Heterocyclics as EGFR inhibitors

Abstract

The present application relates to EGFR inhibitor compounds of Formula (I), as defined herein, and pharmaceutically acceptable salts thereof. The present application also describes pharmaceutical composition comprising a compound of Formula (I), and pharmaceutically acceptable salts thereof, and methods of using the compounds and compositions for inhibiting certain protein-protein interactions, and for treating cancer.

Description

Attorney Docket No.94019-421948 (P30880-WO-PCT) HETEROCYCLICS AS EGFR INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of Indian Provisional Application No.202411037128, filed May 10, 2024, which is incorporated by reference herein in its entirety. TECHNICAL FIELD

[0002] The present application relates to heterocyclic compounds that are useful for treating proliferative disorders such as cancer. BACKGROUND

[0003] The epidermal growth factor receptor (EGFR) is a transmembrane receptor that can transduce mitogenic signaling. Upon binding of extracellular protein ligands, such as EGF and EGF family members, EGFR undergoes a conformational change, leading to homo or heterodimerization, stimulation of its intrinsic tyrosine kinase activity, autophosphorylation of several tyrosine residues in its intracellular domain, and signal transduction of MAPK / ERK, AKT, and JNK pathways. Ultimately, induction of these pathways can lead to DNA synthesis, cell proliferation, and cell migration (Normano et al., Gene 366(1):2-16 (2006)).

[0004] Mutations in the EGFR gene are found in approximately 15-40% of non-small cell lung cancer (NSCLC) and of those, 80% lead to either a short in-frame deletion of exon 19 (Del19) or a single missense mutation in exon 21, L858R (Midha et al., Am J Cancer Res 15;5(9):2892-911 (2015)). Both of these mutations lead to ligand-independent EGFR activation, driving tumor survival and proliferation. While treatment of patients with first and second generation EGFR inhibitors, such as erlotinib, gefitinib, and afatinib, can lead to a marked tumor regression, this response is short-lived. Most treated patients (50-70%) experience disease progression with the acquisition of T790M, a gatekeeper mutation with increased affinity for ATP (Blakely et al., Cancer Discov 2(10):872-5 (2012)).

[0005] Osimertinib, a third-generation EGFR inhibitor, overcomes T790M-driven resistance while maintaining efficacy against del19 or L858R driver mutations (Mok et al., N Engl J Med 376:629-640 (2017)). Relative to earlier EGFR inhibitors, osimertinib has several notable characteristics: 1) greater selectivity for mutants over WT EGFR; 2) lower rates and severity of gastrointestinal and dermatological toxicities; and 3) efficacy against brain metastases owing to CNS exposure. These features led to FDA approval for T790M mutation-positive NSCLC in 2015 and approval as a first line treatment of EGFR- mutant NSCLC in 2018 (Ramalingam et al., N Engl J Med 382(1):41-50 (2020)).Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0006] While osimertinib demonstrates clear clinical efficacy, new on-target resistance mechanisms have emerged in response to treatment with the third generation inhibitor. In particular, the C797S mutation - which prevents osimertinib from forming a covalent bond with a cysteine residue in the binding site - has been observed in patients treated with osimertinib. In relapsed patients that developed the T790M mutation before treatment with osimertinib, 22-40% of patients developed this resistance mutation (Madic et al., Oncotarget 9(100):37393-37406 (2018)). In patients treated with osimertinib in the first line, 7% of patients have been reported to develop the C797S mutation (Leonetti et al., Br J Cancer 21(9):725-737 (2019)).

[0007] Thus, on-target resistance to osimertinib through the EGFR C797S mutation has been observed on its own in patients treated with osimertinib in the first line and in combination with T790M in patients who have progressed after sequential treatment with first generation inhibitors and osimertinib. First generation EGFR compounds retain activity against the C797S mutation in the absence of T790M and have been combined with osimertinib to treat patients who develop T790M and C797S mutations in trans after sequential treatment with first generation and third generation inhibitors (Arunalananda et al., J Thorac Oncol 12(11):1728-1732 (2017)). However, first generation EGFR compounds exhibit poor CNS penetrance, enabling the development of CNS metastases, and only achieve modest selectivity over WT EGFR, which limits their tolerability and utility in combination with other agents. Zorifertinib, which has activity against mutant EGFR and can penetrate the blood brain barrier, is under evaluation in patients with advanced EGFR mutation positive NSCLC with CNS metastasis. However, this compound achieves only modest (<10-fold) mutant EGFR selectivity and has demonstrated high rates of gastrointestinal and skin toxicities associated with inhibition of WT EGFR (Yang et al., Oncotarget.7:78985-78993 (2016); Ahn et al., Lancet Respir Med 5(11):891-902 (2017)). Thus, there is a need to develop brain penetrant compounds that are active against EGFR activating mutations (Del-19 or L858R), spare EGFR WT, and retain activity in the presence of the C797S mutation. SUMMARY

[0008] It has now been found that certain polycyclic heteroaromatic compounds can function as small- molecule tyrosine kinase inhibitors (e.g., inhibitors of EGFR activity), and are useful for treating various diseases and disorders, such as cancers.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0009] Accordingly, provided herein is a compound of Formula (I): or a pharmaceutically acceptable salt R1, n, X, Y, and Z are as defined herein.

[0010] Also provided herein is aincluding a compound of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0011] Also provided herein is a method of inhibiting mammalian cell proliferation, in vitro or in vivo, including contacting a cell with an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0012] Also provided herein is a method of treating cancer in a subject in need of such treatment, including administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0013] Other features and advantages of the invention will be apparent from the following detailed description and figures, and from the claims. DETAILED DESCRIPTION I. GENERAL

[0014] The present application provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and / or hydrate, and / or cocrystal, and / or drug combination of the compound) that inhibit epidermal growth factor receptor (EGFR, ERBB1). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) EGFR activation contributes to the pathology and / or symptoms and / or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). The present application also provides compositions containing the same, as well as methods of using and making the same. II. DEFINITIONS A. General Definitions

[0015] Before the present invention is further described, it is to be understood that this invention is not strictly limited to particular embodiments described, as such may of course vary. It is also to beAttorney Docket No.94019-421948 (P30880-WO-PCT) understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the claims.

[0016] Unless defined otherwise, 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. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed.

[0017] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.

[0018] When ranges of number values are disclosed, and the notation “from n1... to n2” is used, where n1and n2are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values. By way of example, the range “from 2 to 6 carbons” is intended to include two, three, four, five, and six carbons, since carbons come in integer units. Compare, by way of example, the range “from 1 to 3 μM (micromolar),” which is intended to include 1 μM, 3 μM, and everything in between to any number of significant figures (e.g., 1.255 μM, 2.1 μM, 2.9999 μM, etc.).

[0019] The term “about,” as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. When no particular margin of error, such as a standard deviation to a mean value given in a chart or table of data, is recited, the term “about” should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure, taking into account significant figures.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0020] “A,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth. B. Chemical Definitions

[0021] The following chemical functional group definitions are provided to give guidance in understanding their meaning and scope. Those skilled in the art will recognize that these functional groups are being used in a manner consistent with practice of the chemical arts. Any of the following chemical functional groups may be optionally substituted as defined below and each chemical functional group below may itself be an optional substitution.

[0022] As used herein, the term “compounds of the invention” refers to the compounds of formula (I) and all of the embodiments thereof, as described herein, and to the compounds identified in Tables A, B, C, and D.

[0023] As used herein, the term “compound,” when referring to the compounds of the invention, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules. The term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus, the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, colloid, or pharmaceutical composition, or dosage form) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

[0024] The term “alkyl” as used herein, alone or in combination, (sometimes abbreviated Alk) refers to a straight-chain or branched-chain alkyl radical containing from 1 to 20 carbon atoms. In certain embodiments, the alkyl may comprise from 1 to 10 carbon atoms. In further embodiments, the alkyl may comprise from 1 to 6 carbon atoms, or from 1 to 3 carbon atoms. Alkyl can include any number of carbons, such as C2, C3, C4, C5, C6, C7, C8, C9, and C10. For example, C16alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbons atoms, such as, but not limited to heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted. The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (–CH2–). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. When the alkyl is methyl, it may be represented structurally as –CH3, Me, or just a single bond terminating with no end group substitution.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0025] The term “alkenyl” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl may comprise from 2 to 6 carbon atoms, or from 2 to 4 carbons, either of which may be referred to as “lower alkenyl.” The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene (–CH=CH–). Alkenyl can include any number of carbons, such as C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, and C20, and so on up to 20 carbon atoms. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups.

[0026] The term “alkynyl” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, the alkenyl may comprise from 2 to 6 carbon atoms, or from 2 to 4 carbons, either of which may be referred to as “lower alkynyl.” Alkynyl can include any number of carbons, such as C2, C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17, C18, C19, and C20. Alkenyl groups can have any suitable number of triple bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, ethynyl. Alkynyl groups can be substituted or unsubstituted. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups.

[0027] The term “alkoxy” as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined above. Alkoxy groups may have the general formula: alkyl-O–. As for alkyl group, alkoxy groups can have any suitable number of carbon atoms. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, secbutoxy, tertbutoxy, pentoxy, hexoxy, and the like. The alkoxy groups can be further optionally substituted as defined herein.

[0028] The term “halo” or “halogen” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine.

[0029] The term “haloalkyl” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl, trihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different haloAttorney Docket No.94019-421948 (P30880-WO-PCT) radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (–CFH–), difluoromethylene (–CF2–), chloromethylene (–CHCl–) and the like.

[0030] The term “hydroxy” as used herein, alone or in combination, refers to OH.

[0031] The term “hydroxyalkyl” as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group. “Hydroxyalkyl” or “alkylhydroxy” refers to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a hydroxy group. As for the alkyl group, hydroxyalkyl or alkylhydroxy groups can have any suitable number of carbon atoms, such as C1-6. Exemplary C1-4hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (where the hydroxy is in the 1 or 2 position), hydroxypropyl (where the hydroxy is in the 1, 2 or 3 position), hydroxybutyl (where the hydroxy is in the 1, 2, 3 or 4 position), 1,2-dihydroxyethyl, and the like.

[0032] The term “cyanoalkyl” as used herein, alone or in combination, refers to a cyano group (–CN) attached to the parent molecular moiety through an alkyl group. “Cyanoalkyl” or “alkylcyano” refers to an alkyl group, as defined above, where at least one of the hydrogen atoms is replaced with a cyano group. As for the alkyl group, cyanoalkyl or alkylcyano groups can have any suitable number of carbon atoms, such as C1-6or C1-C3. Exemplary C1-4cyanoalkyl groups include, but are not limited to, cyanomethyl, cyanoethyl (where the cyano group is in the 1 or 2 position), cyanopropyl (where the cyano group is in the 1, 2 or 3 position), cyanobutyl (where the cyano group is in the 1, 2, 3 or 4 position), and the like.

[0033] The term “cyanoalkenyl” as used herein, alone or in combination, refers to a cyano group (–CN) attached to the parent molecular moiety through an alkenyl group. “Cyanoalkenyl” or “alkenylcyano” refers to an alkenyl group, as defined above, where at least one of the hydrogen atoms is replaced with a cyano group. As for the alkenyl group, cyanoalkenyl or alkenylcyano groups can have any suitable number of carbon atoms, such as C2-6or C2-C4.

[0034] As used herein, the term “cycloalkyl” refers to a saturated or partially unsaturated mono- or bicyclic carbon group having 3 to 10 carbon atoms, such as C3-C10cycloalkyl groups and C3-C6cycloalkyl groups. Bicyclic cycloalkyl groups include fused, spiro, and bridged ring systems. Non-limiting examples of cycloalkyl groups include phenyl, 2,3-dihydro-1H-indene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2.3]hexyl, spiro[3.3]heptanyl, and bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and spiro[2.5]octyl.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0035] The term “heterocyclyl” refers to a saturated or partially unsaturated hydrocarbon monocyclic or bicyclic ring system, having 3 to 10 ring atoms, that is not aromatic, having at least one heteroatom within the ring selected from N, O and S. Bicyclic heterocyclyl groups include fused, spiro, and bridged ring systems. The heterocyclyl group may be denoted as, for example, a “5 to 10-membered heterocyclyl group,” which is a ring system containing 5, 6, 7, 8, 9 or 10 atoms at least one being a heteroatom. Heterocyclyl groups can, for example, have 1, 2, 3, or more, heteroatoms. In some embodiments, a heterocyclyl group has one or two independently selected heteroatoms. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. The heterocyclyl group may be bonded to the rest of the molecule through any carbon atom or through a heteroatom such as nitrogen. Exemplary heterocyclyl groups include, but are not limited to azepanyl, 1,3-dioxolane, 1,4-dioxolanyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, quinuclidineyl, 4H-pyranyl, azetidinyl, oxetanyl, octahydrocyclopenta[c]pyrrole, 2-azaspiro[3.3]heptanyl, 3-oxabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.1]heptanyl, 4-azaspiro[2.5]octanyl, 6-azaspiro[3.5]nonanyl, 2,6-diazaspiro[3.3]heptanyl, 7-azabicyclo[2.2.1]heptanyl, 2-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.2]octanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxabicyclo[2.1.1]hexanyl, 3-azabicyclo[3.2.1]octanyl, hexahydro-1H-cyclopenta[c]pyrrolyl, 3-oxa-9-azabicyclo[3.3.1]nonanyl, and hexahydro-1H-pyrrolizinyl.

[0036] The term “aryl” as used herein, alone or in combination, refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. Exemplary aryls are hydrocarbon ring system radical comprising hydrogen and 6 to 10 carbon atoms and at least one aromatic ring; hydrocarbon ring system radical comprising hydrogen and 9 to 12 carbon atoms and at least one aromatic ring; hydrocarbon ring system radical comprising hydrogen and 12 to 15 carbon atoms and at least one aromatic ring; or hydrocarbon ring system radical comprising hydrogen and 15 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0037] As used herein, the term “heteroaryl” refers to a 5- to 10-membered mono- or bicyclic group wherein at least one ring in the system is aromatic; and wherein one or more carbon atoms in at least one ring in the system is / are replaced with an heteroatom independently selected from N, O, and S. Non-limiting examples of heteroaryl groups include furanyl, furazanyl, thiofuranyl, benzothiophenyl, phthalazinyl, pyrrolyl, oxazolyl, benzoxazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazole, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, indolyl, indazole, pyrazolyl, benzopyrazolyl, isoxazolyl, benzoisoxazole, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, purinyl, pteridinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, triazinyl, 2,3-dihydrobenzofuranyl, and 5,6,7,8-tetrahydroimidazo[1,5]pyridinyl.

