Quinazolinyl compounds and methods of use

Abstract

Provided herein are compounds and pharmaceutically acceptable salts thereof that are useful for treating the IRE1-associated diseases and disorders described herein. TIFF2022536655000110.tif4987(A)

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to International Patent Application No. PCT / CN2019 / 090714, filed June 11, 2019, the entire contents of which are incorporated herein by reference for all purposes.

[0002] Provided herein are compounds or pharmaceutically acceptable salts thereof, as well as methods of using such compounds to treat cancer. [Background technology]

[0003] The kinase / endoribonuclease inositol-requiring enzyme 1 (IRE1α) is one of the key sensors of misfolded protein accumulation in the endoplasmic reticulum (ER) and triggers the unfolded protein response (UPR). Inhibitors that bind to the ATP-binding site of the kinase portion of IRE1α and block its endoribonuclease activity are potential therapeutic targets for a variety of diseases, including cancer. IRE1α is a transmembrane bifunctional protein with a luminal domain that binds to misfolded proteins, a transmembrane segment, and a cytoplasmic portion consisting of a kinase portion and a tandem endoribonuclease domain. Structure-activity relationship (SAR) studies in a recombinant IRE1α kinase screen yielded compounds that were selective and potent against the endoribonuclease activity of recombinant IRE1α as well as cellular IRE1α. Contrary to previous reports, IRE1α activity mediates certain cytoprotective and pro-survival functions of the UPR, increasing survival and proliferation in certain tumor cell lines and potentially serving as a therapeutic target for specific small molecule inhibitors that block malignant tumor growth (Harrington, P.E. et al. (2015) ACS Med. Chem. Lett. 6:68-72). Furthermore, inhibitors of IRE1α may be therapeutically useful for other types of diseases besides cancer, including certain autoimmune, neurodegenerative, fibrotic, and metabolic disorders (Wang, M., and Kaufman, R.J. (2016) Nature 529:326-335).

[0004] Homeostatic regulation of protein folding in the endoplasmic reticulum (ER) is under the control of three key intracellular signaling pathways: IRE1α, PERK, and ATF6, which together orchestrate the unfolded protein response (UPR) (Schroder, et al. (2005) Mutat Res-Fund Mol Mech Metagenesis 569:29-63). Increased demand for protein folding within the ER or certain cellular insults or stresses can lead to the accumulation of unfolded proteins within the ER, a condition known as ER stress. Cells respond to ER stress by activating the UPR to help regulate or maintain their high-fitness protein synthesis capacity (Walter, P. and Ron, D. (2011) Science 334:1081-1086). IRE1α is the most evolutionarily conserved of the three branches of the UPR. Importantly, the UPR determines cell survival or death depending on the severity and duration of ER stress, with the end result being either cell survival and recovery or programmed cell death (apoptosis) (Sovolyova et al., (2014) Biol Chem 395:1-13). All three pathways of the UPR respond in concert to the accumulation of unfolded proteins. Several studies have demonstrated crosstalk between different pathways (Yamamoto et al., J. Biochem. (2004) 136:343-350; Arai et al., FEBS Letts. (2006) 580:184-190; Adachi et al., Cell Struct. Func. (2008) 33:75-89). Activation of the ER stress and UPR can be triggered by mechanical injury, inflammation, genetic mutations, infection, oxidative stress, metabolic stress, and other types of cellular stress associated with malignancy.ER stress has also been implicated in chronic liver disease (Galligan et al, J. Toxicol. (2012) Vol. 2012, Article ID 207594, 12 pages; Shin et al, Cell Reports (2013) 5:654-665; Ji, Int. J. Hepatol. (2014) Vol. 2014, Article ID 513787, 11 pages), pulmonary fibrosis (Baek et al, Am. J. Resp. Cell Mol. Bio. (2012) 46:731-739; Tanjore et al, Biochim Biophys Acta (2012, online), (2013) 1832:940-947), and renal fibrosis (Chiang et al, Mol. Med. (2011) 17:1295-1305), cardiovascular disease (Spitler & Webb, Hypertension (2014) 63:e40-e45), and diseases that result in fibrotic remodeling of the visceral organs, such as inflammatory bowel disease (Bogaert et al, PLoS One (2011) 6(10) e25589; Cao et al, Gastroent (2013) 144:989-1000).

[0005] Activation of the UPR has been shown to be a critical survival pathway for tumors of secretory cell origin, such as multiple myeloma, which have a very high protein synthesis burden. Therefore, attempts to disrupt the UPR by inhibiting IRE1α endoribonuclease cleavage and XBP1 activation are an active area of ​​cancer research. As a specific IRE1α RNase product, XBP1 is a direct indicator of functional IRE1 inhibition. Potent and selective IRE1α inhibitors would serve as important tools to test the hypothesis that tumor cells can be induced into apoptosis without full UPR activation. IRE1α inhibitors and activators have been reported (Harrington, PE et al., (2015) "ACS Med. Chem. Lett., Vol. 6, pp. 68-72; Volkmann, K. et al., (2011) J. Biol. Chem., Vol. 286, pp. 12743-12755; Cross, B. C. S. et al., (2012) Proc. Natl. Acad. Sci. USA, Vol. 109, pp. E869-E878; Wang, L. et al., (201 2) Nat. Chem. Biol. Vol. 8, pp. 982-989; Ghosh, R. et al. (2014) Cell Vol. 158, pp. 534-548; Ranatunga, S. et al. (2014) J. Med. Chem. Vol. 57, pp. 4289-4301; U.S. Patent Application No. US9382230; U.S. Patent Application No. US8815885). Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there remains a need for potent and selective inhibitors with suitable pharmacological properties for the treatment of IRE1-associated diseases or disorders in patients.

[0007] Solutions to the above problems and other problems in the art are provided herein. [Means for solving the problem]

[0008] Disclosed herein are compounds of Formula (A), as described herein, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, including pharmaceutical compositions thereof, that are inhibitors of IRE1α. The compounds described herein are useful for treating diseases and disorders mediated by IRE1α.

[0009] In one aspect, provided herein are compounds having the formula (A) described herein.

[0010] In another aspect, provided herein are compounds having formula (B) or (C) as described herein.

[0011] In another aspect, provided herein are compounds having formula (D), (E), or (F) as described herein.

[0012] In another aspect, provided herein are compounds having formula (G), (H), or (J) as described herein.

[0013] In one embodiment, the compound is a compound of Table 1 or Table 2 described herein or a pharmaceutically acceptable salt thereof.

[0014] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof.

[0015] In another aspect, provided herein is a method for treating an IRE1-associated disease or disorder, comprising administering an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a subject having an IRE1-associated disease or disorder.

[0016] In another aspect, provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of an IRE1-associated disease or disorder.

[0017] In yet another aspect, provided herein is a compound, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method for the treatment of an IRE1-associated disease or disorder.

[0018] In yet another aspect, the present specification provides a method for inhibiting or killing cancer cells that express Ire1, the method comprising contacting cancer cells that express Ire1 with a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0019] In yet another aspect, provided herein is a method for modulating Ire1 activity, the method comprising contacting Ire1 with a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0020] In another embodiment, there is provided a kit for treating a condition mediated by IRE1, comprising: a) a pharmaceutical composition described herein; and b) Instructions for use Provided herein is a kit comprising:

[0021] The present embodiments can be more fully understood by reference to the detailed description and examples that are intended to illustrate non-limiting embodiments. DETAILED DESCRIPTION OF THE INVENTION

[0022] 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 to which this invention belongs. See, for example, Singleton et al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY 2nd ed., J. Wiley & Sons (New York, NY 1994); Sambrook et al., MOLECULAR CLONING, A LABORATORY MANUAL, Cold Springs Harbor Press (Cold Springs Harbor, NY 1989). In carrying out the present invention, any methods, devices, and materials similar or equivalent to those described herein can be used.

[0023] The following definitions are provided to facilitate understanding of certain terms used frequently herein and are not meant to limit the scope of the present disclosure. All references mentioned herein are incorporated by reference in their entirety.

[0024] As used herein, unless otherwise specified, the terms "about" and "approximately," when referring to a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. The equivalent dose, amount, or weight percent may be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percent.

[0025] As used herein, "alkyl" refers to an alkyl group having a specified number of carbon atoms (i.e., C 1~10 "C" refers to a saturated, linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms ("C 1~20alkyl"), those having 1 to 8 carbon atoms ("C 1~8 alkyl"), those having 1 to 6 carbon atoms ("C 1~6 alkyl"), those with 2 to 6 carbon atoms ("C 2~6 alkyl"), those with 1 to 4 carbon atoms ("C 1~4 alkyl") or those having 1 to 3 carbon atoms ("C 1~3 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0026] As used herein, "cycloalkyl" refers to a group having a specified number of carbon atoms (i.e., C 3~10 "C" refers to a non-aromatic, saturated or unsaturated, cyclic monovalent hydrocarbon structure of 3 to 10 carbon atoms. Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl, but excludes aryl groups. Cycloalkyls containing more than one ring can be fused, spiro, or bridged, or combinations thereof. Particular cycloalkyls have 3 to 7 ring carbon atoms ("C"). 3~7 cycloalkyl) or having 3 to 6 carbon atoms ("C 3~6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.

[0027] As used herein, "heterocycloalkyl" refers to a cycloalkyl, as defined herein, in which one or more of the ring carbon atoms has been replaced by a heteroatom such as, for example, nitrogen, oxygen, or sulfur. Representative examples of heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl, pyrrolidinyl, imidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, dioxolyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, piperidyl, piperidinyl, piperazinyl, piperazin-2-onyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl, dithianyl, pyranyl, dihydrodithiinyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, and tetrahydropyrimidin-2(1H)-one groups.

[0028] As used herein, "aryl" refers to an unsaturated aromatic carbocyclic group having a single ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl), where the fused rings may or may not be aromatic. Particular aryl groups are those having 6 to 14 cyclic (i.e., ring) carbon atoms ("C 6~14 Aryl). Preferred aryl groups include those having 5 to 6 ring carbons. Aryl groups having two or more rings, where 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, aryl groups having two or more rings, where at least one ring is non-aromatic, are attached to the parent structure at an aromatic ring position.

[0029] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 annular (i.e., ring) carbon atoms and at least one annular heteroatom, including, but not limited to, a heteroatom such as nitrogen, phosphorus, oxygen, and sulfur. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl), where the fused rings may or may not be aromatic. Specific heteroaryl groups are 5- to 14-membered rings having 1 to 12 annular (i.e., ring) carbon atoms and 1 to 6 annular (i.e., ring) heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 5- to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; and 5-, 6-, or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variation, heteroaryls include monocyclic aromatic 5-, 6-, or 7-membered rings having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heteroaryls include polycyclic aromatic rings having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. Additionally, heteroaryls described herein can include rings having 5 or 6 members. In preferred embodiments herein, the heteroatoms are independently selected from nitrogen and oxygen. Heteroaryl groups 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, heteroaryl groups having two or more rings, in which at least one ring is non-aromatic, are attached to the parent structure at an aromatic ring position.

[0030] "Halo" or "halogen" refers to fluoro, chloro, bromo, and / or iodo. When a residue is substituted with two or more halogens, it can be referred to using a prefix corresponding to the number of halogen moieties attached, for example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which can be, but are not necessarily, the same halo. Thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl.

[0031] An alkyl group in which one or more hydrogen atoms are replaced by a halo group is called a "haloalkyl," e.g., "C 1~6 An exemplary haloalkyl group is trifluoroalkyl (-CF3). Similarly, "haloalkoxy" refers to an alkoxy group in which a halogen atom replaces one or more hydrogen atoms in the hydrocarbon comprising the alkyl portion of the alkoxy group. An exemplary haloalkoxy group is trifluoromethoxy (-OCF3).

[0032] "Carbonyl" refers to the group C=O.

[0033] "Oxo" refers to the moiety =O.

[0034] The term "chiral" refers to molecules that possess the property of being non-superimposable on their mirror image partners, while the term "achiral" refers to molecules that are superimposable on their mirror image partners.

[0035] The term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0036] "Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high-resolution analytical procedures such as electrophoresis and chromatography.

[0037] "Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

[0038] The definitions and conventions of stereochemistry used herein generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994. The compounds described herein, or pharmaceutically acceptable salts thereof, may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. All stereoisomeric forms of the compounds described herein, or pharmaceutically acceptable salts thereof, including, but not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to be included herein. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning the compound is levorotatory. Compounds with the prefix (+) or D are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers are also referred to as enantiomers, and mixtures of such isomers are sometimes called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur when there is no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species that lacks optical activity. Enantiomers can be separated from racemic mixtures by chiral separation techniques such as supercritical fluid chromatography (SFC).The assignment of configuration at the chiral centers of separated stereoisomers may be tentative before the stereochemistry is definitively established, e.g., from X-ray crystallographic data, and may be shown in the structures of Table 1 for illustrative purposes.

[0039] The term "tautomer" or "tautomeric form" refers to structural isomers with different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0040] "Solvate" refers to an association or complex of one or more solvent molecules with a compound described herein or a pharmaceutically acceptable salt thereof. Examples of solvents that form solvates include, but are not limited to, water (i.e., a "hydrate"), isopropanol, ethanol, methanol, DMSO, ethyl acetate (EtOAc), acetic acid (AcOH), and ethanolamine.

[0041] The term "administering" refers to the act of delivering a compound described herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition to a patient by a route such as, for example, oral, mucosal, topical, suppository, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal, or subcutaneous administration. Parenteral administration includes intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intraperitoneal, and intracranial administration. Administration generally occurs after the onset of a cancer or symptom thereof as described herein. The term includes administering a chemotherapeutic agent or treatment as described herein.

[0042] The term "co-administration" refers to the administration of two or more agents (e.g., a pharmaceutical composition comprising a compound described herein, a pharmaceutically acceptable salt thereof, or another active agent, such as a chemotherapeutic agent). The timing of co-administration depends in part on the composition being administered and can include simultaneous, immediate prior to, or immediate subsequent administration of one or more additional therapies, such as cancer treatments such as chemotherapy, hormonal therapy, radiation therapy, or immunotherapy. The compounds described herein, their pharmaceutically acceptable salts, and pharmaceutical compositions may be administered alone or co-administered to a patient. Co-administration is meant to include simultaneous or sequential administration of compounds individually or in combination (multiple compounds or agents). Thus, preparations can also be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compounds described herein can be used in combination with each other, with other active agents known to be useful in treating cancers described herein or known to be associated with cells expressing a particular kinase described herein, or with adjuvants that are not effective alone but may contribute to the effectiveness of the active agent.

[0043] "1L therapy" refers to the first-line therapy administered to treatment-naive cancer patients. Similarly, 2L, 3L, etc. refer to subsequent treatments administered to patients.

[0044] As used herein, unless otherwise specified, the terms "about" and "approximately," when referring to a dose, amount, or weight percent of a component of a composition or dosage form, mean a dose, amount, or weight percent that would be recognized by one of ordinary skill in the art to provide an equivalent pharmacological effect to that obtained from the specified dose, amount, or weight percent. The equivalent dose, amount, or weight percent may be within 30%, 20%, 15%, 10%, 5%, 1%, or less of the specified dose, amount, or weight percent.

[0045] "Metastatic" refers to cancer that has spread beyond the local tissue and regional lymph nodes. "Locally advanced" refers to cancer that has spread only from the immediate tissue to surrounding tissues.

[0046] The term "clinical response" refers to, among other things, inhibition of disease progression, inhibition of tumor growth, reduction in primary tumor size, alleviation of tumor-related symptoms, inhibition of tumor-secreted factors (including tumor-secreted hormones such as those responsible for carcinoid syndrome), delay in the appearance of primary or secondary tumors, delay in the development of primary or secondary tumors, delay or reduction in the onset of primary or secondary tumors, delay or reduction in the severity of secondary effects of the disease, cessation of tumor growth and tumor regression, increase in time to progression (TTP), increase in progression-free survival (PFS), and increase in overall survival (OS). As used herein, OS refers to the time from the start of treatment to death from any cause. Generally, clinical response refers to primary or secondary measures of efficacy known and understood in the art. The treatments and clinical responses described herein can be assessed using international standards for a given condition.

[0047] "Overall survival" or "OS" refers to the time from enrollment to death from any cause.

[0048] "Objective response rate" or "OPR" refers to the proportion of patients who achieve a confirmed complete or partial response on two consecutive occasions, four weeks apart, as assessed by the investigator according to RECIST v1.1.

[0049] "Time to progression" or "TTP" refers to the time from randomization to objective tumor progression.

[0050] "Duration of response" or "DOR" refers to the time from the first occurrence of a documented objective response to the date of investigator-determined disease progression per RECIST v1.1, or death from any cause, whichever occurs first.

[0051] "Progression-free survival" or "PFS" refers to the time from enrollment to the occurrence of first documented disease progression or death from any cause, whichever occurs first, as determined by the investigator using RECIST v1.1.

[0052] "Clinical benefit rate" or "CBR" refers to the proportion of patients who have stable disease for at least 24 weeks or a confirmed complete or partial response as determined by the investigator according to RECIST v1.1.

[0053] "Complete response" or "CR" refers to the disappearance of all target and non-target lesions and, where applicable, normalization of tumor marker levels.

[0054] "Partial response" or "non-CR / non-PD" refers to the persistence of one or more non-target lesions and / or maintenance of tumor marker levels above normal limits (if applicable). PR may also refer to a 30% or greater decrease in the sum of the diameters of target lesions in the absence of CR, new lesions, and overt progression in non-target lesions.

[0055] "Progressive disease" or "PD" refers to a 20% or greater increase in the sum of the diameters of target lesions, overt progression in non-target lesions, and / or the appearance of new lesions.

[0056] "Stable disease" or "SD" refers to neither sufficient shrinkage to qualify as CR or PR nor sufficient increase in tumor growth to qualify as PD.

[0057] The term "treatment" refers to a clinical intervention designed to alter the natural course of the patient or cells being treated during clinical pathology. Desirable effects of treatment include reducing the rate of disease progression, ameliorating or alleviating the disease state, and ameliorating or improving prognosis. For example, a patient is "treated" if one or more symptoms associated with a disease described herein are reduced or eliminated, including, but not limited to, reducing (or destroying) the proliferation of cancerous cells, alleviating symptoms caused by the disease, improving the quality of life of those suffering from the disease, reducing the dose of other medications required to treat the disease, and / or extending the patient's survival. In certain embodiments, treatment can be indicated by a measured clinical outcome (e.g., an increase in OS, ORR, TTP, DOR, PFS, CBR, PR, CR, or SD).

[0058] The term "delaying progression" of a disease refers to postponing, preventing, delaying, slowing, stabilizing, and / or postponing the onset of a disease as described herein. This delay can be of varying lengths of time, depending on the cancer being treated and / or the medical history of the patient. As will be apparent to one of skill in the art, a sufficient or significant delay can effectively encompass prevention, in that the patient does not develop cancer.

[0059] An "effective amount" is at least the minimum amount required to achieve a measurable improvement or prevention of a disease described herein. An effective amount herein may vary depending on factors such as the patient's disease state, age, sex, and weight, as well as the ability of the agent to elicit a desired response in the patient. An effective amount is also one in which the beneficial effects of the treatment outweigh any toxic or adverse effects of the treatment. Beneficial or desired results include eliminating or reducing the risk, reducing the severity, delaying the onset of a disease (including biochemical, histological, and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes manifesting during the development of the disease), alleviating one or more symptoms resulting from the disease, improving the quality of life of those suffering from the disease, reducing the dose of other agents required to treat the disease, enhancing the effect of another agent by targeting, etc., slowing the progression of the disease, and / or prolonging survival, etc. In some embodiments, an effective amount of a drug may have the effect of reducing the number of cancer cells, reducing tumor size, inhibiting (i.e., slowing or stopping) cancer cell invasion into peripheral organs, inhibiting (i.e., slowing or stopping) tumor metastasis, inhibiting (i.e., slowing or stopping) tumor growth, and / or alleviating one or more symptoms associated with a disorder. An effective amount may be administered in a single dose or multiple doses. An effective amount of a drug, compound, pharmaceutical composition, or combination therapy described herein may be an amount sufficient to directly or indirectly achieve therapeutic treatment. As clinically understood, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition or in a combination therapy. An "effective amount" may be considered in the context of administering 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 result is obtained or achieved.

