progression-free survival and overall survival of a subject to whom an HPK1 antagonist has been administered. As used herein, "progression-free survival" (PFS) refers to the length of time during and after treatment during which the treated disease (e.g., cancer) does not worsen. Progression-free survival may include the amount of time the patient experiences a complete or partial response, as well as the amount of time the patient experiences stability.

[0262] As used herein, "overall survival rate" refers to the proportion in a group of subjects who are likely to be alive after a specified period.

[0263] In some embodiments, the subject to which the HPK1 antagonist is administered is a mammal such as a livestock (e.g., cows, sheep, cats, dogs, and horses), a primate (e.g., a human and non-human primates such as monkeys), a rabbit, and a rodent (e.g., mice and rats). In some embodiments, the subject to be treated is a human.

[0264] A subject in need of cancer treatment can be a human showing symptoms of cancer, a human diagnosed with cancer, a subject in remission from cancer, or a subject at high risk of cancer progression (e.g., genetic predisposition, a specific diet, or environmental exposure).

[0265] In any of the described methods, in one aspect, the subject is a human such as a human in need of the method. The subject can be a human diagnosed with or suspected of having an HPK1-dependent disorder such as cancer. The individual can be a human having no detectable disease but having one or more risk factors for cancer progression.

[0266] There is further provided a kit for carrying out the methods detailed herein, comprising one or more of the compounds described herein, or a pharmaceutical composition comprising a compound described herein. The kit can use any of the compounds disclosed herein. In one variation, the kit uses a compound described herein, or a pharmaceutically acceptable salt thereof. The kit can be used for any one or more of the uses described herein, and thus can contain instructions for use for treating an HPK1-dependent disorder such as cancer. In some embodiments, the kit contains instructions for use for treating cancer.

[0267] The kit generally includes a suitable packaging. The kit can include one or more containers containing any of the compounds described herein. Each component (if there are two or more components) can be packaged in a separate container, or some components can be combined in one container where cross-reactivity and shelf life are acceptable. One or more components of the kit can be sterilized and / or can be contained in a sterile package.

[0268] The kit can be in unit dosage form, bulk package (e.g., multiple-dose package), or sub-unit dosage. For example, a kit containing a sufficient dosage (e.g., an amount effective for treatment) of a compound disclosed herein that is useful for treating an HPK1-dependent disorder (e.g., cancer), and / or a second pharmaceutically active compound, can be provided that provides effective treatment of an individual over a period of time, such as for one week, two weeks, three weeks, four weeks, six weeks, eight weeks, three months, four months, five months, seven months, eight months, nine months, or longer. The kit can also include a plurality of unit doses of the compound, and instructions for use, and can be packaged in an amount sufficient for storage and use at a pharmacy (e.g., a hospital pharmacy and a compounding pharmacy).

[0269] The kit can optionally include a single set of instructions, generally handwritten instructions, although an electronic storage medium (e.g., a magnetic disk or optical disk) containing instructions is also acceptable depending on the use of the components of the methods of the invention. The instructions included with the kit generally include information about the components and their administration to a subject.

[0270] The following examples and detailed description are provided by way of illustration and not limitation.

Example

[0271] TIFF0007698575000139.tif237170All samples were pre-purified and their purity was confirmed in an achiral system prior to chiral purification by SFC LCMS analysis method

[0272] Method J: The experiment was carried out on a Shimadzu 20AD HPLC equipped with a Shimadzu LCMS2020 mass spectrometer, using ESI as the ionization source, a Shim-Pack XR-ODS C18 2.2 μm, 3.0 x 50 column, and a flow rate of 1.2 ml / min. The solvent system was a gradient starting from 95% water containing 0.05% TFA (solvent A) and 5% acetonitrile containing 0.05% TFA (solvent B), and increased to 95% solvent B in 2.0 minutes. The final solvent was held constant for an additional 0.7 minutes.

[0273] Method K: The experiment was carried out on a Shimadzu 20AD HPLC equipped with a Shimadzu LCMS2020 mass spectrometer, using ESI as the ionization source, a Shim-Pack XR-ODS C18 2.2 μm, 3.0 x 50 column, and a flow rate of 1.2 ml / min. The solvent system was a gradient starting from 95% water containing 0.05% TFA (solvent A) and 5% acetonitrile containing 0.05% TFA (solvent B), and increased to 95% solvent B in 2.0 minutes. The final solvent was held constant for an additional 0.7 minutes.

[0274] Method L: The experiment was carried out on a Shimadzu 30AD HPLC equipped with a Shimadzu LCMS2020 mass spectrometer, using ESI as the ionization source, an Ascentis Express C18 2.7 μm, 2.1 x 50 mm column, and a flow rate of 1.0 ml / min. The solvent system was a gradient starting from 95% water containing 0.05% TFA (solvent A) and 5% acetonitrile containing 0.05% TFA (solvent B), and increased to 95% solvent B in 2.0 minutes. The final solvent was held constant for an additional 0.7 minutes.

[0275] Method M: The experiment was carried out on a Shimadzu 20AD XR HPLC equipped with a Shimadzu LCMS2020 mass spectrometer using ESI as the ionization source, a Poroshell HPH-C18 2.7 μm, 3.0 x 50 mm column, and a flow rate of 1.2 ml / min. The solvent system was a gradient starting with 95% water (solvent A) containing 5 mM ammonium bicarbonate and 5% acetonitrile (solvent B), which was increased to 95% solvent B in 2.0 minutes. The final solvent was held constant for an additional 0.7 minutes.

[0276] Method N: The experiment was carried out on an Agilent 1290 UHPLC connected to an Agilent MSD (6140) mass spectrometer using ESI as the ionization source. For LC separation, a Phenomenex XB-C18, 1.7 mm, 50 x 2.1 mm column was used at a flow rate of 0.4 ml / min. Solvent A was water containing 0.1% FA, and solvent B was acetonitrile containing 0.1% FA. The gradient consisted of 2 - 98% solvent B over 7 minutes, and after 1.5 minutes of equilibration, 98% B was held for 1.5 minutes. The temperature of the LC column was 40 °C. UV absorbance was collected at 220 nm and 254 nm, and mass spectrometry full scan was applied to all experiments. Synthesis Example

[0277] The procedures for preparing the general methods and the intermediates used for preparing the compounds described in the tables are as follows. Example 1 Intermediate 1: tert-Butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) 2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000140.tif36170 Step 1: tert-Butyl 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000141.tif27170

[0278] To a solution of 7-bromo-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (1 g, 4.37 mmol) in tetrahydrofuran (2 mL) was added LiHMDS (8.73 mL, 8.73 mmol, 1 mol / L) dropwise at 0 °C. The resulting solution was stirred at 0 °C for 0.5 h under nitrogen. Then, di-tert-butyl dicarbonate (2.85 g, 13.07 mmol) was added and the mixture was stirred at room temperature for 2 h. Methanol (50 mL) was added to quench the reaction. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography (ethyl acetate / petroleum ether, 1 / 4) to afford tert-butyl 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (800 mg, 2.43 mmol) as a yellow oil. LCMS (ESI) [M+H] + = 329.2. Step 2: tert-Butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000142.tif36170

[0279] tert-Butyl 7-bromo-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (6.2 g, 18.83 mmol), bis(pinacolato)diboron (23.93 g, 94.22 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.76 g, 3.77 mmol), and potassium acetate (5.55 g, 56.62 mmol) in a mixture with 1,4-dioxane (2 mL) were stirred at 90 °C for 2.5 h under nitrogen. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (30%) to give tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (5 g, 13.29 mmol) as a yellow oil. LCMS (ESI) + = 376.3. Example 2 Intermediate 2: 7-Bromo-8-chloro-6-fluoroisoquinolin-3-amine TIFF0007698575000143.tif23170 Step 1: 4-Amino-3-bromo-2-chloro-benzonitrile TIFF0007698575000144.tif22170

[0280] To a solution of 4-amino-2-chlorobenzonitrile (1.5 g, 9.83 mmol) in acetonitrile (30 mL) was added 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione (1.5 g, 5.25 mmol). The solution was stirred at 25 °C for 2 h. The reaction was quenched by adding a saturated solution of NaHSO3 (30 mL) and extracted with ethyl acetate (50 mL × 2). The organic layer was concentrated and purified by flash chromatography (10% ethyl acetate in petroleum ether) to give a mixture of 4-amino-3-bromo-2-chloro-benzonitrile and 4-amino-5-bromo-2-chlorobenzonitrile (850 mg, positional isomers in a ratio of 5 / 2, yield 26%) as a yellow solid, which was used directly in the next step.1 1H NMR (400 mHz, CDCl3) δ 7.67 (s, 1H), 7.38 (d, J = 8.4 Hz, 2.6H), 6.80 (s, 1H), 6.65 (d, J = 8.4 Hz, 2.6H), 4.81 (bs, 5H), 4.71 (bs, 2H). Step 2: 3-Bromo-2-chloro-4-iodobenzonitrile TIFF0007698575000145.tif21170

[0281] To a suspension of CuI (51.63 g, 271.74 mmol) in acetonitrile (300 mL) was added tert-butyl nitrite (33.59 g, 326.09 mmol). The mixture was stirred at 65 °C for 10 minutes. 4-Amino-3-bromo-2-chloro-benzonitrile and 4-amino-5-bromo-2-chlorobenzonitrile (ratio 3 / 4, 25 g, 108.7 mmol) were added, and the reaction mixture was stirred at 65 °C for 12 hours. After cooling to room temperature, the mixture was quenched with a saturated solution of Na2S2O4 (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4 and filtered through a filter. The filtrate was concentrated and purified by flash column chromatography (5% ethyl acetate in petroleum ether) to give 3-bromo-2-chloro-4-iodobenzonitrile (5 g, yield 31%) as a yellow solid. 1 1H NMR (400 MHz, CDCl3) 7.91 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H). Step 3: (3-Bromo-2-chloro-4-iodophenyl)methanamine TIFF0007698575000146.tif21170

[0282] To a solution of 3-bromo-2-chloro-4-iodobenzonitrile (3 g, 8.76 mmol) in THF (30 mL) was added borane-THF (30 mL, 1 M in THF, 30 mmol). The mixture was stirred at 65 °C for 3 h under N2. After cooling to room temperature, methanol (10 mL) and HCl (12 N, 10 mL) were added to quench the mixture. The reaction was concentrated to dryness. The residue was taken up in ethyl acetate (100 mL) and extracted with water (50 mL × 2). The organic layer was discarded, and saturated aqueous NaHCO3 was added to adjust the pH of the aqueous layer to 9. The mixture was extracted with ethyl acetate (80 mL × 3). The combined organic layers were washed with water (10 mL × 2) and brine (10 mL), dried (Na2SO4), filtered, concentrated, and (3-bromo-2-chloro-4-iodophenyl)methanamine (3 g, 99% yield) was obtained as a yellow oil and used directly in the next step. LCMS (ESI) [M+H] + =345.9. Step 4: N-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide TIFF0007698575000147.tif21170

[0283] (3-bromo-2-chloro-4-iodophenyl)methanamine (2.5 g, 7.22 mmol) in methanol (20 mL) was added methyl 2,2-diethoxyacetimidate (3.75 g, 23.26 mmol). The solution was stirred at 25 °C for 12 h and then concentrated to dryness. The residue was dissolved in dichloromethane (20 mL), washed with water and brine, dried over MgSO4, filtered, concentrated, and N-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide (3 g, 87% yield) was obtained as a yellow solid and used directly in the next step. LCMS (ESI) [M+H] + =474.9. Step 5: 7-bromo-8-chloro-6-fluoroisoquinolin-3-amine TIFF0007698575000148.tif22170

[0284] A mixture of sulfuric acid (10 mL) and N-(3-bromo-2-chloro-4-iodobenzyl)-2,2-diethoxyacetimidamide (3 g, 6.31 mmol) was stirred at 60 °C for 12 h. After cooling the reaction mixture to 0 °C, NaOH solution was added to adjust the pH to 9. The resulting solution was extracted with dichloromethane (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 7-bromo-8-chloro-6-fluoroisoquinolin-3-amine (2.4 g, 99% yield) as a yellow solid. LCMS (ESI) [M+H] + = 382.8. 1 H NMR (400 mHz, DMSO-d6): δ 8.99 (s, 1H), 8.32 (s, 1H), 6.56 (s, 1H), 6.49 (s, 2H). Example 3 Intermediate 3: 8-chloro-7-fluoro-6-iodoisoquinolin-3-amine TIFF0007698575000149.tif22170 Step 1: 4-amino-2-chloro-3-fluorobenzonitrile TIFF0007698575000150.tif21170

[0285] Copper(I) cyanide (1.2 g, 13.37 mmol), 4-bromo-3-chloro-2-fluoroaniline (1 g, 4.46 mmol) and 1-methyl-2-pyrrolidinone (8 mL) were added to a pressure reaction tube. The mixture was heated at 170 °C for 1 h in a microwave reactor. A saturated solution of NH4Cl (20 mL) was added to quench the reaction mixture, which was then filtered. The filtrate was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (3 × 10 mL), dried over Na2SO4, filtered through a silica gel pad, and concentrated to dryness to give 4-amino-2-chloro-3-fluorobenzonitrile (700 mg, 92% yield) as a yellow solid. LCMS (ESI) [M+H] + = 171.1. Step 2: 2-chloro-3-fluoro-4-iodobenzonitrile TIFF0007698575000151.tif21170

[0286] To a suspension of CuI (3341 mg, 17.59 mmol) in acetonitrile (50 mL) was added tert-butyl nitrite (1811 mg, 17.59 mmol) at 65 °C under N2. The mixture was stirred at 65 °C for 10 minutes, then 4-amino-2-chloro-3-fluorobenzonitrile (2 g, 11.73 mmol) was added. The mixture was stirred at 65 °C for 12 hours. After cooling to room temperature, the mixture was quenched with saturated aqueous Na2S2O4 (30 mL) and aqueous NH4Cl (30 mL), and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by flash chromatography (petroleum ether / ethyl acetate = 5 / 1) to give 2-chloro-3-fluoro-4-iodobenzonitrile (1 g, yield 30%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.80 (dd, J = 5.6, 8.2 Hz, 1H), 7.22 (dd, J = 1.4, 8.2 Hz, 1H). Step 3: (2-Chloro-3-fluoro-4-iodophenyl)methanamine TIFF0007698575000152.tif23170

[0287] 2-Chloro-3-fluoro-4-iodobenzonitrile (1 g, 3.55 mmol) was added to a solution of borane-THF (35.53 mL, 1 M in THF, 35.53 mmol) in THF (30 mL) at 0 °C. Next, the mixture was warmed to room temperature and stirred overnight. After quenching the reaction solution by dropwise addition of HCl solution (6 m, 2 mL), it was neutralized to pH = 8 with aqueous NaHCO3 and extracted with dichloromethane (2 × 200 mL). The combined organic layers were washed with water (2 × 10 mL) and brine (1 × 10 mL), dried (Na2SO4), filtered and concentrated to give (2-chloro-3-fluoro-4-iodophenyl)methanamine (400 mg, crude), which was used directly in the next step without further purification. LCMS (ESI) [M+H] + = 285.9. Step 4: N-(2-Chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide TIFF0007698575000153.tif23170

[0288] To a solution of methyl 2,2-diethoxyacetimidate (0.3 g, 1.88 mmol) in methanol (5 mL) was added (2-chloro-3-fluoro-4-iodophenyl)methanamine (250 mg, 0.88 mmol). The reaction mixture was stirred at 25 °C for 12 h and then concentrated to dryness. The residue was taken up in dichloromethane (20 mL), washed with water (2 × 10 mL) and then brine, dried (MgSO4), filtered and concentrated to give N-(2-chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide (360 mg, crude) as a yellow solid, which was used directly in the next step without further purification. LCMS (ESI) [M+H] + = 415.0. Step 5: 8-Chloro-7-fluoro-6-iodoquinolin-3-amine TIFF0007698575000154.tif22170

[0289] A solution of N-(2-chloro-3-fluoro-4-iodobenzyl)-2,2-diethoxyacetimidamide (0.36 g, 0.87 mmol) and concentrated H2SO4 (10 mL, 26.05 mmol) was stirred at 60 °C for 12 h. The mixture was cooled to 0 °C, adjusted to pH = 9 with NaOH (10 wt%) and then extracted with dichloromethane (5 × 100 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated to give 8-chloro-7-fluoro-6-iodoquinolin-3-amine (0.25 g, crude) as a yellow solid, which was used directly without further purification. LCMS (ESI) [M+H] + = 322.9. 1 H NMR (400 MHz, CD3OD) δ 9.00 (s, 1H), 8.08 (d, J = 5.6 Hz, 1H), 6.70 (s, 1H). Example 4 tert-Butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000155.tif39170