[0038] As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or triple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0039] As used herein, the term “spirocycle” refers to a direct attachment of a ring, including for example a carbocycle, heterocycle, aromatic and heteroaromatic ring, to a single carbon atom of the rest of the molecule, where the carbon at the point of attachment is part of the ring. Spirocyclic moieties include, for example, spirocyclic cycloalkyls (e.g., cyclobutane, cyclopentane, cyclohexane, etc.), spirocyclic dioxane, spirocyclic dioxolane, spirocyclic methylpyrrolidin-2-one, spyrocyclic 3-methyl-4,5-dihydroisoxazole, and spirocyclic tetrahydrofuran.

[0040] The term “cyano” as used herein, alone or in combination, refers to –CN.

[0041] The term “oxo” as used herein, alone or in combination, refers to =O.

[0042] In embodiments of the invention, any one of the positions that is understood to have a hydrogen may also exist or understood to be isotopically enriched. In the compounds of this invention any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Obtaining 100% deuteration at any relevant site of a compound in an amount of milligram or greater can be difficult. Therefore, it is understood that some percentage of hydrogen may still be present, even though a deuterium atom is specifically shown in a chemical structure. Thus, when a chemical structure contains a “D,” the compound represented by the structure is deuterium-enriched at the site represented by “D.” Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen,” the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated specifically as “D” or “deuterium,” the position is understood to have deuterium at an abundance that is at least 3340 times greater than the naturalAttorney Docket No.94019-421948 (P30880-WO-PCT) abundance of deuterium, which is 0.015% (i.e., the term “D” or “deuterium” indicates at least 50.1% incorporation of deuterium). In embodiments, a benzene ring may be optionally exist as –C6D5, –C6DH4, –C6D2H3, –C6D3H2, and –C6D4H. In embodiments, a cyclohexyl group may optionally exist as –C6D11.

[0043] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

[0044] The term “optionally substituted” means the anteceding group or groups may be substituted or unsubstituted. Groups constituting optional substitution may themselves be optionally substituted. For example, where an alkyl group is embraced by an optional substitution, that alkyl group itself may also be optionally substituted. When substituted, the substituents of an “optionally substituted” group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: alkyl, alkenyl, alkynyl, alkanoyl, heteroalkyl, heterocycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, lower perhaloalkyl, perhaloalkoxy, cycloalkyl, phenyl, aryl, aryloxy, alkoxy, haloalkoxy, oxo, acyloxy, carbonyl, carboxyl, alkylcarbonyl, carboxyester, carboxamido, cyano, hydrogen, halogen, hydroxy, amino, alkylamino, arylamino, amido, sulfonamido, thioamido, nitro, thiol, alkylthio, haloalkylthio, perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, pyridinyl, thiophene, furanyl, carbamate, thiocarbamate, thiourea, and urea. Particular subsets of optional substitution include, without limitation: (1) alkyl, halo, and alkoxy; (2) alkyl and halo; (3) alkyl and alkoxy; (4) alkyl, aryl, and heteroaryl; (5) halo and alkoxy; and (6) hydroxyl, alkyl, halo, alkoxy, and cyano. Where an optional substitution includes a heteroatom-hydrogen bond (–NH-, SH, OH), further optional substitution of the heteroatom hydrogen is contemplated and includes, without limitation optional substitution with alkyl, acyl, alkoxymethyl, alkoxyethyl, arylsulfonyl, alkyl sulfonyl, arylsulfoximinyl, alkylsulfoximinyl, any of which are further optionally substituted. These subsets of optional substitutions are intended to be merely exemplary and any combination of 2 to 5, or 2 to 10, or 2 to 20 of the groups recited above up to all the group recited above and any subrange in between are contemplated. “Optionally substituted” may include any of the chemical functional groups defined hereinabove and throughout this disclosure. Two optional substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., –CH2CH3), fully substitutedAttorney Docket No.94019-421948 (P30880-WO-PCT) (e.g., –CF2CF3), monosubstituted (e.g., –CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., –CH2CF3).

[0045] The various optional substitutions need not be the same and any combination of optional substituent groups may be combined. For example, a carbon chain may be substituted with an alkyl group, a halo group, and an alkoxy group. Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, “optionally substituted with.”

[0046] Asymmetric centers, axial asymmetry (non-interchanging rotamers), or the like may exist in the compounds of the various embodiments disclosed herein. Such chirality may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the chiral carbon atom or the relevant axis. It should be understood that embodiments encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms, d-isomers and l-isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the various embodiments disclosed herein may exist as geometric isomers. The various embodiments disclosed herein includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers, including keto-enol tautomers; all tautomeric isomers are embraced by the embodiments disclosed herein.

[0047] Additionally, the compounds of the various embodiments disclosed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the various embodiments disclosed herein.

[0048] Compounds provided herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. That is, an atom, in particular when mentioned in relation to a compound of the invention, includes all isotopes and isotopic mixtures of that atom, either naturally occurring or synthetically produced, either with natural abundance or in an isotopically enriched form. For example, when hydrogen is mentioned, it is understood to refer to1H,2H,3H or mixturesAttorney Docket No.94019-421948 (P30880-WO-PCT) thereof; when carbon is mentioned, it is understood to refer to11C,12C,13C,14C or mixtures thereof; when nitrogen is mentioned, it is understood to refer to13N,14N,15N or mixtures thereof; when oxygen is mentioned, it is understood to refer to14O,15O,16O,17O,18O or mixtures thereof; and when fluoro is mentioned, it is understood to refer to18F,19F or mixtures thereof; unless expressly noted otherwise. For example, in deuteroalkyl and deuteroalkoxy groups, where one or more hydrogen atoms are specifically replaced with deuterium (2H). As some of the aforementioned isotopes are radioactive, the compounds provided herein therefore also comprise compounds with one or more isotopes of one or more atoms, and mixtures thereof, including radioactive compounds, wherein one or more non-radioactive atoms has been replaced by one of its radioactive enriched isotopes. Radiolabeled compounds are useful as therapeutic agents, e.g., cancer therapeutic agents, research reagents, e.g., assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention. Salts and Prodrugs of Compounds

[0049] Unless stated otherwise, any reference to a compound of formula (I) in connection with the invention should be understood to include the tautomers, racemates, and stereoisomers (e.g.atropisomers, enantiomers, diastereomers, etc. and mixtures of any of the foregoing) thereof, if any. In some embodiments, the invention relates to pharmaceutically acceptable salts, solvates, hydrates, polymorphs, physiologically functional derivatives (e.g. deuterated forms), metabolites, and / or prodrugs of a compound of formula (I).

[0050] The compounds disclosed herein can exist as pharmaceutically acceptable salts, including acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002). It is understood that each of the compounds disclosed herein, and each embodiment of the compounds set forth herein, include pharmaceutically acceptable salts of such compounds.

[0051] The compounds of the invention include pharmaceutically acceptable salts thereof. In addition, the compounds of the invention also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and / or purifying compounds of the invention and / or for separating enantiomers of compounds of the invention.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0052] It will further be appreciated that the compounds of the invention or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention. For example, compounds of the invention and salts thereof can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[0053] In some embodiments, the compounds of the invention include the compounds of Examples 1-775 and stereoisomers and pharmaceutically acceptable salts and solvates thereof. In some embodiments, the compounds of Examples 1-775 are in the free base form. In some embodiments, the compounds of Examples 1-775 are in the form of a pharmaceutically acceptable salt.

[0054] The term “pharmaceutically acceptable salt,” as used herein, represents salts or zwitterionic forms of the compounds disclosed herein which are water or oil-soluble or dispersible and pharmaceutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds of the various embodiments disclosed herein can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and benzyl and phenethyl bromides. Examples of acids which can be employed to form pharmaceutically acceptable addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the various embodiments disclosed herein contemplates sodium, potassium, magnesium, and calcium salts of the compounds disclosed herein, and the like.

[0055] The term “prodrug” refers to a compound that is made active in vivo through chemical reaction in vivo thereby releasing an active compound. Compounds disclosed herein can be modified to exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readilyAttorney Docket No.94019-421948 (P30880-WO-PCT) undergo chemical changes under physiological conditions to provide the active compound. Additionally, prodrugs can be converted to the active compounds by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the active compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug is a compound which is administered as an ester (the “prodrug”), which is then metabolically hydrolyzed to the carboxylic acid, as the active entity. Additional examples include peptidyl derivatives of a compound. The term “therapeutically acceptable prodrug,” refers to those prodrugs or zwitterions that are suitable for use in contact with the tissues of subjects without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit / risk ratio, and are effective for their intended use. C. Treatment-related Definitions

[0056] The ability of test compounds to act as inhibitors of EGFR may be demonstrated by the biological assays described herein. Values for inhibiting the activity of EGFR are shown in Tables 111 and 112.

[0057] The term “disease” as used herein is intended to be generally synonymous, and is used interchangeably with, the terms “disorder” and “condition” (as in medical condition), in that all reflect an abnormal condition of the body or of one of its parts that impairs normal functioning and is typically manifested by distinguishing signs and symptoms.

[0058] The indication “cancer” is to be understood in a most general sense as a disease characterized by inappropriate cellular proliferation, migration, apoptosis or angiogenesis, preferably by inappropriate cellular proliferation. Inappropriate cell proliferation means cellular proliferation resulting from inappropriate cell growth, from excessive cell division, from cell division at an accelerated rate and / or from inappropriate cell survival. As used herein, the term “cancer” refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., but not limited to, humans), including leukemia, lymphomas, carcinomas and sarcomas.

[0059] The phrase “effective amount” means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat an EGFR pathway-associated disease or disorder, such as an EGFR-associated cancer, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compoundAttorney Docket No.94019-421948 (P30880-WO-PCT) of the invention, or a pharmaceutically acceptable salt thereof that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

[0060] Activation of the EGFR pathway is associated with the regulation of several cellular responses, including cell proliferation, inflammatory processes, and extracellular matrix regulation (Rayego-Mateos et al., Mediators Inflamm.2018: 8739473 (2018)). Thus, the phrase “an EGFR pathway-associated disease or disorder” includes proliferative diseases (e.g., cancer or benign neoplasm), inflammatory diseases (e.g., fibrosis), and / or neurodegenerative diseases (e.g. Alzheimer disease).

[0061] The term “inflammatory disease” refers to a disease caused by, resulting from, or resulting in inflammation. The term “inflammatory disease” may also refer to a dysregulated inflammatory reaction that causes an exaggerated response by macrophages, granulocytes, and / or T-lymphocytes leading to abnormal tissue damage and / or cell death. An inflammatory disease can be either an acute or chronic inflammatory condition and can result from infections or non-infectious causes. Inflammatory diseases include, without limitation, atherosclerosis, arteriosclerosis, autoimmune disorders, multiple sclerosis, systemic lupus erythematosus, polymyalgia rheumatica (PMR), gouty arthritis, degenerative arthritis, tendonitis, bursitis, psoriasis, cystic fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory arthritis, Sjogren’s syndrome, giant cell arteritis, progressive systemic sclerosis (scleroderma), ankylosing spondylitis, polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes (e.g., Type I), myasthenia gravis, Hashimoto’s thyroiditis, Graves’ disease, Goodpasture’s disease, mixed connective tissue disease, sclerosing cholangitis, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, pernicious anemia, inflammatory dermatoses, usual interstitial pneumonitis (UIP), asbestosis, silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis, sarcoidosis, desquamative interstitial pneumonia, lymphoid interstitial pneumonia, giant cell interstitial pneumonia, cellular interstitial pneumonia, extrinsic allergic alveolitis, Wegener’s granulomatosis and related forms of angiitis (temporal arteritis and polyarteritis nodosa), inflammatory dermatoses, hepatitis, delayed-type hypersensitivity reactions (e.g., poison ivy dermatitis), pneumonia, respiratory tract inflammation, Adult Respiratory Distress Syndrome (ARDS), encephalitis, immediate hypersensitivity reactions, asthma, hayfever, allergies, acute anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis, cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic injury), reperfusion injury, allograft rejection, host-versus-graft rejection, appendicitis, arteritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, chorioamnionitis, conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis,Attorney Docket No.94019-421948 (P30880-WO-PCT) pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, testitis, tonsillitis, urethritis, urocystitis, uveitis, vaginitis, vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis, osteomyelitis, optic neuritis, temporal arteritis, transverse myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An ocular inflammatory disease includes, but is not limited to, post-surgical inflammation. In certain embodiments, the inflammatory disorder is fibrosis, and the fibrosis is idiopathic pulmonary fibrosis, liver cirrhosis, cystic fibrosis, systemic sclerosis, progressive kidney disease, or cardiovascular fibrosis.

[0062] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibition of an EGFR protein or gene. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease.

[0063] The expression “patient” and / or “subject” relates to a human or non-human mammalian patient (e.g., mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, and / or primates) suffering from cancer and thus in need of such treatment, preferably the patient is a human person. Furthermore, the expression “patient” and / or “subject” should be understood to include such cancer patients carrying tumors with wild-type EGF receptor as well as pre-selected cancer patients with tumors harboring activating EGFR mutations. These can be located in the tyrosine kinase domain of the EGF receptor such as for instance the L858R or L861 point mutations in the activation loop (exon 21), or in-frame deletion / insertion mutations in the ELREA sequence (exon 19), or substitutions in G719 situated in the nucleotide binding loop (exon 18). Additional activating mutations have been reported in the extracellular domain of the EGF receptor in various indications (e.g. EGFR vIII displaying exon 2-7 deletions). Other mutations such as the T790M point mutation in exon 20 as well as certain exon 20 insertions (e.g. D770_N771insNPG) which confer resistance to particular drugs should also be included, as well as double mutants such as the combined L858R / T790M mutation or the exon-19-del / T790M. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented.