[0060] An "administration period" or "cycle" refers to a period that includes administration of a compound described herein or a pharmaceutically acceptable salt thereof, as well as any period that does not include administration of a compound described herein or a pharmaceutically acceptable salt thereof. For example, a cycle may be 28 days in total, including 21 days of administration and a 7-day rest period. A "rest period" refers to a period during which a compound described herein or a pharmaceutically acceptable salt thereof is not administered. The rest periods provided herein may, in some cases, include administration of another agent (e.g., an anticancer agent described herein) that is not a compound described herein or a pharmaceutically acceptable salt thereof. In such cases, administration of the other agent during the rest period should not interfere with or impair the administration of a compound described herein or a pharmaceutically acceptable salt thereof.

[0061] A "dosing regimen" refers to a period of administration of a compound described herein, or a pharmaceutically acceptable salt thereof, that comprises one or more cycles, each cycle may comprise administration of a compound described herein, or a pharmaceutically acceptable salt thereof, at a different time or in a different amount.

[0062] "QD" refers to once-daily administration of a compound described herein or a pharmaceutically acceptable salt thereof.

[0063] "BID," "TID," and "QID" refer to administration of a compound described herein, or a pharmaceutically acceptable salt thereof, two, three, and four times daily.

[0064] "QW" refers to once-weekly administration of a compound described herein or a pharmaceutically acceptable salt thereof.

[0065] "Q2W," "Q3W," and "Q4W" refer to administration of a compound described herein, or a pharmaceutically acceptable salt thereof, once every 2, 3, and 4 weeks, respectively.

[0066] The term "cancer" refers to or describes the physiological condition in mammals that is typically characterized by uncontrolled cell growth. A "tumor" contains one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia, or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer, e.g., small cell lung cancer, non-small cell lung cancer ("non-small cell lung cancer": NSCLC), small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, or head and neck cancer.

[0067] Hematological malignancies (British spelling "Haematological" malignancies) are types of cancer that affect the blood, bone marrow, and lymph nodes. Because the three are closely related through the immune system, diseases of one of the three often affect the others. Lymphoma is a disease of the lymph nodes but often spreads to the bone marrow, affecting the blood. Hematological malignancies are malignant neoplasms (i.e., cancers) that are generally treated by hematology and / or oncology specialists. Hematological malignancies originate from one of two major blood cell lineages: myeloid and lymphoid. Lymphoma, lymphocytic leukemia, and myeloma are lymphoid in origin, while acute and chronic myeloid leukemia, myelodysplastic syndromes, and myeloproliferative disorders are myeloid in origin. Exemplary leukemias include acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMOL), and small lymphocytic lymphoma (SLL). Exemplary lymphomas include Hodgkin's lymphoma (all four subtypes) and non-Hodgkin's lymphomas (NHL, all subtypes).

[0068] "IRE1-associated disease" and the like refers to a disease described herein (e.g., a cancer described herein) having a symptom described herein or in need of treatment that is associated, resulting from, a function of, or otherwise correlated, in whole or in part, with IRE1 activity described herein.

[0069] An "anticancer agent" is a compound useful in the treatment of cancer, regardless of mechanism of action. Classes of anticancer agents include, but are not limited to, alkylating agents, antimetabolites, antihormonal therapies, endocrine therapies, immunomodulators, spindle poison plant alkaloids, cytotoxic / antitumor antibiotics, topoisomerase inhibitors, antibodies, photosensitizers, and kinase inhibitors. Anticancer agents include compounds used in targeted therapy and conventional chemotherapy.

[0070] Exemplary anti-cancer agents include proteasome inhibitors such as bortezomib (VELCADE), carfilzomib (KYPROLIS), and ixazomib (NINLARO). Other examples include immunomodulatory agents such as lenalidomide (REVLIMID) and pomalidomide (POMALYST).

[0071] Other exemplary anti-cancer agents include inhibitors of B-cell receptor targets, such as BTK, Bcl-2, and JAK inhibitors, including, for example, venetoclax (VENCLEXTA) and ibrutinib (IMBRUVICA).

[0072] Additional anticancer drugs include, for example, abemaciclib (VERZENIO); abiraterone (ZYTIGA, YONSA); aclarubicin; acivicin; acodazole; acronine; actinomycin; acylfulvene; adecypenol; adzelesin; adriamycin; aldesleukin; altretamine; ambamustine; ambomycin; amethantrone; amidox; amifostine; aminoglutethimide; aminolevulinic acid; amrubicin; amsacrine; anagrelide ;Anastrozole;Andrographolide;Antarelix;Anthramycin;Aphidicolin glycinate;Apurinic acid;ARRY-300;Arabinoside;Asperlin;Asulacrine;Atamestane;Atrimustine;Azasetron;Azatoxin;Azatyrosine;Azacitidine;AZD6244;AZD8330;Azetepa;Azotomycin;Balanol;Batimastat;Bendamustine;Benzochlorin;Benzodopa;Benzoylsulfate Taurosporine; beta-alethine; betaclamycin B; betulinic acid; bicalutamide; binimetinib; bisantrene; bisaziridinylspermine; visnafide; bistratene; bleomycin; busulfan; bizelesin; breflate; bortezomib; brequinar; bropirimine; budotitane; buthionine; bryostatin; cactinomycin; calcipotriol; calcipotriol steroid; calphostin C; camptothecin; capecitabine (XELODA); caracemide; carbetimer; carboplatin; carboquin; carmustine; carubicin; carzelesin; castanospermine; celecoxib; cetrorelix; cetuximab (ERBITUX); chloroquinoxaline; cicaprost; chlorambucil; chlorofusin; cisplatin; clodribine; clomiphene; clotrimazole; crisnatol; cypemycin; cyclophosphamide; cytarabine; cytostatin; dacarbazine; dactinomycin;Daratumumab; Daunorubicin; Decarbazine; Dacliximab; Dasatinib; Decitabine; Deslorelin; Dexamethasone; Dexifosfamide; Dexrazoxane; Dexverapamil; Dexormaplatin; Dezaguanine; Diazicon; Dihydrotaxol; Docosanol; Dolasetron; Docetaxel; Doxorubicin; Doxifluridine; Droloxifene; Dromostanolone; Dronabinol; Duazomycin; Ebselen; Ecomustine; Edelfosine; Edrecolomab; Edatrexate; Eflor Nitin; Elemene; Emitefur; Elsamitrucin; Enloplatin; Enpromate; Epipropizine; Epirubicin; Epristeride; Elbrozole; Erlotinib (TARCEVA); Esorubicin; Estramustine; Etanidazole; Etoposide; Etoprine; Exemestane; Fadrozole; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Flezelastine; Fluasterone; Floxuridine; Fludarabine; Fludarabine; Fluorodaunorubicin; Forfenimex; Formestane ; Fluorouracil; Floxuridine; Flurocitabine; Foskidone; Fostriecin; Fotemustine; Fulvestrant (FASLODEX); Gadolinium; Gallium; Gallocitabine; Ganirelix; Gemcitabine; Geldanamycin; Gefitinib; Gossypol; Hydroxyurea; Hepsulfam; Heregulin; Ibandronate; Ibrutinib; Idarubicin; Idelalisib (ZYDELIG), Ifosfamide; Canfosfamide; Ilmofosine; Iproplatin; Idoxifene; Idramanton (Idra mantone); ilmofosine; ilomastat; imatinib mesylate (GLEEVEC); imiquimod; iobenguane; iododoxorubicin; ipomeanol; irinotecan; itasetron; iimofosine; lanreotide; lapatinib (TYKERB); leinamycin; lenograstim; lentinan; leptolstatin; letrozole; leuprorelin; levamisole; liarozole; lobaplatin; lombricine; lometrexol; lonidamine;Lonafarnib (SARASAR); losoxantrone; lovastatin; loxoribine; raltotecan; lapatinib; leucovorin; lometrexol; lomustine; maytansine; marimastat; massoprocol; maspin; menogaril; melbarone; meterelin; methioninase; metoclopramide; mifepristone; miltefosine; millimostim; mitoguazone; mitolactol; mitonafide; mitonafide; mitoxantrone; mofalotene; molgramostim; mopidamol; maytansine; megestrol acetate ;Melengestrol acetate;Melphalan;Mercaptopurine;Methotrexate;Methotrexate sodium;Metoprine;Meturedepa;Mitinmitomycin;Mitosper;Mitostane;Mitoxantrone;Mycophenolic acid;Nafarelin;Nagrestip;Napavin;Nedaplatin;Nemorubicin;Neridronic acid;Nilutamide;Nisamycin;Oblimesen;Octreotide;Oxenon (okicenone); onapristone; ondansetron; ormaplatin; oxisulan; oxaloplatin; osaterone; oxaliplatin; oxaunomycin; palauamine; palbociclib (IBRANCE); panitumumab (VECTIBIX); panomifen; pegaspargase; picibanil; pirarubicin; piritrexim; prednisone; prednisolone, paclitaxel; nab-paclitaxel (ABRAXANE); prednimustine; procarbazine; puromycin; raltitrexate Do; Ramosetron; Rapamycin (RAPAMUNE); Rhizoxin; Ribociclib (KISQALI), Rituximab; Rogletimide; Rohitukine; Romurtide; Roquinimex; Romidepsin; Safingol; Saintopin; Sargramostim; Semustine; Sizofiran; Sobuzoxane; Sorafenib (NEXAVAR); Sunitinib; Spiromustine; Squalamine; Suradista; Suramin; Swainsonine; Spiroplatin; Streptonigrin; Streptozocin;Surofenur; Talimustine; Tamoxifen; Tauromustine; Tazarotene; Tellurapyrylium; Temoporfin; Temozolomide; Teniposide; Tetrachlorodecaoxide; Tetrazomine; Thrombopoietin; Thymalfasin; Thymotrinan; Tirapazamine; Toremifene; Tretinoin; Trimetrexate; Triptorelin; Tropisetron; Tallysomycin; Taxotere; Teloxylon; Testolactone; Thiamiprine; Thiotepa; Tirapazamine; Toremifene; Trastuzumab; Trastuzumab emtansine; Trestron acetate; Phosphorus These include triciribine acid; trimetrexate; uracil mustard; vandetanib (CAPRELSA); variolin B; velaresol; veramine; verteporfin; vemurafenib; vinorelbine; vinxaltine; vitaxin; vinblastine; vincristine; vindesine; vinepidine; vinglicinate; vinleurosine; vinorelbine; vinrocidine; vinzolidine; vorozole; wortmannin; zanoteron; zeniplatin; zilascorb; zinostatin stimalamer; zinostatin; and zorubicin.

[0073] In some embodiments, anti-cancer agents include, for example, idelalisib (ZYDELIG), docetaxel, fluorouracil, gemcitabine (GEMZAR), cisplatin, cis-diaminetetraacetic acid, carboplatin, paclitaxel, nab-paclitaxel, trastuzumab (HERCEPTIN), temozolomide, tamoxifen, 4-hydroxytamoxifen, and doxorubicin.

[0074] The definition of anti-cancer agent also includes: (i) antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and toremifine citrate; (ii) brilanestrand, GDC-0927, GDC-9545, AZ9496, AZ9833, GNE-274, and fulvest. (iii) aromatase inhibitors such as 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestany, fadrozole, vorozole, letrozole, and anastrozole; (iv) antiandrogens such as apalutamide, abiraterone, enzalutamide, flutamide, nilutamide, bicalutamide, leuprolide, and goserelin.

[0075] The definition of anti-cancer agents further includes: (iv) MEK inhibitors such as cobimetinib; (v) lipid kinase inhibitors such as taselisib; (vi) antisense oligonucleotides such as oblimersen; (vii) ribozymes such as VEGF expression inhibitors such as angiozymes; (viii) gene therapy vaccines, e.g., vaccines such as allogeneic steroids (ALLOVECTIN), leucodenin (LEUVECTIN), and vaxid (VAXID); (ix) topoisomerase 1 inhibitors such as lurtotecan; abarelix rmRH; and (x) anti-angiogenic agents such as bevacizumab.

[0076] In some embodiments herein, the anti-cancer agent is a therapeutic antibody, e.g., atezolizumab, nivolumab, daratumumab, pembrolizumab, alemtuzumab, bevacizumab; cetuximab; panitumumab, rituximab, trastuzumab, pertuzumab, trastuzumab, trastuzumab, emtansine, or tositumomab.

[0077] A "metabolite" is a product produced by metabolism in the body of a particular compound or salt thereof. Metabolites of a compound can be identified using routine techniques, and their activity can be determined using tests such as those described herein. Such products can result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, further provided herein are metabolic products of the compounds described herein, or pharmaceutically acceptable salts thereof, including compounds produced by a process comprising contacting a compound described herein, or a pharmaceutically acceptable salt thereof, with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0078] The term "package insert" is used to refer to instructions customarily included in commercial packaging of therapeutic products that contain information about the indications, uses, dosage, administration, contraindications, and / or warnings regarding the use of such therapeutic product.

[0079] The term "pharmaceutically acceptable salt" means a salt that is not biologically or otherwise undesirable. Pharmaceutically acceptable salts include both acid and base addition salts. The phrase "pharmaceutically acceptable" indicates that a substance or composition must be chemically and / or toxicologically compatible with the other ingredients comprising the formulation and / or the mammal being treated therewith.

[0080] The term "pharmaceutically acceptable acid addition salt" means a pharmaceutically acceptable salt such as formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, and the like, and an organic acid selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic, and sulfonic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0081] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, and polyamine resins.

[0082] "EC 50 The term "half-maximal effective concentration" refers to the plasma concentration of a particular compound required to obtain 50% of the maximum of a particular effect in vivo.

[0083] The term "Ki" is an inhibition constant and indicates the absolute binding affinity of a particular inhibitor to a receptor. Ki values ​​are measured using competitive binding assays and are equal to the concentration at which a particular inhibitor occupies 50% of the receptor in the absence of a competing ligand (e.g., a radioligand). Ki values ​​can be logarithmically converted to pKi values ​​(-log Ki), which indicate exponentially greater potency with higher values.

[0084] "I C 50 The term "half maximal inhibitory concentration" refers to the concentration of a particular compound required to obtain 50% inhibition of a biological process in vitro. 50 Values ​​are logarithmically expressed as pIC 50 Value (-log IC 50), where higher values ​​indicate exponentially greater potency. 50 The IC values ​​are not absolute but depend on the experimental conditions, e.g., the concentrations used, and can be converted to absolute inhibition constants (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973) 22, 3099). 70 ,I C 90 Other percent inhibition parameters may also be calculated, such as:

[0085] Graded adverse events refer to the severity grading scale established by the NCI CTCAE. In one embodiment, adverse events are graded according to the following table: [Table 1]