[0290] Under a nitrogen atmosphere, 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (249.0 g, 772.07 mmol), tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[2,3-B][1,4]oxazine-1-carboxylate (290.0 g, 770.76 mmol), Pd(dppf)Cl2 (57.0 g, 77.98 mmol), and K2CO3 (320.0 g, 2318.8 mmol) were placed in 1,4-dioxane (3000 mL) and water (300 mL), and stirred at 60 °C for 12 hours. The resulting mixture was cooled to room temperature. Anhydrous sodium sulfate (500 g) was added and stirred for 0.5 hour. The solid was filtered. The filtrate was concentrated in vacuo. The residue was washed with ethyl acetate (3 L). The solid was collected by filtration, washed with ethyl acetate, and dried in vacuo to obtain 240 g of the product. The filtrate was concentrated under vacuum and purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (0 - 100%) to obtain 60 g of the product. The two batches were combined to give tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-B][1,4]oxazine-1-carboxylate (300 g, 674.32 mmol, 87.5% yield) as a yellow solid. LCMS(ESI)[M+H] + =445. Example 5 tert-Butyl 7-(3-amino-8-((tert-butoxycarbonyl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000156.tif Project 1: tert-Butyl 7-[8-chloro-3-(1,3-dioxoisoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000157.tif37170

[0291] tert-Butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (300.0 g, 674.32 mmol) in toluene (3000 mL), fresh and dried 4 Å molecular sieves (300 g), and phthalic anhydride (150.0 g, 1012.7 mmol) were stirred at 100 °C for 3 h. The reaction mixture was slowly cooled to room temperature and then the resulting mixture was filtered. The filtrate was concentrated in vacuo. The residue was mashed with ethyl acetate (3 L). The solid was collected by filtration and dried in vacuo to give 200 g of the product. The filtrate was concentrated under vacuum and purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 2) to give 100 g of the product. The two batches were combined to give tert-butyl 7-[8-chloro-3-(1,3-dioxoisoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (300 g, 521.75 mmol, 77.4% yield) as a slightly grayish white solid. LCMS (ESI) [M+H] + =575. Project 2: tert-Butyl 7-(8-((tert-butoxycarbonyl)amino)-3-(1,3-dioxoisoindolin-2-yl)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000158.tif39170

[0292] Under nitrogen, a mixture of tert-butyl 7-[8-chloro-3-(1,3-dioxoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (300.0 g, 521.75 mmol), NH2BoC (916.0 g, 7829.1 mmol), Brettphos Pd G3 (24.0 g, 26.48 mmol), freshly dried 4 Å molecular sieves (300 g), and K2CO3 (227.0 g, 1644.9 mmol) was stirred at 90 °C for 2 hours. The reaction was cooled slowly to room temperature and the mixture was filtered. The filtrate was concentrated in vacuo and the residue was used in the next step without further purification. LCMS (ESI) [M+H] + =656. Step 3: tert-butyl 7-(3-amino-8-((tert-butoxycarbonyl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000159.tif38170

[0293] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-(1,3-dioxoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (crude product from the previous step) and hydrazine hydrate (228.0 g, 4560 mmol) in methyl alcohol (3000 mL) was stirred at 40 °C for 2 hours. The product was precipitated, filtered, and washed with MeOH (3 x 500 mL). The solid was dried in vacuo to give 130 g of the product. The filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with DCM / MeOH (5%) to give 22 g of a crude product. Two batches were combined to give tert-butyl 7-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (152 g, 288.97 mmol, 55.5% yield) as a yellow solid. LCMS (ESI) [M+H] + =526. Example 6 tert-butyl-7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(phenoxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000160.tif47170

[0294] A solution of phenyl chloroformate (0.60 g, 3.82 mmol) in dichloromethane (10 mL) was added to a suspension of tert-butyl 7-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (1.0 g, 1.9 mmol) and 4-dimethylaminopyridine (0.23 g, 1.88 mmol) in pyridine (5 mL) and dichloromethane (5 mL). The mixture was stirred at 0 °C for 2 h. The resulting solution was washed with water and the organic layer was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether to give tert-butyl-7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(phenoxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (1.5 g, 1.553 mmol, 81.7% yield) as a yellowish solid. LCMS (ESI) [[M+H]] + = 646.2. Example 7 tert-Butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000161.tif 38170 Run 1: 5-Bromo-2-iodo-4-methyl-pyridin-3-amine TIFF0007698575000162.tif 22170

[0295] A solution of 5-bromo-4-methyl-pyridin-3-amine (60.0 g, 320.79 mmol) and N-iodosuccinimide (72.2 g, 320.92 mmol) in acetic acid (1000 mL) was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with PE / EA (1 / 20) to give 5-bromo-2-iodo-4-methyl-pyridin-3-amine (72 g, 177.16 mmol, 55.2% yield) as a yellow solid. Step 2: tert-Butyl N-(5-bromo-2-iodo-4-methyl-3-pyridyl)carbamate TIFF0007698575000163.tif22170

[0296] A solution of 5-bromo-2-iodo-4-methyl-pyridin-3-amine (55 g, 175.76 mmol) and NaHMDS (360. mL, 720 mmol) in tetrahydrofuran (500 mL) was stirred at 0 °C for 30 minutes. Then, (Boc)2O (43 g, 197.25 mmol) was added and the mixture was stirred at 25 °C for 1.5 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The combined organic layers were concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (1 / 20) to give tert-butyl N-(5-bromo-2-iodo-4-methyl-3-pyridyl)carbamate (58 g, 140.42 mmol, 79.9% yield) as a yellow oil. Step 3: Methyl 3-[5-bromo-3-(tert-butoxycarbonylamino)-4-methyl-2-pyridyl]propanoate TIFF0007698575000164.tif26170

[0297] Under nitrogen, a mixture of tert-butyl N-(5-bromo-2-iodo-4-methyl-3-pyridyl)carbamate (500.0 mg, 1.21 mmol), bromo(3-methoxy-3-oxopropyl)zinc (15 mL, 6.89 mmol) and Pd(PPh3)4 (115.0 mg, 0.10 mmol) in tetrahydrofuran (10 mL) was stirred at 70 °C for 2 hours. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1:1) to give methyl 3-[5-bromo-3-(tert-butoxycarbonylamino)-4-methyl-2-pyridyl]propanoic acid (313 mg, 0.79 mmol, 65.1% yield) as a yellow solid. LCMS(ESI)[M+H] + =373.0. Step 4: 7-Bromo-8-methyl-3,4-dihydro-1H-1,5-naphthyridin-2-one TIFF0007698575000165.tif21170

[0298] A solution of methyl 3-[5-bromo-3-(tert-butoxycarbonylamino)-4-methyl-2-pyridyl]propanoic acid (313.0 mg, 0.79 mmol) in trifluoroacetic acid (1 mL) and dichloromethane (4 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (2 / 1) to give 7-bromo-8-methyl-3,4-dihydro-1H-1,5-naphthyridin-2-one (140 mg, 0.55 mmol, 70% yield) as a yellow solid. LCMS(ESI)[M+H] + =241.0. Step 5: 7-Bromo-8-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine TIFF0007698575000166.tif21170

[0299] 7-Bromo-8-methyl-3,4-dihydro-1H-1,5-naphthyridin-2-one (120.0 mg, 0.47 mmol) was placed in tetrahydrofuran (10 mL), and a solution obtained by adding BH3·THF (1 M) (1.4 mL, 1.42 mmol) was stirred at 60 °C for 2 hours. The reaction was quenched with methanol and dilute hydrochloric acid. The mixture was concentrated under vacuum. The resulting residue was purified by reverse-phase chromatography (acetonitrile 0 - 70 / 0.1% NH4HCO3 in water) to obtain 7-bromo-8-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (70 mg, 0.29 mmol, yield 61.9%) as a white solid. LCMS (ESI) [M + H] + = 227.0. 1 H NMR (300 MHz, DMSO-d6) δ 7.74 (s, 1H), 5.67 (s, 1H), 3.26 - 3.21 (m, 2H), 2.76 - 2.72 (m, 2H), 2.12 (s, 3H), 1.89 - 1.81 (m, 2H). Step 6: tert-Butyl 7-bromo-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000167.tif23170

[0300] To a solution of 7-bromo-8-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (60.0 mg, 0.26 mmol) in tetrahydrofuran (10 mL) was added NaHDMS (0.5 mL, 0.26 mmol, 0.5 mol / L in THF) at 0 °C, and the mixture was stirred at this temperature for 0.5 hour. Next, (Boc)2O (100.0 mg, 0.46 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with methanol (1 mL). The reaction mixture was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 4) to obtain tert-butyl 7-bromo-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (70 mg, 0.20 mmol, yield 76.9%) as a yellow solid. LCMS (ESI) [M + H] + = 327.0. Step 7: tert-Butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000168.tif27170

[0301] Under nitrogen, a mixture of tert-butyl 7-bromo-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (30.0 g, 91.68 mmol), 4,4,4’,4’,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (117.0 g, 460.63 mmol), Pd(dppf)Cl2 (6.7 g, 9.17 mmol) and KOAC (27.0 g, 275.51 mmol) in 1,4-dioxane (500 mL) was stirred at 100 °C for 3 h. The solid was collected by filtration. The mixture was concentrated under vacuum. The obtained residue was purified by reverse-phase chromatography (acetonitrile 5 - 30 / 0.1% aqueous hydrochloric acid) to give tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (30 g, 80.154 mmol, 87.4% yield) as a white solid. LCMS (ESI) [[M+H]] + = 375.0. Step 8: tert-Butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000169.tif38170

[0302] Under nitrogen, a mixture of tert-butyl 8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (30.0 g, 80.15 mmol), 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (28.5 g, 88.37 mmol), Pd(dppf)Cl2 (5.9 g, 8.07 mmol), and K2CO3 (33.0 g, 239.13 mmol) in 1,4-dioxane (500 mL) and water (50 mL) was stirred at 60 °C for 16 h. The reaction mixture was diluted with ethyl acetate (1000 mL). The resulting solution was washed with water (3 x 100 mL), and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (9:1) to give tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (26 g, 58.703 mmol, 73.2% yield) as a yellow solid. LCMS (ESI) [M+H] + =443. Example 8 Step 1: tert-butyl 7-[8-chloro-3-(1,3-dioxoisoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000170.tif37170

[0303] A solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (26.0 g, 58.7 mmol) and phthalic anhydride (17.5 g, 118.24 mmol) in toluene (3000 mL) was stirred at 100 °C for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1:1) to give tert-butyl 7-[8-chloro-3-(1,3-dioxoisoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (18 g, 31.41 mmol, 53.5% yield) as a yellow solid. LCMS (ESI) [M+H] + =573. Step 2: tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-(1,3-dioxoisoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000171.tif39170

[0304] Under nitrogen, a mixture of tert-butyl 7-[8-chloro-3-(1,3-dioxoisoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (17.0 g, 29.67 mmol), NH2BoC (104.0 g, 888.89 mmol), Pd2(dba)3·CHCl3 (6.1 g, 5.89 mmol), Brettphos (24.0 g, 26.48 mmol) and K2CO3 (12.3 g, 89.13 mmol) in 1,4-dioxane (300 mL) was stirred at 90 °C for 2 h. The mixture was filtered and concentrated in vacuo. The crude product was carried on to the next step without further purification. LCMS (ESI) [M+H] + =654. Step 3: tert-Butyl 7-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000172.tif38170

[0305] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-(1,3-dioxoisoindolin-2-yl)-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (13.0 g, 19.89 mmol) and N2H4 H2O (12.5 g, 200 mmol) in ethanol (130 mL) was stirred at 50 °C for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane / methanol (20 / 1) to give tert-butyl 7-[3-amino-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (8 g, 15.279 mmol, 76.8% yield) as a yellow solid. LCMS (ESI) [M+H] + =524. Example 101 Tetrahydropyran-4-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (Compound 401) TIFF0007698575000173.tif38170 Step 1: tert-Butyl 7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000174.tif37170

[0306] A solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (145 mg, 0.33 mmol) in dichloromethane (1 mL) was added pyridine (1 mL, 12 mmol). To the resulting solution was added dropwise a solution of tetrahydropyran-4-yl carbonochloridate (81 mg, 0.50 mmol) in dichloromethane (0.5 mL). The reaction mixture was then stirred for 90 minutes.

[0307] Thereafter, the reaction mixture was diluted with 20 mL of dichloromethane and washed with 40 mL of saturated aqueous sodium bicarbonate solution. The organic layer was collected and the aqueous layer was further extracted with dichloroethane (2 × 25 mL). The combined organic layers were dried over anhydrous powdered magnesium sulfate, filtered, concentrated to give a brown oil. The crude material was purified by flash column chromatography (0 - 100% isopropyl acetate / heptane) to afford tert-butyl 7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (181 mg, 0.3 mmol) as a white solid. LCMS (ESI, m / z): 575 [M+H] + . Step 2: tert-Butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000175.tif42170

[0308] tert-Butyl 7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (181 mg, 0.3 mmol), tert-butyl carbamate (949.3 mg, 8.1 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (83.4 mg, 0.08 mmol), Brettphos (94.8 mg, 0.17 mmol) and cesium carbonate (624.7 mg, 1.9 mmol) were placed in a 20 mL pressure tube, purged with nitrogen and sealed, and heated at 90 °C for 3.5 h. The reaction mixture was then cooled to room temperature, diluted with 20 mL of dichloromethane and filtered through celite. The filtrate was then concentrated to give a yellowish red solid, which was purified by column chromatography (0 - 50% methanol / dichloromethane) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (197 mg, 0.3 mmol) as a brown oil. LCMS (ESI, m / z): 654 [M+H] + . Step 3: Tetrahydropyran-4-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate TIFF0007698575000176.tif38170

[0309] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (197 mg, 0.3 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (8 mL), and the reaction mixture was stirred at room temperature for 45 minutes. The reaction mixture was then concentrated and purified by reverse-phase HPLC to give tetrahydropyran-4-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (56 mg, 0.12 mmol) as a pale yellow solid. 1 H NMR (400 mHz, DMSO-d6) δ 10.04 (s, 1H), 9.34 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.2 Hz, 1H), 6.20 (s, 2H), 5.66 (d, J = 3.0 Hz, 1H), 4.88 (dt, J = 8.8, 4.6 Hz, 1H), 4.29 (t, J = 4.4 Hz, 2H), 3.88 - 3.83 (m, 2H), 3.50 - 3.45 (m, 2H), 3.38 - 3.36 (m, 2H), 1.92 (d, J = 1.6 Hz, 5H), 1.61 (dt, J = 12.9, 4.5 Hz, 2H). LCMS (ESI, m / z): 454.2 [M + H] + , Rt = 3.502 min, method N. Example 102 1-Methylazetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 402) TIFF0007698575000177.tif48170 Step 1: tert-butyl 7-[3-[(1-tert-butoxycarbonylazetidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000178.tif50170

[0310] To a solution of triphosgene (203 mg, 0.68 mmol) in dichloromethane (1 mL), a solution of 1 - Boc - 3 - hydroxyazetidine (370 mg, 2.14 mmol) and DIEA (275 mg, 2.13 mmol) in dichloromethane (5 mL) was slowly added at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour. The resulting mixture was added to a solution of tert - butyl 7 - (3 - amino - 8 - chloro - 7 - fluoro - 6 - isoquinolyl) - 8 - methyl - 2,3 - dihydropyrido[2,3 - b][1,4]oxazine - 1 - carboxylate (190 mg, 0.43 mmol) and DIEA (111 mg, 0.86 mmol) in dichloromethane (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane / methanol (10 / 1) to give tert - butyl 7 - [3 - [(1 - tert - butoxycarbonylazetidin - 3 - yl)oxycarbonylamino] - 8 - chloro - 7 - fluoro - 6 - isoquinolyl] - 8 - methyl - 2,3 - dihydropyrido[2,3 - b][1,4]oxazine - 1 - carboxylate (180 mg, 0.28 mmol, 65.4% yield) as a yellow solid. Step 2: tert - butyl 7 - [3 - [(1 - tert - butoxycarbonylazetidin - 3 - yl)oxycarbonylamino] - 8 - chloro - 7 - fluoro - 6 - isoquinolyl] - 8 - methyl - 2,3 - dihydropyrido[2,3 - b][1,4]oxazine - 1 - carboxylate TIFF0007698575000179.tif53170