[0064] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, ofAttorney Docket No.94019-421948 (P30880-WO-PCT) symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0065] As used herein the term “inhibit” or “inhibition” in the context of proteins, for example, in the context of EGFR tyrosine kinase, refers to a reduction in the activity of the tyrosine kinase. In some embodiments, the term refers to a reduction of the level of activity of EGFR to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity. In some embodiments, the term refers to a reduction of the level of EGFR activity to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of tyrosine kinase activity.

[0066] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the proliferation of cells. A proliferative disease may be associated with: 1) the pathological proliferation of normally quiescent cells; 2) the pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) the pathological expression of proteolytic enzymes such as the matrix metalloproteinases (e.g., collagenases, gelatinases, and elastases); or 4) the pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases. III. COMPOUND EMBODIMENTS

[0067] In one aspect, the invention relates to a compound of formula (I): , or a pharmaceutically acceptable saltRing A is a C6-C10aryl or 5- to 10-membered heteroaryl;Attorney Docket No.94019-421948 (P30880-WO-PCT) each R1is independently selected from halo, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, C2-C3alkynyl, and C3-C6cycloalkyl; X is N or CR2; Y is N or CR3; Z is N or CR4; R2is selected from H, halo, cyano, –OH, –OR5, –NRaRb, C1-C3alkyl, and C1-C3haloalkyl; R3is selected from H, halo, cyano, –OH, –OR5, –NRaRb, C1-C3haloalkyl, –C(O)NRcRd, C6-C10aryl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with 1-3 R3a; each R3ais independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, –(C1-C3alkylene)-(C1-C3alkoxy), –(C1-C3alkylene)-(4- to 7-membered heterocyclyl), and oxo; R4is selected from H, halo, cyano, –OH, –OR5, –NHR5, –N(C1-C3alkyl)R5, –SR5, and –C(O)NRcRd; each R5is independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, –(C1-C3alkylene)-NMe2, –(C1-C3alkylene)-(C1-C3alkoxy), –(C1-C3alkylene)-C(O)H, –(C1-C3alkylene)-C(O)NMe2, –(C1-C3alkylene)-C(O)-(C1-C3haloalkyl), C4-C7cycloalkyl, C6-C10aryl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and –CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b; or two R5, together with the atoms to which they are attached, join to form a 5- to 7-membered heterocyclyl optionally substituted with 1-3 R5a; each R5ais independently selected from halo, –OH, oxo, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, –(C1-C3alkylene)-C(O)H, –C(O)-(C1-C3alkyl), –C(O)-(C1-C3haloalkyl), –C(O)-(C1-C3cyanoalkyl), –C(O)-(C2-C4alkenyl), –C(O)-(C2-C4haloalkenyl), –C(O)-(C2-C4cyanoalkenyl), –C(O)-(C2-C4alkynyl), –C(O)-(C2-C4alkenylene)-NRaRb, –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl), –S(O)2-halo, –S(O)2-(C1-C3alkenyl), 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl optionally substituted with 1 C1-C3alkyl or C1-C3haloalkyl; each R5bis independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –OCD3, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionallyAttorney Docket No.94019-421948 (P30880-WO-PCT) substituted with 1-2 halo, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo), –(C1-C3alkylene)-(C6-C10aryl), and –S(O)2-(C1-C3alkyl); each Ra, Rb, Rcand Rdare independently selected from H, C1-C3alkyl, and –(C1-C3alkylene)-(4- to 7-membered heterocyclyl); or Rcand Rd, together with the atoms to which they are attached, join to form a 4- to 6-membered heterocyclyl; and n is 0, 1, 2, or 3.

[0068] In another aspect, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: each R1is independently selected from halo, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, C2-C3alkynyl, and C3-C6cycloalkyl; Y is N or CR3; each R3ais independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, –(C1-C3alkylene)-(4- to 7-membered heterocyclyl), and oxo; R4is selected from H, halo, cyano, –OH, –OR5, –NHR5, –SR5, and –C(O)NRcRd; each R5ais independently selected from halo, –OH, oxo, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, –(C1-C3alkylene)-C(O)H, –C(O)-(C1-C3haloalkyl), –C(O)-(C1-C3cyanoalkyl), –C(O)-(C2-C4alkenyl), –C(O)-(C2-C4haloalkenyl), –C(O)-(C2-C4cyanoalkenyl), –C(O)-(C2-C4alkynyl), –C(O)-(C2-C4alkenylene)-NRaRb, –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl), –S(O)2-halo, –S(O)2-(C1-C3alkenyl), and 3- to 6-membered heterocyclyl; each R5bis independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionally substituted with 1-2 halo, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo), and –(C1-C3alkylene)-(C6-C10aryl); and Ra, Rb, Rcand Rdare independently selected from H and C1-C3alkyl.

[0069] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0070] As described herein, the compounds of the invention comprise multiple variable groups (e.g., Ring A, R1, X, Y, Z, R2, R3, R3a, R4, R5, R5a, R5b, Ra, Rb, Rc, Rd, n, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this invention are those combinations that result inAttorney Docket No.94019-421948 (P30880-WO-PCT) the formation of stable or chemically feasible compounds. The term “stable,” in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0071] Unless otherwise specified, the compounds of the invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers including atropisomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. In addition, single stereoisomers, double bond isomers, conformational isomers including atropisomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformational isomers including atropisomers, and tautomers are within the scope of the invention.

[0072] Atropisomers are defined as a subclass of conformers which can be isolated as separate chemical species and which arise from restricted rotation about a single bond. The absolute configuration of atropisomers are designated Raor Sabased on the Cahn-Ingold-Prelog priority rules, wherein the group on the “front” of the atropisomer is assigned the highest priority. Where an atropisomer disclosed herein is described with the stereochemical descriptor “Ra” and “Sa”, the recited chemical name was prepared using ChemDraw Professional (Version 22.0.0.22), unless noted otherwise.

[0073] Enantiomers are defined as one of a pair of molecular entities which are mirror images of each other and non-superimposable. The absolute configuration of enantiomers are designated R or S based on the Cahn-Ingold-Prelog priority rules.

[0074] Diastereomers or diastereoisomers are defined as stereoisomers other than enantiomers. Diastereomers or diastereoisomers are stereoisomers not related as mirror images. Diastereomers or diastereoisomers are characterized by differences in physical properties, and by some differences in chemical behavior towards achiral as well as chiral reagents.

[0075] Tautomers are defined as two or more compounds that differ by the position of a single hydrogen atom. Typically, compounds that demonstrate tautomerism readily interconvert between the two or more tautomeric forms. Examples of tautomerism include, but are not limited to, the keto and enol forms of ketone-containing compounds, the amide and imidic acid forms of compounds containing an amide bond, as well as the hydroxypyridine and pyridone forms of compounds containing a hydroxy-substituted pyridine ring.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0076] As used herein, in any chemical structure or formula, a non-bold, straight bond attached to a stereocenter of a compound, such as in , denotes that the configuration of the The compound may have anyconfiguration, or a mixture of configurations, at the stereocenter.

[0077] Certain compounds of the invention are atropisomers wherein the orientation of the rotational bond is depicted by the group in front in bold and the group in the back is faded, as shown below. 7-(((S)- ((Sa)-3-chloro- 2-4-amine 7-(((S)-1,4- ((Sa)-3-chloro- 2-4-amine Alternatively, the orientation of the rotational bond of an atropisomer may be depicted by drawing the group in front in bold without the group in the back being shown as faded, as shown below.Attorney Docket No.94019-421948 (P30880-WO-PCT) 7-(((S)-1,4- ((Sa)-3-chloro- 2- 4-amine7-(((S)-1,4- ((Sa)-3-chloro- 2-4-amine

[0078] In any designated as a particular isotope in any compound of the invention is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope in any compound of the invention, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.

[0079] As used herein, the term “stable,” when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0080] As used herein in the specification and claims, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely1H and D. In the Examples, where an atom is designated as “H,” no effort was made to enrich that atom in a particular isotope of hydrogen, and therefore a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.

[0081] As used herein, “1H” refers to protium. Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as protium, protium is present at the specified position with at least the natural abundance concentration of protium.

[0082] As used herein, “D,” “d,” and “2H” refer to deuterium.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0083] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include each constituent atom at approximately the natural abundance isotopic composition of the specified element.

[0084] In some embodiments, the compounds of the invention, and pharmaceutically acceptable salts thereof, include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts). Examples of stable isotopes which are commercially available and suitable for the invention include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example2H,13C,15N,18O,17O, and31P, respectively.

[0085] The isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medicaments. In some embodiments, the isotope-labeled compounds and salts are deuterium (2H)-labeled. Deuterium (2H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non-2H-labeled compounds. In general, deuterium (2H)-labeled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labeled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present invention. The isotope-labeled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes, the Examples and the related description, replacing a non-isotope-labeled reactant by a readily available isotope-labeled reactant.

[0086] The deuterium (2H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For example, if deuterium is bonded to a carbon atom at a non-exchangeable position, rate differences of kH / kD= 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem.2011, 46, 403-417, incorporated in its entirety herein by reference.

[0087] The concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope-labeled compound of the invention, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratioAttorney Docket No.94019-421948 (P30880-WO-PCT) between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.

[0088] Where an atom in a compound of the invention, or a pharmaceutically acceptable salt thereof, is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (~45% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 3500 (~52.5% deuterium incorporation), at least 4000 (~60% deuterium incorporation), at least 4500 (~67.5% deuterium incorporation), at least 5000 (~75% deuterium incorporation), at least 5500 (~82.5% deuterium incorporation), at least 6000 (~90% deuterium incorporation), at least 6333.3 (~95% deuterium incorporation), at least 6466.7 (~97% deuterium incorporation), at least 6600 (~99% deuterium incorporation), or at least 6633.3 (~99.5% deuterium incorporation).

[0089] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-C10aryl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

[0090] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, thiophenyl, pyridinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, benzo[d]thiazolyl, and pyrrolo[2,3-b]pyridinyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, thiophenyl, pyridinyl, and quinolinyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is thiophenyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is quinolinyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolo[1,5-a]pyridinyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is benzo[d]thiazolyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrrolo[2,3-b]pyridinyl.

[0091] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 0. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 1. In some embodiments, theAttorney Docket No.94019-421948 (P30880-WO-PCT) invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 3.

[0092] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is independently selected from F, Cl, Br, cyano, –CH3, –CH2CH3, –CHF2, –OCH3, –CH2OH, ethynyl, and cyclopropyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is independently selected from F, Cl, Br, cyano, –CH3, –CHF2, –CH2OH, ethynyl, and cyclopropyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is Cl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is Br. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is –CH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is –OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is –CH2OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is ethynyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1is cyclopropyl.

[0093] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl and n is 0.

[0094] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is selected from halo, C1-C3alkyl, C1-C3haloalkyl, C2-C3alkynyl, and C3-C6cycloalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is C1-C3haloalkyl. In other embodiments, the inventionAttorney Docket No.94019-421948 (P30880-WO-PCT) relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is C2-C3alkynyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is C3-C6cycloalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is selected from Cl, Br, –CH3, –CHF2, ethynyl, and cyclopropyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is Cl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is Br. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is ethynyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 1, and R1is cyclopropyl.

[0095] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and each R1is independently selected from halo, cyano, C1-C3alkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, and C3-C6cycloalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and each R1is independently selected from halo, cyano, C1-C3alkyl, and C1-C3hydroxyalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is C1-C3hydroxyalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is C3-C6cycloalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and each R1is independentlyAttorney Docket No.94019-421948 (P30880-WO-PCT) selected from F, Cl, cyano, –CH3, –CH2CH3, –OCH3, –CH2OH, and cyclopropyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and each R1is independently selected from F, Cl, cyano, –CH3, and –CH2OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is Cl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is –CH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is –OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is –CH2OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 2, and at least 1 R1is cyclopropyl.

[0096] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and each R1is independently selected from halo, C1-C3alkyl, and C1-C3hydroxyalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and at least 1 R1is halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and at least 1 R1is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and at least 1 R1is C1-C3hydroxyalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and each R1is independently selected from F, Cl, –CH3, and –CH2OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and at least 1 R1is F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and at least 1 R1is Cl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and at least 1 R1is –CH3. In other embodiments, the invention relates to a compound ofAttorney Docket No.94019-421948 (P30880-WO-PCT) formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl, n is 3, and at least 1 R1is –CH2OH.

[0097] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl and n is 0.

[0098] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 1, and R1is halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 1, and R1is F or Cl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 1, and R1is F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 1, and R1is Cl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, thiophenyl, pyridinyl, and quinolinyl, n is 1, and R1is halo. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl, n is 1, and R1is halo. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is thiophenyl, n is 1, and R1is halo. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl, n is 1, and R1is halo. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is quinolinyl n is 1, and R1is halo.

[0099] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 2, and each R1is independently selected from halo and C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 2, and at least one R1is halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 2, and at least one R1is C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 2, and each R1is independently selected from F, Cl, and –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 2, and at least one R1is F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 2, and at least one R1is Cl. In otherAttorney Docket No.94019-421948 (P30880-WO-PCT) embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl, n is 2, and at least one R1is –CH3.

[0100] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3, and at least 1 R1is Cl.

[0101] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically , ,(I), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected ,Attorney Docket No.94019-421948 (P30880-WO-PCT) ,a the invention Ring A is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Ring A . In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Ring A . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Ring A . In other embodiments, theinvention relates to a compound of formula (I), or a acceptable salt thereof, wherein Ring other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, whereinRing other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Ring A . In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, whereinRing A . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Ring . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Ring A . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, whereinRing A . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Ring A . In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Ring . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Ring other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Ring . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, whereinRing . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, whereinRing other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Ring other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Ring A . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, whereinRing other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, whereinRing other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Ring other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, whereinAttorney Docket No.94019-421948 (P30880-WO-PCT) Ring . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein .

[0102] In some embodiments, the invention relates (I), or a pharmaceuticallyacceptable salt thereof, wherein X is N.

[0103] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is selected from H, halo, cyano, –OH, –OR5, and C1-C3haloalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is –OR5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is C1-C3haloalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is selected from H, F, cyano, –OH, –OR5, and –CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is –OR5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is –CF3.

