Cancer treatment methods

Abstract

The present disclosure provides a compound of formula (I) that inhibits phosphatidylinositol 4,5-bisphosphate 3 kinase (PI3K) isoform alpha (PI3Kα) and a pharmaceutically acceptable salt thereof. These compounds are useful for treating diseases in which increased PI3Kα activation in the subject is involved in the pathology, symptoms, and / or progression of the disease (e.g., cancer).

Description

Technology Field

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 615,064 filed December 27, 2023 and U.S. Provisional Application No. 63 / 675,810 filed July 26, 2024, the entirety of which is incorporated herein by reference.

[0003] Sequence list

[0004] The present application comprises a sequence list submitted electronically in an XML file named '49366-0056WO3_ST26.SL.XML'. The XML file, created on July 25, 2024, has a size of 2,933 bytes. The contents of the XML file are incorporated herein by reference in their entirety.

[0005] Technology field

[0006] The present disclosure provides a compound of formula (I) that inhibits phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα) and a pharmaceutically acceptable salt thereof. These compounds are useful for treating diseases in which increased PI3Kα activation in the subject is involved in the pathology, symptoms, and / or progression of the disease (e.g., cancer). Background Technology

[0007] PIK3CA Phosphatidyllinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by a gene, is part of the PI3K / AKT / TOR signaling network and is modified in several human cancers.

[0008] Activation of the PI3K pathway occurs in approximately 30–50% of human cancers and is involved in resistance to various anticancer therapies. (See reference [Bauer, TM et al., Pharmacol. Ther. 2015, 146, 53-60].) However, the development of PI3K inhibitors has been problematic for various reasons, particularly the inability to specifically inhibit signaling by mutant PI3Kα while preserving wild-type PI3Kα, and associated dose-limiting toxicity that interferes with sustained inhibition of the PI3K pathway. (See reference [Hanker et al., Cancer Discovery, April 2019;9: 482-491].) For example, alpelisib is a PI3K inhibitor with equivalence to wild-type and mutant PI3Kα, which results in dose-limiting toxicity and hyperglycemia.

[0009] Therefore, selectively targeting PI3Kα represents an approach for treating proliferative disorders such as cancer.

[0010] Some embodiments are compounds of the following chemical formula (I).

[0011] (I)

[0012] or provide a pharmaceutically acceptable salt thereof, wherein in formula (I),

[0013] Z is N or CH, and

[0014] R 1 is a quaternary to 10-membered heterocyclile optionally substituted with hydrogen, halogen, cyano, C3-C6 cycloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl; or (i) a C3-C6 cycloalkyl or (ii) a C1-C6 alkyl optionally substituted with a quaternary to 10-membered heterocyclile, and

[0015] R 2 is 1 to 4 independently selected R 2AA C6-C10 aryl arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-membered heteroaryls arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclils arbitrarily substituted with , 1 to 4 independently selected Rs 2A A C4-C10 cycloalkyl optionally substituted with , 1 to 4 independently selected R 2A 4- to 10-membered heterocyclyloxy oxy arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-won heteroaryloxy, -C(=O)NR arbitrarily substituted with A R C A C1-C6 alkoxyalkyl optionally substituted with -C(=O)NR A R C , C1-C6 alkoxy optionally substituted with a C4-C10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, and

[0016] R 2A are each

[0017] (i) Halogen;

[0018] (ii) Cyan;

[0019] (iii) Hydroxyl;

[0020] (iv) -NR A R B ;

[0021] (v) -C(=O)NR A R B ;

[0022] (vi) ;

[0023] (vii) -NHC(=O)R C ;

[0024] (viii) -C(=O)OR D ;

[0025] (ix) -SO2R D ;

[0026] (x) -NHSO2R D;

[0027] (xi) -SO2NR D R E ;

[0028] (xii) NR A R B -NHC(=O)C1-C6 alkyl arbitrarily substituted with;

[0029] (xiii) C1-C6 haloalkyl;

[0030] (xiv) C1-C6 hydroxyalkyl;

[0031] (xv) Hydroxyl, Cyano, Halogen, -C(=O)NR A R B , -NR A R B , a C1-C6 alkyl optionally substituted with a hydroxyl, and a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclil optionally substituted with a hydroxyl or a C1-C6 alkyl;

[0032] (xvi) hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B 4- to 10-membered heterocyclils optionally substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with , and C1-C6 alkoxy or hydroxyl optionally substituted with hydroxyl;

[0033] (xvii) Hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRA R B or a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl;

[0034] (xviii) -NR A R B , or a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl;

[0035] (xix) hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or a C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl; and

[0036] (xx) Independently selected from 4- to 10 heterocyclyloxy groups optionally substituted with hydroxyl, cyano, halogen, or C1-C6 alkyl groups optionally substituted with hydroxyl, and

[0037] R A and R B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R A and R B They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[0038] R C are C3-C6 cycloalkyl and -C(=O)NHR, respectively. Y1 , and -NR A R BIndependently selected from C1-C6 alkyl or C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 hydroxyalkyl, and

[0039] R D and R E are hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and oxo, respectively, or -NR A R B Independently selected from C1-C6 alkyls arbitrarily substituted with,

[0040] R 3A and R 3B are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R 3A and R 3B They form quaternary to octavalent heterocyclil groups together with the carbon and nitrogen atoms to which they are respectively attached, and

[0041] R 4 is hydrogen, a halogen, a C1-C6 alkyl, or an acrylamido, and

[0042] R 5 -NR 5A R 5B , -NR 5A C(=O)R 5B or -C(=O)NR 5A R 5B And,

[0043] R 5A and R 5B is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl, and

[0044] R 6 is hydrogen, a halogen, or a C1-C6 alkyl, and

[0045] X is a bond, CH2, CH(CH3), C(CH3)2 or And,

[0046] W is NR 3B or O and,

[0047] Y is a phenyl, naphthyl, or 5- to 10-membered heteroaryl, wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryls are independently selected from 1 to 3 Rs. Y or It is arbitrarily and independently substituted as, and * is L 1 This indicates that it is connected to the remaining part of the compound of this chemical formula (I),

[0048] R Y are respectively halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -(CH2) n -C(=O)R F , -(CH2) n -NHC(=O)R F , -(CH2) n -NHC(=O)OR F , -C(=O)C(=O)NHR F , -CO2R G , -(CH2) n -SO2NR H R I , -(CH2) n -NHSO2R J , -(CH2) n -S(=O)(=NR H )R J , -(CH2) n -SO2R J , -(CH2) n -C(=O)NR H R I , -(CH2) n -C(=O)NR H OR I and independently selected from C1-C6 haloalkyls optionally substituted with hydroxyl, and

[0049] R F Each is independently selected from C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl optionally substituted with C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and

[0050] R G Each is independently selected from hydrogen, C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and

[0051] R H and R I are hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2) n -C(=O)NH2, -(CH2) n -SO2NH2, -(CH2) n -SO2(C1-C6 alkyl), hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl and -C(=O)NR K1 R K2 Independently selected from C1-C6 alkyls optionally substituted with 1 to 2 independently selected substituents, or R H and R I They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[0052] R J is a C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, and

[0053] R K1 and R K2 Each is independently hydrogen or a C1-C6 alkyl, and

[0054] Ring A is phenyl, 4- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C4-C10 cycloalkyl, and

[0055] L 1 Silver bond, C1-C6 alkoxylene, -(CH2) n -NHC(=O)-, -C(=O)NH-(CH2) n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NR G )-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or a C1-C6 alkylene optionally substituted with an oxo, and

[0056] R Y1 ≡ cyano, hydroxyl, halogen, -C(=O)R, respectively. F , -NHC(=O)R F , -CO2R G , -SO2NR H R I , -NHSO2R J , -S(=O)(=NR H )R J , -SO2(C1-C6 alkyl), -C(=O)NR H R I , 4~6 won heteroaryl, R Y2 C1-C6 alkoxy, C1-C6 haloalkyl, R optionally substituted with Y2 Independently selected from C1-C6 alkyl and hydroxyl optionally substituted with , or 4- to 6-membered heterocyclies optionally substituted with C1-C6 alkyl, and

[0057] R Y2 is hydroxyl, -NR H R I , -C(=O)NR H R I or -SO2NR H R I And,

[0058] n is 0, 1, or 2, and

[0059] z is 0, 1, 2, or 3.

[0060] In addition, a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients is provided herein.

[0061] A method for treating a subject requiring cancer treatment is provided herein, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0062] In addition, as a method of treating subjects requiring cancer treatment, (a) cancer PIK3CA A method is provided herein comprising the steps of: determining that there is a dysregulation of the expression or activity or level of a gene, PI3Kα protein, or any of these; and (b) administering to a subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0063] A method for treating a PI3Kα-associated disease in a subject is provided herein, comprising the step of administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein to a subject who has been identified or diagnosed as having a PI3Kα-associated disease.

[0064] The present disclosure also provides a method for treating a PI3Kα-associated disease in a subject, comprising the steps of: determining that the cancer of the subject is a PI3Kα-associated disease; and administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0065] A method for treating PI3Kα-associated cancer in a subject is also provided herein, comprising the step of administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein to a subject who has been identified or diagnosed as having PI3Kα-associated cancer.

[0066] The present disclosure also provides a method for treating a PI3Kα-associated cancer in a subject, comprising the steps of: determining that the cancer of the subject is a PI3Kα-associated cancer; and administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0067] As a method of treating the subject, the subject PIK3CA A method is provided herein comprising the step of administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein to a subject having a clinical record indicating dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these.

[0068] The present disclosure also provides a method for inhibiting PI3Kα in mammalian cells, comprising the step of contacting the mammalian cells with an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0069] Other embodiments include specific details for carrying out the invention and / or those described in the claims.

[0070] Additional definition

[0071] To facilitate understanding of the contents of this disclosure, a number of additional terms are defined below. In general, the nomenclature used herein and the laboratory procedures of organic chemistry, medicinal chemistry, and pharmacology described herein are well known and commonly used in the art. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by a person skilled in the art to which this disclosure pertains. Each patent, application, published application, and other publication mentioned throughout this specification and the appended appendices is incorporated herein by reference in its entirety.

[0072] When referring to a number or numerical range, the term 'approximately' means that the referred number or numerical range is an approximation, for example, within experimental variability and / or statistical experimental error, and therefore the number or numerical range may vary by up to ±10% of the specified number or numerical range.

[0073] As used herein, the term 'acceptable' in relation to a formulation, composition, or ingredient means that it does not have a continuously harmful effect on the overall health of the subject being treated.

[0074] As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotope enrichment variants of the described structure. Unless otherwise specified, a compound identified herein in one specific tautomeric form by name or structure is intended to include other tautomeric forms.

[0075] In any compound described herein having one or more chiral centers, where absolute stereochemistry is not explicitly indicated, it is understood that each center may independently be an R configuration or an S configuration, or a mixture thereof. Accordingly, the compounds provided herein may be enantiomerically pure, enantiomerically rich, racemic mixtures, diastereomericly pure, diastereomericly rich, or stereoisomer mixtures. Furthermore, in any compound described herein having one or more double bond(s) that produce geometric isomers that may be defined as E or Z, it is understood that each double bond may independently be E or Z, or a mixture thereof.

[0076] The term 'to suppress' or 'suppression of' means to reduce by a measurable amount or to prevent completely (e.g., 100% suppression).

[0077] The phrase ‘therapeutic effective dose’ means an amount of compound sufficient to (i) treat a PI3Kα protein-associated disease, (ii) attenuate, alleviate, or eliminate one or more symptoms of a specific disease, or (iii) delay the onset of one or more symptoms of a specific disease described herein when administered to a subject requiring such treatment.

[0078] The term 'pharmaceuticalally acceptable salt' refers to a formulation of a compound that does not cause significant irritation to the organism being administered and does not impair the biological activity and properties of the compound.

[0079] As used herein, the term “subject” refers to any animal including primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and mammals such as humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and / or exhibited at least one symptom of the disease to be treated and / or prevented.

[0080] As used herein, the terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical outcomes include, but are not limited to, the complete or partial remission of disease-associated symptoms, whether detectable, a reduction in the severity of the disease, a stabilized (i.e., non-deterioration) state of the disease, a delay or slowing of disease progression, improvement or alleviation of the disease state (e.g., one or more symptoms of the disease), and remission (partial or complete). “Treatment” may also mean extended survival compared to survival expected without treatment.

[0081] The term 'halogen' refers to fluoro(F), chloro(Cl), bromo(Br) or iodo(I).

[0082] The term 'oxo' refers to a divalent double-bonded oxygen atom (i.e., '=O'). As used herein, the oxo group is attached to a carbon atom to form a carbonyl.

[0083] The term 'hydroxyl' refers to the -OH radical.

[0084] The term 'cyano' refers to the -CN radical.

[0085] The term 'alkyl' refers to a saturated acyclic hydrocarbon radical that may be straight-chain or branched and contains the indicated number of carbon atoms. For example, C 1-10 indicates that the group may have 1 to 10 (inclusive) carbon atoms internally. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n - Hexyl is included. As used in this context, the term 'saturated' means a state in which only a single bond exists between constituent carbon atoms and other available valencies are occupied by hydrogen and / or other substituents defined herein.

[0086] The term 'alkenyl' refers to an alkyl group in which one or more hydrogen atoms are removed, and the alkyl group has one or more carbon-carbon double bonds.

[0087] The term 'haloalkyl' refers to an alkyl group in which one or more hydrogen atoms are replaced by independently selected halogens.

[0088] The term 'alkoxy' refers to -O-alkyl radicals (e.g., -OCH3).

[0089] The term 'alkoxyalkyl' refers to -alkyl-O-alkyl radicals (e.g., -CH2CH2OCH3).

[0090] The term 'thioalkyl' refers to -S-alkyl radicals (e.g., -SCH3) or -alkyl-S-alkyl radicals (e.g., -CH2CH2SCH3).

[0091] The term 'hydroxyalkyl' refers to an alkyl group in which one or more hydrogen atoms are replaced by hydroxyl.

[0092] The term 'aryl' refers to all 6- to 20-carbon ring systems, wherein at least one ring in the ring system is aromatic (e.g., 6-carbon monocyclic, 10-carbon dicyclic, or 14-carbon tricyclic aromatic ring systems). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2,3-dihydro-1H-indene, etc.

[0093] As used herein, the term 'cycloalkyl' refers to a cyclic saturated hydrocarbon group having, for example, 3 to 20 cyclic carbons, preferably 3 to 16 cyclic carbons, and more preferably 3 to 12 cyclic carbons, or 3 to 10 cyclic carbons, or 3 to 6 cyclic carbons. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyls may include multiple junctions and / or cross-linked rings. Non-limiting examples of conjugated / bridged cycloalkyls include bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, etc. Cycloalkyls also include spirocyclic rings (e.g., spirocyclic two-rings in which two rings are connected through only one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecaene, etc. As used in this context, the term 'saturated' means that only single bonds exist between constituent carbon atoms.

[0094] As used herein, the term 'heteroaryl' refers to a ring system having 5 to 20 ring atoms, e.g., 5, 6, 9, 10, or 14 ring atoms, wherein at least one ring in the ring system contains one or more heteroatoms independently selected from the group consisting of N, O, S, Si, and B, and at least one ring in the ring system is aromatic (however, it does not need to be a ring containing heteroatoms, e.g., tetrahydroisoquinoline, e.g., tetrahydroquinoline). The heteroaryl group may include monocyclic, crosslinked, conjugated, and spiro-ring systems, as long as one ring in the ring system is aromatic. Examples of heteroaryls include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benztriazolyl, cinnolineyl, indazolyl, indolyl, isoquinolineyl, isothiazolyl, naphthiridinyl, purinyl, thienopyridinyl, pyrido[2,3- d ]pyrimidinyl, pyrrolo[2,3- b ]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c ]pyridinyl, pyrazolo[3,4- b ]pyridinyl, pyrazolo[3,4- c ]pyridinyl, pyrazolo[4,3- c ]pyridine, pyrazolo[4,3- b ]pyridinyl, tetrazolyl, chroman, 2,3-dihydrobenzo[ b ][1,4]dioxin, benzo[ d ][1,3]dioxol, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[ b][1,4]oxacyanes, isoindolines, etc. are included. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolineyl, pyranyl, pyrazinyl, and pyrimidinyl. For clarity, the heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinyl analogs thereof, and each ring nitrogen adjacent to the carbonyl is tertiary (i.e., all three valencies are occupied by non-hydrogen substituents), such as pyridone (e.g., , , or ), pyrimidon (for example, or ), Piridazinon(e.g., or ), pyrazinone (e.g., or ) and imidazolone (e.g., One or more of ) and each ring nitrogen adjacent to the carbonyl is tertiary [i.e., the oxo group of the present invention (i.e., '=O') is a component of the heteroaryl ring].