[0311] A mixture of tert-butyl 7-[3-[(1-tert-butoxycarbonylazetidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (180.0 mg, 0.28 mmol), NH2BoC (981.0 mg, 8.38 mmol), Pd2(dba)3·CHCl3 (29.0 mg, 0.03 mmol), Brettphos (27.0 mg, 0.06 mmol), and Cs2CO3 (273.0 mg, 0.84 mmol) in 1,4-dioxane (5 mL) was stirred at 90 °C for 2 h. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with dichloromethane / methanol (10 / 1) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonylazetidin-3-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (140 mg, 0.19 mmol, 69.1% yield) as a brown solid. Step 3: Azetidin-3-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate TIFF0007698575000180.tif48170

[0312] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonylazetidin-3-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (140.0 mg, 0.19 mmol) in dichloromethane (2 mL) and TFA (0.5 mL) was stirred at 25 °C for 2 h. The reaction was concentrated in vacuo and purified by reverse-phase chromatography (acetonitrile 0 - 40 / 0.1% NH4HCO3 in water) to give azetidin-3-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (40 mg, 0.09 mmol, 48.8% yield) as a yellow solid. Step 4: (1-Methylazetidin-3-yl) N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate TIFF0007698575000181.tif48170

[0313] A solution of azetidin-3-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (40 mg, 0.09 mmol) and formaldehyde (40% aqueous solution, 14 mg, 0.19 mmol) in methanol (2 mL) was stirred at 25 °C for 1 h. Then, NaBH3CN (32 mg, 0.28 mmol) was added and the mixture was stirred at 25 °C for 2 h. The reaction was concentrated in vacuo and purified by reverse-phase chromatography (acetonitrile 0 - 40 / 0.1% NH4HCO3 aqueous solution) to give (1-methylazetidin-3-yl) N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (9.2 mg, 0.021 mmol, 22.1% yield) as a white solid. LCMS (ESI) [M + H]+ =439,R T =1.574 minutes, Method K. 1 H NMR (400 mHz, DMSO-d6) δ 10.25 (s, 1H), 9.35 (s, 1H), 7.96 (s, 1H), 7.33 (s, 1H), 6.84 (d, J = 6.1 Hz, 1H), 6.24 (s, 2H), 5.69 (s, 1H), 4.95 (p, J = 6.0 Hz, 1H), 4.29 (s, 2H), 3.65 (t, J = 7.4 Hz, 2H), 3.36 - 3.33 (m, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.30 (s, 3H), 1.92 (d, J = 1.6 Hz, 3H). Example 103 (±)-Tetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 403) TIFF0007698575000182.tif42170 Step 1: tert-Butyl 7-[8-chloro-7-fluoro-3-(tetrahydrofuran-3-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000183.tif44170

[0314] To a solution of 3-hydroxytetrahydrofuran (790 mg, 8.97 mmol) and N,N-diisopropylethylamine (0.32 mL, 1.86 mmol) in dichloromethane (15 mL) was added triphosgene (414 mg, 1.40 mmol) at 0 °C. The reaction mixture was stirred for 30 minutes, then tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (400 mg, 0.90 mmol) was added. The reaction mixture was stirred at 0 °C for 2 hours. The resulting mixture was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (5 / 1) to give tert-butyl 7-[8-chloro-7-fluoro-3-(tetrahydrofuran-3-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (180 mg, 0.32 mmol, 35.8% yield) as a yellow solid. LCMS (ESI) [M+H] + =559. Step 2: tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydrofuran-3-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000184.tif47170

[0315] tert-Butyl 7-[8-chloro-7-fluoro-3-(tetrahydrofuran-3-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (160 mg, 0.29 mmol), tert-butyl carbamate (1.0 g, 8.54 mmol), cesium carbonate (290 mg, 0.88 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (62 mg, 0.12 mmol), and tris(dibenzylideneacetone)dipalladium-chloroform adduct (60 mg, 0.06 mmol) in 1,4-dioxane (20 mL) were stirred at 100 °C for 2 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with methane / dichloromethane (1 / 10) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydrofuran-3-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (100 mg, 0.16 mmol, 54.6% yield) as a yellow solid. LCMS (ESI) [M+H] + =640. Step 3: (±)-Tetrahydrofuran-3-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate TIFF0007698575000185.tif44170

[0316] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydrofuran-3-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (45 mg, 0.07 mmol) in dichloromethane (5 mL) and TFA (1 mL) was stirred at 25 °C for 30 minutes. The resulting solution was concentrated under vacuum. The pH of the residue was adjusted to pH = 8 with ammonia in methanol (7 M). The resulting solution was concentrated under vacuum and purified by preparative-HPLC (XBridge Shield RP18 OBD column 30*150 mm, 5 μm; water (10 mmol / L NH4HCO3)): ACN = 19% B to 42% B in 7 minutes; 60 mL / min), and tetrahydrofuran-3-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (17.8 mg, 0.041 mmol, 57.6% yield) was obtained as a yellow solid. LCMS (ESI) [[M+H]] + = 440, 2.216 min, method M. 1 H NMR (400 mHz, DMSO-d6) δ 10.12 (s, 1H), 9.33 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.84 (d, J = 6.1 Hz, 1H), 6.21 (s, 2H), 5.67 (s, 1H), 5.31 - 5.24 (m, 1H), 4.29 (t, J = 4.5 Hz, 2H), 3.89 - 3.69 (m, 4H), 3.39 - 3.34 (m, 2H), 2.20 - 2.18 (m, 1H), 1.98 - 1.96 (m, 1H), 1.92 (s, 3H). Example 104 1-methylpiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 407) and Piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 404) TIFF0007698575000186.tif51170Step 1: tert-Butyl 7-(3-((((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)amino)-8-chloro-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000187.tif53170

[0317] To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.26 g, 11.23 mmol) and N,N-diisopropylethylamine (1.95 mL, 11.23 mmol) in dichloromethane (5 mL) was added triphosgene (1 g, 3.43 mmol) in dichloromethane (2 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. Next, the reaction mixture was added to a solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (500 mg, 1.12 mmol) and N,N-diisopropylethylamine (1.95 mL, 11.23 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred at room temperature for 16 h. After quenching the reaction with water, the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (1 / 1) to afford tert-butyl 7-[3-[(1-tert-butoxycarbonyl-4-piperidyl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (500 mg, 0.74 mmol, 66% yield) as a yellow solid. LCMS (ESI) [M+H] + =672. Step 2: tert-butyl 7-(8-((tert-butoxycarbonyl)amino)-3-((((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)carbonyl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000188.tif52170

[0318] tert-Butyl 7-[3-[(1-tert-butoxycarbonyl-4-piperidyl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (500 mg, 0.74 mmol), tert-butyl carbamate (1.75 g, 14.9 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (155 mg, 0.15 mmol), and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (160 mg, 0.30 mmol) (160 mg, 0.30 mmol) in 1,4-dioxane (10 mL) was added cesium carbonate (730 mg, 2.23 mmol) at room temperature. The reaction mixture was stirred at 90 °C for 3 h. The resulting solution was concentrated under vacuum and purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (1 / 1) to afford tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonyl-4-piperidyl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (250 mg, 0.33 mmol, 44.6% yield) as a yellow solid. LCMS (ESI) [M+H] + =753. Step 3: Piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000189.tif49170

[0319] A mixture of tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonyl-4-piperidyl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (250 mg, 0.33 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (2 mL) was stirred at room temperature for 30 minutes. The reaction solution was concentrated under vacuum. The residue was dissolved in dichloromethane and the pH was adjusted to 7 with triethylamine. The mixture was concentrated under vacuum and purified by reverse-phase chromatography (acetonitrile 0 - 40 / 0.1% aqueous NH4HCO3 solution). 4-Piperidyl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (70 mg, 0.15 mmol, 45.5% yield) was obtained as a yellow solid. LCMS (ESI) [M+H] + = 453, 1.479 min, method J; 1 H NMR (400 mHz, DMSO-d6) δ 9.98 (s, 1H), 9.33 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.82 (d, J = 6.4 Hz, 1H), 6.20 (s, 2H), 5.66 (s, 1H), 4.73 - 4.71 (m, 1H), 4.29 (t, J = 4.0 Hz, 2H), 3.49 (s, 3H), 2.97 - 2.94 (m, 2H), 2.58 - 2.55 (m, 2H), 1.92 (s, 3H), 1.89 - 1.85 (m, 2H), 1.53 - 1.48 (m, 2H). Step 4: 1-Methylpiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000190.tif52170

[0320] A solution of -4-piperidyl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (70 mg, 0.15 mmol) and formaldehyde (9 mg, 0.30 mmol) in methanol (8 mL) was stirred at room temperature for 2 hours. Subsequently, sodium cyanoborohydride (18.8 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative-HPLC (XBridge preparative OBD C18 column 30×150 mm 5 μm; water (10 mmol / L NH4HCO3):CH3CN = 31%B to 53%B over 7 minutes; 60 mL / min) to give (1-methyl-4-piperidyl)N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (24.4 mg, 0.052 mmol, 34.8% yield) as a yellow solid. LCMS (ESI) [M+H] + =467,R T =1.545 min, method K; 1 H NMR (400 mHz, DMSO-d6) δ 9.99 (s, 1H), 9.33 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.82 (d, J = 6.4 Hz, 1H), 6.20 (s, 2H), 5.66 (s, 1H), 4.68 - 4.66 (m, 1H), 4.29 (t, J = 4.0 Hz, 2H), 3.36 - 3.33 (m, 2H), 2.64 - 2.62 (m, 2H), 2.15 - 2.12 (m, 5H), 1.90 - 1.87 (m, 5H), 1.65 - 1.63 (m, 2H). Example 105 (R)-Pyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (S)-pyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 405a and Compound 405b) TIFF0007698575000191.tif43170Step 1: tert-Butyl 7-[3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000192.tif50170

[0321] A solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (250 mg, 0.56 mmol), 1-Boc-3-hydroxypyrrolidine (105 mg, 0.56 mmol), and DIEA (72 mg, 0.56 mmol) in dichloromethane (20 mL) was stirred at 0 °C for 5 minutes under nitrogen. Then, triphosgene (168 mg, 0.59 mmol) in dichloromethane (1 mL) was added to the reaction solution at 0 °C. The reaction solution was stirred at room temperature for 1 hour. The reaction was quenched with water and extracted with dichloromethane (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 1) to give tert-butyl 7-[3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (230 mg, 0.33 mmol, 59.1% yield) as a yellow solid. LCMS (ESI) [M+H] + =658.0. Step 2: tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000193.tif52170

[0322] A mixture of tert-butyl 7-[3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (230 mg, 0.35 mmol), tert-butyl carbamate (1.2 g, 10.26 mmol), Pd2(dba)3·CHCl3 (36 mg, 0.03 mmol), Brettphos (35 mg, 0.070 mmol), and Cs2CO3 (350 mg, 1.07 mmol) in 1,4-dioxane (15 mL) was stirred at 90 °C for 4 h. The reaction solution was filtered and the filtrate was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 1) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (220 mg, 0.27 mmol, 76.7% yield) as a yellow solid. LCMS (ESI) [[M+H]] + =739.0. Step 3: (R)-Pyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (S)-pyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000194.tif47170

[0323] A solution of 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (200 mg, 0.27 mmol) and trifluoroacetic acid (3 mL) in dichloromethane (10 mL) was stirred at 28 °C for 1 hour. Then the mixture was concentrated under vacuum. The pH of the residue was adjusted to pH = 9 with triethylamine. The crude product was purified by preparative-HPLC (YMC-Actus Triart C18 30*250,5μm; water (10 mmol / L NH4HCO3):CH3CN = 50%B to 70%B in 7 minutes; 60 mL / min) to give the racemic product. The racemic product was separated by chiral-HPLC to give two enantiomers. The absolute stereochemistry is arbitrarily assigned.

[0324] Enantiomer 1 (Compound 405a) (27.1 mg, 0.062 mmol, yield 22.8%): retention time: 2.075 min (CHIRALPAK IC-3, 0.46*5 cm, 3μm; MTBE (0.1% DEA)):MeOH = 75:25 in 5 minutes; 1 mL / min). LCMS (ESI) [M+H] + = 439.2, R T = 0.935 min, method J; 1 H NMR (400 mHz, DMSO-d6) δ 9.98 (s, 1H), 9.32 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.1 Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 5.14 - 5.11 (m, 1H), 4.29 (t, J = 4.4 Hz, 2H), 3.36 (s, 3H), 3.04 (dd, J = 12.4, 5.6 Hz, 1H), 2.92 - 2.74 (m, 3H), 1.98 (dd, J = 14.3, 7.3 Hz, 1H), 1.92 (s, 3H), 1.78 (q, J = 6.9, 6.1 Hz, 1H).

[0325] Enantiomer 2 (Compound 405b) (25.9 mg, 0.059 mmol, yield 21.8%): Retention time: 3.237 min (CHIRALPAK IC-3, 0.46 * 5 cm, 3 μm; MTBE (0.1% DEA)): MeOH = 75:25 5 min; 1 mL / min). LCMS (ESI) [M + H] + = 439.2, R T = 0.935 min, Method J; 1 H NMR (400 mHz, DMSO-d6) δ 9.98 (s, 1H), 9.32 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.1 Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 5.14 - 5.11 (m, 1H), 4.29 (t, J = 4.4 Hz, 2H), 3.36 (s, 3H), 3.04 (dd, J = 12.4, 5.6 Hz, 1H), 2.92 - 2.74 (m, 3H), 1.98 (dd, J = 14.3, 7.3 Hz, 1H), 1.92 (s, 3H), 1.78 (q, J = 6.9, 6.1 Hz, 1H). Example 106 (S)-Piperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3 - [1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (R)-piperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3 - [1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 408a and Compound 408b) TIFF0007698575000195.tif47170 Step 1: tert-Butyl 7-[3-[(1-tert-butoxycarbonyl-3-piperidyl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3 - [1,4]oxazine-1-carboxylate TIFF0007698575000196.tif46170

[0326] A solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (200 mg, 0.45 mmol) and tert-butyl 3-hydroxypiperidine-1-carboxylate (250 mg, 1.24 mmol) in dichloromethane (15 mL) was added with DIEA (300 mg, 2.33 mmol) at room temperature. Then, triphosgene (120 mg, 0.40 mmol) was added and the reaction mixture was stirred at 0 °C for 1 h. The reaction was diluted with dichloromethane (40 mL) and then washed with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl 7-[3-[(1-tert-butoxycarbonyl-3-piperidyl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (140 mg, 0.21 mmol, 46.3% yield) as a yellow solid. LCMS (ESI) [M+H] + =672.2. Step 2: tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonyl-3-piperidyl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000197.tif49170

[0327] A solution of tert-butyl 7-[3-[(1-tert-butoxycarbonyl-3-piperidyl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (140 mg, 0.21 mmol) and butyl carbamate (1.5 g, 12.82 mmol) in 1,4-dioxane (7 mL) was added with Pd2(dba)3·CHCl3 (50 mg, 0.05 mmol), Brettphos (50 mg, 0.09 mmol), and Cs2CO3 (220 mg, 0.67 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2 hours. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (1 / 3) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonyl-3-piperidyl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.20 mmol, 95.7% yield) as a yellow solid. LCMS (ESI) [[M+H]] + =753.2. Step 3: (S)-Piperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (R)-piperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000198.tif47170

[0328] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonyl-3-piperidyl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (140 mg, 0.19 mmol) in dichloromethane (4 mL) was treated with TFA (1 mL) at room temperature. The mixture was stirred at 25 °C for 1 h and then concentrated in vacuo. The residue was adjusted to pH 8 with triethylamine and purified by preparative-HPLC (YMC-Actus Triart C18 30*250,5μm; water (10 mmol / L NH4HCO3):CH3CN = 23%~49% for 7 min; 60 mL / min) to give the racemic product. The racemic product was separated by chiral-HPLC to give two enantiomers. The absolute stereochemistry is arbitrarily assigned.