[0104] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is selected from H, F, cyano, –OH, –OR5, and –CF3; and R5is selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl,Attorney Docket No.94019-421948 (P30880-WO-PCT) –(C1-C3alkylene)-NMe2, C4-C7cycloalkyl, C6-C10aryl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b. In other embodiments, X is CR2, R2is –OR5, and R5is C1-C3alkyl. In other embodiments, X is CR2, R2is –OR5, and R5is C1-C3haloalkyl. In other embodiments, X is CR2, R2is –OR5, and R5is C1-C3hydroxyalkyl. In other embodiments, X is CR2, R2is –OR5, and R5is –(C1-C3alkylene)-NMe2. In other embodiments, X is CR2, R2is –OR5, and R5is C4-C7cycloalkyl optionally substituted with 1-3 R5a. In other embodiments, X is CR2, R2is –OR5, and R5is C6-C10aryl. In other embodiments, X is CR2, R2is –OR5, and R5is 3- to 8-membered heterocyclyl optionally substituted with 1-3 R5a. In other embodiments, X is CR2, R2is –OR5, and R5is 5- to 10-membered heteroaryl optionally substituted with 1-3 R5b. In other embodiments, X is CR2, R2is –OR5, and R5is –(C1-C3alkylene)-(C6-C10aryl). In other embodiments, X is CR2, R2is –OR5, and R5is –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) optionally substituted with 1-3 R5a. In other embodiments, X is CR2, R2is –OR5, and R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b. In other embodiments, X is CR2, R2is –OR5, and R5is CD3.

[0105] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from –OH, oxo, C1-C3alkyl, and 3- to 6-membered heterocyclyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais oxo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais 3- to 6-membered heterocyclyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from –OH, oxo, –CH3, and oxetanyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais oxetanyl.

[0106] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein saidAttorney Docket No.94019-421948 (P30880-WO-PCT) C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from –OH, oxo, C1-C3alkyl, and 3- to 6-membered heterocyclyl. In other embodiments, at least 1 R5ais –OH. In other embodiments, at least 1 R5ais oxo. In other embodiments, at least 1 R5ais C1-C3alkyl. In other embodiments, at least 1 R5ais 3- to 6-membered heterocyclyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from –OH, oxo, –CH3, and oxetanyl. In other embodiments, at least 1 R5ais –CH3. In other embodiments, at least 1 R5ais oxetanyl.

[0107] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from halo, –OH, C1-C3alkyl, C1-C3haloalkyl, 3- to 8-membered heterocyclyl, and –(C1-C3alkylene)-(C6-C10aryl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis 3- to 8-membered heterocyclyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –(C1-C3alkylene)-(C6-C10aryl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from F, Cl, –OH, –CH3, –CHF2, oxetanyl, and benzyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis Cl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable saltAttorney Docket No.94019-421948 (P30880-WO-PCT) thereof, wherein at least 1 R5bis oxetanyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis benzyl.

[0108] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, R5is 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl), wherein said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b, and each R5bis independently selected from halo, –OH, C1-C3alkyl, C1-C3haloalkyl, 3- to 8-membered heterocyclyl, and –(C1-C3alkylene)-(C6-C10aryl). In other embodiments, at least 1 R5bis halo. In other embodiments, at least 1 R5bis –OH. In other embodiments, at least 1 R5bis C1-C3alkyl. In other embodiments, at least 1 R5bis C1-C3haloalkyl. In other embodiments, at least 1 R5bis 3- to 8-membered heterocyclyl. In other embodiments, at least 1 R5bis –(C1-C3alkylene)-(C6-C10aryl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, R5is 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl), wherein said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b, and each R5bis independently selected from F, Cl, –OH, –CH3, –CHF2, oxetanyl, and benzyl. In other embodiments, at least 1 R5bis F. In other embodiments, at least 1 R5bis Cl. In other embodiments, at least 1 R5bis –CH3. In other embodiments, at least 1 R5bis –CHF2. In other embodiments, at least 1 R5bis oxetanyl. In other embodiments, at least 1 R5bis benzyl.

[0109] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is selected from –CH3, –CHF2, –CH2CHF2, –CH2CF3, ,Attorney Docket No.94019-421948 (P30880-WO-PCT) a othersalt thereof, wherein R5is –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CH(CH3)(OH). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CH(CH3)(NMe2). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH(CH3)CH2NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is phenyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein5R . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a5salt thereof, wherein R is . In other embodiments, the invention relates to a compound of formula (I), or aH N N pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I), s5alt thereof, wherein R . In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt there5of, wherein R is CD3.

[0110] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is selected from –CH3, –CHF2, –CH2CHF2, –CH2CF3, –CH2CH(CH3)(OH), –CH2CH(CH3)(NMe2), –CH(CH3)CH2NMe2, , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) H N N saltto a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is –CH2CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is –CH2CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is –CH2CH(CH3)(OH). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is –CH2CH(CH3)(NMe2). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is –CH(CH3)CH2NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is phenyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is . In other embodiments, the invention relates to a compound of salt thereof, wher2 2 5 5ein X is CR , R is –OR , and R is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, wherein X is CR2, R2is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein X is . In other embodiments, the invention relates to a compound ofsalt thereof, wherein X is CR2, R2is –OR5, and R5isAttorney Docket No.94019-421948 (P30880-WO-PCT) . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and . In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein X is CR2, R2is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein X is CR2, R2. In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and . In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein X is CR2, R2is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein X is CR2, R2Attorney Docket No.94019-421948 (P30880-WO-PCT) H N N other embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to asalt thereof, wherein X is CR2, R2is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein X is CR2, R2. In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and . In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein X is CR2, R2is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein X is CR2, R2is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein X is CR2, R2is –OR5, . In other embodiments, the invention relates to a compound of formula (I), salt thereof,2 2 5 5wherein X is CR , R is –OR , and R is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5InAttorney Docket No.94019-421948 (P30880-WO-PCT) other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is CD3.

[0111] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is N.

[0112] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is selected from H, halo, cyano, –OH, –OR5, –NRaRb, –C(O)NRcRd, C6-C10aryl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is –OR5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is –NRaRb. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is –C(O)NRcRd. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is C6-C10aryl, wherein said aryl is optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is 4- to 10-membered heterocyclyl, wherein said heterocyclyl is optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is 5- to 6-membered heteroaryl, wherein said heteroaryl is optionally substituted with 1-3 R3a.

[0113] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R3ais independently selected from C1-C3alkyl, –(C1-C3alkylene)-(C1-C3alkoxy), –(C1-C3alkylene)-(4- to 7-membered heterocyclyl), and oxo. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R3ais independently selected from C1-C3alkyl, –(C1-C3alkylene)-(4- to 7-membered heterocyclyl), and oxo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R3ais C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R3ais –(C1-C3alkylene)-(C1-C3alkoxy). In other embodiments, the invention relates to aAttorney Docket No.94019-421948 (P30880-WO-PCT) compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R3ais –(C1-C3alkylene)-(4- to 7-membered heterocyclyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R3ais oxo. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R3ais independently selected from , and oxo. In other embodiments, the invention relates to a compound of formula acceptable salt 3athereof, wherein R is –CH3. In other embodiments, the a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R3ais –CH2OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R3a. embodiments, the invention relates to a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, wherein Rais C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Rais –CH3.

[0115] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Rbis C1-C3alkyl or –(C1-C3alkylene)-(4- to 7-membered heterocyclyl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Rbis –CH3or –CH(CH3)CH2-morpholinyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Rbis –CH3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Rbis–CH(CH3)CH2-morpholinyl.

[0116] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Rcand Rd, together with the atoms to which they are attached, join to form a 4-membered heterocyclyl.

[0117] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is selected from H, F, Br, cyano, –OH, –OR5, –NMe2, ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , ,– - to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl) and CD3,wherein said C4- C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10- membered heteroaryl) is optionally substituted with 1-3 R5b. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is ,Attorney Docket No.94019-421948 (P30880-WO-PCT); and R5is selected from C1-C3alkyl, C1-C3haloalkyl, –(C1-C3alkylene)-NMe2, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl),– -(5- to 10-membered heteroaryl) and CD3,wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is Br. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to acompound of formula (I), or a salt thereof, wherein Y is CR3, and R3is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, whereinAttorney Docket No.94019-421948 (P30880-WO-PCT) . In other embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or a acceptable saltthereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein Y is CR3, and R3is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Y is CR3, and R3is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, whereinAttorney Docket No.94019-421948 (P30880-WO-PCT) Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or a acceptable saltthereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein Y is CR3, and R3is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt NOthereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Y is CR3, and R3is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I),acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to aAttorney Docket No.94019-421948 (P30880-WO-PCT) compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), acceptable saltthereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein Y is CR3, and R3is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, embodiments, the invention relates to a saltthereof, . In other embodiments, the invention relates to a compound of salt there3 3of, wherein Y is CR , and R is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formulaAttorney Docket No.94019-421948 (P30880-WO-PCT) (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and . In other embodiments, the invention relates to a compound of formula (I), or a acceptable saltthereof, wherein Y is CR3, and R3is . In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein Y is CR3, and R3is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, whereinY is CR3, and R3. In other embodiments, the invention relates to a compound of formula (I), or a salt the3 3 5 5reof, wherein Y is CR , and R is –OR , and R is selected from C1-C3alkyl, C1-C3haloalkyl, –(C1-C3alkylene)-NMe2, –(C1-C3alkylene)-(C1-C3alkoxy), C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl) and CD3,wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is selected from C1-C3alkyl, C1-C3haloalkyl, –(C1-C3alkylene)-NMe2, C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl) and CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is –(C1-C3alkylene)-NMe2. In other embodiments, the invention relates to a compound ofAttorney Docket No.94019-421948 (P30880-WO-PCT) formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is –(C1-C3alkylene)-(C1-C3alkoxy). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is C4-C7cycloalkyl optionally substituted with 1-3 R5a. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is 3- to 8-membered heterocyclyl optionally substituted with 1-3 R5a. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is 5- to 10-membered heteroaryl optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) optionally substituted with 1-3 R5a. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, and R3is –OR5, and R5is CD3.

[0118] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halo, C1-C3alkyl, and C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais C1-C3haloalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from F, –CH3, and –CH2CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –CH2CF3.

[0119] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from halo, C1-C3alkyl, and C1-C3haloalkyl. In otherAttorney Docket No.94019-421948 (P30880-WO-PCT) embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais C1-C3haloalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from F, –CH3, and –CH2CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –CH2CF3.

[0120] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from C1-C3alkyl. In someAttorney Docket No.94019-421948 (P30880-WO-PCT) embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5bis –CH3.

[0121] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and each R3bis independently selected from C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and each R3bis –CH3.

[0122] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is selected from –CH3, –CHF2, –CH2CF3, –CH(CH3)CHF2, , , saltthereof, wherein R5is selected from –CH3, –CH2CF3, –CH2CH2NMe2, ,acceptable salt thereof, wherein R5is –CH3.In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH(CH3)CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5Attorney Docket No.94019-421948 (P30880-WO-PCT) is –CH2CH2NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH(CH3)CH2NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CH(CH3)(NMe2). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CH2OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a salt t5hereof, wherein R is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I), orsalt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein . In other embodiments, the invention relates to a compound of formula (I), or acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5is CD3.

[0123] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is selected from –CH3, –CHF2, –CH2CF3,acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is selected from –CH3, –CH2CF3, ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , and CD3. In other embodiments, the invention relates to a compound of formula (I), or a 33 5acceptable salt thereof, wherein Y is CR , R is –OR , and R5is –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is –CH2CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is –CH(CH3)CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is –CH2CH2NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is –CH(CH3)CH2NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is –CH2CH(CH3)(NMe2). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is –CH2CH2OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Y is CR3, R3isAttorney Docket No.94019-421948 (P30880-WO-PCT) –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Y is CR3, R3is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or acceptable salt thereof, wherein Y is. In other embodiments, the invention relates to a compound of salt thereof, wherein Y is CR3, R3is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Y is CR3, R3is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I),or a salt thereof, wherein Y is CR3, R3is –OR5, and R5is CD3.

[0124] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is N.

[0125] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is selected from H, halo, –OH, –OR5, –N(C1-C3alkyl)R5,Attorney Docket No.94019-421948 (P30880-WO-PCT) –SR5,and –C(O)NRcRd. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is selected from H, halo, –OH, –OR5, and –C(O)NRcRd. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –OR5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –N(C1-C3alkyl)R5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –SR5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –C(O)NRcRd. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –C(O)NRcRd, and Rcand Rd, together with the atoms to which they are attached, join to form a 4-membered heterocyclyl.

[0126] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is selected from H, Cl, F, –OH, –OR5, –N(C1-C3alkyl)R5, ;and R5 is selected from C1-C3 alkyl, C1-C3 haloalkyl, –(C1-C3 alkylene)-NMe2,C3alkoxy), –(C1-C3alkylene)-C(O)NMe2, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is selected from H, Cl, F, –OH, –OR5, and ; and R5is selected from C1-C3alkyl, C1-C3haloalkyl, –(C1-C3alkylene)-NMe2,-(C1-C3alkoxy), –(C1-C3alkylene)-C(O)NMe2, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- toAttorney Docket No.94019-421948 (P30880-WO-PCT) 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is H. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is Cl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –OR5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –N(C1-C3alkyl)R5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is –SR5. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wh4 4erein Z is CR , R is –OR5, and R5is selected from C1-C3alkyl, C1-C3haloalkyl, –(C1-C3alkylene)-NMe2, –(C1-C3alkylene)-(C1-C3alkoxy), –(C1-C3alkylene)-C(O)NMe2, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –(C1-C3alkylene)-NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –(C1-C3alkylene)-(C1-C3alkoxy). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –(C1-C3alkylene)-C(O)NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is 3- to 8-membered heterocyclyl optionally substituted with 1-3 R5a. In other embodiments, theAttorney Docket No.94019-421948 (P30880-WO-PCT) invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is 5- to 10-membered heteroaryl optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) optionally substituted with 1-3 R5a. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is CD3.

[0127] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halo, oxo, C1-C3alkyl, C1-C3alkoxy, –C(O)-(C1-C3alkyl), –C(O)-(C2-C4alkenyl), and –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from C1-C3alkyl and C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from oxo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from –C(O)-(C1-C3alkyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from –C(O)-(C2-C4alkenyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais F, oxo, –CH3, –OCH3, –OCH2CH3, –C(O)CH2CH3,–C(O)CH=CH2, or –C(O)CH=CHCH2-morpholinyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –CH3or –OCH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptableAttorney Docket No.94019-421948 (P30880-WO-PCT) salt thereof, wherein at least 1 R5ais oxo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –OCH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –C(O)CH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –C(O)CH=CH2, In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –C(O)CH=CHCH2-morpholinyl.