[0095] The term 'heterocyclile' refers to a saturated or partially unsaturated ring system having 3 to 16 ring atoms having at least one heteroatom selected from O, N, S, Si, and B, as long as valence permits, wherein one or more ring atoms may be substituted by 1 to 3 oxos (e.g., forming lactams), and one or more N or S atoms may be substituted by 1 to 2 oxodos (e.g., forming N-oxide, S-oxide, or S,S-dioxides). The heterocyclile group may also include one or two imino (=NH) groups as long as valence permits. The heterocyclile group includes monocyclic, crosslinked, conjugated, and spiro-ring systems. Examples of heterocyclyl groups include piperazine-yl, pyrrolidine-yl, dioxane-yl, morpholin-yl, tetrahydrofuran-yl, tetrahydropyridyl, dihydropyrazine-yl, dihydropyridyl, dihydropyrrolyl, dihydrofuran-yl, dihydrothiophenyl, etc. Heterocyclyls may include multiple junctions and cross-linked rings. Non-limiting examples of conjugated / bridged heterocyclies include 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-Azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, etc. Heterocycliles also include spirocyclic rings (e.g., spirocyclic 2 rings in which two rings are connected through only one atom). Non-limiting examples of spirocyclic heterocyclils include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane, 2,5-diazaspiro[3.6]decane, 3-azaspiro[5.5]undecae, 2-oxaspiro[2.2]pentane, and 4-oxaspiro[2.5]octane. Includes 1-oxaspiro[3.5]nonanein, 2-oxaspiro[3.5]nonanein, 7-oxaspiro[3.5]nonanein, 2-oxaspiro[4.4]nonanein, 6-oxaspiro[2.6]nonanein, 1,7-dioxaspiro[4.5]decanein, 2,5-dioxaspiro[3.6]decanein, 1-oxaspiro[5.5]undecaine, 3-oxaspiro[5.5]undecaine, 3-oxaspiro[5.5]undecaine, etc.

[0096] 'Archyle' refers to an aryl group defined herein that is connected to the rest of the molecule through a divalent C1-C6 alkyl group as described herein. Non-limiting examples of archyle groups include benzyl, ethylphenyl, methylnaphthyl, etc.

[0097] 'Heteroaryl' refers to a heteroaryl group defined herein that is connected to the rest of the molecule through a divalent C1-C6 alkyl group as described herein. Non-limiting examples of arylyl groups include methylpyridyl, ethylpyrimidinyl, methylimidazolyl, etc.

[0098] 'Heterocyclyloxy' refers to the -O-heterocyclyl radical, wherein the heterocyclyl group is as defined herein.

[0099] 'Heteroaryloxy' refers to an -O-heteroaryl radical, wherein the heteroaryl group is as defined herein.

[0100] Examples of aromatic rings used herein include benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazol, oxazole, thiazole, isoxazole, isothiazole, isothiazole, etc.

[0101] As used herein, when a ring is described as 'partially unsaturated,' this means that the ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributable to the ring itself, for example, 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, etc.

[0102] To avoid doubt and unless otherwise specified, in the case of ring and cyclic groups (e.g., aryl, heteroaryl, heterocyclil, cycloalkyl, etc. described herein) containing a sufficient number of ring atoms to form a dicyclic or higher-order cyclic system (e.g., tricyclic, polycyclic cyclic systems), such ring and cyclic groups have bonding points where (i) adjacent ring atoms (e.g., [xx0] cyclic systems, where 0 indicates a zero atom bridge (e.g., )), (ii) single ring atoms (spiro-joined ring systems) (e.g., , , or ), or (iii) a continuous arrangement of ring atoms (a bridged ring system in which all bridge lengths are greater than 0) (e.g., , , or It is understood to encompass things having a connecting ring, including those located on )

[0103] In addition, the atoms constituting the compounds of the present embodiment are intended to include all isotopic forms of these atoms. The isotopes used herein include these atoms that have the same atomic number but different mass numbers. By and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon are 13 C and 14 Includes C.

[0104] Additionally, compounds disclosed herein generally or specifically are intended to include all tautomeric forms. Thus, for example, moiety Compounds containing moiety It encompasses tautomeric forms containing. Likewise, pyridinyl or pyrimidinyl moiety described as optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0105] The compounds provided herein may encompass various stereochemical forms. The compounds also encompass enantiomers (e.g., R and S isomers), diastereomers, as well as mixtures of enantiomers (e.g., R and S isomers) including racemic mixtures and mixtures of diastereomers, and individual enantiomers and diastereomers, which arise as a result of structural asymmetry of a particular compound. Unless otherwise indicated, if the disclosed compound is named or illustrated with a structure that does not specify stereochemistry (e.g., a 'flat' structure) and has one or more chiral centers, it is understood that this represents all possible stereoisomers of the compound. Likewise, unless otherwise indicated, if the disclosed compound is named or illustrated with a structure that specifies stereochemistry (e.g., a structure having 'wedge' and / or 'dashed' bonds) and has one or more chiral centers, it is understood that this represents the indicated stereoisomers of the compound.

[0106] Details of one or more embodiments of the present disclosure are described in the accompanying drawings and the following description. Other features and advantages of the present disclosure will become apparent from the description, drawings, and claims. Specific details for implementing the invention

[0107] The present disclosure provides a compound of formula (I) that inhibits phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα) and a pharmaceutically acceptable salt thereof. These compounds are useful for treating diseases in which increased PI3Kα activation in the subject is involved in the pathology, symptoms, and / or progression of the disease (e.g., cancer).

[0108] Chemical formula (I) compound

[0109] Some embodiments are compounds of the following chemical formula (I).

[0110] (I)

[0111] or provide a pharmaceutically acceptable salt thereof, wherein in formula (I),

[0112] Z is N or CH, and

[0113] R 1 is a quaternary to 10-membered heterocyclile optionally substituted with hydrogen, halogen, cyano, C3-C6 cycloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl; or (i) a C3-C6 cycloalkyl or (ii) a C1-C6 alkyl optionally substituted with a quaternary to 10-membered heterocyclile, and

[0114] R 2 is 1 to 4 independently selected R 2A A C6-C10 aryl arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-membered heteroaryls arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclils arbitrarily substituted with , 1 to 4 independently selected Rs 2A A C4-C10 cycloalkyl optionally substituted with , 1 to 4 independently selected R 2A 4- to 10-membered heterocyclyloxy oxy arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-won heteroaryloxy, -C(=O)NR arbitrarily substituted with A R C A C1-C6 alkoxyalkyl optionally substituted with -C(=O)NR A R C , C1-C6 alkoxy optionally substituted with a C4-C10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, and

[0115] R 2A are each

[0116] (i) Halogen;

[0117] (ii) Cyan;

[0118] (iii) Hydroxyl;

[0119] (iv) -NR A R B ;

[0120] (v) -C(=O)NR A R B ;

[0121] (vi) ;

[0122] (vii) -NHC(=O)R C ;

[0123] (viii) -C(=O)OR D ;

[0124] (ix) -SO2R D ;

[0125] (x) -NHSO2R D ;

[0126] (xi) -SO2NR D R E ;

[0127] (xii) NR A R B -NHC(=O)C1-C6 alkyl arbitrarily substituted with;

[0128] (xiii) C1-C6 haloalkyl;

[0129] (xiv) C1-C6 hydroxyalkyl;

[0130] (xv) Hydroxyl, Cyano, Halogen, -C(=O)NR A R B , -NR A R B , a C1-C6 alkyl optionally substituted with a hydroxyl, and a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclil optionally substituted with a hydroxyl or a C1-C6 alkyl;

[0131] (xvi) hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D RE , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B 4- to 10-membered heterocyclils optionally substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with , and C1-C6 alkoxy or hydroxyl optionally substituted with hydroxyl;

[0132] (xvii) Hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl;

[0133] (xviii) -NR A R B , or a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl;

[0134] (xix) hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or a C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl; and

[0135] (xx) Independently selected from 4- to 10 heterocyclyloxy groups optionally substituted with hydroxyl, cyano, halogen, or C1-C6 alkyl groups optionally substituted with hydroxyl, and

[0136] R A and R Bis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R A and R B They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[0137] R C are C3-C6 cycloalkyl and -C(=O)NHR, respectively. Y1 , and -NR A R B Independently selected from C1-C6 alkyl or C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 hydroxyalkyl, and

[0138] R D and R E are hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and oxo, respectively, or -NR A R B Independently selected from C1-C6 alkyls arbitrarily substituted with,

[0139] R 3A and R 3B are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R 3A and R 3B They form quaternary to octavalent heterocyclil groups together with the carbon and nitrogen atoms to which they are respectively attached, and

[0140] R 4 is hydrogen, a halogen, a C1-C6 alkyl, or an acrylamido, and

[0141] R 5 -NR 5A R 5B , -NR 5A C(=O)R 5Bor -C(=O)NR 5A R 5B And,

[0142] R 5A and R 5B is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl, and

[0143] R 6 is hydrogen, a halogen, or a C1-C6 alkyl, and

[0144] X is a bond, CH2, CH(CH3), C(CH3)2 or And,

[0145] W is NR 3B or O and,

[0146] Y is a phenyl, naphthyl, or 5- to 10-membered heteroaryl, wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryls are independently selected from 1 to 3 Rs. Y or It is arbitrarily and independently substituted as, and * is L 1 This indicates that it is connected to the remaining part of the compound of this chemical formula (I),

[0147] R Y are respectively halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -(CH2) n -C(=O)R F , -(CH2) n -NHC(=O)R F , -(CH2) n -NHC(=O)OR F , -C(=O)C(=O)NHR F , -CO2R G , -(CH2) n -SO2NR H R I , -(CH2) n -NHSO2R J , -(CH2) n -S(=O)(=NR H )R J , -(CH2) n-SO2R J , -(CH2) n -C(=O)NR H R I , -(CH2) n -C(=O)NR H OR I and independently selected from C1-C6 haloalkyls optionally substituted with hydroxyl, and

[0148] R F Each is independently selected from C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl optionally substituted with C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and

[0149] R G Each is independently selected from hydrogen, C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and

[0150] R H and R I are hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2) n -C(=O)NH2, -(CH2) n -SO2NH2, -(CH2) n -SO2(C1-C6 alkyl), hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl and -C(=O)NR K1 R K2 Independently selected from C1-C6 alkyls optionally substituted with 1 to 2 independently selected substituents, or R H and R I They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[0151] R Jis a C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, and

[0152] R K1 and R K2 Each is independently hydrogen or a C1-C6 alkyl, and

[0153] Ring A is phenyl, 4- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C4-C10 cycloalkyl, and

[0154] L 1 Silver bond, C1-C6 alkoxylene, -(CH2) n -NHC(=O)-, -C(=O)NH-(CH2) n -, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NR G )-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or a C1-C6 alkylene optionally substituted with an oxo, and

[0155] R Y1 ≡ cyano, hydroxyl, halogen, -C(=O)R, respectively. F , -NHC(=O)R F , -CO2R G , -SO2NR H R I , -NHSO2R J , -S(=O)(=NR H )R J , -SO2(C1-C6 alkyl), -C(=O)NR H R I , 4~6 won heteroaryl, R Y2 C1-C6 alkoxy, C1-C6 haloalkyl, R optionally substituted with Y2 Independently selected from C1-C6 alkyl and hydroxyl optionally substituted with , or 4- to 6-membered heterocyclies optionally substituted with C1-C6 alkyl, and

[0156] R Y2 is hydroxyl, -NR H R I , -C(=O)NR H R I or -SO2NRH R I And,

[0157] n is 0, 1, or 2, and

[0158] z is 0, 1, 2, or 3.

[0159] Some embodiments are compounds of the following chemical formula (IA).

[0160] (IA)

[0161] or provide a pharmaceutically acceptable salt thereof, wherein in the chemical formula (IA),

[0162] Z is N or CH, and

[0163] R 1 is hydrogen, cyano, C3-C6 cycloalkyl, 4- to 10-membered heterocyclile, C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4- to 10-membered heterocyclile, and

[0164] R 2 is 1 to 4 independently selected R 2A phenyl arbitrarily substituted with , 1 to 4 independently selected Rs 2A 5- to 10-membered heteroaryls arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclils arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered cycloalkyls optionally substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclyloxy oxy arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-won heteroaryloxy, -C(=O)NR arbitrarily substituted with A R C A C1-C6 alkoxyalkyl optionally substituted with -C(=O)NR A R C, a C1-C6 alkoxy optionally substituted with a 4- to 10-membered cycloalkyl, a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, or phenyl, and

[0165] R 2A are each

[0166] (i) Halogen,

[0167] (ii) Cyan,

[0168] (iii) Hydroxyl,

[0169] (iv) -NR A R B ,

[0170] (v) -C(=O)NR A R B ,

[0171] (vi) ,

[0172] (vii) -NHC(=O)R C ,

[0173] (viii) -C(=O)NR D R E ,

[0174] (ix) -C(=O)OR F ,

[0175] (x) -SO2R F ,

[0176] (xi) -NHSO2R F ,

[0177] (xii) -SO2NR F R G ,

[0178] (xiii) NR A R B -NHC(=O)C1-C6 alkyl arbitrarily substituted with

[0179] (xiv) C1-C6 haloalkyl,

[0180] (xv) C1-C6 hydroxyalkyl,

[0181] (xvi) C1-C6 alkyl and -NR A R B5- to 10-membered heteroaryls optionally substituted with 1 to 3 independently selected substituents,

[0182] (xvii) hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR F R G , C1-C6 alkyl optionally substituted with a C1-C6 alkoxy, -C(=O)NR A R B , or -NR A R B 4- to 10-membered heterocyclils optionally substituted with 1 to 3 independently selected substituents from -NHC(=O)C1-C6 alkyls optionally substituted with,

[0183] (xviii) Hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl,

[0184] (xix) -NR A R B , or C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl or -C(=O)C3-C6 cycloalkyl and

[0185] (xx) Selected from C3-C6 cycloalkyls optionally substituted with 4- to 10-membered heterocyclies optionally substituted with C1-C6 alkyls, and

[0186] R A and R Bis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R A and R B They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[0187] R C are C3-C6 cycloalkyl and -C(=O)NHR, respectively. Y1 , or -NR A R B Independently selected from C1-C6 alkyl or C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 hydroxyalkyl, and

[0188] R D and R E Each is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy, and

[0189] R 3A and R 3B are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R 3A and R 3B They form quaternary to octavalent heterocyclil groups together with the carbon and nitrogen atoms to which they are respectively attached, and

[0190] R 4 is hydrogen, C1-C6 alkyl, or acrylamido, and

[0191] R 5 -NR is hydrogen, C1-C6 alkyl, cyano, -NR 5A R 5B , -NR 5A C(=O)R 5B or -C(=O)NR 5A R 5B And,

[0192] R 5A and R 5B is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl, and

[0193] R 6 is hydrogen, a halogen, or a C1-C6 alkyl, and

[0194] X is a bond, CH2, CH(CH3), C(CH3)2 or And,

[0195] Y is 1 to 3 independently selected R Y phenyl arbitrarily substituted with , 1 to 3 independently selected Rs Y Naphthyl arbitrarily substituted with, or 1 to 3 independently selected R Y It is a 5- to 10-membered heteroaryl arbitrarily substituted with,

[0196] R Y are, respectively, halogen, cyano, hydroxyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -NHC(=O)R C , -C(=O)NHR Y1 , -CO2R A , -SO2NR F R G , -NHSO2R F , -S(=O)(=NR F )R G , -SO2(C1-C6 alkyl), -C(=O)NR A R B , 5~6 won heteroaryl, heteroaralkyl, and -CO2R A or R Y1 Independently selected from C1-C6 alkyls optionally substituted with 5- to 6-membered heteroaryls optionally substituted with,

[0197] R Y1 is a -SO2(C1-C6 alkyl) or a C1-C6 alkyl optionally substituted with an oxo, and

[0198] R F and R Gare hydrogen, phenyl, and oxo, or -NR, respectively. A R B It is independently selected from C1-C6 alkyls arbitrarily substituted with .

[0199] Some embodiments are compounds of the chemical formula (IB).