[0329] Enantiomer 1 (Compound 408a) (15.9 mg, 0.035 mmol, 18.9% yield): retention time: 1.937 min (CHIRALPAK IG-3, 0.46*5 cm, 3μm; DCM(0.1% DEA)):MeOH = 50:50 for 3 min; 1.0 mL / min). LCMS (ESI) [M+H] + = 453.2, 1.814 min, method K; 1 H NMR (400 mHz, DMSO-d6) δ 9.95 (s, 1H), 9.33 (s, 1H), 7.96 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.2 Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 4.59 (dt, J = 8.7, 4.4 Hz, 1H), 4.29 (s, 2H), 2.36 - 3.32 (m, 3H), 3.06 - 3.04 (m, 1H), 2.76 - 2.72 (m, 1H), 2.45 - 2.40 (m, 2H), 1.98 - 1.92 (m, 4H), 1.68 - 1.64 (m, 1H), 1.46 (dt, J = 21.7, 10.5 Hz, 2H).

[0330] Enantiomer 2 (Compound 408b) (12.6 mg, 0.0278 mmol, 15% yield): Retention time: 1.235 min (CHIRALPAK IG-3, 0.46 * 5 cm, 3 μm; DCM (0.1% DEA)): MeOH = 50:50; 1.0 mL / min). LCMS (ESI) [M+H] + = 453.2, 1.814 min, Method K; 1 H NMR (400 mHz, DMSO-d6) δ 9.95 (s, 1H), 9.33 (s, 1H), 7.96 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.2 Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 4.59 (dt, J = 8.7, 4.4 Hz, 1H), 4.29 (s, 2H), 2.36 - 3.32 (m, 3H), 3.06 - 3.04 (m, 1H), 2.76 - 2.72 (m, 1H), 2.45 - 2.40 (m, 2H), 1.98 - 1.92 (m, 4H), 1.68 - 1.64 (m, 1H), 1.46 (dt, J = 21.7, 10.5 Hz, 2H). Example 107 Tetrahydropyran-4-yl N-[8-amino-7-fluoro-6-[(4S)-4-hydroxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-3-isoquinolyl]carbamate and Tetrahydropyran-4-yl N-[8-amino-7-fluoro-6-[(4R)-4-hydroxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-3-isoquinolyl]carbamate (Compound 412a and Compound 412b) TIFF0007698575000199.tif39170 Step 4: 6-[4-[tert-Butyl(dimethyl)silyl]oxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-8-chloro-7-fluoro-isoquinolin-3-amine TIFF0007698575000200.tif44170

[0331] A mixture of 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (311 mg, 0.96 mmol), [4-[tert-butyl(dimethyl)silyl]oxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]boronic acid (190 mg, 0.6 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloromethane complex (74.2 mg, 0.09 mmol) and potassium carbonate (294.4 mf, 2.1 mmol) in dioxane (5 mL) and water (1 mL) was purged with nitrogen and heated at 90 °C for 24 h. Then, it was cooled to room temperature, diluted with 20 mL of ethyl acetate and filtered through celite. Then, the filtrate was concentrated and purified by flash column chromatography (0 - 100% isopropyl acetate in heptane) to give 6-[4-[tert-butyl(dimethyl)silyl]oxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-8-chloro-7-fluoro-isoquinolin-3-amine (204 mg, 0.4 mmol) as a brown solid. LCMS (ESI, m / z): 474 [M+H] + . Step 5: Tetrahydropyran-4-yl N-[6-[4-[tert-butyl(dimethyl)silyl]oxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-8-chloro-7-fluoro-3-isoquinolyl]carbamate TIFF0007698575000201.tif43170

[0332] Using 6-[4-[tert-butyl(dimethyl)silyl]oxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-8-chloro-7-fluoro-isoquinolin-3-amine to replace tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (207.8 mg, 0.34 mmol), the title compound was prepared in the same procedure as in Step 1 of Example 101. LCMS (ESI, m / z): 602 [M+H] + . Step 6: Tetrahydropyran-4-yl N-[8-(tert-butoxycarbonylamino)-6-[4-[tert-butyl(dimethyl)silyl]oxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-7-fluoro-3-isoquinolyl]carbamate TIFF0007698575000202.tif47170

[0333] Tetrahydropyran-4-yl N-[6-[4-[tert-butyl(dimethyl)silyl]oxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-8-chloro-7-fluoro-3-isoquinolyl]carbamate, substituting 7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (207.8 mg, 0.34 mmol), and the title compound was prepared in the same procedure as in Step 2 of Example 101. LCMS (ESI, m / z): 602 [M+H] + . The absolute stereochemistry is arbitrarily assigned. Step 7: Tetrahydropyran-4-yl N-[8-amino-7-fluoro-6-[(4S)-4-hydroxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-3-isoquinolyl]carbamate TIFF0007698575000203.tif39170

[0334] Tetrahydropyran-4-yl N-[8-(tert-butoxycarbonylamino)-6-[4-[tert-butyl(dimethyl)silyl]oxy-5-methyl-3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl]-7-fluoro-3-isoquinolyl]carbamate, replacing 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyranyloxycarbonylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate, and the title compound was prepared in a procedure similar to Step 3 of Example 101. The absolute stereochemistry is arbitrarily assigned.

[0335] Enantiomer 1 (Compound 412B): Retention time: 1.556 min (CHIRALPAK IH, 0.46*5 cm, 3 μm; isocratic concentration 40% MeOH 2.5 min). 1 H NMR (400 mHz, DMSO-d6) δ 10.06 (s, 1H), 9.35 (s, 1H), 7.98 (d, J = 2.8 Hz, 2H), 6.84 (d, J = 6.2 Hz, 1H), 6.24 (s, 2H), 5.40 (d, J = 5.5 Hz, 1H), 4.85 (s, 2H), 4.40 - 4.30 (m, 2H), 3.86 (dt, J = 11.7, 4.5 Hz, 2H), 3.48 (ddd, J = 11.8, 9.3, 2.9 Hz, 2H), 2.24 (d, J = 1.4 Hz, 3H), 1.95 (ddd, J = 16.6, 8.0, 3.9 Hz, 4H), 1.65 - 1.56 (m, 2H). LCMS (ESI, m / z): 469.2 [M+H] + , 3.437 min., Method N.

[0336] Enantiomer 2 (Compound 412a): Retention time: 1.082 min (CHIRALPAK IH, 0.46*5 cm, 3 μm; isocratic concentration 40% MeOH 2.5 min). 11H NMR (400 mHz, DMSO-d6) δ 10.06 (s, 1H), 9.35 (s, 1H), 7.98 (d, J = 2.8 Hz, 2H), 6.84 (d, J = 6.2 Hz, 1H), 6.24 (s, 2H), 5.40 (d, J = 5.5 Hz, 1H), 4.85 (s, 2H), 4.40 - 4.30 (m, 2H), 3.86 (dt, J = 11.7, 4.5 Hz, 2H), 3.48 (ddd, J = 11.8, 9.3, 2.9 Hz, 2H), 2.24 (d, J = 1.4 Hz, 3H), 1.95 (ddd, J = 16.6, 8.0, 3.9 Hz, 4H), 1.65 - 1.56 (m, 2H). LCMS (ESI, m / z): 469.2 [M+H] + , 3.437 minutes, Method N. Example 108 1-(8-Amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)-3-(tetrahydro-2H-pyran-4-yl)urea (Compound 701) TIFF0007698575000204.tif47170 Step 1: tert-Butyl 7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000205.tif47170

[0337] Triphosgene (320 mg, 1.08 mmol) in tetrahydrofuran (40 mL) was added to a solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (300 mg, 0.67 mmol) and pyridine (0.16 mL, 2.02 mmol) at 0 °C over 10 minutes. Tetrahydro-2H-pyran-4-amine (700 mg, 6.92 mmol) was added and the reaction mixture was stirred at 0 °C for 2 hours. The resulting mixture was concentrated under vacuum and purified by silica gel flash chromatography eluting with ethyl acetate / petroleum ether (1 / 10) to give tert-butyl 7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (260 mg, 0.45 mmol, 67.4% yield) as a yellow solid. LCMS (ESI) [M+H] + =572. Step 2: tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000206.tif49170

[0338] tert-Butyl 7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (160 mg, 0.28 mmol), tert-butyl carbamate (1 g, 8.54 mmol), cesium carbonate (284 mg, 0.87 mmol), 2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (61 mg, 0.11 mmol), and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (60 mg, 0.06 mmol) in 1,4-dioxane (20 mL) were stirred at 90 °C for 2 h. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel flash chromatography eluting with methanol / dichloroethane (1 / 10) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (100 mg, 0.15 mmol, 54.8% yield) as a yellow solid. LCMS (ESI) [M+H] + =653.0. Step 3: 1-[8-Amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-tetrahydropyran-4-yl-urea TIFF0007698575000207.tif47170

[0339] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-ylcarbamoylamino)-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (100 mg, 0.15 mmol) in dichloromethane (10 mL) and TFA (1 mL) was stirred at 25 °C for 30 minutes. The resulting solution was concentrated under vacuum. The pH of the residue was adjusted to pH = 8 with ammonia in methanol (7 M). The resulting solution was concentrated under vacuum and purified by preparative-HPLC (YMC-Actus Triart C18 30*250, 5 μm; eluted with water (10 mmol / L NH4HCO3): CH3CN = 37% B to 62% B over 7 minutes; flow rate 60 mL / min) to give 1-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]-3-tetrahydropyran-4-yl-urea (59.8 mg, 0.13 mmol, 86.3% yield) as a yellow solid. LCMS (ESI) [M+H] + = 453, R T = 0.893 min., method M; 1 H NMR (300 MHz, DMSO-d6) δ 9.29 (s, 1H), 8.87 (s, 1H), 7.84 (s, 1H), 7.33 (s, 1H), 7.20 (d, J = 7.5 Hz, 1H), 6.74 (d, J = 6.1 Hz, 1H), 6.15 (s, 2H), 5.67 (s, 1H), 4.29 (s, 2H), 3.88 - 3.75 (m, 3H), 3.42 - 3.34 (m, 4H), 1.92 (s, 3H), 1.87 - 1.83 (m, 2H), 1.43 - 1.39 (m, 2H). Example 109 9-Methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 406) TIFF0007698575000208.tif53170 Project 1: tert-Butyl 7-[3-[(9-tert-butoxycarbonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000209.tif53170

[0340] tert-Butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.34 mmol) and DIEA (435.8 mg, 3.37 mmol) in dichloromethane (10 mL) were stirred at 0 °C. Then, triphosgene (150.1 mg, 0.51 mmol) was added dropwise at 0 °C, and the mixture was stirred at 25 °C for 2 h. The reaction was quenched with water. The resulting solution was extracted with dichloromethane, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (2:1) to give tert-Butyl 7-[3-[(9-tert-butoxycarbonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (115 mg, 0.16 mmol, 47.8% yield) as a yellow solid. LCMS (ESI) [M+H] + =714.2. Project 2: tert-Butyl 7-[8-(tert-butoxycarbonylamino)-3-[(9-tert-butoxycarbonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000210.tif53170

[0341] A solution of tert-butyl 7-[3-[(9-tert-butoxycarbonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (105 mg, 0.15 mmol), NH2BoC (516.1 mg, 4.41 mmol), Pd2(dba)3·CHCl3 (31 mg, 0.030 mmol), Brettphos (32 mg, 0.06 mmol), and Cs2CO3 (143.8 mg, 0.44 mmol) in 1,4-dioxane (5 mL) was stirred at 90 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane / methanol (97:3) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(9-tert-butoxycarbonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (85 mg, 0.11 mmol, 72.7% yield) as a yellow solid. LCMS (ESI) [M+H] + =795.5. Step 3: 3-Oxa-9-azabicyclo[3.3.1]nonan-7-yl N-(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolinyl)carbamate TIFF0007698575000211.tif53170

[0342] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(9-tert-butoxycarbonyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (80 mg, 0.10 mmol) and TFA (2 mL) in dichloromethane (2 mL) was stirred at 25 °C for 1 h. The solvent was concentrated under vacuum. The residue was adjusted to pH = 8 with concentrated HCl solution. The resulting mixture was diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 3-oxa-9-azabicyclo[3.3.1]nonan-7-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (40 mg, 0.08 mmol, 80.4% yield) as a pale yellow solid. LCMS (ESI) [M+H] + = 495.3. Step 4: 9-Methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 406) TIFF0007698575000212.tif53170

[0343] To a solution of 3-oxa-9-azabicyclo[3.3.1]nonan-7-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (34.5 mg, 0.07 mmol) in methanol (15 mL) was added formaldehyde (10.5 mg, 0.14 mmol, 40%), and the mixture was stirred at 25 °C for 2 h. Next, NaBH3CN (8.8 mg, 0.14 mmol) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by preparative-HPLC (X Bridge Shield RP18 OBD column 30*150mm, 5μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 31% B in 10 min; Rt: 9.87 min) to give 9-methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (9.9 mg, 0.02 mmol, yield 27.9%) as a yellow solid. LCMS (ESI) [M+H] + =509.2,R T =0.720 min, method L; 1 H NMR (300 MHz, DMSO-d6) δ 9.71 (s, 1H), 9.33 (s, 1H), 8.04 (s, 1H), 7.33 (s, 1H), 6.81 (d, J = 6.2 Hz, 1H), 6.21 (s, 2H), 5.69 (s, 1H), 5.05 - 5.08 (m, 1H), 4.29 (d, J = 4.8 Hz, 2H), 3.80 (dd, J = 11.0, 2.2 Hz, 2H), 3.42 - 3.36 (m, 4H), 2.70 (d, J = 8.4 Hz, 2H), 2.43 - 2.33 (m, 5H), 1.93 (d, J = 1.6 Hz, 3H), 1.62 (dd, J = 13.1, 5.8 Hz, 2H). Example 110 (S)-1-Methyl-6-oxopiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (R)-1-methyl-6-oxopiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 409a and Compound 409b) TIFF0007698575000213.tif53170 Step 1: tert-Butyl 7-[8-chloro-7-fluoro-3-[(1-methyl-5-oxo-pyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000214.tif53170

[0344] tert-Butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (250 mg, 0.56 mmol), 5-hydroxy-1-methyl-piperidin-2-one (90 mg, 0.70 mmol) and DIEA (292 mg, 2.25 mmol) in dichloromethane (25 mL) were added with triphosgene (60 mg, 0.20 mmol) in dichloromethane (3 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water. The resulting solution was extracted with dichloromethane and the organic layers were combined. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (acetonitrile 0 - 40 / 0.1% NH4HCO3 in water) to give tert-butyl 7-[8-chloro-7-fluoro-3-[(1-methyl-5-oxo-pyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (290 mg, 0.495 mmol, 88.1% yield) as a yellow solid. LCMS (ESI) [M+H] + =600. Step 2: tert-Butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-6-oxo-3-piperidyl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000215.tif53170

[0345] A mixture of tert-butyl 7-[8-chloro-7-fluoro-3-[(1-methyl-6-oxo-3-piperidyl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (280 mg, 0.47 mmol), NH2BoC (3.28 g, 28.03 mmol), Pd2(dba)3CHCl3 (97 mg, 0.09 mmol), Brettphos (101 mg, 0.19 mmol), and Cs2CO3 (304 mg, 0.94 mmol) in 1,4-dioxane (20 mL) was stirred at 90 °C for 3 hours. The reaction mixture was diluted with water. The resulting solution was extracted with ethyl acetate, and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane / methanol (88 / 12) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-6-oxo-3-piperidyl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (180 mg, 0.264 mmol, 56.7% yield) as a yellow solid. LCMS (ESI) [M+H] + =681. Step 3: (S)-1-Methyl-6-oxopiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (R)-1-Methyl-6-oxopiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000216.tif52170

[0346] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-6-oxo-3-piperidyl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.22 mmol) in TFA (3 mL) and dichloromethane (10 mL) was stirred at 25 °C for 1 h. The reaction mixture was concentrated in vacuo. The residue was adjusted to pH = 9 with concentrated HCl solution. The crude product was generated by preparative-HPLC (column: X Bridge preparative RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 14% B to 37% B for 7 min; 220 / 254 nm; Rt: 6.57 min) and chiral-HPLC to give two enantiomers. The absolute stereochemistry is arbitrarily assigned.