[0128] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from halo, oxo, C1-C3alkyl, C1-C3alkoxy, –C(O)-(C1-C3alkyl), –C(O)-(C2-C4alkenyl), and –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from C1-C3alkyl or C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least one R5ais oxo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, whereinAttorney Docket No.94019-421948 (P30880-WO-PCT) Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from –C(O)-(C1-C3alkyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from –C(O)-(C2-C4alkenyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and each R5ais independently selected from –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais F, oxo, –CH3, –OCH3, –OCH2CH3, –C(O)CH2CH3,–C(O)CH=CH2, or –C(O)CH=CHCH2-morpholinyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –CH3or –OCH2CH3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais F. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a,Attorney Docket No.94019-421948 (P30880-WO-PCT) and at least 1 R5ais oxo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –CH3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –OCH2CH3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –C(O)CH2CH3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –C(O)CH=CH2. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and at least 1 R5ais –C(O)CH=CHCH2-morpholinyl.

[0129] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –OCD3, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionally substituted with 1-2 halo, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo), and –S(O)2-(C1-C3alkyl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from halo, cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionally substituted with 1-2 halo, 3- to 8-membered heterocyclyl, and –(C1-C3alkylene)-(C3-C6cycloalkylAttorney Docket No.94019-421948 (P30880-WO-PCT) optionally substituted with 1-2 halo). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CD3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C4hydroxyalkyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OCD3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –(C1-C3alkylene)-(C1-C3alkoxy). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C3-C6cycloalkyl optionally substituted with 1-2 halo. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis 3- to 8-membered heterocyclyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from F, –OH, cyano, –CH3, –CH2CH3, –CHF2, –CH2CHF2, –CD3, –CH2C(CH3)2(OH), –OCH3, –OCH2CH3, –OCD3, –CH2OCH3, –CH2CH2OCH3, –C(CH3)2(OCH3), cyclopropyl, 1,1,-difluorocyclopropyl, oxetanyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptanyl, –CH2-(1-flourocyclopropyl), and –S(O)2CH2CH3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from F, cyano, –CH3, –CH2CH3, –CHF2, –CH2CHF2, –CD3, –CH2C(CH3)2(OH), –OCH3, –OCH2CH3, –CH2CH2OCH3, –C(CH3)2(OCH3), 1,1,-difluorocyclopropyl, oxetanyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptanyl, and –CH2-(1-flourocyclopropyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OH. In other embodiments, the invention relates to a compound ofAttorney Docket No.94019-421948 (P30880-WO-PCT) formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH2CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CD3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH2C(CH3)2(OH). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OCH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OCD3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH2OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH2CH2OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –C(CH3)2(OCH3). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis cyclopropyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis 1,1,-difluorocyclopropyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis oxetanyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis tetrahydropyranyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis 2-oxaspiro[3.3]heptanyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH2-(1-flourocyclopropyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –S(O)2CH2CH3.

[0130] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and each R5bis independently selected from halo, –OH,Attorney Docket No.94019-421948 (P30880-WO-PCT) cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –OCD3, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionally substituted with 1-2 halo, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo), and –S(O)2-(C1-C3alkyl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and each R5bis independently selected from halo, cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionally substituted with 1-2 halo, 3- to 8-membered heterocyclyl, and –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis halo. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –OH. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis cyano. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis C1-C3haloalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CD3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis C1-C4hydroxyalkyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis C1-C3alkoxy. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –OCD3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable saltAttorney Docket No.94019-421948 (P30880-WO-PCT) thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –(C1-C3alkylene)-(C1-C3alkoxy). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis C3-C6cycloalkyl optionally substituted with 1-2 halo. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis 3- to 8-membered heterocyclyl. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –S(O)2-(C1-C3alkyl). In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and each R5bis independently selected from F, –OH, cyano, –CH3, –CH2CH3, –CHF2, –CH2CHF2, –CD3, –CH2C(CH3)2(OH), –OCH3, –OCH2CH3, –OCD3, –CH2OCH3, –CH2CH2OCH3, –C(CH3)2(OCH3), cyclopropyl, 1,1,-difluorocyclopropyl, oxetanyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptanyl, –CH2-(1-flourocyclopropyl), and –S(O)2CH2CH3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and each R5bis independently selected from F, cyano, –CH3, –CH2CH3, –CHF2, –CH2CHF2, –CD3, –CH2C(CH3)2(OH), –OCH3, –OCH2CH3, –CH2CH2OCH3, –C(CH3)2(OCH3), 1,1,-difluorocyclopropyl, oxetanyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptanyl, and –CH2-(1-flourocyclopropyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis F. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –OH. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis cyano. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5Attorney Docket No.94019-421948 (P30880-WO-PCT) is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CH2CHF2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CD3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CH2C(CH3)2(OH). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –OCH2CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –OCD3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CH2OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CH2CH2OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –C(CH3)2(OCH3). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis cyclopropyl. In other embodiments, the invention relates to a compound ofAttorney Docket No.94019-421948 (P30880-WO-PCT) formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis 1,1,-difluorocyclopropyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis oxetanyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis tetrahydropyranyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis 2-oxaspiro[3.3]heptanyl. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –CH2-(1-flourocyclopropyl). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b, and at least 1 R5bis –S(O)2CH2CH3.

[0131] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is selected from –CH3, –CH(CH3)2, –CH2CF3, –CH(CH3)CH2NMe2, ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , Dthereof, wherein R5is selected from –CH3, –CH(CH3)2, –CH2CF3, –CH(CH3)CH2NMe2, , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , , ,In other embodiments, the invention salt thereof, wherei5n R is –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH(CH3)2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH(CH3)CH2NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH2CH(CH3)(NMe2). In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH(CH3)CH2OCH3. In other embodiments, the invention relates to aAttorney Docket No.94019-421948 (P30880-WO-PCT) compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is –CH(CH3)C(O)NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, embodiments, the invention relates to asalt thereof, In other embodiments, the invention relates to acompound of formula (I), or a pharmaceutically acceptable salt thereof, wherein In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5. In other embodiments, the invention relates to a compound offormula (I), or a pharmaceutically acceptable salt thereof, wherein R5. In otherAttorney Docket No.94019-421948 (P30880-WO-PCT) embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, other embodiments, the invention relates to a compound offormula (I), or a salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or acceptable saltthereof, wherein R5. In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a5salt thereof, wherein R is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I),salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a5acceptable salt thereof, wherein R is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein R5N is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a5salt thereof, wherein R is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I), or a5salt thereof, wherein R is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, theAttorney Docket No.94019-421948 (P30880-WO-PCT) invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I), acceptable salt ther5eof, wherein R . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein R5Attorney Docket No.94019-421948 (P30880-WO-PCT) . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I), acceptable salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a salt t5hereof, wherein R is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), ora pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a5salt thereof, wherein R other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I),5acceptable salt thereof, wherein R other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I), acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a5salt thereof, wherein R O other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein R5isN . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a a5cceptable salt thereof, wherein R . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein R5Attorney Docket No.94019-421948 (P30880-WO-PCT) . In other embodiments, the invention relates to a compound of formula (I), or a Opharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I), salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I),5salt thereof, wherein R . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a compound of formula (I),salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I), salt thereof, wherein R5other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a compound of formula (I),5acceptable salt thereof, wherein R is CD3.

[0132] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is selected from –CH3, –CH(CH3)2, –CH2CF3, –CH(CH3)CH2NMe2, –CH2CH(CH3)(NMe2), –CH(CH3)CH2OCH3, –CH(CH3)C(O)NMe2,Attorney Docket No.94019-421948 (P30880-WO-PCT) , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , Dthereof, wherein Z is CR4, R4is –OR5, and R5is selected from –CH3, –CH(CH3)2, –CH2CF3, ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , , ,thereof, wherein Z is CR4, R4is –OR5, and R5is –CH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –CH(CH3)2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –CH2CF3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –CH(CH3)CH2NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –CH2CH(CH3)(NMe2). In other embodiments, the invention relates to aAttorney Docket No.94019-421948 (P30880-WO-PCT) compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –CH(CH3)CH2OCH3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –CH(CH3)C(O)NMe2. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein Z is. In other embodiments, the invention relates to a compound salt thereof, wherein Z is CR4, R4is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to asalt thereof, In other embodiments, theacceptable salt thereof, the inventionZ is CR4, R4is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Z is CR4, R4is –OR5, andAttorney Docket No.94019-421948 (P30880-WO-PCT) . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, . In other embodiments, the invention relates to a salt thereof, wherein Z is CR4, R4. In other embodiments, the invention relates to a compound of formula (I),or a salt thereof, wherein Z is CR4, R4is –OR5, and In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, . In other embodiments, the invention relates to a salt thereof, wherein Z is CR4, R4other embodiments, the invention relates to a compound of formula (I),or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Z is CR4, R4Attorney Docket No.94019-421948 (P30880-WO-PCT) . In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to aacceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, whereinZ is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a acceptable salt thereof, wherein Z is CR4, R4is –OR5, andother embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to asalt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5isAttorney Docket No.94019-421948 (P30880-WO-PCT) . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Z is CR4, R4is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and . In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a4 4salt thereof, wherein Z is CR , R . In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein . In other embodiments, the invention relates to aacceptable salt thereof, wherein Z is CR4, R4is –OR5, and other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or acceptable salt thereof, wherein Z isCR4, R4is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or aacceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formulaacceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I),acceptable salt thereof, wherein Z is . In other embodiments, the invention relates to aacceptable salt thereof, wherein Z is CR4, R4is –OR5, and . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a saltthereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein Z is CR4, R4is–OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein Z is CR4, R4is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereo4 4f, wherein Z is CR , R other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to aAttorney Docket No.94019-421948 (P30880-WO-PCT) N acceptable salt thereof, In other embodiments, the invention relates to a salt thereof, wherein Z isCR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein Z is CR4, R4is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), oracceptable salt thereof, wherein Z is . In other embodiments, the invention relates to a compound of salt thereof, wherein Z is CR4, R4is –OR5, an5d R is . In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Z is CR4, R4is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or acceptable salt thereof, wherein Z is. In other embodiments, the invention relates to a compound salt thereof, wherein Z is CR4, R4is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to asalt thereof, . In other embodiments, the invention relates to a salt thereof, wherein Z4 4is CR , R other embodiments, the invention relates to a compound ofsalt thereof, wherein Z is CR4, R4is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to asalt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or a salt thereof, wherein Z is CR4, R4is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5embodiments, the invention relates to a compound of formula (I), or athereof, In other embodiments, the invention relates to a4 4salt thereof, wherein Z is CR , R . In other embodiments, the invention relates to a compound of acceptable sal4 4 5 5t thereof, wherein Z is CR , R is –OR , and R is . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, In other embodiments, the invention relates to a saltNthereof,In other embodiments, the invention relates to a salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula(I), or a pharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to aacceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formulaacceptable salt thereof, . In other embodiments, the invention relates to a salt th4 4ereof, wherein Z is CR , R N other embodiments, the invention relates to a compound ofsalt thereof, wherein Z is CR4, R4is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5InAttorney Docket No.94019-421948 (P30880-WO-PCT) other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or acceptable salt thereof, wherein Z isother embodiments, the invention relates to a compound of salt thereof, wherein Z is CR4, R4is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the invention relates to asalt thereof, . In other embodiments, the invention relates to acceptable salt thereof, wherein Z isother embodiments, the invention relates to a compound of salt thereof, wherein Z i4 4 5 5s CR , R is –OR , and R is N .In other embodiments, the invention relates to a compound of formula (I), or aN pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In otherembodiments, the invention relates to a compound of formula (I), or asaltAttorney Docket No.94019-421948 (P30880-WO-PCT) thereof, In other embodiments, the invention relates to a salt thereof, wherein Z is CR4, R4. In other embodiments, the invention relates to a compound of salt thereof, wherein Z is CR4, R4is –OR5, and R5is. In other embodiments, the invention relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the invention relates to a 44 5salt thereof, wherein Z is CR , R is –OR , and CD3.

[0133] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –N(C1-C3alkyl)R5, and R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is .the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –SR5, and R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –SR5, and .Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0135] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5is selected from –CH3, –CH(CH3)2, –CHF2, –CH2CHF2, –CH2CF3, –CH(CH3)CHF2, –CH2CH(CH3)(OH), –CH2CH2NMe2, –CH2CH(CH3)(NMe2), –CH(CH3)CH2NMe2, ,Attorney Docket No.94019-421948 (P30880-WO-PCT) H N N , , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) O N , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , ,Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0136] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein no more than 1 of X, Y, and Z are N.

[0137] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, Z is CR4, R3is OR5, R4is OR5, and the R5of R3and R4, together with the oxygen atoms to which they are attached, join to form a 5- to 7-membered heterocyclyl optionally substituted with 1-3 R5a. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, Z is CR4, R3is OR5, R4is OR5, and the R5of R3and R4, together with the oxygen atoms to which they are attached, join to form fused 1,4-dioxanyl In other embodiments, the invention acceptable salt 3thereof, wherein Y is CR , Z with the oxygen atoms to which they are attached, join to form fused 1,4-dioxanyl substituted . In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Y is CR3, Z is CR4, R3is OR5, R4is OR5, and the R5of R3and R4, together with the oxygen atoms to which they are attached, join to form fused 1,4-dioxanyl In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, wherein Y is CR3, Z is CR4, R3is OR5, R4is OR5, and the R5of R3and R4, together with the oxygen atoms to which they are attached, join to form fused 1,4-dioxanyl .

[0138] In some embodiments, the invention relates to a compound of formula (I),acceptable salt thereof, wherein the compound is of formula (I-A):Attorney Docket No.94019-421948 (P30880-WO-PCT) .

[0139] In some embodiments, the of formula (I) or formula (I-A), or a pharmaceutically acceptable saltH; and R4is selected from H, –OH, –OR5, –N(C1-C3alkyl)R5, –SR5, and –C(O)NRcRd. In some embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is H; R3is H; and R4is selected from H, –OH, –OR5, and –C(O)NRcRd. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is H; R3is H; and R4is H. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is H; R3is H; and R4is –OH. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is H; R3is H; and R4is –OR5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is H; R3is H; and R4is –N(C1-C3alkyl)R5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is H; R3is H; and R4is –SR5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is H; R3is H; and R4is –C(O)NRcRd.