[0200] (IB)

[0201] or provide a pharmaceutically acceptable salt thereof, wherein in formula (IB),

[0202] Z is N or CH, and

[0203] R 1 is hydrogen, halogen, cyano, C3-C6 cycloalkyl, 4- to 10-membered heterocyclile, C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4- to 10-membered heterocyclile, and

[0204] R 2 is 1 to 4 independently selected R 2A phenyl arbitrarily substituted with , 1 to 4 independently selected Rs 2A 5- to 10-membered heteroaryls arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclils arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered cycloalkyls optionally substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclyloxy oxy arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-won heteroaryloxy, -C(=O)NR arbitrarily substituted with A R C A C1-C6 alkoxyalkyl optionally substituted with -C(=O)NR A R C, a C1-C6 alkoxy optionally substituted with a 4- to 10-membered cycloalkyl, a 4- to 10-membered heterocyclyl, a 5- to 10-membered heteroaryl, or phenyl, and

[0205] R 2A are each

[0206] (i) Halogen,

[0207] (ii) Cyan,

[0208] (iii) Hydroxyl,

[0209] (iv) -NR A R B ,

[0210] (v) -C(=O)NR A R B ,

[0211] (vi) ,

[0212] (vii) -NHC(=O)R C ,

[0213] (viii) -C(=O)NR D R E ,

[0214] (ix) -C(=O)OR F ,

[0215] (x) -SO2R F ,

[0216] (xi) -NHSO2R F ,

[0217] (xii) -SO2NR F R G ,

[0218] (xiii) NR A R B -NHC(=O)C1-C6 alkyl arbitrarily substituted with

[0219] (xiv) C1-C6 haloalkyl,

[0220] (xv) C1-C6 hydroxyalkyl,

[0221] (xvi) C1-C6 alkyl and -NR A R B5- to 10-membered heteroaryls optionally substituted with 1 to 3 independently selected substituents,

[0222] (xvii) hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR F R G , C1-C6 alkyl optionally substituted with a C1-C6 alkoxy, -C(=O)NR A R B , or -NR A R B 4- to 10-membered heterocyclils optionally substituted with 1 to 3 independently selected substituents from -NHC(=O)C1-C6 alkyls optionally substituted with,

[0223] (xviii) Hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl,

[0224] (xix) -NR A R B , or C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl or -C(=O)C3-C6 cycloalkyl and

[0225] (xx) Selected from C3-C6 cycloalkyls optionally substituted with 4- to 10-membered heterocyclies optionally substituted with C1-C6 alkyls, and

[0226] R A and R Bis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R A and R B They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[0227] R C are C3-C6 cycloalkyl and -C(=O)NHR, respectively. Y1 , or -NR A R B Independently selected from C1-C6 alkyl or C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 hydroxyalkyl, and

[0228] R D and R E Each is independently selected from hydrogen, hydroxyl, C1-C6 alkyl, and C1-C6 alkoxy, and

[0229] R 3A and R 3B are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R 3A and R 3B They form quaternary to octavalent heterocyclil groups together with the carbon and nitrogen atoms to which they are respectively attached, and

[0230] R 4 is hydrogen, a halogen, a C1-C6 alkyl, or an acrylamido, and

[0231] R 5 -NR 5A R 5B , -NR 5A C(=O)R 5B or -C(=O)NR 5A R 5B And,

[0232] R 5A and R 5B is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl, and

[0233] R 6 is hydrogen, a halogen, or a C1-C6 alkyl, and

[0234] X is a bond, CH2, CH(CH3), C(CH3)2 or And,

[0235] W is NR 3B or O and,

[0236] Y is 1 to 3 independently selected R Y phenyl arbitrarily substituted with , 1 to 3 independently selected Rs Y Naphthyl arbitrarily substituted with, or 1 to 3 independently selected R Y It is a 5- to 10-membered heteroaryl arbitrarily substituted with,

[0237] R Y are respectively C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, and -NHC(=O)R optionally substituted with halogen, cyano, hydroxyl, and hydroxyl. C , -C(=O)NHR Y1 , -CO2R A , -SO2NR F R G , -NHSO2R F , -S(=O)(=NR F )R G , -SO2(C1-C6 alkyl), -C(=O)NR A R B , 4~6 won Heteroaryl, Heteroarylkill, R Y1 4- to 6-membered heterocycliles arbitrarily substituted with, and -CO2R A or R Y1 Independently selected from C1-C6 alkyls optionally substituted with 4- to 6-membered heteroaryls optionally substituted with,

[0238] R Y1is a -SO2(C1-C6 alkyl) or a C1-C6 alkyl optionally substituted with an oxo, and

[0239] R F and R G are hydrogen, phenyl, and oxo, or -NR, respectively. A R B It is independently selected from C1-C6 alkyls arbitrarily substituted with .

[0240] In some embodiments, Z is CH.

[0241] In some embodiments, Z is N.

[0242] In some embodiments, R 1 It is hydrogen.

[0243] In some embodiments, R 1 is a halogen. In some embodiments, R 1 is I, Br, Cl, or F. In some embodiments, R 1 is Cl or F. In some embodiments, R 1 is F. In some embodiments, R 1 It is Cl.

[0244] In some embodiments, R 1 It is cyano.

[0245] In some embodiments, R 1 is a C3-C6 cycloalkyl. In some embodiments, R 1 It is cyclopropyl or cyclobutyl.

[0246] In some embodiments, R 1 is a quaternary to ten-membered heterocyclile optionally substituted with a C1-C6 alkyl group. In some embodiments, R 1 is a 4- to 10-membered heterocyclile. In some embodiments, R 1 It is a 4- to 10-membered heterocyclile substituted with C1-C6 alkyl groups.

[0247] In some embodiments, R 1 It is a 5 to 8 won heterocyclile.

[0248] In some embodiments, R1 The heterocyclile of is piperidine-yl, piperazine-yl, octahydrocyclopenta[c]pyran-yl, octahydrocyclopenta[b]pyran-yl, 2-oxabicyclo[2.1.1]hexane-yl, 2-oxabicyclo[3.1.1]heptane-yl, or morpholine-yl. In some embodiments, R 1 The heterocyclile of is octahydrocyclopenta[c]pyranyl. In some embodiments, R 1 The heterocyclile of is octahydrocyclopenta[b]pyranyl. In some embodiments, R 1 The heterocyclile of is 2-oxabicyclo[2.1.1]hexanyl. In some embodiments, R 1 The heterocyclile of is 2-oxabicyclo[3.1.1]heptanyl.

[0249] In some embodiments, R 1 is (i) a C3-C6 cycloalkyl or (ii) a C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclyl. In some embodiments, R 1 is (i) a C3-C6 cycloalkyl or (ii) a C1-C6 alkyl substituted with a 4- to 10-membered heterocyclyl. In some embodiments, R 1 is (i) a C3-C6 cycloalkyl or (ii) a C1-C3 alkyl substituted with a 4- to 10-membered heterocyclyl. In some embodiments, R 1 is a C1-C6 alkyl substituted with a C3-C6 cycloalkyl. In some embodiments, R 1 is a C1-C6 alkyl substituted with a 4- to 10-membered heterocyclile. In some embodiments, R 1 is a C1-C6 alkyl. In some embodiments, R 1 is methyl, ethyl, or isopropyl. In some embodiments, R 1 It is methyl.

[0250] In some embodiments, R 1 is a C1-C6 thioalkyl. In some embodiments, R 1 is a C1-C3 thioalkyl. In some embodiments, R 1is thiomethyl, thioethyl, or thiopropyl. In some embodiments, R 1 is methyl-thiomethyl, methyl-thioethyl, or ethyl-thiomethyl. In some embodiments, R 1 It is thiomethyl.

[0251] In some embodiments, R 1 is a C1-C6 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 fluoroalkyl. In some embodiments, R 1 is CF3. In some embodiments, R 1 is CHF2.

[0252] In some embodiments, R 1 is a C1-C6 alkoxy. In some embodiments, R 1 is a C1-C3 alkoxy. In some embodiments, R 1 is -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R 1 It is -OCH3.

[0253] In some embodiments, R 1 is a C1-C6 alkoxyalkyl. In some embodiments, R 1 is a C1-C3 alkoxyalkyl. In some embodiments, R 1 is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R 1 It is -CH2OCH3.

[0254] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a C6-C10 aryl arbitrarily substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a C6-C10 aryl substituted with . In some embodiments, R 2 is 1 R 2A It is a C6-C10 aryl substituted with . In some embodiments, R2 is 2 independently selected R 2A It is a C6-C10 aryl substituted with . In some embodiments, R 2 3 independently selected R 2A It is a C6-C10 aryl arbitrarily substituted with . In some embodiments, R 2 is a C6-C10 aryl.

[0255] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a phenyl arbitrarily substituted with R. In some embodiments, R 2 is one or two independently selected Rs 2A It is a phenyl substituted with . In some embodiments, R 2 is 1 R 2A It is a phenyl substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a phenyl substituted with . In some embodiments, R 2 3 independently selected R 2A It is a phenyl arbitrarily substituted with R. In some embodiments, R 2 It is phenyl.

[0256] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is 2,3-dihydro-1H-indennyl optionally substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is 2,3-dihydro-1H-indennyl substituted with . In some embodiments, R 2 is 1 R 2A It is 2,3-dihydro-1H-indennyl substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is 2,3-dihydro-1H-indennyl substituted with . In some embodiments, R 2 3 independently selected R 2AIt is 2,3-dihydro-1H-indennyl optionally substituted with . In some embodiments, R 2 is 2,3-dihydro-1H-indense.

[0257] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a 5- to 10-membered heteroaryl arbitrarily substituted with R. In some embodiments, R 2 is one or two independently selected Rs 2A It is a 5- to 10-membered heteroaryl substituted with . In some embodiments, R 2 is 1 R 2A It is a 5- to 10-membered heteroaryl substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a 5- to 10-membered heteroaryl substituted with . In some embodiments, R 2 3 independently selected R 2A It is a 5- to 10-membered heteroaryl arbitrarily substituted with R. In some embodiments, R 2 It is a 5 to 10 won heteroaryl.

[0258] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a six-membered heteroaryl arbitrarily substituted with R. In some embodiments, R 2 is one or two independently selected Rs 2A It is a 6-membered heteroaryl substituted with . In some embodiments, R 2 is 1 R 2A It is a 6-membered heteroaryl substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a 6-membered heteroaryl substituted with . In some embodiments, R 2 3 independently selected R 2A It is a six-membered heteroaryl arbitrarily substituted with R. In some embodiments, R 2 is a 6-membered heteroaryl.

[0259] In some embodiments, R2 is 1 to 4 independently selected R 2A It is a nine-membered heteroaryl arbitrarily substituted with R. In some embodiments, R 2 is one or two independently selected Rs 2A It is a 9-membered heteroaryl substituted with . In some embodiments, R 2 is 1 R 2A It is a 9-membered heteroaryl substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a 9-membered heteroaryl substituted with . In some embodiments, R 2 3 independently selected R 2A It is a nine-membered heteroaryl arbitrarily substituted with R. In some embodiments, R 2 is a 9-membered heteroaryl.

[0260] In some embodiments, R 2 The heteroaryls of pyridinyl, pyrimidinyl, pyridazineyl, indole, indazole, azaindole, azaindazole, indoline, azaindolin, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisothiazolyl, quinolineyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, chromanyl, 3,4-dihydro-2H-1l2-quinolineyl, 5,6,7,8-tetrahydroquinazolinyl, 6,7-dihydro-5H-cyclopenta[c]pyridinyl, It is 3,4-dihydro-2H-pyrano[2,3-b]pyridinyl, 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridinyl, 7,8-dihydro-6H-pyrano[3,2-d]pyrimidinyl, 5,6,7,8-tetrahydroquinazolinyl, or isoquinolineyl. In some embodiments, R 2 The heteroaryl of is a pyridineyl or pyrimidineyl. In some embodiments, R 2 The heteroaryl group of is a pyridine. In some embodiments, R 2The heteroaryl of is indole, indazole, azaindole, azaindazole, indoline, azaindolin, isoindoline, or azaisoindoline. In some embodiments, R 2 The heteroaryl is 6,7-dihydro-5H-cyclopenta[c]pyridineyl, 6,7-dihydro-5H-cyclopenta[b]pyridineyl, chromanyl, 3,4-dihydro-2H-1l2-quinolineyl, 5,6,7,8-tetrahydroquinazolinyl, 6,7-dihydro-5H-cyclopenta[c]pyridineyl, 3,4-dihydro-2H-pyrano[2,3-b]pyridineyl, 3,4-dihydro-2H-pyrano[2,3-c]pyridineyl, 3,4-dihydro-2H-pyrano[3,2-b]pyridineyl, 7,8-dihydro-6H-pyrano[3,2-d]pyrimidineyl or It is 5,6,7,8-tetrahydroquinazoline. In some embodiments, R 2 The heteroaryl group of is 6,7-dihydro-5H-cyclopenta[c]pyridine. In some embodiments, R 2 The heteroaryl group of is 6,7-dihydro-5H-cyclopenta[b]pyridine. In some embodiments, R 2 The heteroaryl of is chromalyl. In some embodiments, R 2 The heteroaryl of is 3,4-dihydro-2H-quinolineyl, 5,6,7,8-tetrahydroquinazolinyl, or 6,7-dihydro-5H-cyclopenta[c]pyridineyl. In some embodiments, R 2 The heteroaryl of is 3,4-dihydro-2H-1l2-quinoline. In some embodiments, R 2 The heteroaryl group of is 5,6,7,8-tetrahydroquinazolinyl. In some embodiments, R 2 The heteroaryl group of is 6,7-dihydro-5H-cyclopenta[c]pyridine. In some embodiments, R 2 The heteroaryl group of is 4-dihydro-2H-pyrano[2,3-b]pyridine. In some embodiments, R 2The heteroaryl of is 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl or 5,6,7,8-tetrahydroquinazolinyl. In some embodiments, R 2 The heteroaryl group of is 3,4-dihydro-2H-pyrano[3,2-b]pyridine. In some embodiments, R 2 The heteroaryl of is 7,8-dihydro-6H-pyrano[3,2-d]pyrimidine. In some embodiments, R 2 The heteroaryl group of is 5,6,7,8-tetrahydroquinazolin.

[0261] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a 5- to 10-membered heteroaryloxy optionally substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a 5- to 10-membered heteroaryloxy substituted with . In some embodiments, R 2 is 1 R 2A It is a 5- to 10-membered heteroaryloxy substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a 5- to 10-membered heteroaryloxy substituted with . In some embodiments, R 2 3 independently selected R 2A It is a 5- to 10-membered heteroaryloxy optionally substituted with . In some embodiments, R 2 It is a 5 to 10 won heteroaryloxy.

[0262] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a 6-membered heteroaryloxy arbitrarily substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a 6-membered heteroaryloxy substituted with . In some embodiments, R 2 is 1 R 2A It is a 6-membered heteroaryloxy substituted with . In some embodiments, R 2is 2 independently selected R 2A It is a 6-membered heteroaryloxy substituted with . In some embodiments, R 2 3 independently selected R 2A It is a 6-membered heteroaryloxy arbitrarily substituted with . In some embodiments, R 2 is a 6-membered heteroaryloxy.

[0263] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a 4- to 10-membered heterocyclile arbitrarily substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a 4- to 10-membered heterocyclile substituted with . In some embodiments, R 2 is 1 R 2A It is a 4- to 10-membered heterocyclile substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a 4- to 10-membered heterocyclile substituted with . In some embodiments, R 2 3 independently selected R 2A It is a 4- to 10-membered heterocyclile arbitrarily substituted with . In some embodiments, R 2 It is a 4 to 10 won heterocyclile.

[0264] In some embodiments, R 2 is one or two independently selected Rs 2A It is a tetra- to ten-membered cyclic ether arbitrarily substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a cyclic ether with a 4- to 10-membered bridge arbitrarily substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a tetra- to ten-membered cyclic ether arbitrarily substituted with . In some embodiments, R 2 is one or two independently selected Rs 2AIt is a 4- to 10-membered spirocyclic ether arbitrarily substituted with . In some embodiments, R 2 is an unsubstituted 4- to 10-membered cross-linked cyclic ether. In some embodiments, R 2 is an unsubstituted quaternary to tenary cyclic ether. In some embodiments, R 2 is an unsubstituted 4- to 10-membered spirocyclic ether. In some embodiments, R 2 is one or two independently selected Rs 2A It is a cyclic ether with a 4- to 10-membered bridge substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a quaternary to tenary cyclic ether substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a 4- to 10-membered spirocyclic ether substituted with . In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a 5- to 8-membered heterocyclile arbitrarily substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a 5- to 8-membered heterocyclile substituted with . In some embodiments, R 2 is 1 R 2A It is a 5- to 8-membered heterocyclile substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a 5- to 8-membered heterocyclile substituted with . In some embodiments, R 2 3 independently selected R 2A It is a 5- to 8-membered heterocyclile arbitrarily substituted with . In some embodiments, R 2 It is a 5 to 8 won heterocyclile.