[0347] Enantiomer 1 (Compound 409a) (17.9 mg, 0.0373 mmol, yield 16.9%): retention time: 2.367 (CHIRALPAK IC-3: 0.46*5 cm; 3 μm; (Hex:DCM = 1:1)(0.1% DEA):EtOH = 50:50; 1.0 mL / min; gradient: 50 B to 50 B for 5 min). LCMS (ESI) [M+H] + = 481.2, R T = 1.017 min, method M. 1 H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.34 (s, 1H), 7.96 (s, 1H), 7.33 (s, 1H), 6.84 (d, J = 6.1 Hz, 1H), 6.21 (s, 2H), 5.67 (s, 1H), 5.12 (s, 1H), 4.29 (s, 2H), 3.64 (dd, J = 13.3, 3.9 Hz, 1H), 2.81 (s, 3H), 2.48 - 2.36 (m, 3H), 2.31 - 2.20 (m, 2H), 2.02 (s, 2H), 1.92 (d, J = 1.6 Hz, 3H).

[0348] Enantiomer 2 (Compound 409B) (17.6 mg, 0.0366 mmol, yield 16.6%): retention time: 3.097 (CHIRALPAK IC-3: 0.46 * 5 cm; 3 μm; (Hex:DCM = 1:1)(0.1% DEA):EtOH = 50:50; 1.0 mL / min; gradient: 50B to 50B for 5 min). LCMS (ESI) [M+H] + = 481.2, R T = 1.017 min, method M. 1 H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.34 (s, 1H), 7.96 (s, 1H), 7.33 (s, 1H), 6.84 (d, J = 6.1 Hz, 1H), 6.21 (s, 2H), 5.67 (s, 1H), 5.12 (s, 1H), 4.29 (s, 2H), 3.64 (dd, J = 13.3, 3.9 Hz, 1H), 2.81 (s, 3H), 2.48 - 2.36 (m, 3H), 2.31 - 2.20 (m, 2H), 2.02 (s, 2H), 1.92 (d, J = 1.6 Hz, 3H). Example 111 (S)-1-Methyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (R)-1-Methyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 410a and Compound 410b) TIFF0007698575000217.tif49170 Step 1: tert-Butyl 7-[8-chloro-7-fluoro-3-[(1-methyl-5-oxo-pyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000218.tif47170

[0349] Under nitrogen, to a solution of 4-hydroxy-1-methyl-pyrrolidin-2-one (200 mg, 1.74 mmol), tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (386 mg, 0.87 mmol) and DIEA (903 mg, 6.95 mmol) in dichloromethane (25 mL) was slowly added triphosgene (155 mg, 0.52 mmol) in dichloromethane (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with water. The resulting solution was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 0-70 / 0.1% aqueous NH4HCO3) to give tert-butyl 7-[8-chloro-7-fluoro-3-[(1-methyl-5-oxo-pyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (307 mg, 0.5239 mmol, 30.2% yield) as a yellow solid. LCMS (ESI) [M+H] + =586. Step 2: tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-5-oxo-pyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000219.tif48170

[0350] Under nitrogen, a mixture of tert-butyl 7-[8-chloro-7-fluoro-3-[(1-methyl-5-oxo-pyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (307 mg, 0.52 mmol), NH2BoC (3.7 g, 31.62 mmol), Brettphos (112 mg, 0.21 mmol), Pd2(dba)3CHCl3 (108 mg, 0.10 mmol), and Cs2CO3 (340 mg, 1.05 mmol) was stirred at 90 °C for 1 hour. The reaction mixture was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with dichloromethane / methanol (9 / 1) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-5-oxo-pyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (260 mg, 0.39 mmol, 74.4% yield) as a yellow solid. LCMS (ESI) [[M+H]] + =667. Step 3: (S)-1-Methyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (R)-1-Methyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000220.tif48170

[0351] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methyl-5-oxo-pyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (150 mg, 0.22 mmol) in TFA (3 mL) and dichloromethane (10 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was purified by preparative-HPLC (X Bridge preparative OBD C18 column 30×150mm 5μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 30% B in 10 min; 254 / 220 nm; Rt: 9.58 min) and chiral-HPLC to give two enantiomers. The absolute stereochemistry is arbitrarily assigned.

[0352] Enantiomer 1 (Compound 410a) (37.7 mg, 0.0808 mmol, yield 35.9%): retention time: 2.589 min (CHIRALPAK IC-3, 0.46*5cm, 3μm; MTBE (0.1% DEA)):MeOH = 75:25; 1.0 mL / min; gradient: 50 B to 50 B in 5 min). LCMS (ESI) [M+H] + = 467.2, 1.659 min., method M; 1 H NMR (400 mHz, DMSO-d6) δ 10.22 (s, 1H), 9.34 (s, 1H), 7.98 (s, 1H), 7.34 (s, 1H), 6.85 (d, J = 6.2 Hz, 1H), 6.23 (s, 2H), 5.69 (s, 1H), 5.28 (dd, J = 7.1, 5.5 Hz, 1H), 4.29 (t, J = 4.4 Hz, 2H), 3.79 (dd, J = 11.6, 5.7 Hz, 1H), 3.42 (dd, J = 11.5, 1.5 Hz, 1H), 2.84 - 2.75 (m, 2H), 2.76 (s, 4H), 2.30 (d, J = 17.3 Hz, 1H), 1.93 (d, J = 1.6 Hz, 3H).

[0353] Enantiomer 2 (Compound 410B) (41.6 mg, 0.0892 mmol, yield 39.6%): retention time: 3.581 min (CHIRALPAK IC-3: 0.46 * 5 cm; 3 μm; MTBE (0.1% DEA): MeOH = 75:25; 1.0 ml / min; gradient: 50B to 50B for 5 min), LCMS (ESI) [M+H] + = 467.2, 1.659 min., method M; 1 H NMR (400 mHz, DMSO-d6) δ 10.22 (s, 1H), 9.34 (s, 1H), 7.98 (s, 1H), 7.34 (s, 1H), 6.85 (d, J = 6.2 Hz, 1H), 6.23 (s, 2H), 5.69 (s, 1H), 5.28 (dd, J = 7.1, 5.5 Hz, 1H), 4.29 (t, J = 4.4 Hz, 2H), 3.79 (dd, J = 11.6, 5.7 Hz, 1H), 3.42 (dd, J = 11.5, 1.5 Hz, 1H), 2.84 - 2.75 (m, 2H), 2.76 (s, 4H), 2.30 (d, J = 17.3 Hz, 1H), 1.93 (d, J = 1.6 Hz, 3H). Example 112 (S)-1-Methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (R)-1-methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 411a and Compound 411b) TIFF0007698575000221.tif49170 Step 1: tert-Butyl 7-[3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000222.tif48170

[0354] A solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (1200 mg, 2.7 mmol), 1-BoC-3-hydroxypyrrolidine (660 mg, 3.52 mmol) and DIEA (2000 mg, 15.5 mmol) in dichloromethane (50 mL) was added (COCl2)3 (312 mg, 1.05 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (100 / 1) to give tert-butyl 7-[3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (1600 mg, 2.1881 mmol, 81.1% yield) as a yellow solid. LCMS (ESI) [M+H] + =659.0. Step 2: tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methylpyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000223.tif53170

[0355] Under nitrogen, a mixture of tert-butyl 7-[8-chloro-7-fluoro-3-[(1-methylpyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (1600 mg, 2.8 mmol), NH2BoC (1.40 g, 119.66 mmol), Pd2(dba)3·CHCl3 (250 mg, 0.24 mmol), Brettphos (240 mg, 0.50 mmol) and Cs2CO3 (2400 mg, 7.36 mmol) in 1,4-dioxane (30 mL) was stirred at 90 °C for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (10 / 1) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-[(1-methylpyrrolidin-3-yl)oxycarbonylamino]-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (1300 mg, 1.793 mmol, 64.1% yield) as a yellow solid. LCMS (ESI) [[M+H]] + =739.0. Step 3: Pyrrolidin-3-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate TIFF0007698575000224.tif43170

[0356] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonylpyrrolidin-3-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (380 mg, 0.51 mmol) in dichloromethane (5 mL) and 2,2,2-trifluoroacetic acid (20 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 0 - 40 / 0.1% aqueous NH4HCO3) to give pyrrolidin-3-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (200 mg, 0.4105 mmol, yield 79.8%) as a yellow solid. LCMS (ESI) [M+H] + =439.0. Step 4: (S)-1-Methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (R)-1-Methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000225.tif48170

[0357] A solution of formaldehyde (20 mg, 0.67 mmol) and pyrrolidin-3-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (300 mg, 0.68 mmol) in methanol (30 mL) was stirred at room temperature for 1 hour. Then, NaBH3CN (127 mg, 2.05 mmol) was added and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was purified by reverse-phase chromatography (acetonitrile 0 - 70 / 0.1% NH4HCO3 in water) and chiral-HPLC to afford two enantiomers. The absolute stereochemistry was arbitrarily assigned.

[0358] Enantiomer 1 (Compound 411a) (25 mg, 0.0553 mmol, 8.1% yield): retention time: 7.952 (CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: HEX:DCM = 3:1, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 50B to 50B for 15 minutes). LCMS (ESI) [M+H] + = 453.2, R T 0.931 min, method K; 1 H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.33 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.2 Hz, 1H), 6.21 (s, 2H), 5.68 (s, 1H), 5.14 (dd, J = 8.0, 4.3 Hz, 1H), 4.29 (s, 2H), 3.37 (s, 2H), 2.71 (dt, J = 7.6, 3.9 Hz, 1H), 2.65 (d, J = 4.5 Hz, 2H), 2.32 - 2.17 (m, 5H), 1.93 (d, J = 1.6 Hz, 3H), 1.85 - 1.73 (m, 1H).

[0359] Enantiomer 2 (Compound 411B) (22 mg, 0.0485 mmol, yield 7.1%). Retention time: 12.08 (CHIRALPAK IG, 2 * 25 cm, 5 μm; mobile phase A: HEX:DCM = 3:1, mobile phase B: EtOH; flow rate: 20 mL / min; gradient: 50B to 50B for 15 min). LCMS (ESI) [M + H] + = 453.2, R T 0.931 min., Method K; 1 H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.33 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.2 Hz, 1H), 6.21 (s, 2H), 5.68 (s, 1H), 5.14 (dd, J = 8.0, 4.3 Hz, 1H), 4.29 (s, 2H), 3.37 (s, 2H), 2.71 (dt, J = 7.6, 3.9 Hz, 1H), 2.65 (d, J = 4.5 Hz, 2H), 2.32 - 2.17 (m, 5H), 1.93 (d, J = 1.6 Hz, 3H), 1.85 - 1.73 (m, 1H). Example 113 Tetrahydro-2H-pyran-4-yl (8-amino-7-fluoro-6-(8-hydroxy-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)isoquinolin-3-yl)carbamate (Compound 413) TIFF0007698575000226.tif47170 Step 1: tert-Butyl N-(5-bromo-2-iodo-4-methyl-3-pyridyl)-N-but-3-enyl-carbamate TIFF0007698575000227.tif22170

[0360] A solution of tert-butyl N-(5-bromo-2-iodo-4-methyl-3-pyridyl)carbamate (58 g, 140.42 mmol) in tetrahydrofuran (500 mL) was stirred at room temperature for 1 hour. Then, 4-bromo-1-butene (50 g, 370.37 mmol) and NaI (55 g, 366.67 mmol) were added and the mixture was stirred at 95 °C for 16 hours. The reaction was quenched by adding water and extracted with ethyl acetate. The combined organic layers were dried and concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (4 / 1) to give tert-butyl N-(5-bromo-2-iodo-4-methyl-3-pyridyl)-N-but-3-enyl-carbamate (30 g, 64.42 mmol, 45.7% yield) as a yellow oil, and 8 g of the starting material was recovered. LCMS(ESI)[M+H] + =467. Step 2: tert-butyl 7-bromo-8-methyl-4-methylene-2,3-dihydro-1,5-naphthyridine-1-carboxylate TIFF0007698575000228.tif27170

[0361] A solution of tert-butyl N-(5-bromo-2-iodo-4-methyl-3-pyridyl)-N-but-3-enyl-carbamate (30 g, 64.22 mmol), Pd(dppf)Cl2 (2.4 g, 3.28 mmol) and TEA (13.1 g, 128.43 mmol) in N,N-dimethylformamide (1500 mL) was stirred at 110 °C under nitrogen for 1 hour. The resulting residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (4 / 1) to give tert-butyl 7-bromo-8-methyl-4-methylene-2,3-dihydro-1,5-naphthyridine-1-carboxylate (13 g, 38.32 mmol, 59.7% yield) as a yellow solid. LCMS(ESI)[M+H] + =339. Step 3: tert-Butyl 7-bromo-8-methyl-4-oxo-2,3-dihydro-1,5-naphthyridine-1-carboxylate TIFF0007698575000229.tif27170

[0362] A solution of tert-butyl 7-bromo-8-methyl-4-methylene-2,3-dihydro-1,5-naphthyridine-1-carboxylate (13 g, 38.32 mmol), RuCl3 (2.4 g, 11.59 mmol), and NaIO4 (20.5 g, 95.79 mmol) in acetonitrile (350 mL), carbon tetrachloride (350 mL), and water (350 mL) was stirred at 25 °C for 1.5 h. Then, 300 mL of an aqueous sodium thiosulfate solution was added to quench the reaction. The resulting solution was adjusted to pH 6 - 7 with sodium hydrogen carbonate and extracted with ethyl acetate. The organic phase was concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl 7-bromo-8-methyl-4-oxo-2,3-dihydro-1,5-naphthyridine-1-carboxylate (7 g, 20.52 mmol, 53.5% yield) as a yellow solid. LCMS (ESI) [M+H] + = 341. Step 4: tert-Butyl 7-bromo-4-hydroxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000230.tif27170

[0363] A solution of tert-butyl 7-bromo-8-methyl-4-oxo-2,3-dihydro-1,5-naphthyridine-1-carboxylate (500 mg, 1.47 mmol) and NaBH4 (150 mg, 4.05 mmol) in ethanol (30 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give tert-butyl 7-bromo-4-hydroxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (400 mg, 1.049 mmol, 71.6% yield) as a yellow solid. LCMS(ESI)[M+H] + =343. Step 5: tert-butyl 7-bromo-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000231.tif26170

[0364] Under nitrogen, TBDMSCl (293 mg, 1.95 mmol) was added to a solution of tert-butyl 7-bromo-4-hydroxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (330 mg, 0.96 mmol) and imidazole (200 mg, 2.94 mmol) in dichloromethane (10 mL) at 25 °C. The resulting solution was stirred at 25 °C for 2 h. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl 7-bromo-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (400 mg, 0.874 mmol, 90.9% yield) as a colorless oil. LCMS(ESI)[M+H] + =457. Step 6: tert-Butyl 4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000232.tif36170

[0365] Under nitrogen, to a mixture of tert-butyl 7-bromo-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (400 mg, 0.87 mmol) and bis(pinacolato)diboron (440 mg, 1.73 mmol) in 1,4-dioxane (10 mL) were added Pd(dppf)Cl2 (130 mg, 0.18 mmol) and KOAC (260 mg, 2.65 mmol) at room temperature. The resulting solution was stirred at 100 °C for 2 h. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified by reverse-phase chromatography (acetonitrile 0 - 70 / 0.1% NH4HCO3 in water) to give tert-butyl 4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (320 mg, 0.634 mmol, 72.5% yield) as a colorless oil. LCMS(ESI)[M+H] + =505. Step 7: tert-Butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000233.tif38170

[0366] Under nitrogen, to a solution of tert-butyl 4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (400 mg, 0.79 mmol) and 8-chloro-7-fluoro-6-iodo-isoquinolin-3-amine (400 mg, 1.24 mmol) in 1,4-dioxane (12 mL) and water (1.2 mL) was added Pd(dppf)Cl2 (120 mg, 0.16 mmol) and K2CO3 (330 mg, 2.39 mmol) at room temperature. The resulting mixture was stirred at 60 °C for 2 hours. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (300 mg, 0.523 mmol, 66% yield) as a colorless oil. LCMS(ESI)[M+H] + =573. Step 8: tert-butyl 4-[tert-butyl(dimethyl)silyl]oxy-7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000234.tif48170

[0367] Under nitrogen, to a solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (220 mg, 0.38 mmol) and tetrahydro-2H-pyran-4-ylcarbonochloridate (350 mg, 2.13 mmol) in dichloromethane (10 mL) was added DIEA (268 mg, 2.08 mmol) at 0 °C. The resulting solution was stirred at 0 °C for 2 hours. The reaction was diluted with dichloromethane and then washed with water. The organic phase was dried and concentrated under vacuum. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl 4-[tert-butyl(dimethyl)silyl]oxy-7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (150 mg, 0.214 mmol, 55.7% yield) as a brown solid. LCMS (ESI) [M+H] + =701. Step 9: tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate TIFF0007698575000235.tif49170