[0140] In some embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is selected from H, halo, –OH, –OR5, –NRaRb, –C(O)NRcRd, C6-C10aryl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is H. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is halo. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is –OH. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is –OR5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is –NRaRb. In other embodiments, the inventionAttorney Docket No.94019-421948 (P30880-WO-PCT) relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is –C(O)NRcRd. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is C6-C10aryl optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H; R4is H; and R3is 5- to 6-membered heteroaryl optionally substituted with 1-3 R3a.

[0141] In some embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is H; R4is H; and R2is selected from H, halo, cyano, –OH, –OR5, and C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is H; R4is H; and R2is H. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is H; R4is H; and R2is halo. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is H; R4is H; and R2is cyano. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is H; R4is H; and R2is –OH. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is H; R4is H; and R2is –OR5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is H; R4is H; and R2is C1-C3haloalkyl.

[0142] In some embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is H; R3is halo, cyano,–OR5, or 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a; and R4is halo or –OR5.

[0143] In some embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is halo or –OR5; R3is H; and R4is –OR5.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0144] In some embodiments, the invention relates to a compound of formula (I) or formula (I-A), or a pharmaceutically acceptable salt thereof, wherein: R2is halo; R3is H; and R4is –OR5.

[0145] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-C10aryl. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

[0146] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from benzo[d]thiazolyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyridinyl, quinolinyl, and thiophenyl. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, pyridinyl, quinolinyl, and thiophenyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is benzo[d]thiazolyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolo[1,5-a]pyridinyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is quinolinyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring A is thiophenyl.

[0147] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from F, Cl, Br, cyano, –CH3, –CHF2, –CH2OH, ethynyl, and cyclopropyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is F. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is Cl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is Br. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is cyano. In other embodiments, the invention relates to aAttorney Docket No.94019-421948 (P30880-WO-PCT) compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is –CH3. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is –CHF2. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is –CH2OH. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is ethynyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is cyclopropyl.

[0148] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein n is 0. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein n is 1. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein n is 2. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein n is 3.

[0149] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, halo, cyano, –OH, –OR5, and C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is H. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is halo. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is cyano. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is –OH. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is –OR5. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2is C1-C3 haloalkyl.

[0150] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is selected from H, halo, cyano, –OH, –OR5, –NRaRb, –C(O)NRcRd, C6-C10aryl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is H. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is halo. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is cyano. In other embodiments, the invention relates to a compound of formula (I-A), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein R3is –OH. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is –OR5. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is –NRaRb. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is –C(O)NRcRd. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is C6-C10aryl optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is and 5- to 6-membered heteroaryl optionally substituted with 1-3 R3a.

[0151] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R3ais independently selected from C1-C3alkyl, –(C1-C3alkylene)-(4- to 7-membered heterocyclyl), and oxo. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R3ais C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R3ais –(C1-C3alkylene)-(4- to 7-membered heterocyclyl). In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R3ais oxo.

[0152] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is selected from H, halo, –OH, –OR5, –N(C1-C3alkyl)R5, –SR5, and –C(O)NRcRd. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is selected from H, halo, –OH, –OR5, and –C(O)NRcRd. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is H. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is halo. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is –OH. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is –OR5. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is –N(C1-C3alkyl)R5. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is –SR5. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R4is –C(O)NRcRd.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0153] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, –(C1-C3alkylene)-NMe2, –(C1-C3alkylene)-(C1-C3alkoxy), –(C1-C3alkylene)-C(O)NMe2, C4-C7cycloalkyl, C6-C10aryl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is C1-C3hydroxyalkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is –(C1-C3alkylene)-NMe2. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is –(C1-C3alkylene)-(C1-C3alkoxy). In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is –(C1-C3alkylene)-C(O)NMe2. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is C4-C7cycloalkyl optionally substituted with 1-3 R5a. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is C6-C10aryl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is 3- to 8-membered heterocyclyl optionally substituted with 1-3 R5a. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is 5- to 10-membered heteroaryl optionally substituted with 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is –(C1-C3alkylene)-(C6-C10aryl). In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) optionally substituted with 1-3 R5a. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b. In otherAttorney Docket No.94019-421948 (P30880-WO-PCT) embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is CD3.

[0154] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3is OR5, R4is OR5, and the R5of R3and R4, together with the oxygen atoms to which they are attached, join to form a 5- to 7-membered heterocyclyl optionally substituted with 1-3 R5a.

[0155] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halo, –OH, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, and 3- to 6-membered heterocyclyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais halo. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais –OH. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais 3- to 6-membered heterocyclyl.

[0156] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionally substituted with 1-2 halo, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo), and –(C1-C3alkylene)-(C6-C10aryl). In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis halo. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –OH. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis cyano. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CD3. In other embodiments, the invention relates to aAttorney Docket No.94019-421948 (P30880-WO-PCT) compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C4hydroxyalkyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –(C1-C3alkylene)-(C1-C3alkoxy). In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C3-C6cycloalkyl optionally substituted with 1-2 halo. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis 3- to 8-membered heterocyclyl. In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo). In other embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis–(C1-C3alkylene)-(C6-C10aryl).

[0157] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Rais C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Rais –CH3.

[0158] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Rbis C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Rbis –CH3.

[0159] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Rcand Rd, together with the atoms to which they are attached, join to form a 4- to 6-membered heterocyclyl. In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Rcand Rd, together with the atoms to which they are attached, join to form a 4-membered heterocyclyl.

[0160] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-B): .

[0161] In some embodiments, theof formula (I) or formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R3is H or –OR5and R4is –OR5or –SR5. In some embodiments, the invention relates to a compound of formula (I) or formula (I-B), or a pharmaceuticallyAttorney Docket No.94019-421948 (P30880-WO-PCT) acceptable salt thereof, wherein R3is H and R4is –OR5. In some embodiments, the invention relates to a compound of formula (I) or formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R3is H and R4is –SR5. In some embodiments, the invention relates to a compound of formula (I) or formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R3is –OR5and R4is –OR5.

[0162] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-C10aryl. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

[0163] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolo[1,5-a]pyridinyl, pyridinyl, or pyrrolo[2,3-b]pyridinyl. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolo[1,5-a]pyridinyl. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridinyl. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrrolo[2,3-b]pyridinyl.

[0164] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from halo, cyano, C1-C3alkyl, C1-C3alkoxy, and C3-C6_cycloalkyl. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from halo or C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is halo. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is cyano. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is C3-C6cycloalkyl. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from F, Cl,cyano, –CH3, –CH2CH3, –OCH3, and cyclopropyl. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from F, Cl, and –CH3. In other embodiments, the invention relates to a compoundAttorney Docket No.94019-421948 (P30880-WO-PCT) of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is F. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is Cl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is cyano. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is –CH3. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is –CH2CH3. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is –OCH3. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is cyclopropyl.

[0165] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein n is 2 or 3. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein n is 2. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein n is 3. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein n is 0. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0166] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R3is H or –OR5. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R3is H. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R3is –OR5.

[0167] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R4is –OR5or –SR5. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R4is –OR5. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R4is –SR5.

[0168] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5is C1-C3alkyl, 3- to 8- membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), or –CD3. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5is C1-C3alkyl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl). In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5is C1-C3alkyl. InAttorney Docket No.94019-421948 (P30880-WO-PCT) other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5is 3- to 8-membered heterocyclyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5is 5- to 10-membered heteroaryl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5is –(C1-C3alkylene)-(3- to 8-membered heterocyclyl). In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl). In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5is –CD3.

[0169] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from –C1-C3alkyl, –C1-C3alkoxy, –C(O)-(C1-C3alkyl), –C(O)-(C2-C4alkenyl), and –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl). In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5ais –C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5ais –C1-C3alkoxy. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5ais –C(O)-(C1-C3alkyl). In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5ais –C(O)-(C2-C4alkenyl). In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5ais –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl).

[0170] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from halo, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C3-C6cycloalkyl, –S(O)2(C1-C3alkyl), and –CD3. In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from cyano, C1-C3alkyl, C1-C3haloalkyl, and –CD3. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis halo. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis cyano. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C1-C3alkoxy. In other embodiments,Attorney Docket No.94019-421948 (P30880-WO-PCT) the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis C3-C6cycloalkyl. In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –S(O)2(C1-C3alkyl). In other embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CD3.

[0171] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C): .

[0172] In some embodiments, the of formula (I) or formula (I-C), or apharmaceutically acceptable salt and R4is H, halo, or –OR5. In some embodiments, the invention relates to a compound of formula (I) or formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is H and R4is halo or –OR5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is H. In other embodiments, the invention relates to a compound of formula (I) or formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is H and R4is halo or –OR5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is H and R4is halo. In other embodiments, the invention relates to a compound of formula (I) or formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is H and R4is –OR5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is –OR5and R4is H.

[0173] In some embodiments, the invention relates to a compound of formula (I) or formula (I-C), or a pharmaceutically acceptable salt thereof,wherein R4is H and R2is –OR5.

[0174] In some embodiments, the invention relates to a compound of formula (I) or formula (I-C), or a pharmaceutically acceptable salt thereof,wherein R2is H or –OR5; and R4is H, halo, or –OR5.

[0175] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-C10aryl. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

[0176] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl. In someAttorney Docket No.94019-421948 (P30880-WO-PCT) embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazolo[1,5-a]pyridinyl.

[0177] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from halo and C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least R1is halo. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least R1is C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from F, Cl, and –CH3. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from Cl and –CH3. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is F. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is Cl. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is –CH3.

[0178] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein n is 1. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein n is 2. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein n is 3.

[0179] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is H or –OR5. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is H. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2is –OR5.

[0180] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R4is H, halo, or –OR5. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R4is H. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R4is halo. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R4is –OR5.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0181] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from C1-C3alkyl, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), and –(C1-C3alkylene)-(5- to 10-membered heteroaryl). In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R5is independently selected from C1-C3alkyl and –(C1-C3alkylene)-(5- to 10-membered heteroaryl). In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is 3- to 8-membered heterocyclyl. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is –(C1-C3alkylene)-(3- to 8-membered heterocyclyl). In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl).

[0182] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R5ais indpenendently selected from C1-C3alkoxy. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5ais –OCH2CH3.

[0183] In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R5bis indpenendently selected from cyano, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, and –CD3. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R5bis indpenendently selected from C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5bis cyano. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5bis C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5bis C1-C3haloalkyl. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5bis C3-C6cycloalkyl. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5bis –CD3. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R5bis indpenendently selected from cyano, –CH3, –CHF2, cyclopropyl, and –CD3. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5bisAttorney Docket No.94019-421948 (P30880-WO-PCT) –CH3. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5bis –CHF2. In other embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R5bis cyclopropyl. In some embodiments, the invention relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH3.

[0184] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-D): AR1n .

[0185] In some embodiments, the of formula (I) or formula (I-D), or apharmaceutically acceptable salt –OH, or –OR5, and R3is H, –NRaRb4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a, or 5- to 10-membered heteroaryl optionally substituted with 1-3 R5b. In some embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is H and R3is H or 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is H and R3is H. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is H and R3is 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is halo and R3is H. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is H and R3is 5- to 10-membered heteroaryl optionally substituted 1-3 R5b. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is –NRaRb. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is –OH and R3is H. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is –OR5and R3is H.

[0186] In some embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is H and R2is H, halo, –OH, or –OR5. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceuticallyAttorney Docket No.94019-421948 (P30880-WO-PCT) acceptable salt thereof, wherein R3is H and R2is H. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is H and R2is halo. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is H and R2is –OH. In other embodiments, the invention relates to a compound of formula (I) or formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is H and R2is –OR5.

[0187] In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-C10aryl. In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

[0188] In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein each R1is independently halo or C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is halo. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is C1-C3alkyl. In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from F, Cl, and –CH3. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is F. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is Cl. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein at least 1 R1is –CH3.

[0189] In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3. In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein n is 1. In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein n is 2. In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein n is 3.

[0190] In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, halo, –OH, and –OR5. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is H. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is halo. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is –OH.Attorney Docket No.94019-421948 (P30880-WO-PCT) In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R2is –OR5.

[0191] In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is H, –NRaRb, 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a, or 5- to 10-membered heteroaryl optionally substituted with 1-3 R5b. In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is H or 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is H. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is –NRaRb. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R3is 5- to 10-membered heteroaryl optionally substituted with 1-3 R5b.

[0192] In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R5is selected from C1-C3alkyl, –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), and –(C1-C3alkylene)-(5- to 10-membered heteroaryl). In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R5is selected from C1-C3alkyl, –(C1-C3alkylene)-(C6-C10aryl), and –(C1-C3alkylene)-(5- to 10-membered heteroaryl). In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R5is C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R5is –(C1-C3alkylene)-(C6-C10aryl). In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R5is –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) optionally substituted 1-3 R5a. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) optionally substituted with 1-3 R5b.

[0193] In some embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from C1-C3alkyl. In other embodiments, the invention relates to a compound of formula (I-D), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH3.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0194] In some embodiments, the invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A, i.e., the compound in non-salt form.

[0195] Table A. Exemplary Compounds of the Invention. Compound Name (S)-8-(3-chloro-2-methylphenyl)-5-((tetrahydrofuran-3-yl)oxy)quinazolin-4-amine eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(2,3-dichlorophenyl)-6-morpholinoquinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(2-chlorophenyl)-7-methoxyquinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chlorophenyl)-7-((4-methylmorpholin-2-yl)methoxy)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(2,3-dichlorophenyl)-7-methoxy-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)quinazolin-4-amine -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(2,3-dichlorophenyl)-6-(3-methylmorpholino)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(2,3-dichlorophenyl)-5-(1-(2-(methyl-d3)-2H-tetrazol-5-yl)ethoxy)quinazolin-4-amine eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-5-((1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)methoxy)-7-methoxyquinazolin-4-amine e e e eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-5-((S)-1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)-7-(methoxy-d3)quinazolin- 4-amine e e e ne e -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(2,3-dichlorophenyl)-5-((2-(methyl-d3)-2H-tetrazol-5-yl)methoxy)pyrido[3,4-d]pyrimidin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 6-bromo-8-(3-chlorophenyl)quinazolin-4-amine eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chloro-2,4-difluorophenyl)-5-(1-(1-(2-methoxypropan-2-yl)-1H-1,2,4-triazol-3-yl)ethoxy)quinazolin-4-amine n- n-pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table B, i.e., the compound in non-salt form.