[0265] In some embodiments, R 2The heterocyclile of is piperidine-yl, piperazine-yl, octahydrocyclopenta[c]pyran-yl, octahydrocyclopenta[b]pyran-yl, 2-oxabicyclo[2.1.1]hexane-yl, 2-oxabicyclo[3.1.1]heptane-yl, or morpholine-yl. In some embodiments, R 2 The heterocyclile of is octahydrocyclopenta[c]pyranyl. In some embodiments, R 2 The heterocyclile of is octahydrocyclopenta[b]pyranyl. In some embodiments, R 2 The heterocyclile of is 2-oxabicyclo[2.1.1]hexanyl. In some embodiments, R 2 The heterocyclile of is 2-oxabicyclo[3.1.1]heptanyl. In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a 4- to 10-membered heterocyclyloxy optionally substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a 4- to 10-membered heterocyclyloxy substituted with . In some embodiments, R 2 is 1 R 2A It is a 4- to 10-membered heterocyclyloxy substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a 4- to 10-membered heterocyclyloxy substituted with . In some embodiments, R 2 3 independently selected R 2A It is a 4- to 10-membered heterocyclyloxy optionally substituted with . In some embodiments, R 2 It is a 4 to 10 won heterocyclyloxy.

[0266] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a 5- to 8-membered heterocyclyloxy optionally substituted with . In some embodiments, R 2 is one or two independently selected Rs 2AIt is a 5- to 8-membered heterocyclyloxy substituted with . In some embodiments, R 2 is 1 R 2A It is a 5- to 8-membered heterocyclyloxy substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a 5- to 8-membered heterocyclyloxy substituted with . In some embodiments, R 2 3 independently selected R 2A It is a 5- to 8-membered heterocyclyloxy optionally substituted with . In some embodiments, R 2 It is a 5 to 8 won heterocyclyloxy.

[0267] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a C4-C10 cycloalkyl optionally substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a C4-C10 cycloalkyl substituted with . In some embodiments, R 2 is 1 R 2A It is a C4-C10 cycloalkyl substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a C4-C10 cycloalkyl substituted with . In some embodiments, R 2 3 independently selected R 2A It is a C4-C10 cycloalkyl optionally substituted with . In some embodiments, R 2 is a C4-C10 cycloalkyl.

[0268] In some embodiments, R 2 is 1 to 4 independently selected R 2A It is a C5-C7 cycloalkyl optionally substituted with . In some embodiments, R 2 is one or two independently selected Rs 2A It is a C5-C7 cycloalkyl substituted with . In some embodiments, R 2 is 1 R 2AIt is a C5-C7 cycloalkyl substituted with . In some embodiments, R 2 is 2 independently selected R 2A It is a C5-C7 cycloalkyl substituted with . In some embodiments, R 2 3 independently selected R 2A It is a C5-C7 cycloalkyl optionally substituted with . In some embodiments, R 2 is a C5-C7 cycloalkyl.

[0269] In some embodiments, R 2 The cycloalkyl of is cyclopentyl, [1.1.1]bicyclopentyl, octahydro-1H-indenyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.0]hexanyl, spiro[2.4]heptanyl, or cyclohexyl. In some embodiments, R 2 The cycloalkyl group of is octahydro-1H-indennyl. In some embodiments, R 2 The cycloalkyl group of is bicyclo[2.1.1]hexanyl. In some embodiments, R 2 The cycloalkyl group is bicyclo[3.1.0]hexanyl.

[0270] In some embodiments, R 2 is -C(=O)NR A R C , is a C1-C6 alkoxy optionally substituted with a C4-C10 cycloalkyl or phenyl. In some embodiments, R 2 is -C(=O)NR A R C , is a C1-C6 alkoxy substituted with a C4-C10 cycloalkyl or phenyl. In some embodiments, R 2 is -C(=O)NR A R C It is a C1-C6 alkoxy substituted with . In some embodiments, R 2 is a C1-C6 alkoxy substituted with a C4-C10 cycloalkyl. In some embodiments, R 2 is a C1-C6 alkoxy substituted with a C4-C6 cycloalkyl. In some embodiments, R 2is a C1-C6 alkoxy substituted with phenyl. In some embodiments, R 2 is a C1-C6 alkoxy. In some embodiments, R 2 is a C1-C3 alkoxy. In some embodiments, R 2 is -OCH3 or -OCH2CH3.

[0271] In some embodiments, R 2 is -C(=O)NR A R C It is a C1-C6 alkoxyalkyl optionally substituted with . In some embodiments, R 2 is -C(=O)NR A R C It is a C1-C6 alkoxyalkyl substituted with . In some embodiments, R 2 is -C(=O)NR A R C It is a C3-C6 alkoxyalkyl substituted with . In some embodiments, R 2 is a C1-C6 alkoxyalkyl. In some embodiments, R 2 is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R 2 is -CH2OCH3.

[0272] In some embodiments, R 2 Is , , , , , , , , , , , , , , , , , , , , or am.

[0273] In some embodiments, R 2 Is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or am.

[0274] In some embodiments, R 2 Is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or am.

[0275] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently a halogen. In some embodiments, 1, 2, or 3 R 2A is independently fluoro or chloro. In some embodiments, 1 or 2 Rs 2A is independently fluoro or chloro. In some embodiments, one R 2A is fluoro or chloro.

[0276] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently cyano. In some embodiments, 1 or 2 R 2A is cyano. In some embodiments, 1 R2A is cyano.

[0277] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently a hydroxyl. In some embodiments, one or two Rs 2A is a hydroxyl. In some embodiments, one R 2A is hydroxyl.

[0278] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -NR A R B is. In some embodiments, 1 or 2 R 2A is independently -NR A R B is. In some embodiments, one R 2A is -NR A R B am.

[0279] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -C(=O)NR A R B is. In some embodiments, 1 or 2 R 2A is independently -C(=O)NR A R B is. In some embodiments, one R 2A is -C(=O)NR A R B am.

[0280] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently is. In some embodiments, 1 or 2 R 2A is independently is. In some embodiments, one R 2A Is am.

[0281] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -NHC(=O)R C is. In some embodiments, 1 or 2 R2A is independently -NHC(=O)R C is. In some embodiments, 1, 2, 3, or 4 Rs 2A -C(=O)OR independently D is. In some embodiments, 1 or 2 R 2A -C(=O)OR independently D is. In some embodiments, one R 2A is -C(=O)OR D am.

[0282] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -SO2R D is. In some embodiments, 1 or 2 R 2A is independently -SO2R D is. In some embodiments, one R 2A -SO2R D am.

[0283] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -NHSO2R D is. In some embodiments, 1 or 2 R 2A is independently -NHSO2R D is. In some embodiments, one R 2A -NHSO2R D am.

[0284] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -SO2NR D R E is. In some embodiments, 1 or 2 R 2A is independently -SO2NR D R E is. In some embodiments, one R 2A is -SO2NR D R E am.

[0285] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently NR AR B It is an -NHC(=O)C1-C6 alkyl optionally substituted with R. In some embodiments, 1, 2, or 3 R 2A is independently NR A R B It is a -NHC(=O)C1-C6 alkyl substituted with . In some embodiments, 1, 2, or 3 R 2A is independently -NHC(=O)C1-C6 alkyl. In some embodiments, 1 or 2 R 2A is independently NR A R B It is an -NHC(=O)C1-C6 alkyl optionally substituted with . In some embodiments, 1 or 2 R 2A is independently NR A R B It is a -NHC(=O)C1-C6 alkyl substituted with . In some embodiments, 1 or 2 R 2A is independently -NHC(=O)C1-C6 alkyl. In some embodiments, one R 2A is NR A R B It is an arbitrarily substituted -NHC(=O)C1-C6 alkyl.

[0286] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently a C1-C6 haloalkyl. In some embodiments, one or two Rs 2A is independently a C1-C3 haloalkyl. In some embodiments, 1 or 2 Rs 2A is trifluoromethyl. In some embodiments, one R 2A is a C1-C6 haloalkyl.

[0287] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently a C1-C6 hydroxyalkyl. In some embodiments, one or two Rs 2A is independently a C1-C3 hydroxyalkyl. In some embodiments, one R 2A is a C1-C3 hydroxyalkyl.

[0288] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, cyano, halogen, -C(=O)NR A R B , -NR A R B It is a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclil optionally substituted with a hydroxyl or a C1-C6 alkyl. In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, cyano, C1-C6 alkyl, halogen, -C(=O)NR A R B , -NR A R B It is a 5- to 10-membered heteroaryl substituted with 1 to 3 substituents independently selected from 4- to 10-membered heterocyclels optionally substituted with hydroxyl or C1-C6 alkyl groups. In some embodiments, 1, 2, 3, or 4 R groups 2A is independently a 5- to 10-membered heteroaryl. In some embodiments, one R 2A is a hydroxyl, cyano, halogen, -C(=O)NR A R B , -NR A R B It is a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclil optionally substituted with a hydroxyl or a C1-C6 alkyl.

[0289] In some embodiments, one R 2A is a hydroxyl, cyano, C1-C6 alkyl, halogen, -C(=O)NR A R B , -NR A R BIt is a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from 4- to 10-membered heterocyclels optionally substituted with hydroxyl or C1-C6 alkyl groups. In some embodiments, one R 2A is a hydroxyl, cyano, C1-C6 alkyl, halogen, -C(=O)NR A R B , -NR A R B It is a 5- to 6-membered heteroaryl substituted with 1 to 3 substituents independently selected from 4- to 10-membered heterocyclels optionally substituted with hydroxyl or C1-C6 alkyl groups. In some embodiments, one R 2A It is a 5-6 won heteroaryl.

[0290] In some embodiments, 1, 2, 3, or 4 Rs 2A are independently hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B It is a 4- to 10-membered heterocyclile optionally substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with , and C1-C6 alkoxy or hydroxyl optionally substituted with hydroxyl. In some embodiments, 1 R 2A is hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R BIt is a 4- to 10-membered heterocyclile optionally substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl optionally substituted with -NHC(=O)C1-C6 alkyl and C1-C6 alkoxy or hydroxyl optionally substituted with C1-C6 alkyl.

[0291] In some embodiments, 1, 2, 3, or 4 Rs 2A are independently hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , is a 4- to 10-membered heterocyclile substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl and C1-C6 alkyl. In some embodiments, 1 R 2A is hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NHC(=O)C1-C6 alkyl and C1-C6 alkyl is a 4- to 10-membered heterocyclile substituted with 1 to 3 substituents independently selected from C1-C6 alkyl.

[0292] In some embodiments, 1, 2, 3, or 4 Rs 2A are independently hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R BIt is a 4- to 10-membered heterocyclile substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with , and C1-C6 alkoxy or hydroxyl-substituted C1-C6 alkyl. In some embodiments, 1 R 2A is hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B It is a 4- to 10-membered heterocyclile substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl substituted with C1-C6 alkoxy or hydroxyl substituted with C1-C6 alkyl.

[0293] In some embodiments, 1, 2, 3, or 4 Rs 2A are independently hydroxyl, cyano, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkyl, -C(=O)NR A R B , -NR A R B Or it is a 4- to 10-membered heterocyclile substituted with one substituent independently selected from -NHC(=O)C1-C6 alkyl. In some embodiments, one R 2A is hydroxyl, cyano, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkyl, -C(=O)NR A R B , -NR A R BOr it is a 4- to 10-membered heterocyclile substituted with one substituent independently selected from -NHC(=O)C1-C6 alkyl.

[0294] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently a 4- to 10-membered heterocyclile. In some embodiments, one R 2A It is a 4 to 10 won heterocyclile.

[0295] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C3-C10 cycloalkyl and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or is a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl. In some embodiments, 1 or 2 R 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C3-C10 cycloalkyl and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B Or it is a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl. In some embodiments, 1 R 2A is hydroxyl, iodine, -NR A R B , -C(=O)NR A R B , C3-C10 cycloalkyl and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A RB Or it is a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl.

[0296] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C3-C10 cycloalkyl and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B Or it is a C1-C6 alkyl substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl.

[0297] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C3-C10 cycloalkyl and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B Or it is a C1-C6 alkyl substituted with 1 to 3 substituents independently selected from 4- to 10-membered heterocyclies substituted with -C(=O)C3-C6 cycloalkyl.

[0298] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B It is a C1-C6 alkyl substituted with 1 to 3 substituents independently selected from C3-C10 cycloalkyl and 4- to 10-membered heterocyclils.

[0299] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently a C1-C6 alkyl. In some embodiments, 1, 2, or 3 Rs 2A is independently a C1-C3 alkyl. In some embodiments, 1, 2, or 3 Rs 2A is methyl. In some embodiments, 1 or 2 Rs 2A is independently a C1-C6 alkyl. In some embodiments, 1 or 2 Rs 2A is independently a C1-C3 alkyl. In some embodiments, 1 or 2 Rs 2A is methyl.

[0300] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -NR A R B , or is a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclie optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl. In some embodiments, 1 or 2 R 2A is independently -NR A R B , or is a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclie optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl. In some embodiments, one R 2A is -NR A R B , or is a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclie optionally substituted with a C1-C6 alkyl, aracleyl, heteroaracleyl, or -C(=O)C3-C6 cycloalkyl.

[0301] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -NR A R B, or is a C1-C6 alkoxy substituted with a 4- to 10-membered heterocyclie optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[0302] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -NR A R B , or is a C1-C6 alkoxy substituted with a 4- to 10-membered heterocyclie substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[0303] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently -NR A R B Or it is a C1-C6 alkoxy substituted with a 4- to 10-membered heterocyclile.

[0304] In some embodiments, 1, 2, 3, or 4 Rs 2A It is independently a C1-C6 alkoxy.

[0305] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or a C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl. In some embodiments, 1 or 2 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or a C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl. In some embodiments, one R 2A is a hydroxyl, -C(=O)NR A R B , -C(=N)OR D, or a C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl.

[0306] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or a C3-C6 cycloalkyl substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl.

[0307] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or a C3-C6 cycloalkyl substituted with a 4- to 10-membered heterocyclile substituted with a C1-C6 alkyl.

[0308] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D Or it is a C3-C6 cycloalkyl substituted with a 4- to 10-membered heterocyclile.

[0309] In some embodiments, 1, 2, 3, or 4 Rs 2A is independently a C3-C6 cycloalkyl. In some embodiments, one or two Rs 2A It is independently a C3-C6 cycloalkyl.

[0310] In some embodiments, 1, 2, 3, or 4 Rs 2A is a quaternary to 10-membered heterocyclyloxy independently substituted with a hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, 1, 2, 3, or 4 Rs 2Ais independently a 4- to 10-membered heterocyclyloxy. In some embodiments, 1, 2, 3, or 4 Rs 2A is a quaternary to 10-membered heterocyclyloxy independently substituted with a hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, one or two Rs 2A is a 4- to 10-membered heterocyclyloxy independently substituted with a hydroxyl, cyano, halogen, or a C1-C6 alkyl optionally substituted with a hydroxyl. In some embodiments, one R 2A is a 4- to 10-membered heterocyclyloxy optionally substituted with a hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with a hydroxyl.

[0311] In some embodiments, R 2 is 1 R 2A It is replaced by. In some embodiments, R 2 is 2 independently selected R 2A It is replaced by. In some embodiments, R 2 3 independently selected R 2A It is replaced by. In some embodiments, R 2 4 independently selected R 2A It is replaced with.

[0312] In some embodiments, R 2 is 1 to 2 independently selected R 2A It is a piperidine substituted with . In some embodiments, R 2 2 to 4 independently selected R 2A It is a piperidine substituted with . In some embodiments, R 2 2 to 4 independently selected R 2A It is a morpholine substituted with . In some embodiments, R 2 is a morpholine. In some embodiments, R 2 is 1 to 2 independently selected R 2A It is piperazine substituted with.

[0313] In some embodiments, R 2 is 1 to 2 independently selected R 2A It is a phenyl substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is a pyridine substituted with.

[0314] In some embodiments, R 2 is 1 to 2 independently selected R 2A It is an indolyl substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is an indazolyl substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is 7-azaindollyl substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is 7-azindazolyl substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is 1,2-dihydro-3H-indazole-3-one substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is an isoindolinite substituted with. In some embodiments, R 2 is an isoindolin. In some embodiments, R 2 is 1 to 2 independently selected R 2A It is 2-indolinone substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is benzimidazolyl substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is an imidazopyridine substituted with . In some embodiments, R 2 is 1 to 2 independently selected R 2A It is 1,3-dihydro-2H-benzo[d]imidazole-2-onyl substituted with . In some embodiments, R 2is 1 to 2 independently selected R 2A It is [1,2,4]triazolo[1,5-a]pyridine substituted with [1,5-a].