[0086] Any formula or structure given herein, including those described herein, is intended to represent unlabeled forms of the compound as well as isotopically labeled forms. Isotopically labeled compounds have the structure shown by the formula described herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds described herein or their pharmaceutically acceptable salts include, but are not limited to: 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 and isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as I. Various isotopically labeled compounds described herein or pharmaceutically acceptable salts thereof, e.g., 3 H and 14and those incorporating a radioactive isotope such as 18C. Such isotopically labeled compounds may be useful in metabolic studies, kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radioactive treatment of patients. The deuterium-labeled or substituted therapeutic compounds or pharmaceutically acceptable salts thereof described herein may have improved DMPK (drug metabolism and pharmacokinetics) properties with respect to distribution, metabolism, and excretion (ADME). Substitution with heavier isotopes, such as deuterium, may result in greater metabolic stability, resulting in certain therapeutic advantages, such as prolonged in vivo half-life or reduced dosage requirements. 18F-labeled compounds are useful for PET or SPECT studies. Isotopically labeled compounds described herein, or pharmaceutically acceptable salts thereof, can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents by carrying out the procedures disclosed in the schemes or examples and preparations described below. Additionally, heavier isotopes, particularly deuterium (i.e., 2 Substitution with H or D can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, or improved therapeutic index. In this context, it is understood that deuterium is considered a substituent in the compounds of formula (A). The concentration of such heavy isotopes, particularly deuterium, can be defined in terms of the isotopic enrichment factor. In the compounds described herein or pharmaceutically acceptable salts thereof, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position is understood to have hydrogen at its natural abundance isotopic composition. Thus, in the compounds described herein or pharmaceutically acceptable salts thereof, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0087] compound The following formula: [ka] (A) [In the formula, Ring Q is R E Substituted or unsubstituted C 5~7 aryl or R containing at least one nitrogen heteroatom E substituted or unsubstituted 5- to 7-membered heteroaryl; L A is -NHSO2-, -SO2NH-, -NH-, -NHC(O)-, or -C(O)NH-; R A is R G substituted or unsubstituted bicyclic 7-10 membered spiroheterocycloalkyl; [ka] and; R B and R C are independently hydrogen or R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, or R N substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or R B and R C together with the nitrogen atom to which they are attached, form R N Forming a substituted or unsubstituted 4- to 7-membered heterocycloalkyl; R D is hydrogen, halogen, -CN, -OR I , -S(O)2R I , -NR J R K , R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 1~6 Haloalkyl, R N Substituted or unsubstituted C3~7 Cycloalkyl, R N substituted or unsubstituted 3- to 7-membered heterocycloalkyl, R N Substituted or unsubstituted C 5~7 Aryl, or R N substituted or unsubstituted 5- to 7-membered heteroaryl; Each R E is hydrogen, halogen, -OR I , -CN, -S(O)2R I , R M Substituted or unsubstituted C 1~6 Alkyl, R M Substituted or unsubstituted C 1~6 Haloalkyl, or R M Substituted or unsubstituted C 3~7 is cycloalkyl; n is 0, 1, 2, 3, or 4; R F is R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, R N Substituted or unsubstituted benzyl, R N Substituted or unsubstituted 3- to 7-membered heterocycloalkyl or R containing at least one N atom N substituted or unsubstituted 5- to 7-membered heteroaryl; Each R G are independently halogen, -OR I , R M Substituted or unsubstituted C 1~6 Alkyl, or R M Substituted or unsubstituted C 1~6 is haloalkyl; t is 0, 1, 2, 3, 4, 5, or 6; Each R H are independently halogen, C 1~3 Alkyl, C 1~3 haloalkyl, or cyclopropyl; j is 0, 1, or 2; Each R I , R J , and R K are independently hydrogen, RM Substituted or unsubstituted C 1~6 Alkyl, R M Substituted or unsubstituted C 1~6 Haloalkyl, R M Substituted or unsubstituted C 3~7 Cycloalkyl, R M Substituted or unsubstituted 3- to 7-membered heterocycloalkyl, R M Substituted or unsubstituted C 5~7 aryl, or R M substituted or unsubstituted 5- to 7-membered heteroaryl; Each R M are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl; Each R N are independently hydrogen, halogen, -CN, -OR R , -S(O)2R R , -NR S R T , R P Substituted or unsubstituted C 1~6 Alkyl, R P Substituted or unsubstituted C 1~6 Haloalkyl, R P Substituted or unsubstituted C 1~6 Alkoxy, R P Substituted or unsubstituted C 3~7 Cycloalkyl, R P Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R P Substituted or unsubstituted C 5~7 Aryl, or R P substituted or unsubstituted 5- to 7-membered heteroaryl; Each R R , R S , RT are independently hydrogen, R V Substituted or unsubstituted C 1~6 Alkyl, R V Substituted or unsubstituted C 1~6 Haloalkyl, R V Substituted or unsubstituted C 3~7 Cycloalkyl, or R V substituted or unsubstituted 3- to 7-membered heterocycloalkyl; Each R V are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl; Each R P are independently hydrogen, halogen, -CN, -OR W , -S(O)2R W , -NR X R Y , R U Substituted or unsubstituted C 1~6 Alkyl, R U Substituted or unsubstituted C 1~6 Haloalkyl, R U Substituted or unsubstituted C 3~7 Cycloalkyl, R U Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R U Substituted or unsubstituted C 5~7 Aryl, or R U substituted or unsubstituted 5- to 7-membered heteroaryl; Each R W , R X , and R Y are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7cycloalkyl, or unsubstituted 3- to 7-membered heterocycloalkyl, and Each R U are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0088] In certain embodiments, the compound has the formula: [ka] (A) [In the formula, Ring Q is R E Substituted or unsubstituted phenyl, or R containing at least one nitrogen heteroatom E substituted or unsubstituted 5- to 7-membered heteroaryl; L A are -NHSO2-, -SO2NH-, -NH-, -NHC(O)-, -C(O)NH-; R A is R G substituted or unsubstituted bicyclic 8-10 membered spiroheterocycloalkyl; [ka] R B and R C are independently hydrogen or R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, or R Nsubstituted or unsubstituted 3- to 7-membered heterocycloalkyl, or R B and R C together with the nitrogen atom to which they are attached, form R N Forming a substituted or unsubstituted 4- to 7-membered heterocycloalkyl; R D is hydrogen, halogen, -CN, -OR I , -S(O)2R I , -NR J R K , R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 1~6 Haloalkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, R N Substituted or unsubstituted 3- to 7-membered heterocycloalkyl, R N Substituted or unsubstituted C 5~7 Aryl, or R N substituted or unsubstituted 5- to 7-membered heteroaryl; Each R E is hydrogen, halogen, -OR I , -CN, -S(O)2R I , R M Substituted or unsubstituted C 1~6 Alkyl, R M Substituted or unsubstituted C 1~6 Haloalkyl, or R M Substituted or unsubstituted C 3~7 is cycloalkyl; n is 0, 1, 2, 3, or 4; R F is R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, R N Substituted or unsubstituted 3- to 7-membered heterocycloalkyl or R containing at least one N atom N substituted or unsubstituted 5- to 7-membered heteroaryl; Each R G are independently halogen, -OR I , RM Substituted or unsubstituted C 1~6 Alkyl, or R M Substituted or unsubstituted C 1~6 is haloalkyl; t is 0, 1, 2, 3, 4, 5, or 6; Each R H are independently halogen, C 1~3 Alkyl, C 1~3 haloalkyl, or cyclopropyl; j is 0, 1, or 2; Each R I , R J , and R K are independently hydrogen, R M Substituted or unsubstituted C 1~6 Alkyl, R M Substituted or unsubstituted C 1~6 Haloalkyl, R M Substituted or unsubstituted C 3~7 Cycloalkyl, R M substituted or unsubstituted 3- to 7-membered heterocycloalkyl, R M Substituted or unsubstituted C 5~7 aryl, or R M substituted or unsubstituted 5- to 7-membered heteroaryl; Each R M are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl; Each R N are independently hydrogen, halogen, -CN, -OR R , -S(O)2R R , -NR S R T , R P Substituted or unsubstituted C1~6 Alkyl, R P Substituted or unsubstituted C 1~6 Haloalkyl, R P Substituted or unsubstituted C 3~7 Cycloalkyl, R P Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R P Substituted or unsubstituted C 5~7 Aryl, or R P substituted or unsubstituted 5- to 7-membered heteroaryl; Each R R , R S , R T are independently hydrogen, R V Substituted or unsubstituted C 1~6 Alkyl, R V Substituted or unsubstituted C 1~6 Haloalkyl, R V Substituted or unsubstituted C 3~7 Cycloalkyl, or R V substituted or unsubstituted 3- to 7-membered heterocycloalkyl; Each R V are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl; Each R P are independently hydrogen, halogen, -CN, -OR W , -S(O)2R W , -NR X R Y , R U Substituted or unsubstituted C 1~6 Alkyl, R U Substituted or unsubstituted C 1~6 Haloalkyl, R U Substituted or unsubstituted C 3~7Cycloalkyl, R U Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R U Substituted or unsubstituted C 5~7 Aryl, or R U substituted or unsubstituted 5- to 7-membered heteroaryl; Each R W , R X , and R Y are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 cycloalkyl, or unsubstituted 3- to 7-membered heterocycloalkyl, and Each R U are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0089] In one embodiment, the compound or a pharmaceutically acceptable salt thereof has the following formula: [ka] [In the formula, R A , R D , R E , R F , ring Q, and n are as defined herein.

[0090] In one embodiment, R D is halogen, -CN, -OR I , -S(O)2R I, or -NR J R K In another embodiment, R D is R N Substituted or unsubstituted C 1~6 Alkyl, or R N Substituted or unsubstituted C 1~6 In another embodiment, R D is R N Substituted or unsubstituted C 3~7 Cycloalkyl, R N In yet another embodiment, R is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl. D is R N Substituted or unsubstituted C 5~7 Aryl, or R N It is a substituted or unsubstituted 5- to 7-membered heteroaryl.

[0091] In one embodiment, R D is halogen, -OR I , -NR J R K , R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 1~6 Haloalkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, or R N It is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl.

[0092] In another embodiment, R D -OR I or -NR J R K In another embodiment, R D HA-OR I and R I is the unsubstituted C 1~6 Alkyl or unsubstituted C 1~6 In yet another embodiment, R D HA-OR I and R I is methyl, ethyl, propyl, isopropyl, or butyl. DHA-OR I and R I is ethyl or isopropyl. In one embodiment, R D HA-OR I and R I is R M In one embodiment, R is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl. D Ha-NR J R K and R J and R K are independently hydrogen or R M Substituted or unsubstituted C 1~6 It is alkyl.

[0093] In one embodiment, R D is R N Substituted or unsubstituted C 1~6 Alkyl, or R N Substituted or unsubstituted C 1~6 In one embodiment, R D is methyl, ethyl, propyl, or isopropyl. D is hydrogen, methyl, ethyl, propyl, or isopropyl. In one preferred embodiment, R D is ethyl. In another preferred embodiment, R D is isopropyl. In yet another preferred embodiment, R D is hydrogen. In one embodiment, R D is —C(CH3)2F, —C(CH3)F2, —CH2F, —CHF2, or —CF3.

[0094] Further provided herein is, in one embodiment, R D is R N Substituted or unsubstituted C 3~7 Cycloalkyl or R N In one embodiment, R is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl. D is R N In one embodiment, R is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl. Dis an unsubstituted 3-5 membered heterocycloalkyl having one or more nitrogen or oxygen ring atoms.

[0095] In one embodiment, each R E are independently hydrogen, halogen, -OR I or -CN. In one embodiment, each R E are independently M Substituted or unsubstituted C 1~6 Alkyl, or R M Substituted or unsubstituted C 1~6 In another embodiment, each R E are independently M Substituted or unsubstituted C 3~7 In one embodiment, R E is halogen and n is 1, 2, or 3. In another embodiment, n is 0. In another embodiment, R E is F and n is 1, 2, or 3. In another embodiment, R E is F and n is 1. In yet another embodiment, R E is F and n is 2. In yet another embodiment, R E HA-OR I where R I is hydrogen or C 1~3 Unsubstituted alkyl or C 1~3 unsubstituted haloalkyl, and n is 1. E -OR I In a further embodiment, R I is hydrogen, methyl, or -OCF3.

[0096] In one embodiment, L is -NH-, -NHC(O)-, or -C(O)NH-. A is —NHSO— or —NHC(O)—. In one particular embodiment, L A is -NHSO2-. In another embodiment, L A is -NHC(O)-.

[0097] In one embodiment, R F is R NSubstituted or unsubstituted C 3~7 Cycloalkyl, R N Substituted or unsubstituted 3- to 7-membered heterocycloalkyl or R containing at least one N atom N In one preferred embodiment, R is a substituted or unsubstituted 5- to 7-membered heteroaryl. F is R N Substituted or unsubstituted C 1~6 Alkyl, or R N It is substituted or unsubstituted benzyl.

[0098] In one embodiment, R F is as defined herein, where R N is hydrogen, halogen, —OH, —CN, —CF3, —CHF2, —CH2F, —C(CH3)2F, —C(CH3)F2, methyl, ethyl, or propyl.

[0099] In one embodiment, R F is as defined herein, where R N is halogen, -CN, R P Substituted or unsubstituted C 1~6 Alkoxy, R P Substituted or unsubstituted C 1~6 Alkyl, or R P Substituted or unsubstituted C 1~6 In another embodiment, R F is as defined herein, where R N is R P Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R P Substituted or unsubstituted C 5~7 Cycloalkyl, R P Substituted or unsubstituted C 5~7 Aryl, or R P In one embodiment, R is a substituted or unsubstituted 5- to 7-membered heteroaryl. F is as defined herein, where R N is halogen, -CN, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl or unsubstituted C1~6 In another embodiment, R F is as defined herein, where R N is an unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 Cycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl.

[0100] In one embodiment of the above, R P are independently hydrogen, halogen, -CN, -OR W , -S(O)2R W , or -NR X R Y where RW, RX, and RY are as defined herein. In one embodiment, R P are independently hydrogen, halogen, —CN, —OH, —OCH, —OCF, —S(O)H, —S(O)NH, —NH, —NH(CH), —N(CH), —CF, —CHF, —CHF, —C(CH)F, or —C(CH)F. D is independently hydrogen, methyl, ethyl, propyl, or isopropyl. P is independently hydrogen, butyl, or isobutyl. P are independently hydrogen, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl.

[0101] In one embodiment, R F is R N In a further embodiment, R is substituted or unsubstituted benzyl. F is unsubstituted benzyl. In yet another embodiment, R F is R N substituted benzyl, R N is halogen, —CN, methyl, ethyl, or propyl. F teeth, [ka] (RF1) [In the formula, R N is a halogen and m is 1 or 2. In one embodiment, R F has the formula RF1, where R N is F or Cl and m is 1 or 2. In one embodiment, R F has the formula RF1, where R N is F and m is 1 or 2.

[0102] In one embodiment, R F is R N Substituted or unsubstituted C 1~6 In another embodiment, R F is R N substitution C 1~6 alkyl, and R N is F or -CF3. In yet another embodiment, R F teeth, [ka] (RF2) [In the formula, R N is F or methyl] is.

[0103] In one preferred embodiment, R A teeth, [ka] is.

[0104] In one embodiment, R A teeth, [ka] (RA1) is.

[0105] In one embodiment, R A has the formula (RA1), where RB and R C are independently hydrogen or R N Substituted or unsubstituted C 1~6 In another embodiment, R A has the formula (RA1), where R B and R C are independently N Substituted or unsubstituted C 3~7 Cycloalkyl, or R N In yet another embodiment, R is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl. A has the formula (RA1), where R B and R C independently, together with the nitrogen atom to which they are attached, R N In one preferred embodiment, R forms a substituted or unsubstituted 4- to 7-membered heterocycloalkyl (e.g., azetidinyl, pyrrolidinyl, or piperidinyl). A has the formula (RA1), where R B and R C are independently N Substituted or unsubstituted C 1~6 In another preferred embodiment, R A has the formula (RA1), where R B and R C are each independently an unsubstituted C 1~6 In yet another embodiment, R is alkyl (e.g., methyl or ethyl). A has the formula (RA1), where R B is a 4-membered heterocycloalkyl (e.g., azetidinyl or oxetanyl), and R C is hydrogen or R N Substituted or unsubstituted C 1~6 alkyl (e.g., methyl, ethyl). In one embodiment, R A has the formula (RA1), where R G is a halogen.

[0106] In one embodiment, R A teeth, [ka] (RA2) is.

[0107] In one embodiment, R A has the formula (RA2), where R G is halogen or R M Substituted or unsubstituted C 1~6 Alkyl, or R M Substituted or unsubstituted C 1~6 In one embodiment, R A has the formula (RA2), where R G is F, methyl, ethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, or trifluoroethyl.

[0108] In one embodiment, R A is a 7-10 membered spiroheterocycloalkyl. In one embodiment, R A is a 7-10 membered spiroheterocycloalkyl containing one nitrogen or one oxygen heteroatom. In one preferred embodiment, R A is a 4,5-, 4,6-, or 4,7-spiroheterocycloalkyl containing one nitrogen or one oxygen heteroatom. A is a 5,5- or 6,6-spiroheterocycloalkyl containing one nitrogen or one oxygen heteroatom. A In a preferred embodiment, R is a 7- to 10-membered spiroheterocycloalkyl. A is the expression: [ka] (RA3) wherein X is —NR Q - or -O-, and R Q is hydrogen, methyl, ethyl, propyl, or isopropyl, and y and z are independently 1 or 2. It has.

[0109] In one embodiment, R A is (RA3), where X is —NR QIn one embodiment, R Q is hydrogen. In one embodiment, R Q is methyl. In another embodiment, R A is (RA3), where X is —O—.

[0110] In one embodiment, R A is (RA3), where X is —NR Q -, y is 1, and z is 2.

[0111] In one embodiment, R A has the formula (RA1) or (RA1), where each R G are independently halogen, -OR I , R M Substituted or unsubstituted C 1~6 Alkyl, or R M Substituted or unsubstituted C 1~6 It is haloalkyl.

[0112] In one embodiment, R G are independently halogen or R M Substituted or unsubstituted C 1~6 In one embodiment, R G are independently halogen or unsubstituted C 1~6 In one embodiment, R G is independently methyl or ethyl. In one embodiment, R G are independently M Substituted or unsubstituted C 1~6 In one embodiment, R G are independently unsubstituted C 1~6 In yet another embodiment, R G are independently -CF, -CHF, -CHF, -C(CH)F, -C(CH)F, -CHCHF, -CHCHF, -CHCF. In another embodiment, R G is independently halogen. In yet another embodiment, R G is independently fluoro and t is 1 or 2. In another embodiment, R Gis independently fluoro and t is 1. In yet another embodiment, R G are independently M Substituted or unsubstituted C 1~6 Alkyl, or R M Substituted or unsubstituted C 1~6 In one embodiment, t is 0.

[0113] In one particular embodiment, R A is the expression: [ka] It has.

[0114] In one embodiment of the compounds described herein or pharmaceutically acceptable salts thereof, each R H are independently halogen, C 1~3 Alkyl, or C 1~3 haloalkyl, and j is 1 or 2. In another embodiment, each R H is independently halogen or cyclopropyl, and j is 1 or 2. In yet another embodiment, R H is halogen and j is 1. In another embodiment, R H is methyl, ethyl, propyl, or isopropyl, and j is 1. In one embodiment, R H is R D and j is 1. In a preferred embodiment, R H is fluoro, methyl, ethyl, propyl, or isopropyl; R H is R D is orthogonal to j, and j is 1.

[0115] In another embodiment of the compounds described herein or pharmaceutically acceptable salts thereof, ring Q is R E Substituted or unsubstituted C 5~7 In another embodiment, ring Q is R E In yet another embodiment, ring Q is a substituted or unsubstituted phenyl. [ka] (Q1) (Q2) (Q3) (Q4) (Q5) [In the formula, R E1 , R E2 , R E3 , and R E4 are each independently hydrogen, halogen, or R M Substituted or unsubstituted C 1~6 In one embodiment, R E1 , R E2 , R E3 , and R E4 are each independently hydrogen, halogen, or unsubstituted C 1~6 alkyl (e.g., methyl, ethyl, or propyl). In one embodiment, R E1 , R E2 , R E3 , and R E4 are each independently hydrogen or halogen (e.g., F or Cl). In a preferred embodiment, R E1 , R E2 , R E3 , and R E4 are each independently hydrogen or F.

[0116] In another embodiment of the compounds described herein or pharmaceutically acceptable salts thereof, ring Q contains at least one nitrogen heteroatom, R E In one embodiment, ring Q is a substituted or unsubstituted 5-7 membered heteroaryl. In another embodiment, ring Q is a pyridinyl. In another embodiment, ring Q is a pyrazinyl or pyrimidinyl. In one embodiment, ring Q is a group of the formula: TIFF0007765972000015.tif37150[where, R E1 , R E2 , R E3 , and R E4 are each independently hydrogen, halogen, or R M Substituted or unsubstituted C 1~6 In preferred embodiments where ring Q has formula (Q6) to (Q10), R E1 , R E2 , R E3 , and R E4are each independently hydrogen or unsubstituted C 1~6 alkyl (for example, methyl or ethyl).

[0117] In another embodiment, ring Q has the formula: [ka] [In the formula, R E1 and R E2 are independently unsubstituted C 1~6 alkyl].

[0118] In one embodiment, each R M is independently hydrogen, halogen, —CN, —OH, —OCH, —OCF, —S(O)H, —S(O)NH, —NH, —NH(CH), —N(CH), —CF, —CHF, —CHF, —C(CH)F, or —C(CH)F. In one embodiment, each R M is independently hydrogen or halogen. In one embodiment, each R M is independently -CN, -OH, or -OCH, -OCF. In one embodiment, each R M is independently —S(O)H or —S(O)NH. In one embodiment, each R M is independently -NH, -NH(CH), or -N(CH). In one embodiment, each R M are independently -CF3, -CHF2, -CH2F, -C(CH3)2F, or -C(CH3)F2.

[0119] In one embodiment, each R M are independently hydrogen, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl or unsubstituted C 1~6 In one embodiment, each R M is independently methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In one embodiment, each R M are independently hydrogen, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl.

[0120] In one embodiment, each R N are independently hydrogen, halogen, -CN, -OR R , -S(O)2R R , or -NR S R T In one embodiment, each R N is independently hydrogen. In one embodiment, each R N is independently halogen. In one embodiment, each R N are independently -OR R , -S(O)2R R , or -NR S R T In one embodiment, each R N is independently hydrogen, halogen, —CN, —OH, —OCH, —OCF, —S(O)H, —S(O)NH, —NH, —NH(CH), —N(CH), —CF, —CHF, —CHF, —C(CH)F, or —C(CH)F. In one embodiment, each R N is independently hydrogen, halogen, —CN, —OH, —OCH, or —OCF. In one embodiment, each R N is independently —S(O)H, —S(O)NH, —NH, —NH(CH), or —N(CH). In one embodiment, each R N are independently -CF3, -CHF2, -CH2F, -C(CH3)2F, or -C(CH3)F2.

[0121] In one embodiment, each R N are independently P Substituted or unsubstituted C 1~6 Alkyl or R P Substituted or unsubstituted C 1~6 In one embodiment, each R N are independently P Substituted or unsubstituted C 1~6 In one embodiment, each R N are independently P substitution C1~6 In one preferred embodiment, each R N are independently unsubstituted C 1~6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In one embodiment, each R N are independently P Substituted or unsubstituted C 1~6 In one embodiment, each R N are independently unsubstituted C 1~6 In one embodiment, each R N are independently P Substituted or unsubstituted C 1~6 It is an alkoxy.

[0122] In one embodiment, each R N is R P Substituted or unsubstituted C 3~7 Cycloalkyl, R P Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R P Substituted or unsubstituted C 5~7 Aryl, or R P It is a substituted or unsubstituted 5- to 7-membered heteroaryl.