[0197] Table B. Additional Compounds of the Invention Compound Name 8-(3-chloro-2-meth l hen l)-5-((tetrah drofuran-3- l)ox ) uinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-5-(2-(1,4-dioxan-2-yl)ethoxy)-8-(3-chloro-2-methylphenyl)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (4-amino-8-(3-chloro-2-methylphenyl)quinazolin-6-yl)(azetidin-1-yl)methanoneAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 4-(4-amino-8-(3-chloro-2,4-difluorophenyl)quinazolin-6-yl)morpholin-3-oneAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (Sa)-8-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-1-((4-amino-8-((Ra)-3-chloro-2-methylphenyl)quinazolin-7-yl)oxy)propan-2-olAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chlorophenyl)-7-((4-methylmorpholin-2-yl)methoxy)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (1s,4s)-4-((4-amino-8-(3-chloro-2,4-difluorophenyl)quinazolin-7-yl)oxy)cyclohexan-1-olAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (S)-8-(3-chloro-2-methylphenyl)-6-(pyrrolidin-3-yloxy)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(2,3-dichlorophenyl)-7-fluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)quinazolin-4-amine e n- n- n- n-Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(2,3-dichlorophenyl)-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-7-((pyrrolidin-3-yl)oxy)quinazolin-4-amine e e e eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (Ra)-8-(2,3-dichlorophenyl)-7-fluoroquinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 6-((1R,5R)-3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-8-(3-chloro-2,4-difluorophenyl)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (S)-8-(3-chloro-2,4-difluorophenyl)-5-(1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (Ra)-8-(3-chloro-2,4-difluorophenyl)-7-fluoro-5-((S)-1-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)ethoxy)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (Sa)-8-(3-chloro-2,4-difluorophenyl)-5-((1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)methoxy)-7-fluoroquinazolin-4-amine ne ne ne e neAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-7-(oxetan-3-yloxy)quinazolin-4-amine e e ne ne ne eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(2,3-dichlorophenyl)-7-(methoxy-d3)-5-((R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethoxy)quinazolin-4-amine ne ne e ne ne ne - - - - ne - ne neAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (Ra)-8-(2,3-dichlorophenyl)-5-((S)-1-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)ethoxy)-7-(2,2,2-trifluoroethoxy)quinazolin-4- amine - - - - - - -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (Sa)-8-(3-chloro-2,4-difluorophenyl)-5-((S)-1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)-7-(methoxy- d3) uinazolin-4-amine ne ne neAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-5-methoxy-7-((R)-1-(1-methyl-1H-1,2,4-triazol-3-yl)ethoxy)quinazolin-4-amine ne 4- -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-5-(1-(2-methylpyrimidin-4-yl)ethoxy)pyrido[3,4-d]pyrimidin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (Sa)-8-(2,3-dichlorophenyl)-5-((S)-1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)-7-methoxyquinazolin-4-amine - e neAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 7-(benzyloxy)-8-(3-chlorophenyl)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chlorophenyl)-5-(1-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)ethoxy)quinazolin-4-amine e e ne ne - - ne neAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-5-(((3S,4S)-4-ethoxytetrahydrofuran-3-yl)oxy)quinazolin-4-aminepharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table C, i.e., the compound in non-salt form.

[0199] Table C. Exemplary Compounds of the Invention Compound Name 6-((1R,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-8-(3-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 4-amino-8-(3-chloro-2,4-difluorophenyl)-5-((S)-1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)quinazoline-7- carbonitrile - 2- -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(5-chloropyridin-3-yl)-5-((2-(1-methyl-1H-1,2,4-triazol-3-yl)propan-2-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine 4- le neAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chloro-2,4-difluorophenyl)-5-((2-methyl-5,6,7,8-tetrahydroquinazolin-8-yl)oxy)pyrido[3,4-d]pyrimidin-4- amine n- n- ne e e eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (S)-8-(3-chloro-2,4-difluorophenyl)-5-(1-(5-methoxypyrazin-2-yl)ethoxy)quinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 5-((S)-1-(1H-1,2,4-triazol-3-yl)ethoxy)-8-(3-chloro-2,4-difluorophenyl)-7-fluoroquinazolin-4-amine e e e eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chloro-2,4-difluorophenyl)-6-((1,1-difluoropropan-2-yl)oxy)-5-((1-methyl-1H-1,2,4-triazol-3- l)methox ) uinazolin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chloro-4-fluoropyrazolo[1,5-a]pyridin-5-yl)-5-(1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)-6- (methox -d3) uinazolin-4-amine e e - e e 4- - 4-Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (S)-8-(3,4-difluoropyrazolo[1,5-a]pyridin-5-yl)-5-(1-(1-methyl-1H-1,2,4-triazol-3-yl)ethoxy)pyrido[4,3-d]pyrimidin-4- amine e e eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chloro-4-fluoropyrazolo[1,5-a]pyridin-5-yl)-5-(1-(1-methyl-1H-1,2,4-triazol-3-yl)ethoxy)quinazolin-4-amine 3- - -, , pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table D, i.e., the compound in non-salt form.

[0201] Table D. Additional Compounds of the Invention Compound NameAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 6-((1S,5S)-3-azabicyclo[3.1.0]hexan-3-yl)-8-(3-chloro-2,4-difluorophenyl)pyrido[3,2-d]pyrimidin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (S)-4-amino-8-(3-chloro-2,4-difluorophenyl)-5-(1-(1-methyl-1H-1,2,4-triazol-3-yl)ethoxy)quinazoline-6-carbonitrile le e e le -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (E)-1-(4-((4-amino-8-(3-chloro-2,4-difluorophenyl)pyrido[3,4-d]pyrimidin-5-yl)oxy)piperidin-1-yl)-4-morpholinobut-2- en-1-one n- n- e eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chlorophenyl)-5-(1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)pyrido[3,4-d]pyrimidin-4-amineAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-5-(((3R,4R)-4-ethoxytetrahydrofuran-3-yl)oxy)pyrido[3,4-d]pyrimidin-4-amine e -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(7-fluorobenzo[d]thiazol-6-yl)-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)quinazolin-4-amine - - ne e neAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (S)-8-(3-chloro-4-methoxyphenyl)-5-(1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)pyrido[3,4-d]pyrimidin-4-amine - n-Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name (R)-8-(3-chloro-4-fluoropyrazolo[1,5-a]pyridin-5-yl)-5-(1-(1-methyl-1H-1,2,4-triazol-3-yl)ethoxy)pyrido[4,3-d]pyrimidin- 4-amine ne ne n- in- eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-6-((1,1-difluoropropan-2-yl)oxy)-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)quinazolin- 4-amine 4- - -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 5-(1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)-8-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)-6-(methoxy-d3)quinazolin- 4-amine - - e - eAttorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 5-(1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)ethoxy)-8-(4-fluoropyrazolo[1,5-a]pyridin-5-yl)pyrido[3,4-d]pyrimidin-4- amine n- n- n- e e e e -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 8-(3-chloro-2,4-difluorophenyl)-5-((R)-1-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)-2-methoxyethoxy)-7- fluoro uinazolin-4-amine n- - -Attorney Docket No.94019-421948 (P30880-WO-PCT) Compound Name 6-(3-chloro-2,4-difluorophenyl)-2-(1-(difluoromethyl)-1H-1,2,4-triazol-3-yl)-2,3-dihydro-[1,4]dioxino[2,3-f]quinazolin- 10-amine 4- - -o e e o e , e co pou s a co pou seece o a pes o , o a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a comound selected from Examples 1 to 461, i.e. the compound in non-salt form.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0203] In one embodiment, the compound is a compound selected from Examples 462 to 775, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a comound selected from Examples 462 to 775, i.e. the compound in non-salt form.

[0204] In one embodiment, the compound is a compound selected from Examples 1 to 775, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a comound selected from Examples 1 to 775, i.e. the compound in non-salt form.

[0205] In some embodiments, the invention relates to a compound selected from Table A, Table B, or Examples 1 to 461, or a pharmaceutically acceptable salt thererof. In other embodiments, the invention relates to a compound selected from Table A, Table B, or Examples 1 to 461, i.e. the compound in non- salt form.

[0206] In some embodiments, the invention relates to a compound selected from Table C, Table D, or Examples 462 to 775, or a pharmaceutically acceptable salt thererof. In other embodiments, the invention relates to a compound selected from Table C, Table D, or Examples 462 to 775, i.e. the compound in non- salt form.

[0207] In some embodiments, the invention relates to a compound selected from Table A, Table B, Table C, Table D, or Examples 1 to 775, or a pharmaceutically acceptable salt thererof. In other embodiments, the invention relates to a compound selected from Table A, Table B, Table C, Table D, or Examples 1 to 775, i.e. the compound in non-salt form. Radiolabeled Analogs of the Compounds of the Invention

[0208] In another aspect, the invention relates to radiolabeled analogs of the compounds of the invention. As used herein, the term “radiolabeled analogs of the compounds of the invention” refers to compounds that are identical to the compounds of the invention, as described herein, including all embodiments thereof, except that one or more atoms has been replaced with a radioisotope of the atom present in the compounds of the invention.

[0209] As used herein, the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include3H,14C,32P,35S,18F,36Cl, and the like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0210] The radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium (3H)- and / or carbon-14 (14C)-labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0211] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of X, Y, or Z is CR2, CR3, or CR4, respectively, at least one of R2, R3, or R4is –OR5, and at least one R5is a deuterated alkyl group. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is a deuterated alkyl group. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is a deuterated alkyl group. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is a deuterated alkyl group. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CR2, R2is –OR5, and R5is –CD3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CR3, R3is –OR5, and R5is –CD3. In other embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is –CD3.

[0212] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis a deuterated alkyl group. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CD3.

[0213] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) substituted with 1-3 R5b, and at least 1 R5bis a deuterated alkyl group. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) substituted with 1-3 R5b, and at least 1 R5bis –CD3. In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is . In other embodiments,salt thereof, wherein . In other embodiments, the invention relates to aacceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5is . In other embodiments, the invention relates to a compound of formula (I), or aAttorney Docket No.94019-421948 (P30880-WO-PCT) pharmaceutically acceptable salt thereof, wherein Z is CR4, R4is –OR5, and R5. In other embodiments, the invention relates to a compound of formula (I), or asalt thereof, .

[0214] In some formula (I), or a pharmaceutically acceptable saltX is CR2; R2is –OR5, wherein the R5is a deuterated alkyl group; Z is CR4; CR4is –OR5, wherein the R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) substituted with 1-3 R5b; and at least 1 R5bis a deuterated alkyl group.

[0215] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CR2; R2is –OR5, wherein the R5is –CD3; Z is CR4; CR4is –OR5, wherein the R5is –(C1-C3alkylene)-(5- to 10-membered heteroaryl) substituted with 1-3 R5b; and at least 1 R5bis –CD3.

[0216] In some embodiments, the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CR2; R2is –OR5, wherein the R5is –CD3; Z is CR4; and CR4is –OR5, wherein .

[0217] In another aspect, theanalogs, in accordance with any of the embodiments described herein in connection with the compounds of the invention.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0218] In another aspect, the invention relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0219] In another aspect, the invention relates to methods of inhibiting EGFR and methods of treating or lessening the severity of various diseases and disorders, including various cancers, in a subject comprising administering an effective amount of the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0220] In another aspect, the invention relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0221] In another aspect, the invention relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with the compounds of the invention.

[0222] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the invention. IV. MODES OF ADMINISTRATION A. Pharmaceutical Compositions

[0223] While it may be possible for the compounds disclosed herein to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition (i.e., as a formulation). Accordingly, provided herein are pharmaceutical compositions which comprise one or more of the compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers and optionally one or more other therapeutic ingredients. The carrier(s) should be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0224] In an aspect, provided herein is a pharmaceutical composition including a compound of of the invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions containing a compound of the invention or a pharmaceutically acceptable salt thereof as the active ingredient can be prepared by intimately mixing the compound of the invention, or a pharmaceutically acceptable salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).

[0225] The pharmaceutical compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In embodiments, the individual is a mammal such as a human, or a non- human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition including, for example, a compound of the invention and a pharmaceutically acceptable carrier and / or excipient. Pharmaceutically acceptable carriers and excipients are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In preferred embodiments, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophiles for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as a lotion, cream, or ointment.

[0226] A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self-emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, areAttorney Docket No.94019-421948 (P30880-WO-PCT) nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0227] The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0228] The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, (10) glycols, such as propylene glycol; ( 11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; ( 12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0229] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non- aqueous solutions or suspensions, tablets, capsules (including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin). The compound may also be formulated for inhalation. In embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents and published applications cited therein.

[0230] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated,Attorney Docket No.94019-421948 (P30880-WO-PCT) the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

[0231] Formulations of the compounds disclosed herein suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as mouth washes and the like, each containing a predetermined amount of a compound of the present disclosure as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

[0232] Solid dosage forms for oral administration (e.g., capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), may include the active ingredient mixed with one or more pharmaceutically acceptable earners, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as. for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; ( 50) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (e.g., sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also include buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0233] Compressed tablets may be prepared using binders (for example, gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), and / or surface- active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0234] The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules, pills and granules, may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredients) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

[0235] Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3- butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0236] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0237] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0238] Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

[0239] The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.Attorney Docket No.94019-421948 (P30880-WO-PCT)

[0240] Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbon s and volatile unsubstituted hydrocarbons, such as butane and propane.

[0241] The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion. Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0242] Examples of suitable aqueous and non-aqueous carriers that may be employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0243] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

[0244] For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[0245] Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeuticAttorney Docket No.94019-421948 (P30880-WO-PCT) response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0246] The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof) the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. B. Combination Therapies

[0247] In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with one or more additional therapeutic agent. In some embodiments, the additional therapeutic agent includes an anti- cancer agent. The anti-cancer agent may be a chemotherapeutic, radiation, or surgical removal of the cancer.