[0315] In some embodiments, one R 2A is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, or hydroxyl, and other R 2A is a C1-C6 haloalkyl, C1-C6 hydroxyalkyl, cyano, hydroxyl, halogen, -NR A R B , -C(=O)NR A R B , , -NHC(=O)R C , -C(=O)OR D , -SO2R D , -NHSO2R D , -SO2NR D R E , NR A R B -NHC(=O)C1-C6 alkyl, C1-C6 alkyl and -NR optionally substituted with A R B 5- to 10-membered heteroaryls, hydroxyl, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR optionally substituted with 1 to 3 independently selected substituents D R E , C1-C6 alkyl optionally substituted with a C1-C6 alkoxy, -C(=O)NR A R B , or -NR A R B 4- to 10-membered heterocyclles, hydroxyl, oxo, -NRs optionally substituted with 1 to 3 independently selected substituents from -NHC(=O)C1-C6 alkyls. A R B , -C(=O)NR A R B , C1-C6 alkoxy and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A RB or a C1-C6 alkyl, -NR, optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl. A R B , or independently selected from C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl or -C(=O)C3-C6 cycloalkyl, and C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl.

[0316] In some embodiments, R 2A Each is independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, and acetyl.

[0317] In some embodiments, 1, 2, or 3 Rs 2A is independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, and acetyl.

[0318] In some embodiments, 1 or 2 Rs 2Ais independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N(CH3)2, -C(=O)NH2, -C(=O)NHCH3, -C(=O)N(CH3)2, -C(=O)NHOH, -SO2NH2, -SO2NHCH3, -SO2N(CH3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2-trifluoroethyl, and acetyl.

[0319] In some embodiments, R 2A are each

[0320] (i) Halogen;

[0321] (ii) Hydroxyl, -C(=O)NR A R B or -C(=N)OR D C3-C6 cycloalkyl arbitrarily substituted with;

[0322] (iii) methyl;

[0323] (iv) C1-C2 haloalkyl;

[0324] (v) Halogen, hydroxyl, -C(=O)NR A R B , -C(=O)C1-C6 alkyl, -NR A R B and a quaternary to 6-membered heterocyclile optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyls optionally substituted with hydroxyls; and

[0325] (vi) C1-C6 alkyl, hydroxyl, -C(=O)NR optionally substituted with halogen, cyano, or hydroxyl A R B , -NR A R B , or is independently selected from 5-6 member heteroaryls optionally substituted with 4- to 10 member heterocyclies optionally substituted with hydroxyl or C1-C6 alkyl.

[0326] In some embodiments, 1 or 2 Rs 2A Is

[0327] (i) Halogen;

[0328] (ii) Hydroxyl, -C(=O)NR A R B or -C(=N)OR D C3-C6 cycloalkyl arbitrarily substituted with;

[0329] (iii) methyl;

[0330] (iv) C1-C2 haloalkyl;

[0331] (v) Halogen, hydroxyl, -C(=O)NR A R B , -C(=O)C1-C6 alkyl, -NR A R B and a quaternary to 6-membered heterocyclile optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyls optionally substituted with hydroxyls; and

[0332] (vi) C1-C6 alkyl, hydroxyl, -C(=O)NR optionally substituted with halogen, cyano, or hydroxyl A R B , -NR A R B , or is independently selected from 5-6 member heteroaryls optionally substituted with 4- to 10 member heterocyclies optionally substituted with hydroxyl or C1-C6 alkyl.

[0333] In some embodiments, one R 2A Is

[0334] (i) Halogen;

[0335] (ii) Hydroxyl, -C(=O)NR A R B or -C(=N)OR D C3-C6 cycloalkyl arbitrarily substituted with;

[0336] (iii) methyl;

[0337] (iv) C1-C2 haloalkyl;

[0338] (v) Halogen, hydroxyl, -C(=O)NR A R B , -C(=O)C1-C6 alkyl, -NR A RB and a quaternary to 6-membered heterocyclile optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyls optionally substituted with hydroxyls; or

[0339] (vi) C1-C6 alkyl, hydroxyl, -C(=O)NR optionally substituted with halogen, cyano, or hydroxyl A R B , -NR A R B , or is a 5-6 member heteroaryl optionally substituted with a 4- to 10 member heterocyclil optionally substituted with a hydroxyl or C1-C6 alkyl.

[0340] In some embodiments, X is a combination.

[0341] In some embodiments, X is CH2.

[0342] In some embodiments, X is CH(CH3).

[0343] In some embodiments, X is C(CH3)2.

[0344] In some embodiments, X is am.

[0345] In some embodiments, W is O.

[0346] In some embodiments, R 3A is hydrogen.

[0347] In some embodiments, R 3A is a C1-C6 alkyl. In some embodiments, R 3A is methyl or ethyl. In some embodiments, R 3A is methyl.

[0348] In some embodiments, R 3A is a C1-C6 alkoxy. In some embodiments, R 3A is a C1-C3 alkoxy. In some embodiments, R 3A is -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R 3A is -OCH3.

[0349] In some embodiments, R 3A is a C1-C6 haloalkyl. In some embodiments, R 3A is a C1-C3 haloalkyl. In some embodiments, R 3A is a C1-C3 fluoroalkyl. In some embodiments, R 3A is CF3. In some embodiments, R 3A is CHF2.

[0350] In some embodiments, W is NR 3B am.

[0351] In some embodiments, R 3A and R 3B One of them is hydrogen and R 3A and R 3B The remaining one of them is a C1-C6 alkyl. In some embodiments, R 3A and R 3B One of them is hydrogen and R 3A and R 3B The remaining one of them is methyl. In some embodiments, R 3A and R 3B are each hydrogen. In some embodiments, R 3A and R 3B is each independently selected C1-C6 alkyl. In some embodiments, R 3A and R 3B are methyl respectively.

[0352] In some embodiments, R 3A and R 3B One of them is hydrogen and R 3A and R 3B The remaining one of them is a C1-C6 alkoxy. In some embodiments, R 3A and R 3B One of them is a C1-C6 alkyl and R 3A and R 3B The remaining one of them is a C1-C6 alkoxy. In some embodiments, R 3A is a C1-C6 alkoxy. In some embodiments, R 3A is a C1-C3 alkoxy. In some embodiments, R 3Ais -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R 3A is -OCH3.

[0353] In some embodiments, R 3A and R 3B One of them is hydrogen and R 3A and R 3B The remaining one of them is a C1-C6 haloalkyl. In some embodiments, R 3A and R 3B One of them is a C1-C6 alkyl and R 3A and R 3B The remaining one of them is a C1-C6 haloalkyl. In some embodiments, R 3A is a C1-C6 haloalkyl. In some embodiments, R 3A is a C1-C3 haloalkyl. In some embodiments, R 3A is a C1-C3 fluoroalkyl. In some embodiments, R 3A is CF3. In some embodiments, R 3A is CHF2.

[0354] In some embodiments, R 3A and R 3B They each form a quaternary to 8-membered heterocyclile group together with the carbon and nitrogen atoms to which they are attached. In some embodiments, R 3A and R 3B They each form a 5- to 6-membered heterocyclile group together with the carbon and nitrogen atoms to which they are attached.

[0355] In some embodiments, Y is phenyl, naphthyl, or 5- to 10-membered heteroaryl, wherein phenyl, naphthyl, and 5- to 10-membered heteroaryl are independently selected 1 to 3 Rs Y It is replaced arbitrarily and independently.

[0356] In some embodiments, Y is R Y phenyl, R arbitrarily substituted with Y Naphthyl substituted with, or R Y It is a 5- to 10-won heteroaryl substituted with

[0357] In some embodiments, Y is 1 to 3 independently selected Rs Y It is a phenyl optionally substituted with . In some embodiments, Y is one or two independently selected Rs. Y It is a phenyl substituted with . In some embodiments, Y is one R Y It is a phenyl substituted with . In some embodiments, Y is two independently selected Rs Y It is a phenyl substituted with . In some embodiments, Y is three independently selected Rs Y It is phenyl arbitrarily substituted with . In some embodiments, Y is phenyl.

[0358] In some embodiments, Y is 1 to 3 independently selected Rs Y It is naphthyl arbitrarily substituted with . In some embodiments, Y is one or two independently selected Rs Y It is naphthyl substituted with . In some embodiments, Y is 1 R Y It is naphthyl substituted with . In some embodiments, Y is two independently selected Rs Y It is naphthyl substituted with . In some embodiments, Y is three independently selected Rs Y It is naphthyl arbitrarily substituted with . In some embodiments, Y is naphthyl.

[0359] In some embodiments, Y is 1 to 3 independently selected Rs Y It is a 5- to 10-membered heteroaryl optionally substituted with . In some embodiments, Y is one or two independently selected Rs. Y It is a 5- to 10-membered heteroaryl substituted with . In some embodiments, Y is 1 R Y It is a 5- to 10-membered heteroaryl substituted with . In some embodiments, Y is two independently selected Rs Y It is a 5- to 10-membered heteroaryl substituted with . In some embodiments, Y is three independently selected Rs Y It is a 5- to 10-membered heteroaryl arbitrarily substituted with . In some embodiments, Y is a 5- to 10-membered heteroaryl.

[0360] In some embodiments, Y is 1 to 3 independently selected Rs Y It is a 6-membered heteroaryl optionally substituted with . In some embodiments, Y is one or two independently selected Rs Y It is a 6-membered heteroaryl substituted with . In some embodiments, Y is one R Y It is a 6-membered heteroaryl substituted with . In some embodiments, Y is two independently selected Rs Y It is a 6-membered heteroaryl substituted with . In some embodiments, Y is three independently selected Rs Y It is a 6-membered heteroaryl arbitrarily substituted with . In some embodiments, Y is a 6-membered heteroaryl. In some embodiments, the 6-membered heteroaryl of Y is pyridyl (e.g., 3-pyridyl).

[0361] In some embodiments, Y is 1 to 3 independently selected Rs Y It is a 9-membered heteroaryl optionally substituted with . In some embodiments, Y is one or two independently selected Rs. Y It is a 9-membered heteroaryl substituted with . In some embodiments, Y is one R Y It is a 9-membered heteroaryl substituted with . In some embodiments, Y is two independently selected Rs Y It is a 9-membered heteroaryl substituted with . In some embodiments, Y is three independently selected Rs Y It is a 9-membered heteroaryl arbitrarily substituted with . In some embodiments, Y is a 9-membered heteroaryl.

[0362] In some embodiments, 1, 2, or 3 Rs Y is independently a halogen. In some embodiments, 1, 2, or 3 R Y is independently chloro or fluoro. In some embodiments, 1 or 2 Rs Y It is independently chloro or fluoro.

[0363] In some embodiments, 1, 2, or 3 Rs Yis a hydroxyl. In some embodiments, one or two Rs Y is hydroxyl.

[0364] In some embodiments, 1, 2, or 3 Rs Y is cyano. In some embodiments, 1 or 2 Rs Y is cyano.

[0365] In some embodiments, 1, 2, or 3 Rs Y is independently a C1-C6 alkyl. In some embodiments, 1 or 2 Rs Y is independently a C1-C6 alkyl. In some embodiments, 1 or 2 Rs Y is independently a C1-C3 alkyl.

[0366] In some embodiments, 1, 2, or 3 Rs Y is an independently unsubstituted C1-C6 haloalkyl. In some embodiments, 1 or 2 Rs Y is an independently unsubstituted C1-C3 haloalkyl. In some embodiments, 1 or 2 Rs Y is trifluoromethyl.

[0367] In some embodiments, 1, 2, or 3 Rs Y is an independently hydroxyl-substituted C1-C6 haloalkyl. In some embodiments, one or two Rs Y is an independently hydroxyl-substituted C1-C3 haloalkyl.

[0368] In some embodiments, 1, 2, or 3 Rs Y is independently a C1-C6 alkoxy. In some embodiments, one or two Rs Y is independently a C1-C3 alkoxy. In some embodiments, one or two Rs Y is methoxy.

[0369] In some embodiments, 1, 2, or 3 Rs Y is independently a C1-C6 haloalkoxy. In some embodiments, one or two RsY is independently a C1-C3 haloalkoxy. In some embodiments, one or two Rs Y is trifluoromethoxy.

[0370] In some embodiments, 1, 2, or 3 Rs Y is independently a C1-C6 hydroxyalkyl. In some embodiments, one or two Rs Y is independently a C1-C3 hydroxyalkyl. In some embodiments, one or two Rs Y is independently a mono-hydroxyl C1-C3 alkyl. In some embodiments, 1 or 2 Rs Y is independently a di-hydroxyl C2-C3 alkyl.

[0371] In some embodiments, 1, 2, or 3 Rs Y -(CH2) independently n -C(=O)R F and, where n is 1 or 2. In some embodiments, 1 R Y -(CH2) independently n -C(=O)R F and, here n is 1.

[0372] In some embodiments, 1, 2, or 3 Rs Y is independently -C(=O)R F is. In some embodiments, 1 or 2 R Y is independently -C(=O)R F is. In some embodiments, one R Y is -C(=O)R F is. In some embodiments, Y is 1 R Y It is replaced with, and R Y is -C(=O)R F am.

[0373] In some embodiments, 1, 2, or 3 Rs Y is independently-(CH2) n -NHC(=O)R Fand, where n is 1 or 2. In some embodiments, 1 R Y -(CH2) independently n -NHC(=O)R F and, here n is 1.

[0374] In some embodiments, 1, 2, or 3 Rs Y is independently -NHC(=O)R F is. In some embodiments, 1 or 2 R Y is independently -NHC(=O)R F is. In some embodiments, one R Y is -NHC(=O)R F is. In some embodiments, Y is 1 R Y It is replaced with, and R Y is -NHC(=O)R F am.

[0375] In some embodiments, 1, 2, or 3 Rs Y is independently -C(=O)C(=O)NHR F is. In some embodiments, 1 or 2 R Y is independently -C(=O)C(=O)NHR F is. In some embodiments, one R Y -C(=O)C(=O)NHR F is. In some embodiments, Y is 1 R Y It is replaced with, and R Y -C(=O)C(=O)NHR F am.

[0376] In some embodiments, 1, 2, or 3 Rs Y is independently -CO2R G is. In some embodiments, 1 or 2 R Y is independently -CO2R G is. In some embodiments, one R Y -CO2R G is. In some embodiments, Y is 1 R Y It is replaced with, and R Y -CO2RG is. In some embodiments, Y is 1 R Y It is replaced with, and R Y is -CO2H.

[0377] In some embodiments, 1, 2, or 3 Rs Y -(CH2) independently n -SO2NR H R I and, where n is 1 or 2. In some embodiments, 1 R Y -(CH2) independently n -SO2NR H R I and, here n is 1.

[0378] In some embodiments, 1, 2, or 3 Rs Y is independently -SO2NR H R I is. In some embodiments, 1 or 2 R Y is independently -SO2NR H R I is. In some embodiments, one R Y is -SO2NR H R I is. In some embodiments, Y is 1 R Y It is replaced with, and R Y is -SO2NR H R I am.

[0379] In some embodiments, 1, 2, or 3 Rs Y -(CH2) independently n -NHSO2R J and, where n is 1 or 2. In some embodiments, 1 R Y -(CH2) independently n -NHSO2R J and, here n is 1.

[0380] In some embodiments, 1, 2, or 3 Rs Y is independently -NHSO2R J is. In some embodiments, 1 or 2 RY is independently -NHSO2R J is. In some embodiments, one R Y -NHSO2R J is. In some embodiments, Y is 1 R Y It is replaced with, and R Y -NHSO2R J am.

[0381] In some embodiments, 1, 2, or 3 Rs Y -(CH2) independently n -S(=O)(=NR H )R J and, where n is 1 or 2. In some embodiments, 1 R Y -(CH2) independently n -S(=O)(=NR H )R J and, here n is 1.

[0382] In some embodiments, 1, 2, or 3 Rs Y is independently -S(=O)(=NR H )R J is. In some embodiments, 1 or 2 R Y is independently -S(=O)(=NR H )R J is. In some embodiments, one R Y is -S(=O)(=NR H )R J is. In some embodiments, Y is 1 R Y It is replaced with, and R Y is -S(=O)(=NR H )R J am.

[0383] In some embodiments, 1, 2, or 3 Rs Y -(CH2) independently n -SO2R J and, where n is 1 or 2. In some embodiments, 1 R Y -(CH2) independently n -SO2R Jand, here n is 1.

[0384] In some embodiments, 1, 2, or 3 Rs Y is independently -SO2R J is. In some embodiments, 1 or 2 R Y is independently -SO2R J is. In some embodiments, one R Y -SO2R J is. In some embodiments, 1, 2, or 3 Rs Y is independently -SO2(C1-C6 alkyl). In some embodiments, one or two Rs Y is -SO2CH3. In some embodiments, one R Y is -SO2CH3. In some embodiments, Y is one R Y It is replaced with, and R Y is -SO2CH3.