[0123] In one embodiment, each R R , R S and R T are independently hydrogen, R V Substituted or unsubstituted C 1~6 Alkyl, or R V Substituted or unsubstituted C 1~6 In one embodiment, each R R , R S and R T is independently hydrogen, halogen, —CN, —OH, —OCH, —OCF, —S(O)H, —S(O)NH, —NH, —NH(CH), —N(CH), —CF, —CHF, —CHF, —C(CH)F, or —C(CH)F. In one embodiment, each R R , R S and R Tis independently hydrogen, halogen, —CN, —OH, —OCH, or —OCF. In one embodiment, each R R , R S and R T is independently —S(O)H, —S(O)NH, —NH, —NH(CH), or —N(CH). In one embodiment, each R R , R S and R T are independently -CF 3 , -CHF2, -CH2F, -C(CH3)2F, or -C(CH3)F2.

[0124] In one embodiment, each R R , R S and R T are independently V Substituted or unsubstituted C 3~7 Cycloalkyl, or R V In one embodiment, each R R , R S and R T are independently unsubstituted C 3~7 It is a cycloalkyl or an unsubstituted 3- to 7-membered heterocycloalkyl.

[0125] In one embodiment, each R V is independently hydrogen, halogen, —CN, —OH, —OCH, —OCF, —S(O)H, —S(O)NH, —NH, —NH(CH), —N(CH), —CF, —CHF, —CHF, —C(CH)F, or —C(CH)F. In one embodiment, each R V is independently hydrogen or halogen. In one embodiment, each R V is independently -CN, -OH, or -OCH, -OCF. In one embodiment, each R V is independently —S(O)H or —S(O)NH. In one embodiment, each R V is independently -NH, -NH(CH), or -N(CH). In one embodiment, each R Vare independently -CF3, -CHF2, -CH2F, -C(CH3)2F, or -C(CH3)F2.

[0126] In one embodiment, each R V are independently hydrogen, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl or unsubstituted C 1~6 In one embodiment, each R V is independently methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In one embodiment, each R V are independently hydrogen, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl.

[0127] In one embodiment, each R P are independently hydrogen, halogen, -CN, -OR W , -S(O)2R W , -NR X R Y , R U Substituted or unsubstituted C 1~6 Alkyl, R U Substituted or unsubstituted C 1~6 Haloalkyl, R U Substituted or unsubstituted C 3~7 Cycloalkyl, R U Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R U Substituted or unsubstituted C 5~7 Aryl, or R U It is a substituted or unsubstituted 5- to 7-membered heteroaryl.

[0128] In one embodiment, each R P are independently hydrogen, halogen, -CN, -OR W , -S(O)2R W , or -NR X R Y In one embodiment, each R P is independently hydrogen. In one embodiment, each R Pis independently halogen. In one embodiment, each R P are independently -OR W , -S(O)2R W , or -NR X R Y In one embodiment, each R P is independently hydrogen, halogen, —CN, —OH, —OCH, —OCF, —S(O)H, —S(O)NH, —NH, —NH(CH), —N(CH), —CF, —CHF, —CHF, —C(CH)F, or —C(CH)F. In one embodiment, each R P is independently hydrogen, halogen, —CN, —OH, —OCH, or —OCF. In one embodiment, each R P is independently —S(O)H, —S(O)NH, —NH, —NH(CH), or —N(CH). In one embodiment, each R P are independently -CF3, -CHF2, -CH2F, -C(CH3)2F, or -C(CH3)F2.

[0129] In one embodiment, each R P are independently U Substituted or unsubstituted C 1~6 Alkyl or R U Substituted or unsubstituted C 1~6 In one embodiment, each R P are independently U Substituted or unsubstituted C 1~6 In one embodiment, each R P are independently U substitution C 1~6 In one preferred embodiment, each R P are independently unsubstituted C 1~6 alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In one embodiment, each R P are independently U Substituted or unsubstituted C 1~6 In one embodiment, each R P are independently unsubstituted C 1~6 It is haloalkyl.

[0130] In one embodiment, each R P is R U Substituted or unsubstituted C 3~7 Cycloalkyl, R U Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R U Substituted or unsubstituted C 5~7 Aryl, or R U It is a substituted or unsubstituted 5- to 7-membered heteroaryl.

[0131] In one embodiment, each R W , R X and R Y are independently hydrogen, unsubstituted C 1~6 Alkyl or unsubstituted C 1~6 In one embodiment, each R W , R X and R Y is independently methyl, ethyl, propyl, or isopropyl. W , R X and R Y are independently -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, -CH3CH2F, -CH3CHF2, -CH3CF3.

[0132] In one embodiment, each R W , R X and R Y are independently hydrogen, unsubstituted C 3~7 cycloalkyl, or unsubstituted 3- to 7-membered heterocycloalkyl.

[0133] In one embodiment, each R U is independently hydrogen, halogen, —CN, —OH, —OCH, —OCF, —S(O)H, —S(O)NH, —NH, —NH(CH), —N(CH), —CF, —CHF, —CHF, —C(CH)F, or —C(CH)F. In one embodiment, each R U is independently hydrogen or halogen. In one embodiment, each R Uis independently -CN, -OH, or -OCH, -OCF. In one embodiment, each R U is independently —S(O)H or —S(O)NH. In one embodiment, each R U is independently -NH, -NH(CH), or -N(CH). In one embodiment, each R U are independently -CF3, -CHF2, -CH2F, -C(CH3)2F, or -C(CH3)F2.

[0134] In one embodiment, each R U are independently hydrogen, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl or unsubstituted C 1~6 In one embodiment, each R U is independently methyl, ethyl, propyl, isopropyl, butyl, or isobutyl. In one embodiment, each R U are independently hydrogen, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl.

[0135] In one embodiment of the compounds described herein or pharmaceutically acceptable salts thereof, the compound or pharmaceutically acceptable salt thereof has the formula: [ka] or [ka] [In the formula, R B , R C , R D , R E , R F , R G , n, and t are as defined herein].

[0136] In another embodiment of the compounds described herein, or a pharmaceutically acceptable salt thereof, the compound, or a pharmaceutically acceptable salt thereof, has the formula: [ka] [ka] [In the formula, R B , R C , R D , R E , R F , R G , n, and t are as defined herein].

[0137] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is a compound set forth in Table 1.

[0138] Table 1: [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0139] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is a compound set forth in Table 2.

[0140] Table 2: [Table 7] [Table 8] [Table 9] [Table 10] Table 11 Table 12

[0141] Synthesis of Compounds and Their Pharmaceutically Acceptable Salts The compounds described herein and their pharmaceutically acceptable salts can be synthesized by synthetic routes that include processes analogous to those well known in the chemical arts, particularly in light of the description contained herein, as well as other heterocyclic processes described in: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g., Vol. 3; Liebigs Annalen der Chemie, (9): 1910-16, (1985); Helvetica Chimica Acta, 41: 1052-60, (1958); Arzneimittel-Forschung, 40(12): 1328-31, (1990), each of which is expressly incorporated by reference. The starting materials are generally available from commercial sources, such as Aldrich Chemicals (Milwaukee, Wis.), or are readily prepared using methods (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, NY (1967-2006 ed.), or Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available from the Beilstein online database)). The compounds described herein and pharmaceutically acceptable salts thereof can also be prepared according to procedures found in U.S. Pat. No. 8,476,434, U.S. Pat. No. 7,880,000, WO 2005 / 113494, U.S. Pat. No. 7,868,177, and WO 2007 / 100646.

[0142] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein and pharmaceutically acceptable salts thereof, as well as the necessary reagents and intermediates, include those described, for example, in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Buts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0143] The compounds described herein and pharmaceutically acceptable salts thereof can be prepared singly or as compound libraries comprising at least two, e.g., 5 to 1000 compounds, or 10 to 100 compounds. Libraries of the compounds described herein and pharmaceutically acceptable salts thereof can be prepared by a combinatorial "split and mix" approach or by multiple parallel syntheses using, e.g., either solution-phase or solid-phase chemistry. Thus, according to a further aspect provided herein, there is provided a compound library comprising at least two compounds described herein or pharmaceutically acceptable salts thereof.

[0144] The Examples provide exemplary methods for preparing the compounds described herein and pharmaceutically acceptable salts thereof. Those skilled in the art will appreciate that other synthetic routes may be used to prepare the compounds described herein. It will be understood that compounds of formula (I) and pharmaceutically acceptable salts thereof can be synthesized. While specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. Additionally, many of the exemplary compounds prepared by the described methods and their pharmaceutically acceptable salts can be further modified in light of this disclosure using conventional chemistry.

[0145] In preparing the compounds described herein and their pharmaceutically acceptable salts, protection of remote functional groups (e.g., primary or secondary amines) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation method. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined. For a general description of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0146] In the processes for preparing the compounds described herein and their pharmaceutically acceptable salts, it may be advantageous to separate reaction products from one another and / or from starting materials. The desired product of each step or series of steps is separated and / or purified to the desired degree of homogeneity by techniques common in the art. Typically, such separation involves multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any number of methods, including, for example, reverse-phase and normal-phase, size exclusion, ion exchange, high-, medium-, and low-pressure liquid chromatography methods and apparatus, small-scale analytical, simulated moving bed (SMB) and preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography techniques.

[0147] Another class of separation methods involves treating the mixture with a selected reagent to bind or otherwise render separable the desired product, unreacted starting materials, reaction by-products, etc. Such reagents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent can be an acid in the case of basic substances, a base in the case of acidic substances, a binding reagent such as an antibody, a binding protein, a selective chelating agent such as crown ethers, liquid-liquid ion extraction reagents (LIX), etc. The selection of an appropriate separation method depends on the properties of the materials involved, such as boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, the stability of the material in acidic and basic media in multiphase extraction, etc.

[0148] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods such as, for example, chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture to a diastereomeric mixture by reaction with a suitable optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mossha acid chloride), separating the diastereomers, and converting the individual diastereomers to the corresponding pure enantiomers (e.g., by hydrolysis). Some of the compounds described herein or their pharmaceutically acceptable salts may also be atropisomers (e.g., substituted biaryls). Enantiomers can also be separated using a chiral HPLC column.

[0149] A single stereoisomer, e.g., an enantiomer, can be obtained substantially free of its stereoisomer by resolving a racemic mixture using methods such as the formation of diastereomers with an optically active resolving agent (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds," John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.H., (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds described herein or pharmaceutically acceptable salts thereof can be separated and isolated by any suitable method, including: (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional recrystallization or other methods; (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereomers, and conversion to pure stereoisomers; and (3) separation of substantially pure or enriched stereoisomers under chiral conditions. See "Drug Stereochemistry, Analytical Methods and Pharmacology," Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

[0150] In method (1), diastereomeric salts can be formed by reacting enantiomerically pure chiral bases, such as brucine, quinine, ephedrine, strychnine, and α-methyl-β-phenylethylamine (amphetamine), with asymmetric compounds containing acidic functional groups, such as carboxylic and sulfonic acids. The diastereomeric salts can be induced to separate by fractional recrystallization or ionic chromatography. To separate the optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid, can form diastereomeric salts.

[0151] Alternatively, by method (2), the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed by reacting the asymmetric compound with an enantiomerically pure chiral derivatizing agent, such as a methyl derivative, followed by separation and hydrolysis of the diastereomers to obtain the pure or enriched enantiomer. A method for determining optical purity involves making a chiral ester of the racemic mixture, for example, a methyl ester (such as (-)methyl chloroformate in the presence of a base) or the Mosher ester α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob III. Chem., (1982) 47:4165), and then determining the presence of two atropisomeric enantiomers or diastereomers. 1 and analyzing the H NMR spectrum. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal-phase and reverse-phase chromatography, following the method for separating atropisomeric naphthyl-isoquinolines (WO 96 / 15111). Method (3) allows the separation of racemic mixtures of two enantiomers by chromatography using a chiral stationary phase ("Chiral Liquid Chromatography" (1989) W. J. Lough, Ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

[0152] Compound administration The compounds described herein or their pharmaceutically acceptable salts can be administered by any route appropriate to the condition being treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous, intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, topical (including buccal and sublingual), intravaginal, intraperitoneal, intrapulmonary, and intranasal. For localized immunosuppressive treatment, the compounds can be administered intralesionally, including by perfusing or otherwise contacting the graft with an inhibitor prior to transplantation. It will be understood that the preferred route may vary, for example, with the recipient's condition. When the compound is administered orally, it may be formulated as a pill, capsule, tablet, or the like with a pharmaceutically acceptable carrier or excipient. In one preferred embodiment, the compound or its pharmaceutically acceptable salt is formulated for oral administration as a pill, capsule, or tablet. Where the compound or a pharmaceutically acceptable salt thereof is administered parenterally, it may be formulated in a unit dosage form for injection with a pharmaceutically acceptable parenteral vehicle, as detailed below.

[0153] Thus, in one embodiment, provided herein is a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable additives. In one embodiment, the compound described herein is administered as a pharmaceutical composition that can be administered to a subject orally or parenterally. The compound described herein can be formulated for topical or parenteral use, and the compound is dissolved or otherwise suspended in a solution suitable for injection, suspension, syrup, cream, ointment, gel, spray, solution, and emulsion.

[0154] Oral administration can facilitate patient compliance when taking a compound (e.g., formulated as a pharmaceutical composition), thereby increasing compliance and efficacy. Oral administration can facilitate patient compliance when taking a compound (e.g., formulated as a pharmaceutical composition), thereby increasing compliance and efficacy. Oral pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof include, but are not limited to, tablets (e.g., coated, uncoated, and chewable) and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric-coated capsules, and sustained-release capsules). Tablets can be prepared by direct compression, wet granulation, or dry granulation. Oral pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof can be formulated for delayed release or extended release. In one preferred embodiment, the oral pharmaceutical composition comprises a compound or a pharmaceutically acceptable salt thereof formulated into a tablet.

[0155] Doses for treating human patients can range from about 10 mg to about 1000 mg of a compound described herein or a pharmaceutically acceptable salt thereof. A typical dosage can be about 100 mg to about 300 mg of the compound. Doses can be administered once daily (QD), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion, of the particular compound. As used herein, "dosing" refers to the frequency of administration and not, for example, the number of individual units a patient must take for administration as described herein. Thus, in some embodiments, a patient may take two or more dosage units (e.g., two or more pills / tablets / capsules) QD. In addition, toxicity factors can affect the dose and administration regimen. When administered orally, pills, capsules, or tablets may be taken orally daily for a specified time period or at more spaced intervals. This regimen can be repeated for a predetermined number of treatment cycles.

[0156] Treatment method In one aspect provided herein, the compound or a pharmaceutically acceptable salt thereof is useful for treating a patient having a disease or disorder resulting from aberrant cell proliferation, function, or behavior associated with the UPR pathway, such as cancer, an immune disorder, a cardiovascular disease, a viral infection, inflammation, a metabolic / endocrine disorder, or a neurological disorder, by administering an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. In one embodiment of the methods provided herein, the compound or a pharmaceutically acceptable salt thereof is useful for treating a patient having an IRE1-associated disease or disorder resulting from aberrant cell proliferation, function, or behavior associated with the UPR pathway, such as cancer, an immune disorder, a cardiovascular disease, a viral infection, inflammation, a metabolic / endocrine disorder, or a neurological disorder, by administering an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof.

[0157] Provided herein are methods for treating an IRE1-associated disease or disorder by administering to a patient having an IRE1-associated disease or disorder described herein an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In another embodiment, provided are methods for treating cancer by administering to a patient having cancer an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof. In one embodiment, the cancer is an IRE1-associated disease or disorder.

[0158] The methods provided herein include treating solid tumors / cancers by administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a patient having the solid tumor / cancer provided herein. For example, administration of an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof can treat breast cancer, ovarian cancer, cervical cancer, prostate cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, glioblastoma, neuroblastoma, stomach cancer, skin cancer, keratoacanthoma, lung cancer, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer (NSCLC), small cell carcinoma, lung adenocarcinoma, bone cancer, colon cancer, adenoma, pancreatic cancer, adenocarcinoma, thyroid cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminiferous carcinoma, melanoma, sarcoma, bladder carcinoma, and the like. It can be performed on patients with liver and biliary tract cancer, renal carcinoma, oral cancer, nasopharyngeal cancer, pharyngeal cancer, lip cancer, tongue cancer, oral cancer, small intestine cancer, colorectal cancer, colon cancer, rectal cancer, bronchial cancer, hepatocellular carcinoma, gastric cancer, endometrial cancer, melanoma, kidney cancer, urinary bladder cancer, uterine cancer, and cervical cancer.

[0159] In another embodiment, the methods provided herein include treating cancer by administering an effective amount of a compound or a pharmaceutically acceptable salt thereof to a patient with cancer, including squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, or head and neck cancer.

[0160] In certain embodiments, the cancer is breast cancer. The breast cancer can be stage I, II, III, or IV, as understood in the art. In one embodiment, the breast cancer is triple negative breast cancer (TNBC). In another embodiment, the breast cancer is Her2-negative breast cancer. In yet another embodiment, the breast cancer is HR+ breast cancer.

[0161] Also provided herein are methods for treating a hematological cancer in a patient having such a hematological cancer by administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. The hematological cancer can be, for example, lymphoma, lymphocytic leukemia (acute (ALL) and chronic (CLL)), multiple myeloma (MM), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), or non-Hodgkin's lymphoma. In one embodiment, the method herein comprises treating a patient having multiple myeloma (MM), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or myelodysplastic syndrome (MDS) by administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.

[0162] In one embodiment, a method is provided for treating MM by administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a patient with MM. MM can be stage I, II, III, or IV, as understood in the art. In another embodiment, a method is provided for treating AML by administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a patient with AML. AML can be stage I, II, III, or IV, as understood in the art. In another embodiment, a method is provided for treating CML by administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a patient with CML. CML can be stage I, II, III, or IV, as understood in the art. In another embodiment, a method is provided for treating MDS by administering an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof to a patient with MDS. It is further understood that such cancers can be relapsed or refractory, as provided herein.

[0163] In one embodiment, the cancer is an IRE1-mediated cancer (i.e., a cancer with abnormal expression or activity of IRE1 compared to a control). In one embodiment, the IRE1-mediated cancer has increased expression of IRE1. In another embodiment, the IRE1-mediated cancer has increased activity of IRE1. Such an increase can be measured in a control (e.g., in a patient with a given IRE1 function, expression, or activity; or, e.g., in a single patient before, during, or after treatment with a compound described herein or a pharmaceutically acceptable salt thereof). The above cancers include IRE1-mediated cancers.

[0164] The methods and uses described herein also include embodiments in which the compound or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional therapeutic agents selected from the group consisting of an anti-inflammatory agent, a corticosteroid, an immunomodulatory agent, an anti-cancer agent described herein, a pro-apoptotic agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a blood disorder, an agent for treating diabetes, an agent for treating a metabolic disorder, an agent for treating an autoimmune disorder, an agent for treating an immunodeficiency disorder, and combinations thereof.

[0165] In one embodiment of the methods provided herein, the compound, or a pharmaceutically acceptable salt thereof, is administered in combination with one or more additional therapeutic agents including a corticosteroid, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 antibody, an anti-VEGF-A antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-interleukin-6 antibody, or a combination thereof.

[0166] In another embodiment of the methods provided herein, the compound or a pharmaceutically acceptable salt thereof is administered in combination as described herein, and the additional therapeutic agent is a corticosteroid, a proteasome inhibitor, an IMiD, an antibody, or a combination thereof.