[0248] In any case, the multiple therapeutic agents (at least one of which is a compound of the various embodiments disclosed herein) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.

[0249] In some embodiments, the one or more additional therapies or therapeutic agents are independently selected from: secondary EGFR inhibitors (e.g., afatinib, erlotinib, gefitinib, lapatinib, cetuximab, panitumumab, osimertinib, and olmutinib), ErbB2 / Her2 inhibitors (e.g., afatinib, lapatinib, trastuzumab, and pertuzumab), ALK inhibitors (e.g., crizotinib, alectinib, entrectinib, brigatinib), ROS1 inhibitors (e.g., crizotinib, entrectinib, lorlatinib, ceritinib, and merestinib), MEK inhibitors (e.g., trametinib, cobimetinib, binimetinib, selumetinib, refametinib), RAS (KRas, HRas, and / or NRas) inhibitors (e.g., MRTX849, LY3499446, JNJ-74699157, AMG 510, and AZD4785), Bcr-Abl inhibitors (e.g., imatinib, dasatinib, nilotinib), FGFR1, 2, or 3 inhibitors (e.g., nintedanib), MET inhibitors (e.g., capmatinib), AXL inhibitors (e.g., sitravatinib), RET inhibitors (e.g., sunitinib and selpercatinib), ERK inhibitors (e.g., ulixertinib), Shp2 inhibitors (e.g., RLY-1971, RMC-4630, TNO155, and JAB-3068), Bcl-2 inhibitors (e.g., ABT-263, obatoclax, ABT-737, and navitoclax), mTOR inhibitors (e.g., everolimus and tacrolimus), Trk inhibitors (e.g., larotrectinib and entrectinib), checkpoint inhibitorsAttorney Docket No.94019-421948 (P30880-WO-PCT) (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, and pidilizumab) or other immunotherapies (e.g., monoclonal antibodies), PARP inhibitors (e.g., olaparib), PI3K inhibitors (e.g., buparlisib), BET inhibitors (e.g., GSK1210151A), Raf i...

Claims

Attorney Docket No.94019-421948 (P30880-WO-PCT) CLAIMS What is claimed is:

1. A compound of formula (I): , or a pharmaceutically acceptable salt Ring A is a C -C aryl or6105- to each R1is independently selected from halo, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, C1-C3hydroxyalkyl, C2-C3alkynyl, and C3-C6cycloalkyl; X is N or CR2; Y is N or CR3; Z is N or CR4; R2is selected from H, halo, cyano, –OH, –OR5, –NRaRb, C1-C3alkyl, and C1-C3haloalkyl; R3is selected from H, halo, cyano, –OH, –OR5, –NRaRb, C1-C3haloalkyl, –C(O)NRcRd, C6-C10aryl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with 1-3 R3a; each R3ais independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, –(C1-C3alkylene)-(C1-C3alkoxy), –(C1-C3alkylene)-(4- to 7-membered heterocyclyl), and oxo; R4is selected from H, halo, cyano, –OH, –OR5, –NHR5, –N(C1-C3alkyl)R5, –SR5, and –C(O)NRcRd; each R5is independently selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, –(C1-C3alkylene)-NMe2, –(C1-C3alkylene)-(C1-C3alkoxy), –(C1-C3alkylene)-C(O)H, –(C1-C3alkylene)-C(O)NMe2, –(C1-C3alkylene)-C(O)-(C1-C3haloalkyl), C4-C7cycloalkyl, C6-C10aryl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and –CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b;Attorney Docket No.94019-421948 (P30880-WO-PCT) or two R5, together with the atoms to which they are attached, join to form a 5- to 7-membered heterocyclyl optionally substituted with 1-3 R5a; each R5ais independently selected from halo, –OH, oxo, cyano, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxy, –(C1-C3alkylene)-C(O)H, –C(O)-(C1-C3alkyl), –C(O)-(C1-C3haloalkyl), –C(O)-(C1-C3cyanoalkyl), –C(O)-(C2-C4alkenyl), –C(O)-(C2-C4haloalkenyl), –C(O)-(C2-C4cyanoalkenyl), –C(O)-(C2-C4alkynyl), –C(O)-(C2-C4alkenylene)-NRaRb, –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl), –S(O)2-halo, –S(O)2-(C1-C3alkenyl), 3- to 6-membered heterocyclyl, and 5- to 10-membered heteroaryl optionally substituted with 1 C1-C3alkyl or C1-C3haloalkyl; each R5bis independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –OCD3, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionally substituted with 1-2 halo, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo), –(C1-C3alkylene)-(C6-C10aryl), and –S(O)2-(C1-C3alkyl); each Ra, Rb, Rcand Rdare independently selected from H, C1-C3alkyl, and –(C1-C3alkylene)-(4- to 7-membered heterocyclyl); or Rcand Rd, together with the atoms to which they are attached, join to form a 4- to 6-membered heterocyclyl; and n is 0, 1, 2, or 3.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is C6-C10aryl.

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is 5- to 10-membered heteroaryl.

5. The compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyrazolyl, thiophenyl, pyridinyl, quinolinyl, pyrazolo[1,5-a]pyridinyl, benzo[d]thiazolyl, and pyrrolo[2,3-b]pyridinyl.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 1.Attorney Docket No.94019-421948 (P30880-WO-PCT) 7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 2.

8. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 3.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein each R1is independently selected from F, Cl, Br, cyano, –CH3, –CH2CH3, –CHF2, –OCH3, –CH2OH, ethynyl, and cyclopropyl.

10. The compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3, and at least 1 R1is Cl.

11. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 0.

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) .wherein X is N.

14. The compound of any one of claims 1 to12, or a pharmaceutically acceptable salt thereof, wherein X is CR2and R2is selected from H, halo, cyano, –OH, –OR5, and C1-C3haloalkyl.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein R2is selected from H, F, cyano, –OH, –OR5, and –CF3; and R5is selected from C1-C3alkyl, C1-C3haloalkyl, C1-C3hydroxyalkyl, –(C1-C3alkylene)-NMe2, C4-C7cycloalkyl, C6-C10aryl, 3- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from –OH, oxo, C1-C3alkyl, and 3- to 6-membered heterocyclyl.

17. The compound of claim 15 or 16, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from –OH, oxo, –CH3, and oxetanyl.

18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from halo, –OH, C1-C3alkyl, C1-C3haloalkyl, 3- to 8-membered heterocyclyl, and –(C1-C3alkylene)-(C6-C10aryl).Attorney Docket No.94019-421948 (P30880-WO-PCT) 19. The compound of claim 15 or 18, or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from F, Cl, –OH, –CH3, –CHF2, oxetanyl, and benzyl.

20. The compound of any one of claims 15 to 19, or a pharmaceutically acceptable salt thereof, wherein R5is selected from –CH3, –CHF2, –CH2CHF2, –CH2CF3, –CH2CH(CH3)(OH), , ,wherein Y is N.

22. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Y is CR3and R3is selected from H, halo, cyano, –OH, –OR5, –NRaRb, –C(O)NRcRd, C6-C10aryl, 4- to 10-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein said aryl, heterocyclyl, or heteroaryl is optionally substituted with 1-3 R3a.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein each R3ais independently selected from C1-C3alkyl, –(C1-C3alkylene)-(C1-C3alkoxy), –(C1-C3alkylene)-(4- to 7-membered heterocyclyl), and oxo.Attorney Docket No.94019-421948 (P30880-WO-PCT) 24. The compound of claim 22 or 23, or a pharmaceutically acceptable salt thereof, wherein each R3ais independently selected from –CH3, , and oxo.

25. The compound of claim 22, or asalt thereof, wherein Rais –CH3.

26. The compound of claim 22 or 25, or a pharmaceutically acceptable salt thereof, wherein Rbis –CH3or –CH(CH3)CH2-morpholinyl.

27. The compound of claim 24, or a pharmaceutically acceptable salt thereof, wherein Rcand Rd, together with the atoms to which they are attached, join to form a 4-membered heterocyclyl.

28. The compound of any one of claims 22 to 27, or a pharmaceutically acceptable salt thereof, wherein R3is selected from H, F, Br, cyano, –OH, –OR5, ,,–(C1-C3alkylene)-(C1-C3alkoxy), C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, 5- to 10-memberedAttorney Docket No.94019-421948 (P30880-WO-PCT) heteroaryl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and CD3, wherein said C4-C7cycloalkyl, 3- to 8-membered heterocyclyl, or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b.

29. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halo, C1-C3alkyl, and C1-C3haloalkyl.

30. The compound of claim 28 or 29, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from F, –CH3, and –CH2CF3.

31. The compound of claim 28, or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from C1-C3alkyl.

32. The compound of claim 28 or 31, or a pharmaceutically acceptable salt thereof, wherein at least 1 R5bis –CH3.

33. The compound of any one of claims 28 to 32, or a pharmaceutically acceptable salt thereof, wherein R5is selected from –CH3, –CHF2, –CH2CF3, –CH(CH3)CHF2, –CH2CH2NMe2, , ,any one or a wherein Z is N.

35. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein Z is CR4and R4is selected from H, halo, –OH, –OR5, –N(C1-C3alkyl)R5, –SR5, and –C(O)NRcRd.Attorney Docket No.94019-421948 (P30880-WO-PCT) 36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein Rcand Rd, together with the atoms to which they are attached, join to form a 4-membered heterocyclyl.

37. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein R4isselected from H, Cl, F, –OH, –OR5, –N(C1-C3R5is selected from C1-C3alkyl, C1-C3–(C -C alkylene)-(C -C alkoxy), –(C -C13 1 3 1 3- heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(3- to 8-membered heterocyclyl), –(C1-C3alkylene)-(5- to 10-membered heteroaryl), and CD3, wherein said 3- to 8-membered heterocyclyl or –(C1-C3alkylene)-(3- to 8-membered heterocyclyl) is optionally substituted with 1-3 R5a, and said 5- to 10-membered heteroaryl or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 R5b.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein each R5ais independently selected from halo, oxo, C1-C3alkyl, C1-C3alkoxy, –C(O)-(C1-C3alkyl), –C(O)-(C2-C4alkenyl), and –C(O)-(C2-C4alkenylene)-(3- to 8-membered heterocyclyl).

39. The compound of claim 37 or 38, or a pharmaceutically acceptable salt thereof, wherein at least 1 R5ais F, oxo, –CH3, –OCH3, –OCH2CH3, –C(O)CH2CH3,–C(O)CH=CH2, or –C(O)CH=CHCH2-morpholinyl.

40. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from halo, –OH, cyano, C1-C3alkyl, C1-C3haloalkyl, –CD3, C1-C4hydroxyalkyl, C1-C3alkoxy, –OCD3, –(C1-C3alkylene)-(C1-C3alkoxy), C3-C6cycloalkyl optionally substituted with 1-2 halo, 3- to 8-membered heterocyclyl, –(C1-C3alkylene)-(C3-C6cycloalkyl optionally substituted with 1-2 halo), and –S(O)2-(C1-C3alkyl).

41. The compound of claim 37 or 40, or a pharmaceutically acceptable salt thereof, wherein each R5bis independently selected from F, –OH, cyano, –CH3, –CH2CH3, –CHF2, –CH2CHF2, –CD3, –CH2C(CH3)2(OH), –OCH3, –OCH2CH3, –OCD3, –CH2OCH3, –CH2CH2OCH3, –C(CH3)2(OCH3), cyclopropyl, 1,1,-difluorocyclopropyl, oxetanyl, tetrahydropyranyl, 2-oxaspiro[3.3]heptanyl, –CH2-(1-flourocyclopropyl), and –S(O)2CH2CH3.

42. The compound of any one of claims 37 to 41, or a pharmaceutically acceptable salt thereof, wherein R5is selected from –CH3, –CH(CH3)2, –CH2CF3, –CH(CH3)CH2NMe2,Attorney Docket No.94019-421948 (P30880-WO-PCT) , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) , , ,Attorney Docket No.94019-421948 (P30880-WO-PCT) N D Dwherein no more than 1 of X, Y, and Z are N.

44. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein Y is CR3, Z is CR4, R3is OR5, R4is OR5, and the R5of R3and R4, together with the oxygen atoms to which they are attached, join to form a 5- to 7-membered heterocyclyl optionally substituted with 1-3 R5a.

45. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein the 5- to N 7-membered heterocyclyl is a fused 1,4-dioxanyl or.

46. The compound of any one of claims 1 to 12, 14 to 20, 22 to 33, and 35 to 42, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-A): .

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein: R2is H;Attorney Docket No.94019-421948 (P30880-WO-PCT) R3is halo, cyano,–OR5, or 4- to 10-membered heterocyclyl optionally substituted with 1-3 R3a; and R4is halo or –OR5.

48. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein: R2is halo or –OR5; R3is H; and R4is –OR5.

49. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein: R2is halo; R3is H; and R4is –OR5.

50. A compound selected from Table A or Examples 1 to 461, or a pharmaceutically acceptable salt thereof.

51. A compound selected from Table B, or a pharmaceutically acceptable salt thereof.

52. A compound selected from Table C or Examples 462 to 775, or a pharmaceutically acceptable salt thereof.

53. A compound selected from Table D, or a pharmaceutically acceptable salt thereof.

54. The compound of any one of claims 1 to 53, or a pharmaceutically acceptable salt thereof, wherein the compound is an EGFR inhibitor selective to a mutant EGFR protein or gene.

55. The compound of any one of claims 1 to 54, wherein the compound is in a non-salt form.

56. A pharmaceutical composition comprising a compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, or the compound of claim 55 and one or more pharmaceutically acceptable carriers or vehicles.

57. A method of inhibiting EGFR in a subject comprising administering to the subject the compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, the compound of claim 55, or the pharmaceutical composition of claim 56.Attorney Docket No.94019-421948 (P30880-WO-PCT) 58. A method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, the compound of claim 55, or the pharmaceutical composition of claim 56.

59. The method of claim 58, wherein the cancer is an EGFR-associated cancer.

60. The method of any one of claims 57 to 59, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

61. Use of the compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, the compound of claim 55, or the pharmaceutical composition of claim 54, as a medicament.

62. Use of the compound of any one of claims 1 to 54, or a pharmaceutically acceptable salt thereof, the compound of claim 55, or the pharmaceutical composition of claim 56 in the manufacture of a medicament for treating cancer.

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