[0385] In some embodiments, 1, 2, or 3 Rs Y -(CH2) independently n -C(=O)NR H R I and, where n is 1 or 2. In some embodiments, 1 R Y -(CH2) independently n -C(=O)NR H R I and, here n is 1.

[0386] In some embodiments, 1, 2, or 3 Rs Y is independently -C(=O)NR H R I is. In some embodiments, 1 or 2 R Y is independently -C(=O)NR H R I is. In some embodiments, one R Y is -C(=O)NR H R I is. In some embodiments, Y is 1 R Y It is replaced with, and R Yis -C(=O)NR H R I am.

[0387] In some embodiments, 1, 2, or 3 Rs Y -(CH2) independently n -C(=O)NR H OR I and, where n is 1 or 2. In some embodiments, 1 R Y -(CH2) independently n -C(=O)NR H OR I and, here n is 1.

[0388] In some embodiments, 1, 2, or 3 Rs Y -(CH2) independently n -C(=O)NR H OR I is. In some embodiments, 1 or 2 R Y -(CH2) independently n -C(=O)NR H OR I is. In some embodiments, one R Y -(CH2) n -C(=O)NR H OR I is. In some embodiments, Y is 1 R Y It is replaced with, and R Y -(CH2) n -C(=O)NR H OR I am.

[0389] In some embodiments, R Y are halogen, -CO2H, -SO2NH2, -SO2CH3, -C(=O)NH2, and -C(=O)NHR, respectively. H , -(CH2) n -C(=O)NHOR I and -(CH2) n -S(=O)(=NH)R J It is selected independently from.

[0390] In some embodiments, 1 or 2 RsY is a halogen, -CO2H, -SO2NH2, -SO2CH3, -C(=O)NH2, -C(=O)NHR H , -(CH2) n -C(=O)NHOR I and -(CH2) n -S(=O)(=NH)R J It is selected independently from.

[0391] In some embodiments, one R Y is a halogen, -CO2H, -SO2NH2, -SO2CH3, -C(=O)NH2, -C(=O)NHR H , -(CH2) n -C(=O)NHOR I or -(CH2) n -S(=O)(=NH)R J am.

[0392] In some embodiments, Y is phenyl, naphthyl, or 5- to 10-membered heteroaryl, wherein phenyl, naphthyl, and 5- to 10-membered heteroaryl are It is arbitrarily and independently substituted as, and * is L 1 This indicates that it is connected to the rest of the compound of this chemical formula (I).

[0393] In some embodiments, Y is phenyl and phenyl is It is replaced with, and * is L 1 This indicates that it is connected to the rest of the compound of this chemical formula (I).

[0394] In some embodiments, Y is naphthyl and naphthyl is It is replaced with, and * is L 1 This indicates that it is connected to the rest of the compound of this chemical formula (I).

[0395] In some embodiments, Y is a 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl is It is replaced with, and * is L 1 This indicates that it is connected to the rest of the compound of this chemical formula (I).

[0396] In some embodiments, ring A is phenyl.

[0397] In some embodiments, ring A is a 4- to 10-membered heteroaryl. In some embodiments, ring A is a 9- to 10-membered heteroaryl. In some embodiments, ring A is a 4- to 6-membered heteroaryl.

[0398] In some embodiments, ring A is a 4- to 10-membered heterocyclile. In some embodiments, ring A is a 9- to 10-membered heterocyclile. In some embodiments, ring A is a 4- to 6-membered heterocyclile.

[0399] In some embodiments, ring A is a C4-C10 cycloalkyl. In some embodiments, ring A is a C9-C10 cycloalkyl. In some embodiments, ring A is a C4-C6 cycloalkyl.

[0400] In some embodiments, L 1 It is a combination.

[0401] In some embodiments, L 1 It is a C1-C6 alkoxylene.

[0402] In some embodiments, L 1 -(CH2) n -NHC(=O)- is.

[0403] In some embodiments, L 1 -C(=O)NH-(CH2) n -am.

[0404] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0405] In some embodiments, L 1 It is -CO2-.

[0406] In some embodiments, L 1 It is -SO2-.

[0407] In some embodiments, L 1 It is -NHSO2-.

[0408] In some embodiments, L1 It is -SO2NH-.

[0409] In some embodiments, L 1 -S(=O)(=NR G )-am.

[0410] In some embodiments, L 1 It is -SO2(C1-C6 alkylene)-.

[0411] In some embodiments, L 1 is -C(=O)C(=O)NH-.

[0412] In some embodiments, L 1 It is a C1-C6 alkylene optionally substituted with an iodine. In some embodiments, L 1 is an unsubstituted C1-C6 alkylene. In some embodiments, L 1 It is an iodine-substituted C1-C6 alkylene.

[0413] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3.

[0414] In some embodiments, 1, 2, or 3 Rs Y1 is independently a halogen. In some embodiments, 1, 2, or 3 Rs Y1 is independently chloro or fluoro. In some embodiments, 1 or 2 Rs Y1 It is independently chloro or fluoro.

[0415] In some embodiments, 1, 2, or 3 Rs Y1 is a hydroxyl. In some embodiments, one or two Rs Y1 It is hydroxyl.

[0416] In some embodiments, 1, 2, or 3 Rs Y1 It is cyano. In some embodiments, 1 or 2 Rs Y1 It is cyano.

[0417] In some embodiments, 1, 2, or 3 Rs Y1is independently a C1-C6 alkyl. In some embodiments, 1 or 2 Rs Y1 is independently a C1-C6 alkyl. In some embodiments, 1 or 2 Rs Y1 is independently a C1-C3 alkyl.

[0418] In some embodiments, 1, 2, or 3 Rs Y1 R independently Y2 It is a C1-C6 alkyl substituted with . In some embodiments, 1 or 2 R Y1 R independently Y2 It is a C1-C6 alkyl substituted with . In some embodiments, 1 or 2 R Y1 R independently Y2 It is a C1-C3 alkyl substituted with .

[0419] In some embodiments, 1, 2, or 3 Rs Y1 is an independently unsubstituted C1-C6 haloalkyl. In some embodiments, 1 or 2 Rs Y1 is an independently unsubstituted C1-C3 haloalkyl. In some embodiments, 1 or 2 Rs Y1 It is trifluoromethyl.

[0420] In some embodiments, 1, 2, or 3 Rs Y1 R independently Y2 It is a C1-C6 alkoxy substituted with . In some embodiments, 1 or 2 R Y1 R independently Y2 It is a C1-C3 alkoxy substituted with . In some embodiments, 1 or 2 R Y1 is R Y2 It is a methoxy substituted with .

[0421] In some embodiments, R Y2 is hydroxyl.

[0422] In some embodiments, R Y2 is -NR H R I am.

[0423] In some embodiments, R Y2is -C(=O)NR H R I am.

[0424] In some embodiments, R Y2 is -SO2NR H R I am.

[0425] In some embodiments, 1, 2, or 3 Rs Y1 is independently a C1-C6 alkoxy. In some embodiments, one or two Rs Y1 is independently a C1-C3 alkoxy. In some embodiments, one or two Rs Y1 It is methoxy.

[0426] In some embodiments, 1, 2, or 3 Rs Y1 is independently -C(=O)R F is. In some embodiments, 1 or 2 R Y1 is independently -C(=O)R F is. In some embodiments, one R Y1 -C(=O)R F is. In some embodiments, ring A is 1 R Y1 It is replaced with, and R Y1 -C(=O)R F am.

[0427] In some embodiments, 1, 2, or 3 Rs Y1 is independently -NHC(=O)R F is. In some embodiments, 1 or 2 R Y1 is independently -NHC(=O)R F is. In some embodiments, one R Y1 -NHC(=O)R F is. In some embodiments, ring A is 1 R Y1 It is replaced with, and R Y1 -NHC(=O)R F am.

[0428] In some embodiments, 1, 2, or 3 Rs Y1 is independently -CO2R Gis. In some embodiments, 1 or 2 R Y1 is independently -CO2R G is. In some embodiments, one R Y1 -CO2R G is. In some embodiments, Y is 1 R Y1 It is replaced with, and R Y1 -CO2R G is. In some embodiments, ring A is 1 R Y1 It is replaced with, and R Y1 It is -CO2H.

[0429] In some embodiments, 1, 2, or 3 Rs Y1 is independently -SO2NR H R I is. In some embodiments, 1 or 2 R Y1 is independently -SO2NR H R I is. In some embodiments, one R Y1 -SO2NR H R I is. In some embodiments, ring A is 1 R Y1 It is replaced with, and R Y1 -SO2NR H R I am.

[0430] In some embodiments, 1, 2, or 3 Rs Y1 is independently -NHSO2R J is. In some embodiments, 1 or 2 R Y1 is independently -NHSO2R J is. In some embodiments, one R Y1 -NHSO2R J is. In some embodiments, ring A is 1 R Y1 It is replaced with, and R Y1 -NHSO2R J am.

[0431] In some embodiments, 1, 2, or 3 Rs Y1 is independently -S(=O)(=NR H )RJ is. In some embodiments, 1 or 2 R Y1 is independently -S(=O)(=NR H )R J is. In some embodiments, one R Y1 -S(=O)(=NR H )R J is. In some embodiments, ring A is 1 R Y1 It is replaced with, and R Y1 -S(=O)(=NR H )R J am.

[0432] In some embodiments, 1, 2, or 3 Rs Y1 is independently -SO2(C1-C6 alkyl). In some embodiments, one or two Rs Y1 It is -SO2CH3. In some embodiments, one R Y is -SO2CH3. In some embodiments, ring A has one R Y1 It is replaced with, and R Y1 It is -SO2CH3.

[0433] In some embodiments, 1, 2, or 3 Rs Y1 is independently -C(=O)NR H R I is. In some embodiments, 1 or 2 R Y1 is independently -C(=O)NR H R I is. In some embodiments, one R Y1 -C(=O)NR H R I is. In some embodiments, ring A is 1 R Y1 It is replaced with, and R Y1 -C(=O)NR H R I am.

[0434] In some embodiments, 1, 2, or 3 Rs Y1 is independently a 4- to 6-membered heteroaryl. In some embodiments, one R Y1It is a 4- to 6-membered heteroaryl. In some embodiments, ring A has one R Y1 It is replaced with, and R Y1 It is a 4- to 6-membered heteroaryl.

[0435] In some embodiments, 1, 2, or 3 Rs Y1 is independently a 5- to 6-membered heteroaryl. In some embodiments, one R Y1 It is a 5- to 6-membered heteroaryl. In some embodiments, ring A has one R Y1 It is replaced with, and R Y1 It is a 5 to 6 won heteroaryl.

[0436] In some embodiments, 1, 2, or 3 Rs Y1 is a quaternary to six-membered heterocyclile independently optionally substituted with a hydroxyl or C1-C6 alkyl. In some embodiments, 1, 2, or 3 Rs Y1 is a quaternary to six-membered heterocyclile independently substituted with a hydroxyl or C1-C6 alkyl group. In some embodiments, 1, 2, or 3 Rs Y1 It is independently a 4- to 6-membered heterocyclile.

[0437] In some embodiments, R Y1 ≠ hydroxyl, cyano, -SO2NH2, -C(=O)R, respectively. F , -C(=O)NH2, C1-C3 alkoxy optionally substituted with hydroxyl and C1-C3 alkyl optionally substituted with hydroxyl are independently selected.

[0438] In some embodiments, 1 or 2 Rs Y1 -SO2NH2, -C(=O)R F , -C(=O)NH2, C1-C3 alkoxy optionally substituted with hydroxyl and C1-C3 alkyl optionally substituted with hydroxyl are independently selected.

[0439] In some embodiments, one R Y1 -SO2NH2, -C(=O)R F, -C(=O)NH2, C1-C3 alkoxy optionally substituted with hydroxyl and C1-C3 alkyl optionally substituted with hydroxyl.

[0440] In some embodiments, 1, 2, or 3 Rs Y is independently heteroarkill. In some embodiments, one R Y is independently heteroarkill.

[0441] In some embodiments, 1, 2, or 3 Rs Y R independently Y1 It is a 4- to 6-membered heterocyclile arbitrarily substituted with. In some embodiments, one R Y is a 4- to 6-membered heterocyclile. In some embodiments, one R Y is R Y1 It is a 4- to 6-membered heterocyclile substituted with. In some embodiments, Y is one R Y It is replaced with, and R Y is R Y1 It is a 4- to 6-membered heterocyclile substituted with, where R Y1 is a hydroxyl. In some embodiments, R Y Is is. In some embodiments, R Y Is am.

[0442] In some embodiments, Y is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and It is selected from a group consisting of.

[0443] In some embodiments, Y is , , , , , and It is selected from a group consisting of.

[0444] In some embodiments, Y is , , , , and It is selected from a group consisting of.

[0445] In some embodiments, Y is , , , , , , , , , , , , , , , , , , and It is selected from a group consisting of.

[0446] In some embodiments, 1, 2, or 3 Rs Y is independently -CO2R A A C1-C6 alkyl or R optionally substituted with Y1 It is a 5- to 6-membered heteroaryl optionally substituted with . In some embodiments, 1, 2, or 3 R Y is independently -CO2R A C1-C6 alkyl or R substituted with Y1 It is a 5- to 6-membered heteroaryl optionally substituted with . In some embodiments, 1, 2, or 3 R Y is independently -CO2R A C1-C6 alkyl or R substituted with Y1 It is a 5- to 6-membered heteroaryl substituted with . In some embodiments, 1, 2, or 3 R Y is independently -CO2R A It is a C1-C6 alkyl or 5- to 6-membered heteroaryl substituted with . In some embodiments, Y is one R Y It is replaced with, and R Y -CO2R A It is a C1-C6 alkyl substituted with . In some embodiments, Y is one R Y It is replaced with, and R Y is a C1-C6 alkyl substituted with -CO2H.

[0447] In some embodiments, 1 or 2 Rs Y is independently -CO2R A A C1-C6 alkyl or R optionally substituted withY1 It is a 5- to 6-membered heteroaryl optionally substituted with . In some embodiments, 1 or 2 R Y is independently -CO2R A C1-C6 alkyl or R substituted with Y1 It is a 5- to 6-membered heteroaryl optionally substituted with . In some embodiments, 1 or 2 R Y is independently -CO2R A C1-C6 alkyl or R substituted with Y1 It is a 5- to 6-membered heteroaryl substituted with . In some embodiments, 1 or 2 R Y is independently -CO2R A It is a C1-C6 alkyl or 5- to 6-membered heteroaryl substituted with .

[0448] In some embodiments, 1 or 2 Rs Y is independently -CO2R A It is a C1-C6 alkyl substituted with . In some embodiments, 1 or 2 R Y R independently Y1 It is a C1-C6 alkyl substituted with a 5- to 6-membered heteroaryl optionally substituted with . In some embodiments, 1 or 2 R Y R independently Y1 It is a C1-C6 alkyl substituted with a 5- to 6-membered heteroaryl substituted with . In some embodiments, 1 or 2 R Y is a C1-C6 alkyl independently substituted with a 5- to 6-membered heteroaryl.

[0449] In some embodiments, 1, 2, or 3 Rs Y is independently a C1-C6 alkyl. In some embodiments, 1 or 2 Rs Y is independently a C1-C3 alkyl. In some embodiments, 1, 2, or 3 Rs Y is methyl. In some embodiments, R Y1 is -SO2(C1-C6 alkyl). In some embodiments, R Y1 It is -SO2CH3.

[0450] In some embodiments, R Y1 It is a C1-C6 alkyl optionally substituted with an oxo. In some embodiments, R Y1 It is an oxo-substituted C1-C6 alkyl. In some embodiments, R Y1 is acetyl, 1-oxoethyl, or 1-oxopropyl. In some embodiments, R Y1 is a C1-C6 alkyl. In some embodiments, R Y1 is methyl. In some embodiments, R 4 is hydrogen.

[0451] In some embodiments, R 4 is a halogen. In some embodiments, R 4 is fluoro or chloro. In some embodiments, R 4 is a fluoro. In some embodiments, R 4 is chloro.

[0452] In some embodiments, R 4 is a C1-C6 alkyl. In some embodiments, R 4 is methyl or ethyl. In some embodiments, R 4 is methyl.

[0453] In some embodiments, R 4 is acrylamide.

[0454] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is a C1-C6 alkyl. In some embodiments, R 5 is methyl or ethyl. In some embodiments, R 5 is methyl.

[0455] In some embodiments, R 5 is a halogen. In some embodiments, R 5 is fluoro or chloro. In some embodiments, R 5 is a fluoro. In some embodiments, R 5 is chloro.

[0456] In some embodiments, R 5 is cyano.

[0457] In some embodiments, R 5 is -NR 5A R 5B am.