[0368] Under nitrogen, to a solution of tert-butyl 4-[tert-butyl(dimethyl)silyl]oxy-7-[8-chloro-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (150 mg, 0.21 mmol) and NH2-BoC (1.5 g, 12.82 mmol) in 1,4-dioxane (8 mL) were added Pd(dba)3CHCl3 (45 mg, 0.04 mmol), Brettphos (45 mg, 0.08 mmol) and Cs2CO3 (225 mg, 0.69 mmol) at room temperature. The resulting mixture was stirred at 90 °C for 2 h. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (1 / 1) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (140 mg, 0.179 mmol, 83.7% yield) as a yellow solid. LCMS(ESI)[M+H] + =782. Step 10: Tetrahydropyran-4-yl N-[8-amino-6-[8-[tert-butyl(dimethyl)silyl]oxy-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl]-7-fluoro-3-isoquinolyl]carbamate TIFF0007698575000236.tif47170

[0369] To a solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-7-fluoro-3-(tetrahydropyran-4-yloxycarbonylamino)-6-isoquinolyl]-4-[tert-butyl(dimethyl)silyl]oxy-8-methyl-3,4-dihydro-2H-1,5-naphthyridine-1-carboxylate (140 mg, 0.18 mmol) in dichloromethane (4 mL) was added I2,2,2-trifluoroacetic acid (1 mL) at room temperature. The resulting solution was stirred at 25 °C for 1 h and concentrated under vacuum. The residue was adjusted to pH = 8 with TEA. The resulting mixture was purified by reverse phase chromatography (acetonitrile 0 - 40 / 0.1% aqueous hydrochloric acid) to give tetrahydropyran-4-yl N-[8-amino-6-[8-[tert-butyl(dimethyl)silyl]oxy-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl]-7-fluoro-3-isoquinolyl]carbamate (60 mg, 0.103 mol, yield 57.6%) as a yellow solid. LCMS(ESI)[M+H] + =58 Step 11: Tetrahydropyran-4-yl N-[8-amino-7-fluoro-6-(8-hydroxy-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)-3-isoquinolyl]carbamate TIFF0007698575000237.tif47170

[0370] A solution of tetrahydropyran-4-yl N-[8-amino-6-[8-[tert-butyl(dimethyl)silyl]oxy-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl]-7-fluoro-3-isoquinolyl]carbamate (60 mg, 0.10 mmol) in tetrahydrofuran (10 mL) was added with tetrabutylammonium fluoride (120 mg, 0.46 mmol) at 25 °C. The resulting solution was stirred at 25 °C for 2 h. The resulting mixture was concentrated and purified by reverse phase chromatography (acetonitrile in water 0 - 40 / 0.1% TFA) to obtain tetrahydropyran-4-yl N-[8-amino-7-fluoro-6-(8-hydroxy-4-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)-3-isoquinolyl]carbamate (9 mg, 0.019 mmol, yield 18.7%) as a yellow solid. LCMS(ESI)[M+H] + =468.2, 1.275 min, method J; 1 H NMR(400 mHz, DMSO-d6) δ 10.05(s, 1H), 9.35(s, 1H), 7.98(s, 1H), 7.65(s, 1H), 6.84(s, 1H), 6.23(s, 2H), 5.65(s, 1H), 5.19(s, 1H), 4.87(dq, J = 8.7, 4.4 Hz, 1H), 4.61(d, J = 3.9 Hz, 1H), 3.90 - 3.81(m, 2H), 3.53 - 3.42(m, 2H), 3.34(m, 2H), 1.97 - 1.87(m, 6H), 1.81(s, 1H), 1.61(dtd, J = 12.9, 9.1, 4.0 Hz, 2H). Example 114 (1S,2S)-2-Acetamidocyclohexyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (1R,2R)-2-acetamidocyclohexyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 414a and Compound 414b) TIFF0007698575000238.tif Project 1: (±)-N-((1R,2R)-2-Hydroxycyclohexyl)acetamide TIFF0007698575000239.tif 21170

[0371] A solution of (±)-(1s,2s)-2-Aminocyclohexanol (1.0 g, 8.68 mmol) and MeONa (474.0 mg, 8.62 mmol) in methanol (50 mL) was stirred at room temperature for 15 minutes. Next, acetic anhydride (1.0 g, 9.8 mmol) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and purified by flash chromatography on silica gel eluting with dichloromethane / methanol (9 / 1) to give (±)-N-[(trans)-2-Hydroxycyclohexyl]acetamide (1 g, 6.361 mmol, 73.3% yield) as a white solid. LCMS (ESI) + = 157.2. Project 2: (±)-tert-Butyl 7-(3-(((((1R,2R)-2-Acetamidocyclohexyl)oxy)carbonyl)amino)-8-chloro-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000240.tif 46170

[0372] A solution of N-[(trans)-2-hydroxycyclohexyl]acetamide (133 mg, 0.85 mmol), tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (250 mg, 0.56 mmol) and DIEA (363 mg, 2.81 mmol) in dichloromethane (20 mL) was stirred at 0 °C. Then triphosgene (75.0 mg, 0.25 mmol) was added and the reaction was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with dichloromethane / methanol (9 / 1) to give (±)-tert-butyl 7-[3-[[(trans)-2-acetamidocyclohexoxy]carbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (310 mg, 0.494 mmol, 87.8% yield) as a yellow solid. LCMS (ESI) [[M+H]] + = 628.1. Step 3: (±)-tert-butyl 7-(3-(((((trans)-2-acetamidocyclohexyl)oxy)carbonyl)amino)-8-((tert-butoxycarbonyl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000241.tif48170

[0373] (±)-tert-Butyl 7-[3-[[(trans)-2-Acetamidocyclohexoxy]carbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (300 mg, 0.48 mmol), tert-butyl carbamate (2800 mg, 23.9 mmol), Pd2(dba)3·CHCl3 (99 mg, 0.10 mmol), Brettphos (103 mg, 0.19 mmol), and Cs2CO3 (467 mg, 1.43 mmol) in 1,4-dioxane (10 mL) were stirred at 90 °C for 5 h under nitrogen. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with dichloromethane / methanol (97:3) to give (±)-tert-butyl 7-[3-[[(trans)-2-acetamidocyclohexoxy]carbonylamino]-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (220 mg, 0.3104 mmol, 65% yield) as a yellow solid. LCMS (ESI) [[M+H]] + =708.8. Step 4: (1S,2S)-2-Acetamidocyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (1R,2R)-2-Acetamidocyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000242.tif48170

[0374] A solution of (±)-tert-butyl 7-[3-[[(trans)-2-acetamidocyclohexyl]oxy]carbonylamino]-8-(tert-butoxycarbonylamino)-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (200 mg, 0.28 mmol) and TFA (1.0 mL, 0.28 mmol) in dichloromethane (20 mL) was stirred at room temperature for 1.5 h. The reaction mixture was diluted with dichloromethane and then adjusted to pH 6 - 7 with triethylamine. The resulting mixture was concentrated in vacuo and purified by preparative-HPLC (X Bridge Shield RP18 OBD column, 30*150 mm, 5 μm; water (10 mmol / L NH4HCO3)): ACN = 20% - 45% for 7 min; 60 mL / min) to give the racemic product. The racemic product was separated by chiral-HPLC to give two enantiomers. The absolute stereochemistry is arbitrarily assigned.

[0375] Enantiomer 1 (Compound 414a) (29.6 mg, 0.0582 mmol, yield 20.6%): retention time: 1.225 min (CHIRALPAK IG-3, 0.46*5 cm, 3 μm; MTBE (0.2% IPAmiNe)): EtOH 50:50 for 5 min; 1 mL / min). LCMS (ESI) + = 509.2, R T = 2.029 min, method K; 1 H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.30 (s, 1H), 7.92 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 6.82 (d, J = 6.1 Hz, 1H), 6.19 (s, 2H), 5.67 (s, 1H), 4.61 - 4.44 (m, 1H), 4.27 - 4.26 (m, 2H), 3.82 - 3.76 (m, 1H), 3.34 - 3.33 (m, 2H), 2.05 - 2.04 (m, 1H), 1.95 (s, 3H), 1.91 - 1.90 (m, 1H), 1.84 (s, 3H), 1.74 - 1.61 (m, 2H), 1.45 - 1.28 (m, 4H).

[0376] Enantiomer 2 (Compound 414b) (28.3 mg, 0.0556 mmol, yield 19.7%): Retention time: 2.338 min (CHIRALPAK IG-3, 0.46 * 5 cm; 3 μm; MTBE (0.2% IPAmiNe): EtOH 50:50 5 min; 1 mL / min). LCMS (ESI) [M+H] + =509.2, R T =2.029 min., Method K. 1 H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.30 (s, 1H), 7.92 (s, 1H), 7.86 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 6.82 (d, J = 6.1 Hz, 1H), 6.19 (s, 2H), 5.67 (s, 1H), 4.61 - 4.44 (m, 1H), 4.27 - 4.26 (m, 2H), 3.82 - 3.76 (m, 1H), 3.34 - 3.33 (m, 2H), 2.05 - 2.04 (m, 1H), 1.95 (s, 3H), 1.91 - 1.90 (m, 1H), 1.84 (s, 3H), 1.74 - 1.61 (m, 2H), 1.45 - 1.28 (m, 4H). Example 115 (1S,2S)-2-(Methylamino)cyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (1R,2R)-2-(methylamino)cyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 415a and Compound 415b) TIFF0007698575000243.tif48170 Step 1: trans-tert-butyl (2-hydroxycyclohexyl)(methyl)carbamate TIFF0007698575000244.tif21170

[0377] To a solution of trans-2-(methylamino)cyclohexanol (200 mg, 1.55 mmol) in 1,4-dioxane was added a solution of sodium hydroxide (80.0 mg, 1.86 mmol) and Boc2O (503.0 mg, 2.31 mmol) in water (30 mL). The mixture was stirred at room temperature for 16 h. The resulting solution was adjusted to pH 6 - 7 with 1N HCl. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried and concentrated in vacuo to afford trans-tert-butyl (2-hydroxycyclohexyl)(methyl)carbamate (310 mg, 1.3518 mmol, 87.3% yield) as a white solid. LCMS (ESI) [M+H] + =229.3. Step 2: trans-tert-Butyl 7-(3-((((2-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)oxy)carbonyl)amino)-8-chloro-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000245.tif45170

[0378] A solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (250.0 mg, 0.560 mmol), trans-tert-butyl (2-hydroxycyclohexyl)(methyl)carbamate (194.0 mg, 0.850 mmol) and DIEA (362.0 mg, 2.81 mmol) in dichloromethane (20 mL) was added with triphosgene (75.0 mg, 0.250 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (1:1) to give trans-tert-butyl 7-(3-((((2-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)oxy)carbonyl)amino)-8-chloro-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (330 mg, 0.4713 mmol, 83.9% yield) as a yellow solid. LCMS (ESI) [M+H] + =700.2. Step 3: trans-tert-butyl 7-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((((2-(methylamino)cyclohexyl)oxy)carbonyl)amino)isoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000246.tif49170

[0379] trans-tert-Butyl 7-(3-((((2-((tert-butoxycarbonyl)(methyl)amino)cyclohexyl)oxy)carbonyl)amino)-8-chloro-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (320.0 mg, 0.460 mmol), tert-butyl carbamate (2698.0 mg, 23.03 mmol), Pd2(dba)3·CHCl3 (94.0 mg, 0.090 mmol), Brettphos (98.0 mg, 0.180 mmol), and Cs2CO3 (447.0 mg, 1.37 mmol) in 1,4-dioxane (10 mL) were stirred at 90 °C for 5 h under nitrogen. The reaction mixture was concentrated under vacuum and purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (1:2) to afford trans-tert-butyl 7-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-((((2-(methylamino)cyclohexyl)oxy)carbonyl)amino)isoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (250 mg, 0.3202 mmol, 70.1% yield) as a yellow solid. LCMS (ESI) [[M+H]] + = 780.9. Step 4: (1S,2S)-2-(Methylamino)cyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (1R,2R)-2-(methylamino)cyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000247.tif49170

[0380] trans-tert-Butyl 7-(8-((tert-butoxycarbonyl)amino)-7-fluoro-3-(((2-(methylamino)cyclohexyl)oxy)carbonyl)amino)isoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (230.0 mg, 0.290 mmol) and TFA (1.0 mL, 0.290 mmol) in dichloromethane (3 mL) were stirred at room temperature for 1.5 h. The reaction was diluted with dichloromethane and then adjusted to pH 6 - 7 with triethylamine. The reaction mixture was concentrated under vacuum and purified by preparative-HPLC (YMC-Actus Triart C18 30*250, 5 μm; water (10 mmol / L NH4HCO3): ACN = 31% - 44% over 7 min; 60 mL / min) to give the racemic product. The racemic product was separated by chiral-HPLC to give two enantiomers. The absolute stereochemistry is arbitrarily assigned.

[0381] Enantiomer 1 (Compound 415a) (22.9 mg, 0.0477 mmol, yield 16.2%): retention time: 1.553 min (CHIRALPAK IG-3: 0.46*5 cm; 3 μm; (Hex:DCM = 1:1)(0.1% DEA):EtOH 50:50 over 7 min; 1 mL / min). LCMS (ESI) [M+H] + = 481.3, R T = 1.030 min. Method J. 1 H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.32 (s, 1H), 7.95 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 6.1 Hz, 1H), 6.19 (s, 2H), 5.67 (s, 1H), 4.46 - 4.40 (m, 1H), 4.27 (s, 2H), 3.34 - 3.33 (m, 3H), 2.49 - 2.42 (m, 1H), 2.33 (s, 3H), 2.06 - 1.90 (m, 5H), 1.65 - 1.63 (m, 2H), 1.39 - 1.33 (m, 4H).

[0382] Enantiomer 2 (Compound 415b) (24.6 mg, 0.0512 mmol, yield 17.4%): retention time: 3.752 min (CHIRALPAK IG-3, 0.46 * 5 cm; 3 μm; (Hex:DCM = 1:1)(0.1% DEA):EtOH 50:50 7 min; 1 mL / min). LCMS (ESI) [M + H] + = 481.3, R T = 1.030 min. Method J. 1 H NMR (300 MHz, DMSO-d6) δ 9.92 (s, 1H), 9.32 (s, 1H), 7.95 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 6.82 (d, J = 6.1 Hz, 1H), 6.19 (s, 2H), 5.67 (s, 1H), 4.46 - 4.40 (m, 1H), 4.27 (s, 2H), 3.34 - 3.33 (m, 3H), 2.49 - 2.42 (m, 1H), 2.33 (s, 3H), 2.06 - 1.90 (m, 5H), 1.65 - 1.63 (m, 2H), 1.39 - 1.33 (m, 4H). Example 116 (R)-1-Methylpiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate and (S)-1-methylpiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 416a and Compound 416b) TIFF0007698575000248.tif48170

[0383] A solution of 3-piperidyl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (100 mg, 0.22 mmol) (from Example 106) in methanol (10 mL) was added with formaldehyde (0 mg, 0.27 mmol, 40%) at room temperature. The resulting solution was stirred at 25 °C for 1 hour. Then, NaBH4 (20 mg, 0.53 mmol) was added and the mixture was stirred at 25 °C for 1 hour. The reaction was quenched with water and concentrated under vacuum, and then purified by preparative-HPLC (column: Kinetex EVO C18 column 21.2*150, 5 μm; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 25 mL / min; gradient: 15% B to 41% B in 10 min; 254 nm; Rt: 9.75 min) and chiral-HPLC (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: Hex:DCM = 3:1 (10 mM NH3-MeOH)-HPLC, mobile phase B: EtOH = HPLC; flow rate: 20 mL / min; gradient: 50% B to 50% B in 21 min) to obtain two enantiomers. The absolute stereochemistry is arbitrarily assigned.