[0167] In one embodiment, the compound or a pharmaceutically acceptable salt thereof is administered in combination with a proteasome inhibitor. In one embodiment, the proteasome inhibitor comprises carfilzomib, bortezomib, or ixazomib. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is administered in combination with an IMiD, where the IMiD is lenalidomide or pomalidomide. In one embodiment of the methods provided herein, the compound or a pharmaceutically acceptable salt thereof is administered in combination with a corticosteroid, and the corticosteroid comprises dexamethasone.

[0168] In another embodiment, the compound or a pharmaceutically acceptable salt thereof is administered in combination with an anti-PD-L1 antibody. The anti-PD-L1 antibody can be avelumab, durvalumab, or atezolizumab. In yet another embodiment, the compound or a pharmaceutically acceptable salt thereof is administered in combination with an anti-PD-1 antibody. The anti-PD-1 antibody can be pembrolizumab or nivolumab.

[0169] The methods provided herein can also further include administering radiation therapy. In certain embodiments, radiation therapy can be administered prior to administration of a compound described herein or a pharmaceutically acceptable salt thereof.

[0170] Further provided is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in a method for treating an IRE1-associated disease or disorder, wherein the IRE1-associated disease or disorder is as described herein. In one embodiment, the compound described herein, or a pharmaceutically acceptable salt thereof, is for use in a method for treating cancer as set forth above. In a preferred embodiment, the cancer is MM, AML, CML, or MDS.

[0171] Further provided herein is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating an IRE1-associated disease or disorder, wherein the IRE1-associated disease or disorder is as described herein. In one embodiment, the IRE1-associated disease or disorder is a cancer as described above. In preferred embodiments, the cancer is MM, AML, CML, or MDS. It is understood that embodiments herein that refer to methods (e.g., methods of treatment) may also refer to the uses or compounds for use described herein.

[0172] The methods and uses described herein are also applicable to patients who have been previously treated with one or more therapies before receiving a compound described herein or a pharmaceutically acceptable salt thereof. It is well known in the art that patients can be treated with one or more treatment regimens, particularly for hematological cancers such as those described herein. Cancers can be relapsed or refractory (r / r) (e.g., patients with rrMM, rrAML, rrCML, or rrMDS). A "refractory" cancer refers to a cancer that progresses despite aggressive treatment. A "recurrent" cancer generally refers to a cancer that occurs in the untreated state after successful treatment with one or more anti-cancer agents. Thus, in one embodiment, provided herein is a method for treating r / r cancer (e.g., rrMM, rrAML, rrCML, or rrMDS) in patients with such cancer by administering a compound described herein or a pharmaceutically acceptable salt thereof. Such a method may include co-administration with one or more anti-cancer agents described herein, as set forth above.

[0173] Thus, in one embodiment, the patient may have been treated with one or more anti-cancer agents. In a particular embodiment, the patient has been treated with two or more anti-cancer agents as provided herein to treat a hematological disease (e.g., MM or AML). In one embodiment, the patient treated according to the methods provided herein has previously been administered one or more proteasome inhibitors (e.g., bortezomib, carfilzomib, or ixazomib). In one embodiment, the patient treated according to the methods provided herein has previously been administered one or more IMiDs, such as thalidomide, lenalidomide, or pomalidomide. In another embodiment, the patient treated according to the methods provided herein has previously been administered chemotherapy (e.g., cytalbine, cladribine, fludarabine, mitoxantrone, etoposide, 6-TG, hydroxyurea, methotrexate, decitabine, or an anthracycline). In another embodiment, a patient treated according to the methods provided herein has previously received one or more corticosteroids, such as dexamethasone. Such corticosteroids are often administered in conjunction with other anti-cancer agents, as is understood in the art. In yet another embodiment, a patient treated according to the methods provided herein has previously received one or more antibodies, such as, for example, daratumumab, gemtuzumab ozogamicin, atezolizumab, alemtuzumab, rituximab, obinutuzumab, or ofatumumab. In yet another embodiment, a patient treated according to the methods provided herein has previously received one or more FLT3 inhibitors (e.g., midostaurin or gliterutinib). In yet another embodiment, a patient treated according to the methods provided herein has previously received one or more Bcl-2 inhibitors, such as venetoclax or navitoclax. In yet another embodiment, the patient treated according to the methods provided herein has previously received one or more of ibrutinib, idelalisib, or dublisib. In another embodiment, the patient treated according to the methods provided herein has previously received an IMiD described herein in combination with a proteasome inhibitor and, optionally, a corticosteroid.

[0174] The compounds described herein, or pharmaceutically acceptable salts thereof, can be administered as first-line (1L) therapy (e.g., administered before administration of another anti-cancer agent, including chemotherapy). Thus, in certain instances, the patient can be chemotherapy-naive.

[0175] It is understood that the methods described herein include administering a pharmaceutical composition comprising a compound provided herein or a pharmaceutically acceptable salt thereof. Such pharmaceutical compositions also include one or more pharmaceutically acceptable carrier additives. In some embodiments, the compound is selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is listed in Table 1. In one embodiment, the compound or a pharmaceutically acceptable salt thereof is listed in Table 2.

[0176] Also provided herein is a method for treating a disease caused by an abnormal level of IRE1 activity in a human or animal patient in need of such treatment with a compound described herein or a pharmaceutically acceptable salt thereof. The disease may be caused by too little or too much IRE1 activity. For example, the disease may be caused by decreased IRE1 activity or abnormally high IRE1 activity (e.g., hyperactivity of IRE1). The method comprises administering to the patient an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof that modulates IRE1 activity (an IRE1 modulator compound).

[0177] IRE1 deficiency can be measured as a decreased amount of IRE1 activity in a particular subject or in a population of healthy subjects, relative to normal levels of IRE1 activity. Decreased amounts of IRE1 activity can lead to the accumulation of excessive amounts of misfolded proteins, thereby causing pathology.

[0178] IRE1 hyperactivity can be measured as an increased amount of IRE1 activity in a particular subject or in a population of healthy subjects, relative to normal levels of IRE1 activity. Increased amounts of IRE1 activity can result, for example, in excessive amounts of cell proliferation, thereby causing a disease state.

[0179] In some embodiments, the disease is associated with IRE1 deficiency. Such diseases include, but are not limited to, cystic fibrosis, retinitis pigmentosa, diabetes, or neurodegenerative diseases. Neurodegenerative diseases can include Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia-telangiectasia, and Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease). Bovine spongiform encephalopathy (BSF), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Lewy body disease, Machado-Joseph disease (Spinocerebellar ataxia type 3), multiple sclerosis, multiple atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, Refsum disease, Sandhoff disease, Schilda disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar ataxia (various types with different characteristics), spinal muscular atrophy, or spinal cord deafness.

[0180] In other embodiments, the disease is associated with abnormally high IRE1. Such diseases include, but are not limited to, cancer, inflammatory diseases, and autoimmune diseases. Exemplary cancers include, but are not limited to, breast cancer and multiple myeloma. In one embodiment, the disease is multiple myeloma. In one embodiment, the disease is triple-negative breast cancer. Exemplary inflammatory diseases include, but are not limited to, asthma, chronic inflammation, chronic prostatitis, glomerulonephritis, hypersensitivity, inflammatory bowel disease, pelvic inflammatory disease; reperfusion injury, rheumatoid arthritis, transplant rejection, and vasculitis. Exemplary autoimmune diseases include, but are not limited to, XBP1-associated Crohn's disease, celiac disease, type 1 diabetes (IDDM), systemic lupus erythematosus (SLE), Sjogren's syndrome, Churg-Strauss syndrome, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, and rheumatoid arthritis. In one embodiment, the disease is XBP1-associated Crohn's disease.

[0181] Pharmaceutical preparations The compounds described herein, or pharmaceutically acceptable salts thereof, can be formulated in accordance with standard pharmaceutical practice as pharmaceutical compositions. Accordingly, further provided herein are pharmaceutical compositions comprising the compounds, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients.

[0182] A typical formulation is prepared by mixing a compound described herein or a pharmaceutically acceptable salt thereof with an additive. Suitable carriers, diluents, and additives include, but are not limited to, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and other materials. The specific additives used depend on the means and purpose for which the compound described herein or a pharmaceutically acceptable salt thereof is being administered. Solvents are generally selected based on solvents recognized as safe (GRAS) for mammalian administration. 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), and the like, and mixtures thereof. The formulation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, fragrances, flavoring agents, and other known additives to provide proper presentation of the drug (i.e., a compound described herein or a pharmaceutical composition thereof) or to aid in the manufacture of a pharmaceutical product (i.e., a medicament).

[0183] Formulations can be prepared using conventional dissolution and mixing procedures. For example, a bulk drug substance (i.e., a compound described herein or a pharmaceutically acceptable salt thereof, or a stabilized form thereof (e.g., a complex with a cyclodextrin derivative or other known complexing agent) is dissolved in a suitable solvent in the presence of one or more of the additives described above. The compounds described in the present invention or a pharmaceutically acceptable salt thereof are typically formulated into pharmaceutical dosage forms to provide easily controllable drug dosage and enable patient compliance with a prescribed regimen.

[0184] Pharmaceutical compositions (or formulations) for application can be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having the pharmaceutical formulation disposed therein in an appropriate form. Suitable containers include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, and metal cylinders. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, the container has disposed thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0185] Pharmaceutical formulations of the compounds described herein or pharmaceutically acceptable salts thereof can be prepared for various routes and types of administration. For example, a compound described herein or a pharmaceutically acceptable salt thereof having the desired purity can be mixed with one or more pharmaceutically acceptable additives (Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.) in the form of a lyophilized formulation, a pulverized powder, or an aqueous solution, as needed. Formulations can be made by mixing the compound at ambient temperature, at an appropriate pH, and to the desired degree of purity with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to recipients at the dosage and concentration used. The pH of the formulation will depend primarily on the specific application and the concentration of the compound, but may range from about 3 to about 8. For example, formulation in acetate buffer at pH 5 may be a preferred embodiment.

[0186] Pharmaceutical compositions may generally be stored as a solid composition, a lyophilized formulation, or an aqueous solution.

[0187] The pharmaceutical compositions described herein can be formulated, prescribed, and administered in a manner consistent with full medical utility, i.e., in amounts, concentrations, schedules, courses, vehicles, and routes of administration. Factors to be considered in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to physicians. The effective amount of the compound to be administered will be governed by such considerations and will be the minimum amount necessary to ameliorate or treat the hyperproliferative disorder.

[0188] As a general proposition, an initial pharmaceutically effective amount of a parenterally administered inhibitor would be in the range of about 0.01 to 100 mg / kg, i.e., about 0.1 to 20 mg / kg, of the patient's body weight per day, with a typical initial range of the compound used being 0.3 to 15 mg / kg / day. In another embodiment, the pharmaceutical compositions described herein contain an effective amount of the compound or a pharmaceutically acceptable salt thereof in an amount of about: 1 mg to 10 mg; 10 mg to 25 mg; 20 mg to 50 mg; 50 mg to 75 mg; 70 mg to 100 mg; 100 mg to 150 mg; 100 mg to 200 mg; 100 mg to 500 mg; 200 mg to 500 mg; 250 mg to 500 mg; 500 mg to 1000 mg; or 750 mg to 1000 mg.

[0189] Acceptable pharmaceutically acceptable additives are nontoxic to recipients at the dosages and concentrations employed and include buffers (such as phosphate, citric acid, and other organic acids); antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl 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); low molecular weight (about 10 residues) less than 1000 bases); 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 sugar chains (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 non-ionic surfactants (TWEEN TM , PLURONICS TM , or polyethylene glycol (PEG), etc. The active pharmaceutical ingredient may also be incorporated into microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, e.g., hydroxymethylcellulose or gelatin-microcapsules and poly-(methyl methacrylate) microcapsules, respectively, colloidal drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules) or macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980.

[0190] Sustained-release preparations of the compounds described herein or their pharmaceutically acceptable salts may be prepared. Suitable examples of sustained-release formulations include semipermeable matrices of solid hydrophobic polymers containing the compounds described herein or their pharmaceutically acceptable salts, which matrices are in the form of shaped articles such as films or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl methacrylate) or poly(vinyl alcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene vinyl acetate, LUPRON DEPOT TM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0191] Formulations include those suitable for the routes of administration detailed herein. Formulations may conveniently be presented in unit dosage form and may be prepared by any method. Techniques and formulations are generally found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. In general, formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0192] Formulations of the compounds described herein or their pharmaceutically acceptable salts suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets, or tablets, each containing a predetermined amount of such compound or its pharmaceutically acceptable salt. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active agent, or dispersing agent, in a suitable machine. Molded tablets can be made by molding a mixture of moistened powdered active ingredient and an inert liquid diluent in a suitable machine. Tablets can be optionally coated or grooved, and are optionally formulated to provide a slow or controlled release of the active ingredient therefrom. 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 described herein or their pharmaceutically acceptable salts intended for oral use may be prepared according to any method for preparing pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable preparation. Tablets containing the active ingredient mixed with non-toxic pharmaceutically acceptable additives suitable for the manufacture of tablets are acceptable. These additives may be, for example, inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate, granulating and disintegrating agents such as corn starch or alginic acid, binders such as starch, gelatin, or acacia, and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or 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, a time-delay material such as glyceryl monostearate or glyceryl distearate may be employed, alone or with a wax.

[0193] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are 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 paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base. 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 PEG 400), and mixtures thereof. Topical formulations can optionally contain a compound that enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues. The oily phase of the emulsions of the compositions provided herein can be constituted from known ingredients in a known manner. The phase may simply comprise an emulsifier, but preferably comprises a mixture of at least one emulsifier with a fat or oil, or both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is also preferred to include both an oil and a fat. Taken together, the emulsifier, with or without a stabilizer, constitutes the so-called emulsifying wax, and the wax together with the oil and fat constitutes the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream formulation. Suitable emulsifiers and emulsion stabilizers for use in the formulations described herein include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0194] Aqueous suspensions containing the compounds described herein or their pharmaceutically acceptable salts may contain the active material in admixture with additives suitable for the manufacture of aqueous suspensions. Such additives include suspending agents such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia; dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), and condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0195] Pharmaceutical compositions of the compounds described herein or their pharmaceutically acceptable salts may be in the form of sterile injectable preparations, such as sterile aqueous or oily injectable suspensions. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents as described above. Sterile injectable preparations can also be prepared as sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol, or as lyophilized powders. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating, fixed oil, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, can also be used in the preparation of injectables.

[0196] The amount of active ingredient that can be combined with carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. For example, a sustained-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active ingredient, compounded with an appropriate and convenient amount of carrier material, which may vary from about 5 to about 95% (weight:weight) of the total composition. Pharmaceutical compositions may be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain about 3 to 500 μg of active ingredient per milliliter of solution to result in infusion of a suitable volume at a rate of about 30 mL / hour.

[0197] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0198] Formulations suitable for topical administration to the eye also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in 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.

[0199] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0200] Formulations for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

[0201] Formulations suitable for pulmonary or nasal administration have, for example, particle sizes in the range of 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns in increments of microns, such as 0.5, 1, 30 microns, 35 microns, etc.), which are administered by rapid inhalation through the nostrils to reach the alveolar sacs, or by inhalation through the mouth. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents, such as compounds previously used to treat or prevent the disorders described below.

[0202] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, such carriers as are deemed appropriate.

[0203] 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 (lyophilized) condition requiring only the addition of a sterile liquid carrier, for example, water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules, and tablets of the kind described above. Preferred unit dosage formulations are those containing a daily dose or daily unit sub-dose, as herein above recited, of the active ingredient, or an appropriate fraction thereof.

[0204] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used in veterinary compositions comprising at least one active ingredient, as defined above, together with a veterinary carrier. The veterinary carrier is a material useful for the purpose of administering the composition and may be an otherwise inert, or a solid, liquid, or gaseous material that is acceptable in the veterinary arts and compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally, or by any other desired route.

[0205] Combination therapy The compounds described herein and their pharmaceutically acceptable salts can be used alone or in combination with an additional therapeutic agent for treating a disease or disorder described herein, such as an inflammatory or hyperproliferative disorder (e.g., cancer). In certain embodiments, the compounds described herein or their pharmaceutically acceptable salts are combined in a combined pharmaceutical formulation or dosing regimen as a combination therapy with an additional second therapeutic compound that has anti-inflammatory or anti-hyperproliferative properties or is useful for treating an inflammatory, immunoresponsive, or hyperproliferative disorder (e.g., cancer). The additional therapeutic agent can be a Bcl-2 inhibitor, a JAK inhibitor, a PI3K inhibitor, an mTOR inhibitor, an anti-inflammatory agent, an immunomodulatory agent, an anti-cancer agent described herein, a pro-apoptotic agent, a neurotropic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an antiviral agent, an agent for treating a blood disorder, an agent for treating diabetes, or an agent for treating an immunodeficiency disorder. The second therapeutic agent can be an NSAID anti-inflammatory agent. The second therapeutic agent can be an anti-cancer agent described herein. The second compound of the combined pharmaceutical formulation or administration regimen preferably has complementary activity to the compound described herein or its pharmaceutically acceptable salt so that they do not adversely affect each other. Such compounds are suitably present in combination in amounts effective for the intended purpose. In one embodiment, the compositions provided herein include a compound, or a stereoisomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt thereof, in combination with a therapeutic agent, such as an NSAID.

[0206] The combination therapy can be administered simultaneously or sequentially. When administered sequentially, the combination is administered in two or more doses. The combination administration includes co-administration using separate formulations or a single pharmaceutical formulation, and sequential administration in any order, preferably with time for both (or all) active agents to simultaneously exert their biological activity.

[0207] Suitable dosages for any of the above co-administered agents are those currently in use and may be lowered by newly identified agents and by combined (synergistic) action with other therapeutic agents or treatments.

[0208] Combination therapy can provide "synergy," an effect achieved when the active ingredients used together are greater than the sum of the effects resulting from using the compounds separately. Synergistic effects can be achieved when the active ingredients are (1) co-formulated in a combined unit dose formulation and administered or delivered simultaneously, (2) delivered alternately or in parallel as separate formulations, or (3) by some other regimen. When delivered in alternation therapy, synergistic effects can be achieved, for example, when the compounds are administered or delivered sequentially by different injections in separate syringes, separate pills or capsules, or separate infusion solutions. Generally, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e., sequentially, while in combination therapy, effective dosages of two or more active ingredients are administered together.

[0209] In certain embodiments of the treatment, the compounds described herein or their pharmaceutically acceptable salts can be combined with other therapeutic agents, such as those described herein, hormonal agents, or antibody agents, and can also be combined with surgical treatment and radiation therapy. Thus, the combination therapy provided herein includes the administration of at least one compound described herein or its pharmaceutically acceptable salt and the use of at least one other cancer treatment method provided herein. The amounts and relative timing of administration of the compound(s) described herein or their pharmaceutically acceptable salts and other pharmaceutically active therapeutic agents are selected to achieve the desired combined therapeutic effect.

[0210] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is used in combination with an aromatase inhibitor, a phosphoinositide 3-kinase (PI3K) / mTOR pathway inhibitor, a CDK4 / 6 inhibitor, a HER-2 inhibitor, a SERM, a SERD, an EGFR inhibitor, a PD-1 inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, an HSP90 inhibitor, a VEGFR inhibitor, an AKT inhibitor, chemotherapy, or any combination thereof.

[0211] In some embodiments, a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof is administered in combination with a therapeutic agent selected from paclitaxel, anastrozole, exemestane, cyclophosphamide, epirubicin, fulvestrant, letrozole, palbociclib, gemcitabine, trastuzumab (HERCEPTIN®, Genentech), trastuzumab emtansine (KADCYLA®, Genentech), pegfilgrastim, filgrastim, tamoxifen, docetaxel, toremifene, vinorelbine, capecitabine, and ixabepilone.