[0458] In some embodiments, R 5 is -NR 5A C(=O)R 5B am.

[0459] In some embodiments, R 5 is -C(=O)NR 5A R 5B am.

[0460] In some embodiments, R 5A and R 5B One of them is hydrogen and R 5A and R 5B The remaining one is a C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, R 5A and R 5B One of them is a C1-C6 alkyl and R 5A and R 5B The remaining one is a C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, R 5A and R 5B are each hydrogen. In some embodiments, R 5A and R 5B is each independently selected C1-C6 alkyl. In some embodiments, R 5A and R 5B are each methyl. In some embodiments, R 5A and R 5B The C1-C6 hydroxyalkyl group is hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, dihydroxypropyl, or dihydroxybutyl.

[0461] In some embodiments, R 5 is acrylamide.

[0462] In some embodiments, R 6 is hydrogen.

[0463] In some embodiments, R6 is a halogen. In some embodiments, R 6 is a fluoro. In some embodiments, R 6 is chloro.

[0464] In some embodiments, R 6 is a C1-C6 alkyl. In some embodiments, R 6 is methyl.

[0465] In some embodiments, R A and R B Each is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

[0466] In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one is a hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or a C1-C6 alkyl optionally substituted with a hydroxyl or C1-C6 alkoxy.

[0467] In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one is a hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or a C1-C6 alkyl substituted with a hydroxyl or C1-C6 alkoxy.

[0468] In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one is a hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.

[0469] In some embodiments, R A and R B One of them is hydrogen and RA and R B The remaining one of them is a hydroxyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one of them is a C1-C6 alkoxy. In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one of them is a C3-C6 cycloalkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one of them is a C2-C6 alkenyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one is a C1-C6 alkyl optionally substituted with a hydroxyl or a C1-C6 alkoxy. In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one is a C1-C6 alkyl substituted with a C1-C6 alkoxy.

[0470] In some embodiments, R A and R B One of them is hydrogen and R A and R B The remaining one of them is a C1-C6 alkyl. In some embodiments, R A and R B are each hydrogen. In some embodiments, R A and R Bis independently selected from C1-C6 alkyls optionally substituted with a hydroxyl or a C1-C6 alkoxy. In some embodiments, R A and R B is each independently selected C1-C6 alkyl. In some embodiments, R A and R B are methyl respectively.

[0471] In some embodiments, R A and R B They form a 4- to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogen, C1-C6 alkyl, hydroxyl, and -C(=O)C1-C6 alkyl, together with the nitrogen atom to which they are attached.

[0472] In some embodiments, R A and R B They form 4- to 10-membered heterocyclies substituted with 1 to 2 substituents independently selected from halogen, C1-C6 alkyl, hydroxyl, and -C(=O)C1-C6 alkyl, together with the nitrogen atoms to which they are attached.

[0473] In some embodiments, R A and R B They form a quaternary to 10-membered heterocyclile substituted with a halogen, C1-C6 alkyl, hydroxyl, or -C(=O)C1-C6 alkyl together with the nitrogen atom to which they are attached. In some embodiments, R A and R B They form 4- to 10-membered heterocyclies substituted with 1 to 2 substituents independently selected from fluoro, hydroxyl, methyl, and acetyl, together with the nitrogen atoms to which they are attached.

[0474] In some embodiments, R A and R B They form quaternary to tenary heterocyclies together with the nitrogen atoms to which they are attached. In some embodiments, R A and R B They form 4- to 6-membered heterocyclines together with the nitrogen atoms to which they are attached.

[0475] In some embodiments, R C are C3-C6 cycloalkyl and -C(=O)NHR, respectively. Y1 , and -NR A R B R is independently selected from C1-C6 alkyls substituted with quaternary to 10-membered heterocyclies optionally substituted with C1-C6 alkyls or C1-C6 hydroxyalkyls. In some embodiments, R C Each independently consists of C3-C6 cycloalkyl, -C(=O)NHR Y1 , or -NR A R B It is a C1-C6 alkyl substituted with a 4- to 10-membered heterocyclile substituted with a C1-C6 alkyl or a C1-C6 hydroxyalkyl. In some embodiments, R C Each independently consists of C3-C6 cycloalkyl, -C(=O)NHR Y1 , or -NR A R B It is a C1-C6 alkyl substituted with rho or a 4- to 10-membered heterocyclile. In some embodiments, R C Each independently consists of C3-C6 cycloalkyl, -C(=O)NHR Y1 or it is a C1-C6 alkyl.

[0476] In some embodiments, R C Each is independently a C3-C6 cycloalkyl. In some embodiments, R C -C(=O)NHR each independently Y1 is. In some embodiments, R C -NR each independently A R B It is a C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl or a C1-C6 hydroxyalkyl. In some embodiments, R C -NR each independently A R BIt is a C1-C6 alkyl substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl or a C1-C6 hydroxyalkyl.

[0477] In some embodiments, R D are hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and oxo, respectively, or -NR A R B It is independently selected from C1-C6 alkyls arbitrarily substituted with .

[0478] In some embodiments, R D is hydrogen.

[0479] In some embodiments, R D is hydroxyl.

[0480] In some embodiments, R D is phenyl.

[0481] In some embodiments, R D is a C1-C6 alkoxy.

[0482] In some embodiments, R D is iodine or -NR A R B It is a C1-C6 alkyl optionally substituted with . In some embodiments, R D is an unsubstituted C1-C6 alkyl. In some embodiments, R D is iodine or -NR A R B It is a C1-C6 alkyl substituted with . In some embodiments, R D is -NR A R B It is a C1-C6 alkyl substituted with .

[0483] In some embodiments, R E are hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and oxo, respectively, or -NR A R B It is independently selected from C1-C6 alkyls arbitrarily substituted with .

[0484] In some embodiments, R E is hydrogen.

[0485] In some embodiments, R E is hydroxyl.

[0486] In some embodiments, R E is phenyl.

[0487] In some embodiments, R E is a C1-C6 alkoxy.

[0488] In some embodiments, R E is iodine or -NR A R B It is a C1-C6 alkyl optionally substituted with . In some embodiments, R E is an unsubstituted C1-C6 alkyl. In some embodiments, R E is iodine or -NR A R B It is a C1-C6 alkyl substituted with . In some embodiments, R E is -NR A R B It is a C1-C6 alkyl substituted with .

[0489] In some embodiments, R D and R E One of them is hydrogen and R D and R E The remaining one of them is a hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, R D and R E One of them is hydrogen and R D and R E The remaining one of them is a hydroxyl. In some embodiments, R D and R E One of them is hydrogen and R D and R E The remaining one of them is a C1-C6 alkyl. In some embodiments, R D and R E One of them is hydrogen and R D and R E The remaining one of them is a C1-C6 alkoxy. In some embodiments, R D and R E One of them is hydrogen and R D and R EThe remaining one of them is hydroxyl, methyl, or methoxy. In some embodiments, R D and R E are each hydrogen. In some embodiments, R D and R E is each independently selected C1-C6 alkyl. In some embodiments, R D and R E are methyl respectively.

[0490] In some embodiments, R F is independently selected from C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl).

[0491] In some embodiments, R F is a C3-C6 cycloalkyl.

[0492] In some embodiments, R F It is a 5-6 won heteroaryl.

[0493] In some embodiments, R F is a quaternary to six-membered heterocyclile optionally substituted with a C1-C6 alkyl group. In some embodiments, R F is a 4- to 6-membered heterocyclile. In some embodiments, R F is a quaternary to 6-membered heterocyclile substituted with C1-C6 alkyl groups.

[0494] In some embodiments, R F is a C1-C6 alkyl optionally substituted with a hydroxyl or -SO2(C1-C6 alkyl). In some embodiments, R F is an unsubstituted C1-C6 alkyl. In some embodiments, R F is a C1-C6 alkyl substituted with a hydroxyl or -SO2(C1-C6 alkyl). In some embodiments, R F is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R F is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl).

[0495] In some embodiments, R G is independently selected from hydrogen, C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl).

[0496] In some embodiments, R G is hydrogen.

[0497] In some embodiments, R G is a C3-C6 cycloalkyl.

[0498] In some embodiments, R G It is a 5-6 won heteroaryl.

[0499] In some embodiments, R G It is a 4- to 6-won heterocyclile.

[0500] In some embodiments, R G is a C1-C6 alkyl optionally substituted with a hydroxyl or -SO2(C1-C6 alkyl). In some embodiments, R G is an unsubstituted C1-C6 alkyl. In some embodiments, R G is a C1-C6 alkyl substituted with a hydroxyl or -SO2(C1-C6 alkyl). In some embodiments, R G is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R G is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl).

[0501] In some embodiments, R H and R I are hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2) n -C(=O)NH2, -(CH2) n -SO2NH2, -(CH2) n -SO2(C1-C6 alkyl), hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl and -C(=O)NR K1 RK2 It is independently selected from C1-C6 alkyls optionally substituted with 1 to 2 independently selected substituents.

[0502] In some embodiments, R H is hydrogen.

[0503] In some embodiments, R H is a C1-C6 alkoxy.

[0504] In some embodiments, R H is a C3-C6 cycloalkyl.

[0505] In some embodiments, R H is a C2-C6 alkenyl.

[0506] In some embodiments, R H -(CH2) n -C(=O)NH2

[0507] In some embodiments, R H -(CH2) n It is SO2NH2.

[0508] In some embodiments, R H -(CH2) n It is -SO2(C1-C6 alkyl).

[0509] In some embodiments, R H is hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl and -C(=O)NR K1 R K2 It is a C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from. In some embodiments, R H is an unsubstituted C1-C6 alkyl. In some embodiments, R H is a C1-C6 alkyl substituted with a hydroxyl or -SO2(C1-C6 alkyl). In some embodiments, R H is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R H is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, RH is a C1-C6 alkyl substituted with a C1-C6 alkoxy. In some embodiments, R H is a C1-C6 alkyl substituted with a 5- to 6-membered heteroaryl. In some embodiments, R H is a C1-C6 alkyl substituted with a C3-C6 cycloalkyl. In some embodiments, R H is -C(=O)NR K1 R K2 It is a C1-C6 alkyl substituted with .

[0510] In some embodiments, R K1 and R K2 Both are hydrogen.

[0511] In some embodiments, R K1 and R K2 Both are C1-C6 alkyls.

[0512] In some embodiments, R K1 and R K2 One of them is hydrogen and R K1 and R K2 The remaining one is a C1-C6 alkyl.

[0513] In some embodiments, R I is hydrogen.

[0514] In some embodiments, R I is a C1-C6 alkoxy.

[0515] In some embodiments, R I is a C3-C6 cycloalkyl.

[0516] In some embodiments, R I is a C2-C6 alkenyl.

[0517] In some embodiments, R I -(CH2) n -C(=O)NH2

[0518] In some embodiments, R I -(CH2) n It is SO2NH2.

[0519] In some embodiments, R I -(CH2)n It is -SO2(C1-C6 alkyl).

[0520] In some embodiments, R I is hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl and -C(=O)NR K1 R K2 It is a C1-C6 alkyl optionally substituted with 1 to 2 substituents independently selected from. In some embodiments, R I is an unsubstituted C1-C6 alkyl. In some embodiments, R I is a C1-C6 alkyl substituted with a hydroxyl or -SO2(C1-C6 alkyl). In some embodiments, R I is a hydroxyl-substituted C1-C6 alkyl. In some embodiments, R I is a C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R I is a C1-C6 alkyl substituted with a C1-C6 alkoxy. In some embodiments, R I is a C1-C6 alkyl substituted with a 5- to 6-membered heteroaryl. In some embodiments, R I is a C1-C6 alkyl substituted with a C3-C6 cycloalkyl. In some embodiments, R I is -C(=O)NR K1 R K2 It is a C1-C6 alkyl substituted with .

[0521] In some embodiments, R H and R I One of them is hydrogen and R H and R I The remaining one is phenyl, or oxo, or -NR A R B It is a C1-C6 alkyl optionally substituted with . In some embodiments, R H and R I One of them is hydrogen and R H and R I The remaining one is phenyl, or oxo, or -NR A R BIt is a C1-C6 alkyl substituted with . In some embodiments, R H and R I One of them is hydrogen and R H and R I The remaining one of them is a phenyl or C1-C6 alkyl. In some embodiments, R H and R I One of them is hydrogen and R H and R I The remaining one of them is phenyl. In some embodiments, R H and R I One of them is hydrogen and R H and R I The remaining one is iodine or -NR A R B It is a C1-C6 alkyl optionally substituted with . In some embodiments, R H and R I One of them is hydrogen and R H and R I The remaining one is iodine or -NR A R B It is a C1-C6 alkyl substituted with . In some embodiments, R H and R I are each hydrogen. In some embodiments, R H and R I is each independently selected C1-C6 alkyl. In some embodiments, R H and R I are methyl respectively.

[0522] In some embodiments, R H and R I Each is hydrogen.

[0523] In some embodiments, R H and R I One of them is hydrogen and R H and R I The remaining one is a C1-C6 alkoxy, C3-C6 cycloalkyl, or C2-C6 alkenyl.

[0524] In some embodiments, R H and R I One of them is hydrogen and RH and R I The remaining one is a C1-C6 alkyl optionally substituted with a hydroxyl, -SO2(C1-C6 alkyl), or C1-C6 alkoxy.

[0525] In some embodiments, R H and R I One of them is hydrogen and R H and R I The remaining one is -(CH2) n -C(=O)NH2, -(CH2) n -SO2NH2 or -(CH2) n It is -SO2(C1-C6 alkyl).

[0526] In some embodiments, R H and R I They form a quaternary to ten-membered heterocyclile optionally substituted with one or two substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atom to which they are attached. In some embodiments, R H and R I They form unsubstituted quaternary to decary heterocyclies together with the nitrogen atoms to which they are attached. In some embodiments, R H and R I They form a quaternary to 10-membered heterocyclile substituted with one or two substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached. In some embodiments, R H and R I They form a quaternary to ten-membered heterocyclile substituted with one substituent independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atom to which they are attached. In some embodiments, R H and R I They form a quaternary to 10-membered heterocyclile substituted with two substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached.

[0527] In some embodiments, R J is a C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0528] In some embodiments, R J is a C1-C6 alkyl. In some embodiments, R J is a C1-C3 alkyl.

[0529] In some embodiments, R J is a C3-C6 cycloalkyl.

[0530] In some embodiments, R J is a C1-C6 alkoxy.

[0531] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A1) below

[0532] (I-A1)

[0533] Or it is a pharmaceutically acceptable salt thereof.

[0534] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-B1) below

[0535] (I-B1)

[0536] Or it is a pharmaceutically acceptable salt thereof.

[0537] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A2) below

[0538] (I-A2)

[0539] Or it is a pharmaceutically acceptable salt thereof.

[0540] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A3) below

[0541] (I-A3)

[0542] Or it is a pharmaceutically acceptable salt thereof.

[0543] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B2) below

[0544] (I-B2)

[0545] Or it is a pharmaceutically acceptable salt thereof.

[0546] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A5) below

[0547] (I-A4)

[0548] Or it is a pharmaceutically acceptable salt thereof.

[0549] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B3) below

[0550] (I-B3)

[0551] Or it is a pharmaceutically acceptable salt thereof.

[0552] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A5) below

[0553] (I-A5)

[0554] Or it is a pharmaceutically acceptable salt thereof.

[0555] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B4) below

[0556] (I-B4)

[0557] Or it is a pharmaceutically acceptable salt thereof.

[0558] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A6) below

[0559] (I-A6)

[0560] Or it is a pharmaceutically acceptable salt thereof.

[0561] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A6a) below

[0562] (I-A6a)

[0563] Or it is a pharmaceutically acceptable salt thereof.

[0564] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B5) below

[0565] (I-B5)

[0566] Or it is a pharmaceutically acceptable salt thereof.

[0567] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-B5a) below

[0568] (I-B5a)

[0569] Or it is a pharmaceutically acceptable salt thereof.

[0570] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A7) below

[0571] (I-A7)

[0572] Or it is a pharmaceutically acceptable salt thereof.

[0573] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A7a) below

[0574] (I-A7a)

[0575] Or it is a pharmaceutically acceptable salt thereof.

[0576] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A8) below

[0577] (I-A8)

[0578] Or it is a pharmaceutically acceptable salt thereof.

[0579] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B6) below

[0580] (I-B6)

[0581] Or it is a pharmaceutically acceptable salt thereof.

[0582] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A9) below

[0583] (I-A9)

[0584] Or it is a pharmaceutically acceptable salt thereof.

[0585] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-B7) below

[0586] (I-B7)

[0587] Or it is a pharmaceutically acceptable salt thereof.

[0588] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-A10).

[0589] (I-A10)

[0590] Or it is a pharmaceutically acceptable salt thereof.