[0384] Enantiomer 1 (Compound 416a) (22.6 mg, 0.0484 mmol, yield 21.9%): retention time: 2.690 min (CHIRALPAK IE-3, 0.46*5 cm; 3 μm, (Hex:DCM = 3:1)(0.1% DEA):EtOH = 50:50 in 5 min; 1.0 mL / miN). LCMS (ESI) [M+H] + = 467.3, R T = 1.514 min., Method J; 11H NMR (400 mHz, DMSO-d6) δ 10.02 (s, 1H), 9.33 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.2 Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 4.72 (dt, J = 8.4, 4.3 Hz, 1H), 4.29 (t, J = 4.4 Hz, 2H), 3.33 (t, J = 4.4 Hz, 2H), 2.78 (d, J = 10.8 Hz, 1H), 2.48 (d, J = 10.8 Hz, 1H), 2.18 (s, 3H), 2.13 - 2.01 (d, J = 10.3 Hz, 2H), 1.92 - 1.87 (s, 4H), 1.75 - 1.71 (m, 1H), 1.55 - 1.34 (m, 2H).

[0385] Enantiomer 2 (Compound 416B) (19.8 mg, 0.0424 mmol, yield 19.2%): retention time: 3.558 min (CHIRALPAK IE-3, 0.46 * 5 cm; 3 μm, (Hex:DCM = 3:1) (0.1% DEA):EtOH = 50:50 5 min; 1.0 mL / min). LCMS (ESI) [M+H] + = 467.3, R T = 1.514 min., Method J; 1 1H NMR (400 mHz, DMSO-d6) δ 10.02 (s, 1H), 9.33 (s, 1H), 7.97 (s, 1H), 7.33 (s, 1H), 6.83 (d, J = 6.2 Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 4.72 (dt, J = 8.4, 4.3 Hz, 1H), 4.29 (t, J = 4.4 Hz, 2H), 3.33 (t, J = 4.4 Hz, 2H), 2.78 (d, J = 10.8 Hz, 1H), 2.48 (d, J = 10.8 Hz, 1H), 2.18 (s, 3H), 2.13 - 2.01 (d, J = 10.3 Hz, 2H), 1.92 - 1.87 (s, 4H), 1.75 - 1.71 (m, 1H), 1.55 - 1.34 (m, 2H). Example 117 2-Methyl-2-azaspiro[3.3]heptan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate (Compound 417) TIFF0007698575000249.tif Project 1: tert-Butyl 7-(3-((((2-(tert-Butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)carbonyl)amino)-8-chloro-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000250.tif 41170

[0386] Under nitrogen, a solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (200 mg, 0.45 mmol), tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (195 mg, 0.91 mmol), and DIEA (285 mg, 2.21 mmol) in dichloromethane (2 mL) was stirred at 0 °C for 10 minutes. Then, triphosgene (95 mg, 0.32 mmol) was added at 0 °C and the mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated in vacuo and purified by silica gel flash chromatography eluting with petroleum ether / ethyl acetate (60 / 30) to give tert-butyl 7-[3-[(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinonyl]-8-methyl-2,3-dihydropyrrolido[2,3-B][1,4]oxazine-1-carboxylate (190 mg, 0.278 mmol, 61.8% yield) as a yellow solid. LCMS (ESI) [M+H] + = 684. Project 2: tert-Butyl 7-(3-((((2-(tert-Butoxycarbonyl)-2-azaspiro[3.3]heptan-6-yl)oxy)carbonyl)amino)-8-((tert-butoxycarbonyl)amino)-7-fluoroisoquinolin-6-yl)-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000251.tif43170

[0387] A mixture of tert-butyl 7-[3-[(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (300 mg, 0.44 mmol), Pd2(dba)3CHCl3 (90 mg, 0.090 mmol), Brettphos (93 mg, 0.17 mmol), Cs2CO3 (420 mg, 1.29 mmol), and NH2BoC (1250 mg, 10.68 mmol) in 1,4-dioxane (5 mL) was stirred at 90 °C for 2 h. The reaction was concentrated in vacuo and purified by flash chromatography on silica gel eluting with petroleum ether / ethyl acetate (2 / 1) to give tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (190 mg, 0.248 mmol, 89.5% yield) as a yellow solid. LCMS (ESI) [M+H] + =765. Step 3: 2-Azaspiro[3.3]heptan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000252.tif46170

[0388] A solution of tert-butyl 7-[8-(tert-butoxycarbonylamino)-3-[(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (190 mg, 0.25 mmol) in dichloromethane (5 mL) and TFA (5 mL, 0.25 mmol) was stirred at room temperature for 2 h. The organic layer was concentrated under vacuum and purified by reverse-phase HPLC with CH3CN / H2O (10 / 2) to give 2-azaspiro[3.3]heptan-6-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (90 mg, 0.194 mmol, 78% yield) as a white solid. LCMS (ESI) [M+H] + =465. Step 4: 2-Methyl-2-azaspiro[3.3]heptan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate TIFF0007698575000253.tif48170

[0389] A solution of 2-azaspiro[3.3]heptan-6-yl N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (20 mg, 0.040 mmol) and formaldehyde (3 mg, 0.10 mmol, 40%) in methanol (2 mL) was stirred at room temperature for 1 hour. Then, NACNBH3 (8 mg, 0.13 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum and purified by reverse-phase HPLC with ACN / water (10 mmol / L NH4HCO3) (45 / 15) to give (2-methyl-2-azaspiro[3.3]heptan-6-yl) N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (4.6 mg, 0.0096 mmol, 22.3% yield) as a pale yellow solid. LCMS (ESI) [M+H] + =479.2,R T =1.584 min., method J. 1 H NMR (300 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.34 (s, 1H), 8.19 (s, 1H), 7.95 (s, 1H), 6.87 - 6.80 (d, J = 6 Hz, 1H), 6.20 (s, 2H), 5.67 (s, 1H), 4.89 - 4.81 (m, 1H), 4.29 - 4.27 (m, 2H), 3.19 - 3.07 (d, J = 15 Hz, 4H), 2.20 - 2.14 (m, 5H), 1.96 - 1.89 (m, 3H), 1.24 (s, 4H). Example 118 (1-Isopropylazetidin-3-yl) N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate (Compound 419) TIFF0007698575000254.tif Project 1: tert-Butyl 7-[3-[(1-tert-butoxycarbonylazetidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate TIFF0007698575000255.tif 39170

[0390] Under nitrogen, DIEA (3.5 g, 27.13 mmol) was added to a solution of tert-butyl 7-(3-amino-8-chloro-7-fluoro-6-isoquinolyl)-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (1.5 g, 3.37 mmol) and 1-Boc-3-hydroxyazetidine (3.0 g, 17.32 mmol) in dichloromethane (250 mL) at room temperature. Then, triphosgene (1.4 g, 4.72 mmol) was added at 0 °C and the reaction was stirred at 0 °C for 1 hour. The reaction mixture was washed with water. The organic layer was dried and concentrated under vacuum and purified by silica gel flash chromatography eluting with PE / EA (1 / 1) to give tert-butyl 7-[3-[(1-tert-butoxycarbonylazetidin-3-yl)oxycarbonylamino]-8-chloro-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate (1.1 g, 1.71 mmol, 50.7% yield) as a yellow solid. LCMS (ESI) [M+H] + =644. Project 2: tert-Butyl 7-[8-(tert-butoxycarbonylamino)-3-[(1-tert-butoxycarbonylazetidin-3-yl)oxycarbonylamino]-7-fluoro-6-isoquinolyl]-8-methyl-2,3-dihydropyrido[2,3-b...

Claims

1. Formula (I): (wherein R １５ is -OR １６ and Each R １６ is independently C １－６ alkyl, C ３－１０ cycloalkyl, 7- to 14-membered heteroaryl, or 3- to 14-membered heterocyclyl; R １６ 's C １－６ alkyl, C ３－１０ cycloalkyl, 7- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R １０ ; R ３ is hydrogen, halogen, cyano, C １－６ alkyl, C ３－８ cycloalkyl, 3- to 14-membered heterocyclyl, or -OR ７ ; R ３ 's C １－６ alkyl, C ３－８ cycloalkyl, and 3- to 14-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R １０ ; R ４ is (wherein the wavy line indicates the bonding point)) is; R ５ is hydrogen, halogen, cyano, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－８ cycloalkyl, C ６－１４ aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, halogen, cyano, -C(O)R ６ , -C(O)OR ７ , -C(O)NR ８ａ R ８ｂ , -OR ７ , -OC(O)R ６ , -OC(O)NR ８ａ R ８ｂ , -SR ７ , -S(O)R ９ , -S(O) ２ R ９ , -S(O) ２ NR ８ａ R ８ｂ , -P(O)R ９ａ R ９ｂ , -NR ８ａ R ８ｂ , -N(R ８ )(C(O)R ６ ), -N(R ８ )(C(O)OR ７ , -N(R ８ )(C(O)NR ８ａ R ８ｂ , -N(R ８ )(S(O) ２ R ９ , or -N(R ８ )(S(O) ２ NR ８ａ R ８ｂ ; the C ５ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ cycloalkyl, C ３－８ aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl of R ６－１４ may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R １０ ; Each R ６ is independently hydrogen, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; and the C ６ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ cycloalkyl, C ３－８ aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ６－１０ ; and １０ may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R Each R ７ is independently hydrogen, C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; and the C ７ alkyl, C １－６ cycloalkyl, C ３－８ aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl of R ６－１０ may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R １０ ; Each R ８ is independently hydrogen or C １－６ alkyl; Each R ８ａ and R ８ｂ is independently hydrogen, C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C ８ａ of R ８ｂ and R １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R １０ ; and may be substituted; Or, R ８ａ And R ８ｂ Together with the nitrogen atom to which they are attached, may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R １０ To form a 4- to 12-membered heterocyclyl which may be substituted; Each R ９ is independently C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C ９ of R １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R １０ ; and may be substituted; Each R ９ａ and R ９ｂ is independently C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, 3- to 12-membered heterocyclyl, or -O-C １－６ alkyl; R ９ａ and R ９ｂ 's C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R １０ ; Or, R ９ａ and R ９ｂ together with the phosphorus atom to which they are attached may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from １０ to form a 4- to 12-membered heterocyclyl which may be substituted; Each R １０ is independently oxo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, halogen, cyano, -C(O)R ａ , -C(O)OR ｂ , -C(O)NR ｃ R ｄ , -OR ｂ , -OC(O)R ａ , -OC(O)NR ｃ R ｄ , -SR ｂ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)(=NH)R ｅ , -S(O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -N(R ｆ )(C(O)R ａ , -N(R ｆ )(C(O)OR ｂ , -N(R ｆ )(C(O)NR ｃ R ｄ , -N(R ｆ )(S(O) ２ R ｅ , -N(R ｆ )(S(O) ２ NR ｃ R ｄ , or -P(O)R ｇ R ｈ ; the C １０ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ cycloalkyl, C ３－８ aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl of ６－１４ R １１ may each be substituted with 1, 2, 3, or 4 substituents independently selected from Each R ａ is independently hydrogen, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C ａ of R １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １１ ; and may be substituted; Each R ｂ is independently hydrogen, C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; and the C ｂ alkyl, C １－６ cycloalkyl, C ３－８ aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl of R ６－１０ may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １１ ; Each R ｃ and R ｄ is independently hydrogen, C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; R ｃ and R ｄ of C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １１ ; and may be substituted Or, R ｃ and R ｄ together with the nitrogen atom to which they are attached, may be substituted with 1, 2, 3, or 4 substituents independently selected from １１ to form a 4- to 12-membered heterocyclyl which may be substituted; Each R ｅ is independently C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl; the C ｅ of R １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １１ ; Each R ｆ is independently hydrogen or C １－６ alkyl; Each R ｇ and R ｈ is independently C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or -O-C １－６ alkyl; R ｇ and R ｈ 's C １－６ alkyl, C ３－８ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １１ ; Or, R ｇ and R ｈ together with the phosphorus atom to which they are attached, may be substituted with 1, 2, 3, or 4 substituents independently selected from R １１ to form a 4- to 12-membered heterocyclyl which may be substituted; Each R １１ is independently oxo, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, halogen, cyano, -C(O)R ａ１ , -C(O)OR ｂ１ , -C(O)NR ｃ１ R ｄ１ , -OR ｂ１ , -OC(O)R ａ１ , -OC(O)NR ｃ１ R ｄ１ , -SR ｂ１ , -S(O)R ｅ１ , -S(O) ２ R ｅ１ , -S(O) ２ NR ｃ１ R ｄ１ , -NR ｃ１ R ｄ１ , -N(R ｆ１ )(C(O)R ａ１ , -N(R ｆ１ )(C(O)OR ｂ１ , -N(R ｆ１ )(C(O)NR ｃ１ R ｄ１ , -N(R ｆ１ )(S(O) ２ R ｅ１ , -N(R ｆ１ )(S(O) ２ NR ｃ１ R ｄ１ , or -P(O)R ｇ１ R ｈ１ ; Each of the C １１ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ cycloalkyl, C ３－６ aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl of R ６－１４ may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １２ ; Each R ａ１ is independently hydrogen, C １－６ alkyl, C ２－６ alkenyl, C ２－６ alkynyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and the C ａ１ alkyl, C １－６ alkenyl, C ２－６ alkynyl, C ２－６ cycloalkyl, C ３－６ aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R ６－１０ ; and １２ may be substituted with 1, 2, 3, or 4 substituents independently selected from R Each R ｂ１ is independently hydrogen, C １－６ alkyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and the C ｂ１ alkyl, C １－６ cycloalkyl, C ３－６ aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R ６－１０ may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １２ ; Each R ｃ１ and R ｄ１ is independently hydrogen, C １－６ alkyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; the C ｃ１ of R ｄ１ and R １－６ alkyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １２ ; and may be substituted with; Or, R ｃ１ and R ｄ１ together with the nitrogen atom to which they are attached, may be substituted with 1, 2, 3, or 4 substituents independently selected from R １２ to form a 4- to 8-membered heterocyclyl which may be substituted; Each R ｅ１ is independently C １－６ alkyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl; and the C ｅ１ alkyl, C １－６ cycloalkyl, C ３－６ aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl of R ６－１０ may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １２ ; Each R ｆ１ is independently hydrogen or C １－６ alkyl; Each R ｇ１ and R ｈ１ is independently C １－６ alkyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or -O-C １－６ alkyl; R ｇ１ and R ｈ１ of C １－６ alkyl, C ３－６ cycloalkyl, C ６－１０ aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １２ ; Or, R ｇ１ and R ｈ１ together with the phosphorus atom to which they are attached, may be substituted with 1, 2, 3, or 4 substituents independently selected from １２ to form a 4- to 8-membered heterocyclyl which may be substituted; Each R １２ is independently oxo, C １－６ alkyl, C ３－６ cycloalkyl, C ６ aryl, 5- to 6-membered heteroaryl, 3- to 6-membered heterocyclyl, halogen, cyano, -C(O)R ａ２ , -C(O)OR ｂ２ , -C(O)NR ｃ２ R ｄ２ , -OR ｂ２ , -OC(O)R ａ２ , -OC(O)NR ｃ２ R ｄ２ , -S(O) ２ R ｅ２ , -S(O) ２ NR ｃ２ R ｄ２ , -NR ｃ２ R ｄ２ , -N(R ｆ２ )(C(O)R ａ２ , -N(R ｆ２ )(C(O)OR ｂ２ , -N(R ｆ２ )(C(O)NR ｃ２ R ｄ２ , -N(R ｆ２ )(S(O) ２ R ｅ２ , -N(R ｆ２ )(S(O) ２ NR ｃ２ R ｄ２ , or -P(O)R ｇ２ R ｈ２ ; C １２ alkyl, C １－６ cycloalkyl, C ３－６ aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl of R ６ may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １３ ; Each R ａ２ is independently hydrogen, C １－６ alkyl, C ３－６ cycloalkyl, C ６ aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; the C ａ２ of R １－６ alkyl, C ３－６ cycloalkyl, C ６ aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １３ ; and may be substituted; Each R ｂ２ is independently hydrogen, C １－６ alkyl, C ３－６ cycloalkyl, or 3- to 6-membered heterocyclyl; and the C ｂ２ alkyl, C １－６ cycloalkyl, and 3- to 6-membered heterocyclyl of R ３－６ may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １３ ; Each R ｃ２ and R ｄ２ is independently hydrogen, C １－６ alkyl, C ３－６ cycloalkyl, or 3- to 8-membered heterocyclyl; R ｃ２ and R ｄ２ 's C １－６ alkyl, C ３－６ cycloalkyl, and 3- to 8-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １３ ; and may be substituted; or R ｃ２ and R ｄ２ together with the nitrogen atom to which they are attached, may be substituted with 1, 2, 3, or 4 substituents independently selected from R １３ to form a 4- to 6-membered heterocyclyl which may be substituted; Each R ｅ２ is independently C １－６ alkyl, C ３－６ cycloalkyl, C ６ aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl; the C ｅ２ of R １－６ alkyl, C ３－６ cycloalkyl, C ６ aryl, 5- to 6-membered heteroaryl, and 3- to 6-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １３ ; and may be substituted; Each R ｆ２ is independently hydrogen or C １－６ alkyl; Each R ｇ２ and R ｈ２ is independently C １－６ alkyl, C ３－６ cycloalkyl, 3- to 8-membered heterocyclyl, or -O-C １－６ alkyl; R ｇ２ and R ｈ２ of C １－６ alkyl, C ３－６ cycloalkyl, and 3- to 8-membered heterocyclyl may each be substituted with 1, 2, 3, or 4 substituents independently selected from R １３ ; and may be substituted; Or, R ｇ２ and R ｈ２ together with the phosphorus atom to which they are attached may be substituted with 1, 2, 3, or 4 substituents independently selected from R １３ to form a 4- to 6-membered heterocyclyl which may be substituted; and Each R １３ is independently oxo, halogen, hydroxyl, -O(C １－６ alkyl), cyano, C １－６ alkyl, or C １－６ haloalkyl). a compound of, or a pharmaceutically acceptable salt thereof (provided that 3-methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate, 3-methyloxetan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate, 1,1-dioxidotetrahydrothiophen-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate, 1,3-dimethyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate, and 1-acetyl-3-methylazetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate are excluded).