[0212] In some embodiments, a compound described herein, or a pharmaceutically acceptable salt thereof, is used in combination with hormone deprivation therapy, chemotherapy, radiation therapy, a monoclonal antibody, or a combination thereof.

[0213] Also provided herein are methods for inhibiting or killing cancer cells that express Ire1 by contacting the cancer cells with a compound described herein or a pharmaceutically acceptable salt thereof. In one embodiment of the method, the contacting occurs in vivo (e.g., the contacting is the result of administering a compound described herein or a pharmaceutically acceptable salt thereof). Thus, in another embodiment of the method, the inhibition or killing of the cancer cells occurs in vivo. In yet another embodiment, the cancer cells that express IRE1 are present in a human patient as described herein.

[0214] Metabolites of the compounds described herein Also provided herein are in vivo metabolic products of the compounds described herein, or pharmaceutically acceptable salts thereof. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, provided herein are compounds produced by a process comprising contacting a compound described herein, or a pharmaceutically acceptable salt thereof, with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0215] The metabolites are typically radiolabeled (e.g., 14 C or 3 Identification of metabolites is accomplished by preparing a H isotope, parenterally administering it to an animal, such as a rat, mouse, guinea pig, monkey, or human, at a detectable dose (e.g., greater than about 0.5 mg / kg), allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours), and isolating the conversion products from urine, blood, or other biological samples. These products are easily isolated because they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolites). The structures of the metabolites are determined by conventional methods, for example, by MS, LC / MS, or NMR analysis. Metabolite analysis is generally performed in the same manner as conventional drug metabolism studies. Metabolites, unless otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds described herein or their pharmaceutically acceptable salts.

[0216] manufactured goods Also provided herein are articles of manufacture or kits containing materials useful for treating the above-mentioned diseases and disorders (e.g., cancer). In one embodiment, the kit includes a container containing a compound described herein or a pharmaceutically acceptable salt thereof. The kit may further include a label or package insert on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like. The container can be formed from a variety of materials known in the art, such as metal, glass, or plastic. The container may hold a compound described herein or a pharmaceutically acceptable salt thereof, or a formulation thereof, effective for treating a condition, and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper pierceable by a hypodermic injection needle). At least one active agent in the composition is a compound described herein or a pharmaceutically acceptable salt thereof. The label or package insert indicates that the composition is used for treating the selected condition, such as cancer. Furthermore, the label or package insert may indicate that the patient to be treated is a patient with a disorder such as a hyperproliferative disorder, atherosclerosis, neurodegeneration, cardiac hypertrophy, pain, migraine, or a neurotraumatic disease or event. In one embodiment, the label or package insert indicates that a composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, can be used to treat a disorder resulting from abnormal cell proliferation. In one embodiment, the label or package insert indicates that a composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, can be used to treat a disorder resulting from atherosclerosis. The label or package insert may also indicate that the composition can be used to treat other disorders. Alternatively, or in addition, the article of manufacture may further comprise a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution, and dextrose solution. The article of manufacture may further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0217] The kit can further include instructions for administering a compound described herein or a pharmaceutically acceptable salt thereof, and, if present, a second pharmaceutical formulation. For example, if the kit includes a first composition and a second pharmaceutical formulation comprising a compound described herein or a pharmaceutically acceptable salt thereof, the kit can further include instructions for administering the first and second pharmaceutical compositions simultaneously, sequentially, or separately to a patient in need thereof (e.g., according to a co-administration route described herein). Thus, in one embodiment, the kit is for treating a condition mediated by IRE1, comprising a compound or a pharmaceutically acceptable salt thereof (formulated as a pharmaceutical composition described herein) and instructions for use.

[0218] In another embodiment, the kit is suitable for delivery of a solid oral form (e.g., tablet or capsule) of a compound described herein or a pharmaceutically acceptable salt thereof. Such a kit preferably includes several unit dosages. Such a kit may include a card with the dosages arranged in the order of their intended use. An example of such a kit is a blister pack. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, a memory-aid, for example, in the form of numbers, letters, or other markings, or using a calendar insert, can be provided to designate the days in the treatment schedule on which the dosages can be administered.

[0219] According to one embodiment, the kit can comprise (a) a first container comprising a compound described herein or a pharmaceutically acceptable salt thereof; and, optionally, (b) a second container comprising a second pharmaceutical formulation, the second pharmaceutical formulation comprising a second compound having anti-hyperproliferative activity. Alternatively, or in addition, the kit can further comprise a third container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline, Ringer's solution, and dextrose solution. The article of manufacture can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, needles, and syringes.

[0220] In certain other embodiments, where the kit includes a composition containing a compound according to the present invention or a pharmaceutically acceptable salt thereof and a second therapeutic agent, the kit can include containers for containing the separate compositions, such as divided bottles or divided foil packets, although the separate compositions may also be contained in a single, undivided container. Typically, the kit includes instructions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.

[0221] Implementation: Embodiment 1: Formula (A): [ka] , (A) [In the formula, Ring Q is R E Substituted or unsubstituted C 5~7 aryl or R containing at least one nitrogen heteroatom E substituted or unsubstituted 5- to 7-membered heteroaryl; L A is -NHSO2-, -SO2NH-, -NH-, -NHC(O)-, or -C(O)NH-; R A is R G substituted or unsubstituted bicyclic 7-10 membered spiroheterocycloalkyl; [ka] and; R B and R C are independently hydrogen or R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, or R Nsubstituted or unsubstituted 3- to 7-membered heterocycloalkyl, or R B and R C together with the nitrogen atom to which they are attached, form R N Forming a substituted or unsubstituted 4- to 7-membered heterocycloalkyl; R D is hydrogen, halogen, -CN, -OR I , -S(O)2R I , -NR J R K , R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 1~6 Haloalkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, R N Substituted or unsubstituted 3- to 7-membered heterocycloalkyl, R N Substituted or unsubstituted C 5~7 Aryl, or R N substituted or unsubstituted 5- to 7-membered heteroaryl; Each R E is hydrogen, halogen, -OR I , -CN, -S(O)2R I , R M Substituted or unsubstituted C 1~6 Alkyl, R M Substituted or unsubstituted C 1~6 Haloalkyl, or R M Substituted or unsubstituted C 3~7 is cycloalkyl; n is 0, 1, 2, 3, or 4; R F is R N Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, R N Substituted or unsubstituted benzyl, R N Substituted or unsubstituted 3- to 7-membered heterocycloalkyl or R containing at least one N atom N substituted or unsubstituted 5- to 7-membered heteroaryl; Each R Gare independently halogen, -OR I , R M Substituted or unsubstituted C 1~6 Alkyl, or R M Substituted or unsubstituted C 1~6 is haloalkyl; t is 0, 1, 2, 3, 4, 5, or 6; Each R H are independently halogen, C 1~3 Alkyl, C 1~3 haloalkyl, or cyclopropyl; j is 0, 1, or 2; Each R I , R J , and R K are independently hydrogen, R M Substituted or unsubstituted C 1~6 Alkyl, R M Substituted or unsubstituted C 1~6 Haloalkyl, R M Substituted or unsubstituted C 3~7 Cycloalkyl, R M Substituted or unsubstituted 3- to 7-membered heterocycloalkyl, R M Substituted or unsubstituted C 5~7 aryl, or R M substituted or unsubstituted 5- to 7-membered heteroaryl; Each R M are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl; Each R N are independently hydrogen, halogen, -CN, -OR R , -S(O)2R R , -NR S RT , R P Substituted or unsubstituted C 1~6 Alkyl, R P Substituted or unsubstituted C 1~6 Haloalkyl, R P Substituted or unsubstituted C 1~6 Alkoxy, R P Substituted or unsubstituted C 3~7 Cycloalkyl, R P Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R P Substituted or unsubstituted C 5~7 Aryl, or R P substituted or unsubstituted 5- to 7-membered heteroaryl; Each R R , R S , R T are independently hydrogen, R V Substituted or unsubstituted C 1~6 Alkyl, R V Substituted or unsubstituted C 1~6 Haloalkyl, R V Substituted or unsubstituted C 3~7 Cycloalkyl, or R V substituted or unsubstituted 3- to 7-membered heterocycloalkyl; Each R V are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl; Each R P are independently hydrogen, halogen, -CN, -OR W , -S(O)2R W , -NR X R Y , R U Substituted or unsubstituted C 1~6Alkyl, R U Substituted or unsubstituted C 1~6 Haloalkyl, R U Substituted or unsubstituted C 3~7 Cycloalkyl, R U Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R U Substituted or unsubstituted C 5~7 Aryl, or R U substituted or unsubstituted 5- to 7-membered heteroaryl; Each R W , R X , and R Y are independently hydrogen, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 cycloalkyl, or unsubstituted 3- to 7-membered heterocycloalkyl; and Each R U are independently hydrogen, halogen, -CN, -OH, -OCH3, -OCF3, -S(O)2H, -S(O)2NH2, -NH2, -NH(CH3), -N(CH3)2, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, unsubstituted C 1~6 Alkoxy, unsubstituted C 1~6 Alkyl, unsubstituted C 1~6 Haloalkyl, unsubstituted C 3~7 Cycloalkyl, unsubstituted 3- to 6-membered heterocycloalkyl, unsubstituted C 5~7 aryl, or unsubstituted 5- to 7-membered heteroaryl] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0222] Embodiment 2: The compound has the following formula: [ka] 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having the formula:

[0223] Embodiment 3: R D But halogen, -OR I , -NR J R K , RN Substituted or unsubstituted C 1~6 Alkyl, R N Substituted or unsubstituted C 1~6 Haloalkyl, R N Substituted or unsubstituted C 3~7 Cycloalkyl, or R N 3. The compound according to claim 1 or 2, which is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

[0224] Embodiment 4: R D But, -OR I or -NR J R K 4. The compound according to claim 1, wherein:

[0225] Embodiment 5: R D But, -OR I and R I But R M Substituted or unsubstituted C 1~6 Alkyl, or R M Substituted or unsubstituted C 1~6 5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

[0226] Embodiment 6: R D But, -OR I and R I But unsubstituted C 1~6 Alkyl or unsubstituted C 1~6 6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

[0227] Embodiment 7: R D But, -OR I and R I 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is methyl, ethyl, propyl, isopropyl, or butyl.

[0228] Embodiment 8: R D But, -OR I and RI 8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein is ethyl or isopropyl.

[0229] Embodiment 9: R D But, -OR I and R I But R M 5. The compound according to claim 1, which is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

[0230] Embodiment 10: R D But, -NR J R K and R J and R K are independently hydrogen or R M Substituted or unsubstituted C 1~6 5. The compound according to claim 1, wherein R is alkyl, or a pharmaceutically acceptable salt thereof.

[0231] Embodiment 11: R D But R N Substituted or unsubstituted C 1~6 Alkyl or R N Substituted or unsubstituted C 1~6 4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

[0232] Embodiment 12: R D 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein is methyl, ethyl, propyl, or isopropyl.

[0233] Embodiment 13: R D 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein is -C(CH3)2F, -C(CH3)F2, -CH2F, -CHF2, or -CF3.

[0234] Embodiment 14: R D But R N Substituted or unsubstituted C 3~7 Cycloalkyl or RN 4. The compound according to claim 1, which is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

[0235] Embodiment 15: R D But R N 4. The compound according to claim 1, which is a substituted or unsubstituted 3- to 7-membered heterocycloalkyl, or a pharmaceutically acceptable salt thereof.

[0236] Embodiment 16: R E 16. The compound according to any one of claims 1 to 15, wherein is halogen and n is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0237] Embodiment 17: R E 17. The compound according to any one of claims 1 to 16, wherein is F and n is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

[0238] Embodiment 18: R E -OR I and; R I is hydrogen or C 1~3 Unsubstituted alkyl or C 1~3 unsubstituted haloalkyl; and n is 1 16. The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof.

[0239] Embodiment 19: L A 19. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein is -NHSO2- or -NHC(O)-.

[0240] Embodiment 20: L A 20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein is -NHSO2-.

[0241] Embodiment 21: L A20. The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein is -NHC(O)-.

[0242] Embodiment 22: R F But R N Substituted or unsubstituted C 1~6 Alkyl or R N 22. The compound according to any one of claims 1 to 21, which is substituted or unsubstituted benzyl, or a pharmaceutically acceptable salt thereof.

[0243] Embodiment 23: R F But R N 23. The compound according to any one of claims 1 to 22, which is substituted or unsubstituted benzyl, or a pharmaceutically acceptable salt thereof.

[0244] Embodiment 24: R F But R N Substituted or unsubstituted C 1~6 23. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, which is alkyl.

[0245] Embodiment 25: R N But halogen, -CN, R P Substituted or unsubstituted C 1~6 Alkoxy, R P Substituted or unsubstituted C 1~6 Alkyl, or R P Substituted or unsubstituted C 1~6 25. The compound according to any one of claims 22 to 24, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

[0246] Embodiment 26: R N But R P Substituted or unsubstituted 3- to 6-membered heterocycloalkyl, R P Substituted or unsubstituted C 5~7 Cycloalkyl, R P Substituted or unsubstituted C 5~7 Aryl, or R P 25. The compound according to any one of claims 22 to 24, which is a substituted or unsubstituted 5- to 7-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[0247] Embodiment 27: R N 26. The compound according to any one of claims 22 to 25, or a pharmaceutically acceptable salt thereof, wherein is hydrogen, halogen, -OH, -CN, -CF3, -CHF2, -CH2F, -C(CH3)2F, -C(CH3)F2, methyl, ethyl, or propyl.

[0248] Embodiment 28: R F 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted benzyl.

[0249] Embodiment 29: R F But R N substituted benzyl, R N 24. The compound of claim 23, or a pharmaceutically acceptable salt thereof, wherein is halogen, -CN, methyl, ethyl, or propyl.

[0250] Embodiment 30: R F but, [ka] [In the formula, R N is a halogen and m is 1 or 2. 24. The compound of claim 23, wherein:

[0251] Embodiment 31: R F But R N substitution C 1~6 alkyl, and R N But halogen, unsubstituted C 1~6 Haloalkyl, or R P 25. The compound according to claim 24, which is a substituted or unsubstituted 5- to 7-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[0252] Embodiment 32: R F But R N substitution C 1~6 alkyl, and R N 25. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein is F or -CF3.

[0253] Embodiment 33: R F but, [ka] [In the formula, R N is F or methyl] 25. The compound of claim 24, wherein:

[0254] Embodiment 34: A compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein j is 0.

[0255] Embodiment 35: R B and R C However, each independently, R N Substituted or unsubstituted C 1~6 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0256] Embodiment 36: R N But independently, R P 36. The compound according to claim 35, which is a substituted or unsubstituted 3- to 5-membered heterocycloalkyl or halogen, or a pharmaceutically acceptable salt thereof.

[0257] Embodiment 37: R B and R C are each independently an unsubstituted C 1~6 36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein:

[0258] Embodiment 38: R B is a 4-membered heterocycloalkyl, and R C is hydrogen or R N Substituted or unsubstituted C 1~6 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0259] Embodiment 39: R A but, [ka] (RA1) 39. The compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein:

[0260] Embodiment 40:R A but, [ka] (RA2) 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein:

[0261] Embodiment 41: R A 35. The compound according to any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein is 7- to 10-membered spiroheterocycloalkyl.

[0262] Embodiment 42: R A But the expression: [ka] (RA3) [In the formula, X is NR Q or O; R Q is hydrogen, methyl, ethyl, propyl, or isopropyl; y and z are independently 1 or 2. 42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, having the formula:

[0263] Embodiment 43: X is NR Q 43. The compound of claim 42, wherein:

[0264] Embodiment 44: A compound according to claim 42 or 43, or a pharmaceutically acceptable salt thereof, wherein y is 1 and z is 2.

[0265] Embodiment 45: R G are independently halogen or RM Substituted or unsubstituted C 1~6 45. The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0266] Embodiment 46: R G 46. ​​The compound according to any one of claims 1 to 45, or a pharmaceutically acceptable salt thereof, wherein are independently halogen.

[0267] Embodiment 47: R G is independently fluoro; and t is 1 or 2; or a pharmaceutically acceptable salt thereof.

[0268] Embodiment 48: R G 47. The compound according to any one of claims 1 to 46, wherein is fluoro and t is 1, or a pharmaceutically acceptable salt thereof.

[0269] Embodiment 49: R G But independently, R M Substituted or unsubstituted C 1~6 Alkyl or R M Substituted or unsubstituted C 1~6 45. The compound according to any one of claims 1 to 44, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

[0270] Embodiment 50: R A But the expression: [ka] 50. The compound according to any one of claims 1 to 49, or a pharmaceutically acceptable salt thereof, having the formula:

[0271] Embodiment 51: R H 51. The compound according to any one of claims 1 to 50, wherein j is halogen and j is 1, or a pharmaceutically acceptable salt thereof.

[0272] Embodiment 52: R H51. The compound according to any one of claims 1 to 50, wherein j is methyl, ethyl, propyl, or isopropyl, and j is 1, or a pharmaceutically acceptable salt thereof.

[0273] Embodiment 53: R H R D and j is 1; or a pharmaceutically acceptable salt thereof.

[0274] Embodiment 54: Ring Q is R E Substituted or unsubstituted C 5~7 54. The compound according to any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, which is aryl.

[0275] Embodiment 55: Ring Q is R E 55. The compound according to any one of claims 1 to 54, which is substituted or unsubstituted phenyl, or a pharmaceutically acceptable salt thereof.

[0276] Embodiment 56: Ring Q is a group of the formula: [ka] [In the formula, R E1 , R E2 , R E3 , and R E4 are each independently hydrogen, halogen, or R M Substituted or unsubstituted C 1~6 56. The compound according to any one of claims 1 to 55, or a pharmaceutically acceptable salt thereof, wherein R is an integer of 1 to 56, and R is an integer of 1 to 56.

[0277] Embodiment 57: R E1 , R E2 , R E3 , and R E4 57. The compound of claim 56, or a pharmaceutically acceptable salt thereof, wherein each is independently hydrogen or halogen.

[0278] Embodiment 58: Ring Q is R E54. The compound according to any one of claims 1 to 53, which is a substituted or unsubstituted 5- to 7-membered heteroaryl, or a pharmaceutically acceptable salt thereof.

[0279] Embodiment 59: The compound has the formula: [ka] or [ka] 58. The compound according to any one of claims 1 to 57, or a pharmaceutically acceptable salt thereof, having the formula:

[0280] Embodiment 60: The compound has the formula: [ka] [ka] 57. The compound according to any one of claims 1 to 56, or a pharmaceutically acceptable salt thereof, having the formula:

[0281] Embodiment 61: A compound according to Table 1 or a pharmaceutically acceptable salt thereof.

[0282] Embodiment 62: A compound according to Table 2, or a pharmaceutically acceptable salt thereof.

[0283] Embodiment 63: A pharmaceutical composition comprising a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0284] Embodiment 64: A method for treating an IRE1-associated disease or disorder, comprising administering an effective amount of a compound described in any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 63, to a subject having an IRE1-associated disease or disorder.

[0285] Embodiment 65: The method of claim 64, wherein the IRE1-associated disease or disorder is cancer.

[0286] Embodiment 66: The method of claim 65, wherein the cancer is squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, or head and neck cancer.

[0287] Embodiment 67: The method of claim 65, wherein the cancer is lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or myeloproliferative disorder (MPD).

[0288] Embodiment 68: The method of claim 65, wherein the cancer is multiple myeloma.

[0289] Embodiment 69: The method of claim 65, wherein the cancer is triple-negative breast cancer (TNBC).