2. R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.

3. R ５ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, fluoro or chloro.

4. R ５ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is halogen.

5. R ５ The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R is fluoro.

6. R １６ wherein R １０ is a 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R １６ has one or two heteroatoms independently selected from the group consisting of N, O and S, and R １０ is a 4- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R, or a pharmaceutically acceptable salt thereof, according to Claim 6.

8. R １６ has one or two heteroatoms independently selected from the group consisting of N, O and S, and R １０ is a 4- to 10-membered heterocyclyl substituted with one substituent selected from, the compound according to claim 6, or a pharmaceutically acceptable salt thereof.

9. R １６ wherein R １０ is cycloalkyl of C which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ３－８ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. R １６ where R １０ is a C ３－８ cycloalkyl substituted with one substituent independently selected from R, or a pharmaceutically acceptable salt thereof.

11. R １６ is -(C １－６ alkylene)-R １９ and R １９ is independently C ３－１０ cycloalkyl, C ６－１４ aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, cyano, -OR ７ , -NR ８ａ R ８ｂ , or -S(O) ２ R ９ and; the C １９ of R ３－１０ cycloalkyl, C ６－１４ aryl, 5- to 14-membered heteroaryl and 3- to 14-membered heterocyclyl are each independently optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from R １０ , or a pharmaceutically acceptable salt thereof, a compound according to claim 1.

12. R １９ wherein R １０ is a 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from R, according to claim 11, or a pharmaceutically acceptable salt thereof.

13. R １６ is (wherein the wavy line indicates the bonding point) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

14. R １６ is selected from the group consisting of, each being R １０ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from

15. R １０ is independently C １－６ alkyl or cyano, a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. R １０ The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R is independently methyl or cyano.

17. R １０ The compound according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R is independently methyl.

18. The compound according to claim 1, wherein the compound is a compound of formula (IA-1): (wherein, R ４ and R １６ are as defined in any one of claims 1 to 17 when applicable) or a pharmaceutically acceptable salt thereof.

19. The compound is tetrahydro-2H-pyran-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-methylazetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-Tetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-Tetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (Piperidin-4-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-Pyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-Pyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (9-Methyl-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-Methylpiperidin-4-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-Piperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-Piperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-(1-Methyl-6-oxopiperidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-Methyl-6-oxopiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-1-Methyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-Methyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-1-Methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-Methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2S)-2-Acetamidocyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2R)-2-Acetamidocyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2S)-2-(Methylamino)cyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2R)-2-(Methylamino)cyclohexyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-1-Methylpiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-Methylpiperidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (2-Methyl-2-azaspiro[3.3]heptan-6-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-Acetylpyrrolidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-(1-Acetylpyrrolidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-(1-Acetylpyrrolidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-Isopropylazetidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-(2,2,2-Trifluoroethyl)azetidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-(Oxetan-3-yl)piperidin-4-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-(2,2,2-Trifluoroethyl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 2-Acetyl-2-azaspiro[3.3]heptan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-Acetylazetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 7-Methyl-7-azaspiro[3.5]nonan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 6-Methyl-6-azaspiro[3.4]octan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6r)-3-Methyl-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6s)-3-Methyl-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-3-Fluoro-1-methylpiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-3-Fluoro-1-methylpiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-(2,2-difluoroethyl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1,3,3-trimethylpiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; isopropyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-1-acetyl-3-fluoropiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-1-acetyl-3-fluoropiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 7-(oxetan-3-yl)-7-azaspiro[3.5]nonan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,9s)-7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,9r)-7-methyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-4-methyl-1,4-oxazepan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-4-Methyl-1,4-oxazepan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; [(3S,4S)-1,4-Dimethylpyrrolidin-3-yl] N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate; [(3R,4R)-1,4-Dimethylpyrrolidin-3-yl] N-[8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-3-isoquinolyl]carbamate; (3S,4R)-1,4-Dimethylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-1,4-Dimethylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 2-(Oxetan-3-yl)-2-azaspiro[3.3]heptan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-Methyl-5-oxopyrrolidin-3-yl (8-amino-6-(8-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoroisoquinolin-3-yl)carbamate; (R)-1-Methyl-5-oxopyrrolidin-3-yl (8-amino-6-(8-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoroisoquinolin-3-yl)carbamate; (3S,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-3-Fluoro-1-(oxetan-3-yl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1,3-Dimethylazetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(dimethylamino)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-(dimethylamino)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 3-(pyrrolidin-1-yl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3-fluorooxetan-3-yl)methyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3-fluoro-1-methylazetidin-3-yl)methyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-(3-fluoro-1-methylpyrrolidin-3-yl)methyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-(3-fluoro-1-methylpyrrolidin-3-yl)methyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-fluoro-1-methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-fluoro-1-methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Fluoro-1-methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Fluoro-1-methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (5-(Difluoromethyl)-1-methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (2-(Difluoromethyl)-1-methylpyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3-Cyanocyclobutyl (8-amino-7-cyano-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1,4-Dimethyl-1,4-diazepan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3-Methyl-3-azabicyclo[3.1.0]hexan-1-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,5S)-7-Methyl-1-oxa-7-azaspiro[4.4]nonan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,5R)-7-Methyl-1-oxa-7-azaspiro[4.4]nonan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,5R)-7-Methyl-1-oxa-7-azaspiro[4.4]nonan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,5S)-7-Methyl-1-oxa-7-azaspiro[4.4]nonan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (7-Acetyl-7-azaspiro[3.5]nonan-2-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-(N-Methylsulfamoyl)azetidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-Methylazetidin-3-yl) (8-amino-6-(8-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoroisoquinolin-3-yl)carbamate; (1-(Oxetan-3-yl)azetidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-(2-Methoxyethyl)azetidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3-Methyl-3-azabicyclo[4.1.0]heptan-6-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-(1-Methyl-1H-pyrazol-4-yl)ethyl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 4-Fluorotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Fluorotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Fluorotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Fluorotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Fluorotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-1-Ethyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-Ethyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-Isopropyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-1-Isopropyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1,4,4-Trimethyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-1,4,4-Trimethyl-5-oxopyrrolidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2S)-2-Cyanocyclopentyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2R)-2-Cyanocyclopentyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2S)-2-Cyanocyclopentyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2R)-2-Cyanocyclopentyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Cyanocyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Cyanocyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Hydroxycyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Hydroxy-3-methylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxy-3-methylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-(1-Methyl-1H-pyrazol-4-yl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 2-(Methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 3-Ethyl-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6r)-3-Isopropyl-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6s)-3-Isopropyl-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 3-(2,2-Difluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 3-(2,2,2-Trifluoroethyl)-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6r)-3-(Oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6s)-3-(oxetan-3-yl)-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,9s)-7-isopropyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,9r)-7-isopropyl-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,9s)-7-(2,2-difluoroethyl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,9r)-7-(2,2-difluoroethyl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-2-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-2-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-2-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-2-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-8-(Oxetan-3-yl)-8-azaspiro[4.5]decan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-8-(Oxetan-3-yl)-8-azaspiro[4.5]decan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3r)-3-Ethyl-3-hydroxycyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3s)-3-Ethyl-3-hydroxycyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3S)-3-(3,3-Difluoroazetidin-1-yl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,3R)-3-(3,3-Difluoroazetidin-1-yl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,3R)-3-(1H-Imidazol-1-yl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3S)-3-(1H-Imidazol-1-yl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Ethyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Ethyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Ethyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Ethyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Cyclopropyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Cyclopropyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Cyclopropyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Cyclopropyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-(Azetidine-1-carbonyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(Azetidine-1-carbonyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (Tetrahydrofuran-3-yl) (8-amino-7-fluoro-6-(3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-(Tetrahydrofuran-3-yl) (8-amino-7-fluoro-6-((R)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-(Tetrahydrofuran-3-yl) (8-amino-7-fluoro-6-((S)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-Tetrahydrofuran-3-yl (8-amino-7-fluoro-6-((R)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-Tetrahydrofuran-3-yl (8-amino-7-fluoro-6-((S)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-(Dimethylcarbamoyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(Dimethylcarbamoyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-(Methylcarbamoyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(Methylcarbamoyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-(2-Fluoroethyl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6s)-3-(Methylsulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6r)-3-(Methylsulfonyl)-3-azabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-1-(Dimethylamino)propan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-(Dimethylamino)propan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-(Cyclopropylsulfonyl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-(3-Fluoroazetidin-1-yl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(3-Fluoroazetidin-1-yl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2R,3S)-3-Hydroxy-2,3-dimethylcyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2S,3R)-3-Hydroxy-2,3-dimethylcyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2R,3S)-3-Hydroxy-2,3-dimethylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2S,3R)-3-Hydroxy-2,3-dimethylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2S,3S)-3-Hydroxy-2,3-dimethylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2R,3R)-3-Hydroxy-2,3-dimethylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2S,3S)-3-Hydroxy-2,3-dimethylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2R,3R)-3-Hydroxy-2,3-dimethylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Methoxy-3-methylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Methoxy-3-methylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(((8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamoyl)oxy)-1-methylcyclobutyl acetate; (1s,3s)-3-(((8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamoyl)oxy)-1-methylcyclobutyl acetate; (R)-1-hydroxypropan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-1-hydroxypropan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,3S)-3-hydroxy-3-methylcyclopentyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3R)-3-hydroxy-3-methylcyclopentyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,3R)-3-hydroxy-3-methylcyclopentyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3S)-3-hydroxy-3-methylcyclopentyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2R)-2-cyanocyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2S)-2-Cyanocyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2S)-2-Cyanocyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2R)-2-Cyanocyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3s)-3-(Cyanomethyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3r)-3-(Cyanomethyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Cyano-3-methylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Cyano-3-methylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Cyanotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Cyanotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Cyanotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Cyanotetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(Methylamino)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-(Methylamino)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1-Cyclopropylazetidin-3-yl) (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Fluorocyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Fluorocyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2R)-2-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2S)-2-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2S)-2-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2R)-2-Hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6s)-3-Oxabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,6r)-3-Oxabicyclo[3.1.0]hexan-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-((1R,2S)-2-Fluorocyclopropane-1-carbonyl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-((1S,2R)-2-Fluorocyclopropane-1-carbonyl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-((1R,2R)-2-Fluorocyclopropane-1-carbonyl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-((1S,2S)-2-Fluorocyclopropane-1-carbonyl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Methoxytetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Methoxytetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Methoxytetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Methoxytetrahydrofuran-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-(2-Cyanopropan-2-yl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(2-Cyanopropan-2-yl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Morpholinocyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Morpholinocyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Cyclopropyl-3-hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Cyclopropyl-3-hydroxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 1-(Methylsulfonyl)azetidin-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Hydroxy-1-methylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Hydroxy-1-methylcyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-6-(8-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoroisoquinolin-3-yl)carbamate; (3S,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-6-(8-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoroisoquinolin-3-yl)carbamate; (3R,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-6-(8-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoroisoquinolin-3-yl)carbamate; (3S,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-6-(8-ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-7-fluoroisoquinolin-3-yl)carbamate; (3R,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-Cyanocyclobutyl(8-amino-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-Cyanocyclobutyl(8-amino-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2S)-2-Methylcyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2R)-2-Methylcyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,2R)-2-Methylcyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,2S)-2-Methylcyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-7-cyano-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-7-cyano-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-7-cyano-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-7-cyano-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,3aR,6aR)-Hexahydrofuro[3,4-b]furan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,3aS,6aS)-Hexahydrofuro[3,4-b]furan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,3aR,6aR)-Hexahydrofuro[3,4-b]furan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,3aS,6aS)-Hexahydrofuro[3,4-b]furan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-1-(2,2-Difluoroethyl)-3-fluoropiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-1-(2,2-difluoroethyl)-3-fluoropiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-1-(2,2-difluoroethyl)-3-fluoropiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-1-(2,2-difluoroethyl)-3-fluoropiperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-((S)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-4-methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-((R)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-((S)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-4-methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-((R)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-((S)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-4-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-((R)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-((S)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-4-Methyltetrahydrofuran-3-yl (8-amino-7-fluoro-6-((R)-3-fluoro-8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,3aR,6aS)-Hexahydrofuro[2,3-b]furan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,3aR,6aS)-Hexahydrofuro[2,3-b]furan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,3aS,6aR)-Hexahydrofuro[2,3-b]furan-3-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-3-Fluoro-1-((S)-tetrahydrofuran-3-yl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-3-Fluoro-1-((R)-tetrahydrofuran-3-yl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-3-Fluoro-1-((S)-tetrahydrofuran-3-yl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-3-Fluoro-1-((R)-tetrahydrofuran-3-yl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4S)-3-Fluoro-1-(2-methoxyethyl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4R)-3-Fluoro-1-(2-methoxyethyl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3R,4R)-3-Fluoro-1-(2-methoxyethyl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (3S,4S)-3-Fluoro-1-(2-methoxyethyl)piperidin-4-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(Hydroxymethyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3S)-3-(Hydroxymethyl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3S)-3-(Methylsulfonyl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,3R)-3-(Methylsulfonyl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3S)-3-((R)-1-Hydroxyethyl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3R)-3-((S)-1-Hydroxyethyl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,3R)-3-((R)-1-Hydroxyethyl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,3S)-3-((S)-1-Hydroxyethyl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,3R)-3-(2-Hydroxypropan-2-yl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1S,3S)-3-(2-Hydroxypropan-2-yl)cyclobutyl(8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,9s)-7-(oxetan-3-yl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1R,5S,9r)-7-(oxetan-3-yl)-3-oxa-7-azabicyclo[3.3.1]nonan-9-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-methoxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-methoxycyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1s,3s)-3-(difluoromethyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (1r,3r)-3-(difluoromethyl)cyclobutyl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (R)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; (S)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-6-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate; 7-azaspiro[3.5]nonan-2-yl (8-amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl)carbamate The compound according to claim 1, which is a compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

21. The pharmaceutical composition according to claim 20, further comprising a chemotherapeutic agent.

22. A medicament for inhibiting HPK1, comprising an effective amount of the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition according to claim 20 or 21.

23. A medicament for enhancing an immune response, comprising an effective amount of the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition according to claim 20 or 21.

24. A medicament for treating an HPK1-dependent disorder, comprising an effective amount of the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition according to claim 20 or 21.

25. The medicament according to claim 24, wherein the HPK1-dependent disorder is cancer.

26. The medicament according to claim 25, wherein the cancer comprises at least one cancer selected from the group consisting of colorectal cancer, melanoma, non-small cell lung cancer, ovarian cancer, breast cancer, pancreatic cancer, hematological malignancies, and renal cell carcinoma.

27. The medicament according to any one of claims 22 to 26, further comprising a chemotherapeutic agent.

28. Use of the compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof; or the pharmaceutical composition according to claim 20 or 21, for manufacturing the medicament according to any one of claims 22 to 27.

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