[0290] Embodiment 70: The method of any one of claims 64 to 69, further comprising administering one or more additional therapeutic agents selected from the group consisting of anti-inflammatory agents, corticosteroids, immunomodulatory agents, anti-cancer agents, pro-apoptotic agents, neurotropic factors, agents for treating cardiovascular disease, agents for treating liver disease, antiviral agents, agents for treating blood disorders, agents for treating diabetes, agents for treating metabolic disorders, agents for treating autoimmune disorders, and agents for treating immunodeficiency disorders.

[0291] Embodiment 71: The method of claim 70, wherein the additional therapeutic agent is a corticosteroid, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 antibody, an anti-VEGF-A antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-interleukin-6 antibody, or a combination thereof.

[0292] Embodiment 72: The method of claim 71, wherein the corticosteroid comprises dexamethasone.

[0293] Embodiment 73: The method of claim 71, wherein the proteasome inhibitor comprises carfilzomib, ixazomib, or bortezomib.

[0294] Embodiment 74: The method of claim 71, wherein the immunomodulatory agent comprises lenalidomide or pomalidomide.

[0295] Embodiment 75: The method of claim 71, wherein the anti-PD-L1 antibody comprises avelumab, durvalumab, or atezolizumab.

[0296] Embodiment 76: The method of claim 71, wherein the anti-PD-1 antibody comprises pembrolizumab or nivolumab.

[0297] Embodiment 77: The method of any one of claims 64 to 76, further comprising administering radiation therapy.

[0298] Embodiment 78: Use of a compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 63 in the manufacture of a medicament for treating an IRE1-associated disease or disorder.

[0299] Embodiment 79: The use described in claim 78, wherein the IRE1-associated disease or disorder is cancer.

[0300] Embodiment 80: The use of claim 79, wherein the cancer is squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, or head and neck cancer.

[0301] Embodiment 81: The use of claim 79, wherein the cancer is lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or myeloproliferative disorder (MPD).

[0302] Embodiment 82: The use of claim 79, wherein the cancer is multiple myeloma.

[0303] Embodiment 83: The use of claim 79, wherein the cancer is triple-negative breast cancer (TNBC).

[0304] Embodiment 84: A compound according to any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 63, for use in a method for treating an IRE1-associated disease or disorder.

[0305] Embodiment 85: The compound for use according to claim 84, wherein the IRE1-associated disease or disorder is cancer.

[0306] Embodiment 86: The compound for use according to claim 85, wherein the cancer is squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, or head and neck cancer.

[0307] Embodiment 87: The compound for use according to claim 85, wherein the cancer is lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS), or myeloproliferative disorder (MPD).

[0308] Embodiment 88: A compound for use according to claim 85, wherein the cancer is multiple myeloma.

[0309] Embodiment 89: The compound for use according to claim 85, wherein the cancer is triple-negative breast cancer (TNBC).

[0310] Embodiment 90: The compound for use according to any one of claims 84 to 89, further comprising administering one or more additional therapeutic agents selected from the group consisting of anti-inflammatory agents, corticosteroids, immunomodulatory agents, anti-cancer agents, pro-apoptotic agents, neurotropic factors, agents for treating cardiovascular disease, agents for treating liver disease, antiviral agents, agents for treating blood disorders, agents for treating diabetes, agents for treating metabolic disorders, agents for treating autoimmune disorders, and agents for treating immunodeficiency disorders.

[0311] Embodiment 91: The compound for use according to claim 90, wherein the additional therapeutic agent is a corticosteroid, a proteasome inhibitor, an immunomodulatory agent, an anti-CD38 antibody, an anti-VEGF-A antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-interleukin-6 antibody, or a combination thereof.

[0312] Embodiment 92: A compound for use according to claim 91, wherein the corticosteroid comprises dexamethasone.

[0313] Embodiment 93: A compound for use according to claim 91, wherein the proteasome inhibitor comprises carfilzomib, ixazomib, or bortezomib.

[0314] Embodiment 94: A compound for use according to claim 91, wherein the immunomodulator comprises lenalidomide or pomalidomide.

[0315] Embodiment 95: A compound for use according to claim 91, wherein the anti-PD-L1 antibody comprises avelumab, durvalumab, or atezolizumab.

[0316] Embodiment 96: A compound for use according to claim 91, wherein the anti-PD-1 antibody comprises pembrolizumab or nivolumab.

[0317] Embodiment 97: A compound for use according to any one of claims 84 to 96, further comprising administering radiation therapy.

[0318] Embodiment 98: A method for inhibiting or killing cancer cells expressing Ire1, comprising contacting the cancer cells expressing Ire1 with a compound described in any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 63.

[0319] Embodiment 99: The method of claim 98, wherein the inhibition or killing is carried out in vivo.

[0320] Embodiment 100: The method of claim 98, wherein the cancer cells expressing Ire1 are in a human.

[0321] Embodiment 101: A method for regulating Ire1 activity, comprising contacting Ire1 with a compound described in any one of claims 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 63.

[0322] Embodiment 102: A kit for treating a condition mediated by IRE1, comprising: a) the pharmaceutical composition of claim 63; and b) Instructions for use Kit including: [Example]

[0323] Working Example: The following examples are offered by way of illustration and not by way of limitation.

[0324] Abbreviation ACN: acetonitrile DCM: dichloromethane DMFN, N-dimethylformamide DMSO: dimethyl sulfoxide EtOAc: ethyl acetate EtOH: ethanol h: time HCl: Hydrochloric acid HPLC: High-Performance Liquid Chromatography IPA: Isopropyl acetate LCMS: Liquid Chromatography Mass Spectrometry Na2SO4: Sodium sulfate THF: tetrahydrofuran

[0325] Example 1 :

[0326] Example 1001: (S)-N-(2,3-difluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1001 [ka]

[0327] Step 1: tert-Butyl (S)-3-((6-bromoquinazolin-2-yl)amino)piperidine-1-carboxylate [ka]

[0328] A mixture of 6-bromo-2-chloroquinazoline (2.0 g, 8.2 mmol), tert-butyl (3S)-3-amino-1-piperidinecarboxylate (2.0 g, 10 mmol), N,N-diisopropylethylamine (5.0 mL, 30 mmol), and cesium fluoride (4.0 g, 26 mmol) in dimethyl sulfoxide (50 mL) was stirred at 80° C. for 2 hours. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The organic layer was concentrated in vacuo. The residue was purified by silica flash chromatography eluting with ethyl acetate / petroleum ether (1:1) to afford the title compound (2.0 g, 59.8% yield) as a yellow solid.

[0329] Step 2: tert-Butyl (S)-3-((6-(4-amino-2,3-difluorophenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate [ka]

[0330] To a solution of tert-butyl (S)-3-((6-(4-amino-2,3-difluorophenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate (896 mg, 2.2 mmol) in 1,4-dioxane (50 mL) and water (5 mL) under nitrogen, 2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (673 mg, 2.6 mmol), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (160 mg, 0.2 mmol), and sodium bicarbonate (554 mg, 6.6 mmol) were added. The mixture was stirred at 90° C. for 5 hours. The solvent was removed in vacuo. The residue was purified by silica flash chromatography eluting with ethyl acetate / petroleum ether (30%) to give the title compound (850 mg, 84.8% yield) as a yellow solid.

[0331] Step 3: tert-Butyl (S)-3-((6-(2,3-difluoro-4-((phenylmethyl)sulfonamido)phenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate [ka]

[0332] To a solution of tert-butyl (S)-3-((6-(4-amino-2,3-difluorophenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate (300 mg, 0.66 mmol) and α-toluenesulfonyl chloride (251 mg, 1.32 mmol) in dichloromethane (2.0 mL), pyridine (780 mg, 9.9 mmol) was added and stirred at 20° C. for 20 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica flash chromatography eluting with ethyl acetate / petroleum ether (70%) to give the title compound (350 mg, 87.2% yield) as a yellow oil. LCMS (ESI): [M+H] + =610.2

[0333] Step 4: (S)—N-(2,3-difluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide hydrochloride [ka]

[0334] A solution of tert-butyl (S)-3-((6-(2,3-difluoro-4-((phenylmethyl)sulfonamido)phenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate (100 mg, 0.16 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at 20° C. for 0.5 h. The solvent was removed in vacuo. The residue was purified by preparative HPLC to give the title compound (48 mg, 53.6% yield) as a yellow solid as the HCl salt.

[0335] Example 1002: (S)—N-(2,3-difluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-3,3,3-trifluoropropane-1-sulfonamide Compound 1002 [ka]

[0336] The title compound was prepared according to Example 1001. This affords the title compound (26.5 mg, 35.2% yield) as a white solid.

[0337] Example 1003: (S)-1-Phenyl-N-(2,3,6-trifluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)methanesulfonamide Compound 1003 [ka]

[0338] The title compound was prepared according to Example 1001. This affords the title compound (44.3 mg, 32.9%) as a white solid.

[0339] Example 1004: (S)-N-(2,4-difluoro-3-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1004 [ka]

[0340] The title compound was prepared according to Example 1001. This affords the title compound (41.4 mg, 25.9% yield) as a yellow solid.

[0341] Example 1005: (S)—N-(4-fluoro-3-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1005 [ka]

[0342] Step 1: Benzyl (S)-3-((6-(2-fluoro-5-((phenylmethyl)sulfonamido)phenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate [ka]

[0343] The title compound was prepared according to Step 3 of Example 1001. This affords the title compound (150 mg, 80.7% yield) as a yellow solid. LCMS (ESI): [M+H] + =626.2

[0344] Step 2: (S)—N-(4-fluoro-3-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide [ka]

[0345] To a mixture of benzyl (S)-3-((6-(2-fluoro-5-((phenylmethyl)sulfonamido)phenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate (150 mg, 0.24 mmol) in acetonitrile (1 mL) and dichloromethane (1 mL), dimethyl sulfide (0.5 mL) and boron trifluoride diethyl etherate (0.5 mL) were added, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated sodium carbonate and dichloromethane. The solvent was concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound (38.9 mg, 32.9% yield) as a white solid.

[0346] Example 1006: (S)-N-(2-fluoro-3-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1006 [ka]

[0347] The title compound was prepared according to Example 1005. This affords the title compound (41.4 mg, 25.8% yield) as a yellow solid. LCMS (ESI) [M+H] + =492.2; 1 H NMR

[0348] Example 1007: (S)-N-(2,3-difluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-2,2-difluorobutane-1-sulfonamide Compound 1007 [ka]

[0349] The title compound was prepared according to Example 1001. This affords the title compound (80 mg, 63.8% yield) as a white solid.

[0350] Example 1008: (S)-N-(4-chloro-2-fluoro-3-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1008 [ka]

[0351] The title compound was prepared according to Example 1005. This affords the title compound (44.7 mg, 31.1% yield) as a yellow solid.

[0352] Example 1009:(S)-N-(2,3-Difluoro-5-methyl-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1009 [ka]

[0353] Step 1: tert-butyl (2,3-difluoro-4-hydroxy-5-methylphenyl)carbamate [ka]

[0354] To a solution of 4-amino-2,3-difluoro-6-methyl-phenol (350 mg, 2.2 mmol) in 1,4-dioxane (12 mL) and water (6 mL) was added sodium bicarbonate (370 mg, 4.4 mmol) and di-tert-butyl dicarbonate (576 mg, 2.6 mmol). The mixture was stirred at 20° C. for 16 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 under vacuum. The residue was purified by silica flash chromatography eluting with ethyl acetate / petroleum ether (16%) to give the title compound (200 mg, 35.1% yield) as a white solid. LCMS (ESI): [M+H] + =260.1.

[0355] Step 2: 4-((tert-butoxycarbonyl)amino)-2,3-difluoro-6-methylphenyl trifluoromethanesulfonate [ka]

[0356] To a solution of tert-butyl (2,3-difluoro-4-hydroxy-5-methylphenyl)carbamate (0.53 g, 2.0 mmol) in dichloromethane (3 mL) was added pyridine (0.32 g, 4.1 mmol) and trifluoromethanesulfonic anhydride (0.69 g, 2.5 mmol) at 0° C. The resulting solution was stirred at the same temperature for 2 hours. The reaction mixture was quenched with water. The resulting solution was extracted with dichloromethane, and the organic layers were combined. The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (650 mg, 83% yield) as a yellow oil. The crude product would be used directly in the next step reaction without purification. LCMS (ESI): [M+H] + =392.1.

[0357] Step 3: tert-butyl (2,3-difluoro-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)carbamate [ka]

[0358] Under nitrogen, a solution of 4-((tert-butoxycarbonyl)amino)-2,3-difluoro-6-methylphenyl trifluoromethanesulfonate (650 mg, 1.6 mmol), bis(pinacolato)diboron (633 mg, 2.5 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (68 mg, 0.08 mmol), and potassium acetate (490 mg, 5.0 mmol) in 1,4-dioxane (7 mL) was stirred at 90°C for 16 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 under vacuum. The residue was purified by silica flash chromatography eluting with ethyl acetate / petroleum ether (3%) to give the title compound (340 mg, 55.4% yield) as a yellow oil. LCMS (ESI): [M+H] + =370.2.

[0359] Step 4: Benzyl (S)-3-((6-(4-((tert-butoxycarbonyl)amino)-2,3-difluoro-6-methylphenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate [ka]

[0360] The title compound was prepared according to Step 3 of Example 1001. This affords the title compound (440 mg, 83.7% yield) as a yellow solid. LCMS (ESI): [M+H]+ = 604.2.

[0361] Step 5: Benzyl (S)-3-((6-(4-amino-2,3-difluoro-6-methylphenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate [ka]

[0362] To a solution of benzyl (S)-3-((6-(4-((tert-butoxycarbonyl)amino)-2,3-difluoro-6-methylphenyl)quinazolin-2-yl)amino)piperidine-1-carboxylate (120 mg, 0.20 mmol) in dichloromethane (1 mL) was added 4 M HCl in 1,4-dioxane (3 mL). The resulting solution was stirred at 25° C. for 1 h. The solvent was removed in vacuo to give the title compound (100 mg, 100% yield) as a yellow solid. LCMS (ESI): [M+H] + =541.0.

[0363] Step 6: (S)—N-(2,3-difluoro-5-methyl-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide [ka]

[0364] The title compound was prepared according to Step 2 of Example 1005. This affords the title compound (21.9 mg, 27.2% yield) as an off-white solid.

[0365] Example 10: (S)-N-(2-fluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1010 [ka]

[0366] The title compound was prepared according to Example 1005. This affords the title compound (20 mg, 37.2% yield) as a yellow solid.

[0367] Example 1011: (S)-N-(2,6-difluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1011 TIFF0007765972000068.tif3180

[0368] The title compound was prepared according to Example 1005. This affords the title compound (16.0 mg, 12.5% ​​yield) as a yellow solid. LCMS (ESI): [M+H] + =510.1; 1 H NMR

[0369] Example 1012: (S)-N-(2,3-difluoro-4-(5-fluoro-2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1012 [ka]

[0370] The title compound was prepared according to Example 1001. This affords the title compound (65.3 mg, 50.2% yield) as a white solid.

[0371] Example 1013: N-(2,6-difluoro-4-(2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1013 [ka]

[0372] The title compound was prepared according to Example 1005. This affords the title compound (20.2 mg, 28% yield) as a yellow solid.

[0373] Example 1014: (S)-1-Phenyl-N-(2,3,5-trifluoro-4-(2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)methanesulfonamide hydrochloride Compound 1014 [ka]

[0374] The title compound was prepared according to Example 1009. This affords the title compound (20.0 mg, 26.1% yield) as a white solid as the HCl salt.

[0375] Example 1015: (S)—N-(2,3-difluoro-4-(7-fluoro-2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide Compound 1015 [ka]

[0376] Step 1: 5-Bromo-4-fluoro-2-nitro-benzaldehyde [ka]

[0377] To a mixture of nitric acid (3 mL, 67 mmol) in sulfuric acid (20 mL) was added 3-bromo-4-fluorobenzaldehyde (5 g, 24 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The mixture was poured into ice water, extracted with ethyl acetate, and concentrated. The residue was purified by silica flash chromatography eluting with ethyl acetate / petroleum ether (2%) to give the title compound (5 g, 81.9% yield) as a yellow solid. 1 H NMR(400MHz,CDCl3) δ 10.40(s,1H),8.24(d,J=6.7Hz,1H),7.92(d,J=7.5Hz,1H).

[0378] Step 2: 2-Amino-5-bromo-4-fluoro-benzaldehyde [ka]

[0379] A mixture of 5-bromo-4-fluoro-2-nitro-benzaldehyde (5.0 g, 20 mmol), iron (3.5 g, 63 mmol), and acetic acid (20 mL, 349 mmol) in water (20 mL) and ethanol (100 mL) was stirred at 80° C. for 2 hours. The solid was filtered off. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica flash chromatography eluting with ethyl acetate / petroleum ether (1 / 4) to give the title compound (3.5 g, 79.6% yield) as a yellow solid. LCMS (ESI): [M+H] + =218.0.

[0380] Step 3: 6-Bromo-7-fluoroquinazolin-2(1H)-one [ka]

[0381] A mixture of 2-amino-5-bromo-4-fluoro-benzaldehyde (3.5 g, 16 mmol) and urea (14 g, 240 mmol) in 1-methyl-2-pyrrolidone (60 mL) was stirred at 115 °C overnight. The resulting solution was diluted with methanol and purified by reverse phase chromatography (acetonitrile / 0.1% aqueous NH4HCO3) to give the title compound (730 mg, 18.7% yield) as a white solid. LCMS (ESI): [M+H] + =242.9.

[0382] Step 4: 6-Bromo-2-chloro-7-fluoro-quinazoline [ka]

[0383] A mixture of 6-bromo-7-fluoroquinazolin-2(1H)-one (720 mg, 2.96 mmol) in phosphorus oxychloride (20 mL) was stirred at 105° C. for 2 hours. After evaporating most of the solvent, the resulting solution was poured into ice water, extracted with ethyl acetate, and concentrated in vacuo. The residue was purified by silica flash chromatography eluting with ethyl acetate / petroleum ether (1 / 4) to give the title compound (380 mg, 49.1% yield) as a white solid. LCMS (ESI): [M+H] + =260.9.

[0384] Step 5: (S)—N-(2,3-difluoro-4-(7-fluoro-2-(piperidin-3-ylamino)quinazolin-6-yl)phenyl)-1-phenylmethanesulfonamide [ka]

[0385] The title compound was prepared according to Example 1001. This affords the title compound (33.3 mg, 32.9% yield) as a yellow solid.

[0386] Example 1016:N-(4-(8-ethyl-2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)quinazolin-6-yl)-3-fluorophenyl)-1-phenylmethanesulfonamide formate Compound 1016 [ka]

[0387] Step 1: 4-Bromo-1-fluoro-2-vinylbenzene [ka]

[0388] Methyltriphenylphosphonium bromide (17.1 g, 47.8 mmol) was suspended in diethyl ether (100 mL) and cooled to 0 °C. Potassium tert-butoxide (5.37 g, 47.8 mmol) was then added, and the resulting yellow suspension was stirred at 0 °C for 15 minutes. 5-Bromo-2-fluorobenzaldehyde (8.09 g, 39.9 mmol) was then added dropwise, and the cooling bath was removed. After stirring at room temperature for 30 minutes, the mixture was diluted with pentane (200 mL), stirred at room temperature for 20 minutes, and then the solid was filtered off. The filtrate was concentrated under reduced pressure, and pentane (200 mL) was added to the crude residue. The suspension was stirred for 20 minutes, and then the solid was filtered off. The filtrate was concentrated under reduced pressure, and the crude material was purified by silica flash chromatography (5% EtOAc / pentane) to give the title compound (7.5 g, 93% yield). 1 H NMR(400MHz,CDCl3)δ 7.59(dd,J=6.6,2.5Hz,1H),7.32-7.28(m,1H),6.92(dd,J=10.0,8.8Hz,1H),6.78( dd,J=17.7,11.2Hz,1H),5.81(dd,J=17.7,0.6Hz,1H),5.41(dd,J=11.2,0.6Hz,1H).

[0389] Step 2: 4-Bromo-2-chloro-1-fluorobenzene [ka]

[0390] To a solution of 4-bromo-1-fluoro-2-vinylbenzene (14.0 g, 69.6 mmol) in methanol (40 mL) was added 10% w / w Pd / C (1.4 g), the flask was sealed, purged with N, then with H, and stirred under a H balloon (1 atm) at room temperature overnight. After 16 h, the flask was purged with N, filtered through Celite, and the filtrate was concentrated under reduced pressure. The filtrate was then dissolved in pentane and filtered through a short pad of silica gel. The filtrate was then concentrated under reduced pressure to give the title compound (12.3 g, 87% yield). 1 H NMR(400MHz,CDCl3) 7.32(dd,J=6.7,2.5Hz,1H),7.29-7.21(m,1H),6.93-6.84(m,1H),2.64(q,J=7.6Hz,2H),1.22(t,J=7.6Hz,3H).

[0391] Step 3: 5-Bromo-3-ethyl-2-fluorobenzaldehyde [ka]

[0392] To a solution of 4-bromo-2-ethyl-1-fluorobenzene (12.3 g, 60.6 mmol) in THF (70 mL) at −78 °C was added a 2 M solution of lithium diisopropylamide in THF / heptane (36.0 mL, 72.7 mmol). The mixture was stirred at −78 °C for 1 h, and then anhydrous DMF (7.03 mL, 90.9 mmol) was added dropwise. After the addition was complete, the cooling bath was removed and the mixture was stirred at room temperature for 3 h. Ethyl acetate (200 mL) was then added, and the solution was washed with 1 N HCl, then water, and then saturated aqueous sodium chloride. The organic extract was dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by silica flash chromatography (0–50% EtOAc / heptane) to give the title compound (10.3 g, 73% yield). 1H NMR(400MHz,CDCl3) 10.30(s,1H),7.80(dd,J=5.6,2.6Hz,1H),7.58(dd,J=6.5,2.6Hz,1H),2.72(q,J=7.6Hz,2H),1.28-1.24(t,J=7.6Hz,3H)

[0393] Step 4: 6-Bromo-8-ethylquinazolin-2-amine [ka]

[0394] Guanidine carbonate (6.86 g, 76.2 mmol) and 5-bromo-3-ethyl-2-fluorobenzaldehyde (11.0 g, 47.6 mmol) were mixed in dimethylacetamide (165 mL) and stirred in a 160 °C oil bath for 1 h. The mixture was then cooled to room temperature, diluted with water (250 mL) and ethyl acetate (200 mL), and the phases were separated. The organic extract was washed with water, then saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (10-100% EtOAc / heptane) to give the title compound (1.3 g, 11% yield). LCMS (ESI) [M+H] + =252.0.

[0395] Step 5: 6-Bromo-2-chloro-8-ethylquinazoline [ka]

[0396] To a mixture of 6-bromo-8-ethylquinazolin-2-amine (1000 mg, 3.97 mmol), chlorotrimethylsilane (0.76 mL, 5.95 mmol), and tetrabutylammonium chloride hydrate (1.65 g, 5.95 mmol) in DMF (1.67 mL) and DCM (19.4 mL) was added tert-butyl nitrite (1.23 g, 11.9 mmol), and the mixture was placed in a 50 °C oil bath overnight. After 16 h, the mixture was diluted with DCM and saturated aqueous sodium bicarbonate, and the phases were separated. The aqueous phase was extracted twice with DCM, and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash chromatography (0–50% EtOAc / heptane) to afford the title compound (430 mg, 40% yield). LCMS (ESI) [M+H] + =272.9.

[0397] Step 6: (3S,5S)-tert-butyl 3-((6-bromo-8-ethylquinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate [ka]

[0398] To a solution of 6-bromo-2-chloro-8-ethylquinazoline (210 mg, 0.77 mmol) in acetonitrile (3.9 mL) were added (3S,5S)-tert-butyl 3-amino-5-fluoropiperidine-1-carboxylate (202 mg, 0.93 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (353 mg, 2.32 mmol), and the mixture was placed in an oil bath at 90 °C. After 4.5 h, the mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate, and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash chromatography (0–40% EtOAc / DCM) to give the title compound (283 mg, 81% yield). LCMS (ESI) [M+H]+ =453.1.

[0399] Step 7: (3S,5S)-tert-butyl 3-((6-(4-amino-2-fluorophenyl)-8-ethylquinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate [ka]

[0400] To a solution of (3S,5S)-tert-butyl 3-((6-bromo-8-ethylquinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate (92 mg, 0.20 mmol) in a mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL), 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (96 mg, 0.41 mmol), sodium carbonate (43 mg, 0.41 mmol), palladium(II) acetate (9.1 mg, 0.04 mmol), and tri-o-tolylphosphine (25 mg, 0.08 mmol) were added in that order. The reaction flask was sealed and purged with N for 10 minutes, then placed in an oil bath at 85 °C. After 3 h, the mixture was cooled to room temperature and diluted with EtOAc and water. The phases were separated, and the organic extract was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (0-40% EtOAc / DCM) to give the title product (62 mg, 63% yield). LCMS (ESI) [M+H] + =484.3.

[0401] Step 8: N-(4-(8-ethyl-2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)quinazolin-6-yl)-3-fluorophenyl)-1-phenylmethanesulfonamide formate [ka]

[0402] To a solution of (3S,5S)-tert-butyl 3-((6-(4-amino-2-fluorophenyl)-8-ethylquinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate (62 mg, 0.13 mmol) in pyridine (0.7 mL) was added phenylmethanesulfonyl chloride (32 mg, 0.17 mmol), and the mixture was stirred at room temperature. After 1 h, the mixture was diluted with methanol, silica gel was added, and the volatiles were removed under reduced pressure. The crude product was adsorbed onto silica gel and purified by silica flash chromatography (10% EtOAc / heptane) to give sulfonamide (3S,5S)-tert-butyl 3-((8-ethyl-6-(2-fluoro-4-(phenylmethylsulfonamido)phenyl)quinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate (56 mg, 68% yield). The thus obtained (3S,5S)-tert-butyl 3-((8-ethyl-6-(2-fluoro-4-(phenylmethylsulfonamido)phenyl)quinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate (56 mg, 0.09 mmol) was treated with 4 N HCl in dioxane (0.6 mL, 2.4 mmol) and stirred at room temperature. After 1 h, the volatiles were removed under reduced pressure, and the crude residue was purified by C18 reverse-phase flash chromatography (0-100% MeCN / 10 mM aqueous ammonium formate, pH = 3.8) to give the title product (29 mg, 55% yield over two steps).

[0403] Example 1017: N-(4-(8-ethyl-2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-1-phenylmethanesulfonamide Compound 1017 [ka]

[0404] Step 1: (3S,5S)-tert-butyl 3-((6-(4-amino-3-fluorophenyl)-8-ethylquinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate [ka]

[0405] Prepared according to Example 1016 (Step 7) to provide the title compound (93 mg, 95% yield). LCMS (ESI) [M+H] + =484.0.

[0406] Step 2: (3S,5S)-tert-butyl 3-((8-ethyl-6-(3-fluoro-4-(phenylmethylsulfonamido)phenyl)quinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate [ka]

[0407] To a solution of (3S,5S)-tert-butyl 3-((6-(4-amino-3-fluorophenyl)-8-ethylquinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate (93 mg, 0.19 mmol) in pyridine (1.0 mL) was added phenylmethanesulfonyl chloride (48 mg, 0.25 mmol), and the mixture was stirred at room temperature. After 90 min, the mixture was diluted with methanol, silica gel was added, the volatiles were removed under reduced pressure, and the crude product was adsorbed onto silica gel and purified by silica flash chromatography (0-100% EtOAc / heptane) to give the title compound (93 mg, 76% yield). LCMS (ESI) [M+H] + =638.0.

[0408] Step 3: N-(4-(8-ethyl-2-(((3S,5S)-5-fluoropiperidin-3-yl)amino)quinazolin-6-yl)-2-fluorophenyl)-1-phenylmethanesulfonamide [ka]

[0409] To a solution of (3S,5S)-tert-butyl 3-((8-ethyl-6-(3-fluoro-4-(phenylmethylsulfonamido)phenyl)quinazolin-2-yl)amino)-5-fluoropiperidine-1-carboxylate (93 mg, 0.15 mmol) in 1,4-dioxane (1.0 mL) was added 4N HCl in dioxane (1 mL, 4 mmol), and the mixture was stirred at room temperature. After 90 min, the volatiles were removed under reduced pressure, and the crude residue was purified by C18 reverse-phase flash chromatography (0-50% MeCN / 10 mM ammonium formate in water, pH = 3.8) to give the title product (44 mg, 56% yield).

[0410] Example 1018: N-(4-(2-(((1,4-trans)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-3,3,3-trifluoropropane-1-sulfonamide Compound 1018 [ka]

[0411] Step 1: (1,4-trans)-N 1 -(6-bromo-8-ethylquinazolin-2-yl)-N 4 ,N 4 -Dimethylcyclohexane-1,4-diamine [ka]

[0412] To a solution of 6-bromo-2-chloro-8-ethylquinazoline (100 mg, 0.37 mmol) in acetonitrile (1.8 mL) was added (1,4-trans)-N 1 ,N 1-Dimethylcyclohexane-1,4-diamine (92 mg, 0.52 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (168 mg, 1.10 mmol) were added. The mixture was placed in a 60 °C oil bath. After 3 h, the mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate, and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, and the combined organic extracts were washed with saturated aqueous sodium chloride, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica flash chromatography (0-100% EtOAc / DCM) to give the title compound (61 mg, 44% yield). LCMS (ESI) [M+H] + =377.1.

[0413] Step 2: (1,4-trans)-N 1 -(6-(4-amino-3-fluorophenyl)-8-ethylquinazolin-2-yl)-N 4 ,N 4 -Dimethylcyclohexane-1,4-diamine [ka]

[0414] (1,4-trans)-N in a mixture of 1,2-dimethoxyethane (4 mL) and water (1 mL) 1 -(6-bromo-8-ethylquinazolin-2-yl)-N 4 ,N 4To a solution of 2-dimethylcyclohexane-1,4-diamine (63 mg, 0.17 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (79 mg, 0.33 mmol), sodium carbonate (35 mg, 0.33 mmol), palladium(II) acetate (3.8 mg, 0.02 mmol), and tri-o-tolylphosphine (10 mg, 0.03 mmol) were added in that order. The reaction flask was sealed and purged with N for 10 minutes, then placed in an oil bath at 85 °C. After 3 hours, the mixture was cooled to room temperature and diluted with EtOAc and water. The phases were separated, and the organic extract was washed with saturated aqueous sodium chloride, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by C18 reverse-phase flash chromatography (10-70% acetonitrile / 10 mM aqueous ammonium formate) to give a yellow solid. This solid was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, and the phases were separated. The organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (24 mg, 35% yield). LCMS (ESI) [M+H] + =408.3.

[0415] Step 3: N-(4-(2-(((1,4-trans)-4-(dimethylamino)cyclohexyl)amino)-8-ethylquinazolin-6-yl)-2-fluorophenyl)-3,3,3-trifluoropropane-1-sulfonamide [ka]

[0416] (1,4-trans)-N in a mixture of DCM (0.29 mL) and pyridine (0.095 mL, 1.18 mmol) 1 -(6-(4-amino-3-fluorophenyl)-8-ethylquinazolin-2-yl)-N 4 ,N 4To a solution of 24 mg (0.06 mmol) of 3,3,3-dimethylcyclohexane-1,4-diamine (3,3,3-trifluoropropane-1-sulfonyl chloride) was added 16 mg (0.08 mmol), and the mixture was stirred at room temperature. After 3 h, the mixture was diluted with MeOH, and the volatiles were removed under reduced pressure. The crude material thus obtained was purified by C18 reverse-phase chromatography (20–100% MeCN / 10 mM aqueous ammonium bicarbonate, pH = 10). The appropriate fractions were combined and lyophilized to give the title product (13.5 mg, 40% yield).

[0417] Example 1019. IRE1α TR-FRET competitive binding assay

[0418] To determine the affinity of compounds for binding to the kinase domain of IRE1α, a time-resolved fluorescence resonance energy transfer (TR-FRET) competition assay was used.

[0419] A His-tagged IRE1α kinase-dead construct containing the kinase and RNase domains (KR, AA G547-L977, D688N) was expressed in Sf9 insect cells. Purified protein (final concentration 0.25 nM) was preincubated with an anti-His europium-labeled antibody (Life Technologies, PV5596, final concentration 2 nM) in TR-FRET assay buffer (50 mM HEPES, pH 7.5, 10 mM MgCl2, 0.083 mM Brij35, 1 mM DTT, and 0.1% bovine gamma globulin) at 4°C for 1 h before adding test compounds. Alexa fluor 647-labeled probes based on ATP-competitive inhibitors were added to a final concentration of 2 nM. Reactions were performed at room temperature for 1 h in 384-well white ProxiPlates (Perkin Elmer 6008289) with a final volume of 20 μL. Binding of the probe to the IRE1α protein was detected on an Envision instrument (PerkinElmer) equipped with the TRF laser option and a LANCE / Delfia Dual / Bias D400 / D630 mirror (Ex 347 nm, 1st Em 665 nm, 2nd Em 615 nm).

[0420] Example 1020. IRE1α RNase activity assay.

[0421] Inhibitors of IRE1α RNase activity were evaluated by using mini-XBP-1 stem-loop RNA as a substrate for IRE1α RNase activity. A 5'-carboxyfluorescein (FAM) and 3'-Black Hole Quencher (BHQ)-labeled XBP1 single stem-loop minisubstrate (5'FAM-CAUGUCCGCAGCGCAUG-3'BHQ) was cleaved by IRE1α. When the oligo was intact, the fluorescent signal was quenched by BHQ. Upon cleavage, the fluorescence was no longer quenched and could be quantified.

[0422] The IRE1α construct (LKR, AA Q470-L977) corresponding to the linker, kinase, and RNase domains was expressed in Sf9 insect cells. All reagent preparations and procedures were performed under RNase-free conditions. Test compounds and purified enzyme were combined in RNase assay buffer (20 mM HEPES, pH 7.5, 50 mM KAc, 1 mM MgAc, 1 mM DTT, and 0.05% Triton X-100) in a 384-well white ProxiPlate (Perkin Elmer 6008289). After addition of RNA substrate (final assay volume 20 μL), the plate was placed in a Flexstation 3 instrument (Molecular Devices), and kinetic fluorescence measurements were performed at 2-minute intervals (Ex485, Em535). Reaction rates over the first 50 minutes were used to calculate RNase activity and inhibition of test compounds.

[0423] Example 1021: IRE1α Ribonucleic Acid Luciferase Reporter Assay

[0424] HEK293 cells expressing the pBABE.puro_HA-2xXBP1delta DBD firefly luciferase reporter (obtained from the University of California, San Francisco (UCSF, Walter Laboratory)) were cultured in DMEM high-glucose medium containing L-glutamine, 10% fetal bovine serum, 100 units / mL penicillin and 100 μg / mL streptomycin, and 2 μg / mL puromycin to maintain selection pressure. Upon stimulation of IRE1 and activation of endogenous RNase activity, a 26-nt intron is removed from XBP1, resulting in a frameshift and allowing transcription of luciferase.

[0425] Cells were seeded at 10,000 / well in 25 μL of 384-well clear-bottom white tissue culture plates (Corning 3707) without puromycin. The following morning, test compounds were added and incubated at 37°C for 1 hour, after which the cells were stimulated with thapsigargin at a final concentration of 50 μM for an additional 5 hours. After equilibration to room temperature, 25 μL of One-Glo Luciferase Detection Reagent (Promega, Cat. No. E6120) was added, the plate was sealed, and shaken for 5 minutes to lyse the cells. Luciferase was then quantified by luminescence detection using an Envision instrument (PerkinElmer).

[0426] XBP1 reporter cell line reference: Mendez AS, Alfaro J, Morales-Soto MA, Dar AC, McCullagh E, Gotthardt K, Li H, Acosta-Alvear D, Sidrauski C, Korennykh AV, Bernales S, Shokat KM, Walter P. 2015. Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule Referenced in ATP-mimic.eLife 2015;4:e05434. All technical and scientific terms used herein have the same meaning. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental errors and deviations should be accounted for.

[0427] Throughout this specification and the claims, the words "comprise / comprises / comprising" are used in a non-exclusive sense unless the context requires otherwise. Embodiments described herein are understood to include embodiments "consisting of" and / or "consisting essentially of."

[0428] Where a range of values ​​is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, between the upper and lower limit of that range and any other value or intervening value stated within that range is included herein, unless the context dictates otherwise. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also included therein, subject to any specifically excluded limit in the stated range. When the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included herein.

[0429] Many modifications of the inventions described herein and other embodiments of the inventions will come to mind to one skilled in the art to which these inventions pertain having the benefit of the teachings presented in the foregoing descriptions and the accompanying drawings. It is to be understood, therefore, that the invention is not to be limited to the specific embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

1. Formula (A): 【Chemistry 1】 (A) [In the formula, Ring Q is R Ｅ is a substituted or unsubstituted phenyl; L Ａ is -NHSO ２ -, where the nitrogen is attached to ring Q; R Ａ teeth, 【Chemistry 2】 and R Ｂ and R Ｃ is methyl; R Ｄ is hydrogen or ethyl; Each R Ｅ is hydrogen, —F, —Cl, or methyl; n is 0, 1, 2, 3, or 4; R Ｆ is benzyl or R Ｎ Substitution C １～６ is alkyl; Each R Ｇ is fluorine; t is 0 or 1; Each R Ｈ is fluorine; j is 0 or 1; Each R Ｎ are independently hydrogen, fluorine, or C １～６ alkyl] or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.

2. 1. The compound of formula: 【Transformation 3】 2. The compound of claim 1, wherein:

3. R Ｄ 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein is ethyl.

4. R Ｅ The compound according to any one of claims 1 to 3, wherein n is F and n is 1, 2, or 3, or a pharmaceutically acceptable salt thereof.

5. R Ｆ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is benzyl.

6. R Ｆ but, 【Chemistry 4】 [In the formula, R Ｎ is F or methyl.

6. The compound of claim 5, wherein:

7. R Ａ but, 【Transformation 5】 (RA1) 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein:

8. R Ａ but, 【Transformation 6】 (RA2) 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein:

9. The compound according to any one of claims 1 to 8, wherein j is 1, or a pharmaceutically acceptable salt thereof.

10. L Ａ and the ring Q linked to the formula: 【Transformation 7】 [In the formula, R Ｅ１ , R Ｅ２ , R Ｅ３ , and R Ｅ４ are each independently hydrogen, —F, —Cl, or methyl. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, having the formula:

11. The compound is Table 1 Table 2 Table 3 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition according to claim 12 for treating an IRE1-associated disease or disorder, wherein the IRE1-associated disease or disorder is cancer.

14. 14. The pharmaceutical composition of claim 13, wherein the cancer is squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer (NSCLC), lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastric cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, uterine cancer, salivary gland carcinoma, kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, hepatocellular carcinoma (HCC), anal carcinoma, penile carcinoma, head and neck cancer, lymphoma, lymphocytic leukemia, multiple myeloma (MM), acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), multiple myeloma, or triple-negative breast cancer (TNBC).

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