[0591] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A11) below

[0592] (I-A11)

[0593] Or it is a pharmaceutically acceptable salt thereof.

[0594] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A12) below

[0595] (I-A12)

[0596] Or it is a pharmaceutically acceptable salt thereof.

[0597] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A13) below

[0598] (I-A13)

[0599] Or it is a pharmaceutically acceptable salt thereof.

[0600] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A14) below

[0601] (I-A14)

[0602] Or it is a pharmaceutically acceptable salt thereof.

[0603] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-A15).

[0604] (I-A15)

[0605] Or it is a pharmaceutically acceptable salt thereof.

[0606] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B8) below

[0607] (I-B8)

[0608] Or it is a pharmaceutically acceptable salt thereof.

[0609] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B9) below

[0610] (I-B9)

[0611] Or it is a pharmaceutically acceptable salt thereof.

[0612] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-B10).

[0613] (I-B10)

[0614] Or it is a pharmaceutically acceptable salt thereof.

[0615] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-B11) below

[0616] (I-B11)

[0617] Or it is a pharmaceutically acceptable salt thereof.

[0618] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B12) below

[0619] (I-B12)

[0620] Or it is a pharmaceutically acceptable salt thereof.

[0621] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-A16).

[0622] (I-A16)

[0623] Or it is a pharmaceutically acceptable salt thereof.

[0624] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A17) below

[0625] (I-A17)

[0626] Or it is a pharmaceutically acceptable salt thereof.

[0627] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-A18).

[0628] (I-A18)

[0629] Or it is a pharmaceutically acceptable salt thereof.

[0630] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A19) below

[0631] (I-A19)

[0632] Or it is a pharmaceutically acceptable salt thereof.

[0633] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-A20).

[0634] (I-A20)

[0635] Or it is a pharmaceutically acceptable salt thereof.

[0636] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A20a) below

[0637] (I-A20a)

[0638] Or it is a pharmaceutically acceptable salt thereof.

[0639] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A20b) below

[0640] (I-A20b)

[0641] Or it is a pharmaceutically acceptable salt thereof.

[0642] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A21) below

[0643] (I-A21)

[0644] Or it is a pharmaceutically acceptable salt thereof.

[0645] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A21a) below

[0646] (I-A21a)

[0647] Or it is a pharmaceutically acceptable salt thereof.

[0648] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A22) below

[0649] (I-A22)

[0650] Or it is a pharmaceutically acceptable salt thereof.

[0651] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A23) below

[0652] (I-A23)

[0653] Or it is a pharmaceutically acceptable salt thereof.

[0654] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A24) below

[0655] (I-A24)

[0656] or a pharmaceutically acceptable salt thereof, wherein ring B in formula (I-A24) is one or two independently selected Rs Y It is a C6 aryl or C5-C6 heteroaryl arbitrarily substituted with

[0657] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A25) below

[0658] (I-A25)

[0659] or a pharmaceutically acceptable salt thereof, wherein ring B in formula (I-A25) is one or two independently selected Rs Y It is a C6 aryl or C5-C6 heteroaryl arbitrarily substituted with

[0660] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-A26) below

[0661] (I-A26)

[0662] Or it is a pharmaceutically acceptable salt thereof.

[0663] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A26a) below

[0664] (I-A26a)

[0665] Or it is a pharmaceutically acceptable salt thereof.

[0666] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A27) below

[0667] (I-A27)

[0668] Or it is a pharmaceutically acceptable salt thereof.

[0669] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-A28).

[0670] (I-A28)

[0671] Or it is a pharmaceutically acceptable salt thereof.

[0672] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-A29).

[0673] (I-A29)

[0674] Or it is a pharmaceutically acceptable salt thereof.

[0675] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of the following formula (I-A30).

[0676] (I-A30)

[0677] Or it is a pharmaceutically acceptable salt thereof.

[0678] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is the compound of formula (I-A31) below

[0679] (I-A31)

[0680] Or it is a pharmaceutically acceptable salt thereof.

[0681] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (I-B13) below

[0682] (I-B13)

[0683] Or it is a pharmaceutically acceptable salt thereof.

[0684] In some embodiments, the compound of formula (I) or the pharmaceutically acceptable salt thereof is a compound of formula (I-B14) below

[0685] (I-B14)

[0686] Or it is a pharmaceutically acceptable salt thereof.

[0687] Also, compounds of the following chemical formula (II)

[0688]

[0689] or a pharmaceutically acceptable salt thereof is provided herein, wherein in formula (II),

[0690] Z 1 , Z 2 and Z 3 Each is independently N or CH, but Z 1 , Z 2 and Z 3 One or two of them are N,

[0691] Z is N or CH, and

[0692] R 2 is 1 to 4 independently selected R 2A phenyl arbitrarily substituted with , 1 to 4 independently selected Rs 2A 5- to 10-membered heteroaryls arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclils arbitrarily substituted with , 1 to 4 independently selected Rs 2A A C4-C10 cycloalkyl optionally substituted with , 1 to 4 independently selected R 2A 4- to 10-membered heterocyclyloxy oxy arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-won heteroaryloxy, -C(=O)NR arbitrarily substituted with A R C A C1-C6 alkoxyalkyl optionally substituted with -C(=O)NR A R C , C1-C6 alkoxy optionally substituted with a C4-C10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, and

[0693] R 2A are each

[0694] (i) Halogen;

[0695] (ii) Cyan;

[0696] (iii) Hydroxyl;

[0697] (iv) -NR A R B ;

[0698] (v) -C(=O)NR A R B ;

[0699] (vi) ;

[0700] (vii) -NHC(=O)R C ;

[0701] (viii) -C(=O)OR D ;

[0702] (ix) -SO2R D ;

[0703] (x) -NHSO2R D ;

[0704] (xi) -SO2NR D R E ;

[0705] (xii) NR A R B -NHC(=O)C1-C6 alkyl arbitrarily substituted with;

[0706] (xiii) C1-C6 haloalkyl;

[0707] (xiv) C1-C6 hydroxyalkyl;

[0708] (xv) Hydroxyl, cyano, optionally hydroxyl-substituted C1-C6 alkyl, halogen, -C(=O)NR A R B , -NR A R B , and a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclil optionally substituted with a hydroxyl or C1-C6 alkyl;

[0709] (xvi) hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B 4- to 10-membered heterocyclils optionally substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with , and C1-C6 alkoxy or hydroxyl optionally substituted with hydroxyl;

[0710] (xvii) Hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl;

[0711] (xviii) -NR A R B , or a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl; and

[0712] (xix) hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or independently selected from C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl, and

[0713] R A and R Bis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R A and R B They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[0714] R C are C3-C6 cycloalkyl and -C(=O)NHR, respectively. Y1 , and -NR A R B Independently selected from C1-C6 alkyl or C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 hydroxyalkyl, and

[0715] R D and R E are hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and oxo, respectively, or -NR A R B Independently selected from C1-C6 alkyls arbitrarily substituted with,

[0716] R 3A and R 3B Each is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or

[0717] R 3A and R 3B They each form a quaternary to 8-membered heterocyclile group together with the carbon and nitrogen atoms to which they are attached, and

[0718] R 4 is hydrogen, a halogen, a C1-C6 alkyl, or an acrylamido, and

[0719] R 5 -NR 5A R 5B , -NR5A C(=O)R 5B or -C(=O)NR 5A R 5B And,

[0720] R 5A and R 5B is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl, and

[0721] R 6 is hydrogen, a halogen, or a C1-C6 alkyl, and

[0722] X is a bond, CH2, CH(CH3), C(CH3)2 or And,

[0723] W is NR 3B or O and,

[0724] Y is a phenyl, naphthyl, or 5- to 10-membered heteroaryl, wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryls are independently selected from 1 to 3 Rs. Y or It is arbitrarily and independently substituted as, and * is L 1 This indicates that it is connected to the remaining part of the compound of this chemical formula (I),

[0725] R Y are respectively halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -(CH2) n -C(=O)R F , -(CH2) n -NHC(=O)R F , -(CH2) n -NHC(=O)OR F , -CO2R G , -(CH2) n -SO2NR H R I , -(CH2) n -NHSO2R J , -(CH2) n -S(=O)(=NR H )R J , -(CH2) n-SO2R J , -(CH2) n -C(=O)NR H R I , -(CH2) n -C(=O)NR H OR I and independently selected from C1-C6 haloalkyls optionally substituted with hydroxyl, and

[0726] R F Each is independently selected from C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and

[0727] R G Each is independently selected from hydrogen, C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and

[0728] R H and R I are, respectively, hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, hydroxyl, -SO2(C1-C6 alkyl), or C1-C6 alkyl optionally substituted with C1-C6 alkoxy, -(CH2) n -C(=O)NH2, -(CH2) n -SO2NH2 and -(CH2) n Independently selected from -SO2(C1-C6 alkyl), or R H and R I They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[0729] R J is a C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, and

[0730] Ring A is phenyl, 4- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C4-C10 cycloalkyl, and

[0731] L 1 Silver bond, C1-C6 alkoxylene, -(CH2) n -NHC(=O)-, -C(=O)NH-(CH2) n -, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NR G )-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or a C1-C6 alkylene optionally substituted with an oxo, and

[0732] R Y1 ≡ cyano, hydroxyl, halogen, -C(=O)R, respectively. F , -NHC(=O)R F , -CO2R G , -SO2NR H R I , -NHSO2R J , -S(=O)(=NR H )R J , -SO2(C1-C6 alkyl), -C(=O)NR H R I , 4~6 won heteroaryl, R Y2 C1-C6 alkoxy, C1-C6 haloalkyl, R optionally substituted with Y2 Independently selected from C1-C6 alkyl and hydroxyl optionally substituted with , or 4- to 6-membered heterocyclies optionally substituted with C1-C6 alkyl, and

[0733] R Y2 is hydroxyl, -NR H R I , -C(=O)NR H R I or -SO2NR H R I And,

[0734] n is 0, 1, or 2, and

[0735] z is 0, 1, 2, or 3.

[0736] Z, R 2 , R 2A , R 3A , R 3B , R 4 , R 5 , R 5A , R 5B , R 6 , R A , R B , R C , R D , R E , R F , R G , R H , R I , R J , X, W, Y, R Y , R Y1 , R Y2 , ring A, L 1 , n and z are additionally defined as disclosed in the above chemical formula (I).

[0737] Z in some embodiments 1 is N.

[0738] Z in some embodiments 1 It is CH.

[0739] Z in some embodiments 2 is N.

[0740] Z in some embodiments 2 is CH.

[0741] Z in some embodiments 3 is N.

[0742] Z in some embodiments 3 is CH.

[0743] A compound of the following formula (II-A) or a pharmaceutically acceptable salt thereof is provided herein, wherein

[0744] Chemical formula (II-A)

[0745] In chemical formula (II-A),

[0746] R 2 , R 3A , R 4 , R5 , R 6 , X, W, and Y are defined as disclosed in the above chemical formula (I).

[0747] A compound of the following formula (II-B) or a pharmaceutically acceptable salt thereof is provided herein, wherein

[0748] Chemical formula (II-B)

[0749] In chemical formula (II-B),

[0750] R 2 , R 3A , R 4 , R 5 , R 6 , X, W, and Y are defined as disclosed in the above chemical formula (I).

[0751] A compound of the following formula (II-C) or a pharmaceutically acceptable salt thereof is provided herein, wherein

[0752] Chemical formula (II-C)

[0753] In the chemical formula (II-C),

[0754] R 2 , R 3A , R 4 , R 5 , R 6 , X, W, and Y are defined as disclosed in the above chemical formula (I).

[0755] A compound of the following formula (II-D) or a pharmaceutically acceptable salt thereof is provided herein, wherein

[0756] Chemical formula (II-D)

[0757] In chemical formula (II-D),

[0758] R 2 , R 3A , R 4 , R 5 , R 6 , X, W, and Y are defined as disclosed in the above chemical formula (I).

[0759] A compound of the following formula (II-E) or a pharmaceutically acceptable salt thereof is provided herein, wherein

[0760] Chemical formula (II-E)

[0761] In chemical formula (II-E),

[0762] R 2 , R 3A , R 4 , R 5 , R 6 , X, W, and Y are defined as disclosed in the above chemical formula (I).

[0763] A compound of the following formula (II-F) or a pharmaceutically acceptable salt thereof is provided herein, wherein

[0764] Chemical formula (II-F)

[0765] In the chemical formula (II-F),

[0766] R 2 , R 3A , R 4 , R 5 , R 6 , X, W, and Y are defined as disclosed in the above chemical formula (I).

[0767] Non-limiting example compounds

[0768] In some embodiments, the compound is selected from the group consisting of the compounds of Examples 1 to 668 (e.g., compound 1, compound 2, or compound 620) or a pharmaceutically acceptable salt thereof.

[0769] In some embodiments, the compound is selected from the group consisting of the compounds in Table A or a pharmaceutically acceptable salt thereof. The stereochemistry shown for the compounds in Table A is optional.

[0770] [Table A]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854]

[0855]

[0856]

[0857]

[0858]

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873]

[0874]

[0875]

[0876]

[0877]

[0878]

[0879]

[0880]

[0881]

[0882]

[0883]

[0884]

[0885]

[0886]

[0887]

[0888]

[0889]

[0890]

[0891]

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903] In some embodiments, the compound is selected from the group consisting of the compounds in Table B or is a pharmaceutically acceptable salt thereof. The stereochemistry shown for the compounds in Table B is optional.

[0904] [Table B]

[0905]

[0906]

[0907] Pharmaceutical composition

[0908] Some embodiments provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0909] Some embodiments provide a pharmaceutical composition comprising a compound of formula (II) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

[0910] Treatment methods

[0911] The term 'PI3Kα inhibitor' as used herein [e.g., compounds of formula (I) and pharmaceutically acceptable salts thereof, and compounds of formula (II) and pharmaceutically acceptable salts thereof] includes any compound exhibiting PI3Kα inactivating activity (e.g., inhibition or reduction). In some embodiments, the PI3Kα inhibitor may be selective for PI3Kα relative to one or more other kinases. In some embodiments, the PI3Kα inhibitor may be selective for PI3Kα having one or more mutations.

[0912] The ability of a test compound to act as an inhibitor of PI3Kα can be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3Kα inhibitors can be analyzed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of kinases. Alternative in vitro assays quantify the ability of an inhibitor to bind to a protein kinase and can be measured by radiolabeling the compound before binding, isolating the compound / kinase complex, and determining the amount of the bound radiolabel, or by performing a competitive experiment in which a new compound is incubated with a kinase bound to a known radioligand.

[0913] The efficacy of the PI3Kα inhibitor provided herein is EC 50 It can be determined by the value. EC determined under substantially similar conditions. 50 Compounds with lower values ​​are EC 50 It is a more potent inhibitor compared to compounds with higher values.

[0914] The efficacy of the PI3Kα inhibitor provided herein is also IC 50 It can be determined by the value. IC determined under substantially similar conditions. 50 Compounds with lower IC values 50 It is a more potent inhibitor compared to compounds with higher values. In some embodiments, substantially similar conditions include determining PI3Kα-dependent phosphorylation levels in vitro or in vivo.

[0915] As described herein, the selectivity between wild-type PI3Kα and PI3Kα containing one or more mutations can also be measured using in vitro assays such as surface plasmon resonance and fluorescence-based binding assays, and cell assays such as proliferation assays in which pAKT levels, which are biomarkers of PI3Kα activity, and / or cell proliferation depend on mutant PI3Kα kinase activity.

[0916] In some embodiments, the compounds provided herein may exhibit potent and selective inhibition of PI3Kα. For example, the compounds provided herein may bind to the helical phosphatidylinositol kinase homologous domain and catalytic domain of PI3Kα. In some embodiments, the compounds provided herein may exhibit nanomolar efficacy against PI3Kα kinases comprising one or more mutations, for example, the mutations in Table 1.

[0917] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may selectively target PI3Kα. For example, the compound of formula (I) or a pharmaceutically acceptable salt thereof may selectively target PI3Kα compared to another phosphokinase or non-phosphokinase target.

[0918] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof may selectively target PI3Kα. For example, the compound of formula (II) or a pharmaceutically acceptable salt thereof may selectively target PI3Kα compared to another phosphokinase or non-phosphokinase target.

[0919] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof [or the compound of formula (II) or a pharmaceutically acceptable salt thereof] may exhibit greater inhibition of PI3Kα containing one or more mutations described herein (e.g., one or more mutations described in Table 1) compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit at least 2, 3, 5, 10, 25, 50, or 100 times greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit up to 1,000 times greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit up to 10,000 times greater inhibition of PI3Kα having the combination of mutations described herein compared to inhibition of wild-type PI3Kα.

[0920] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit about 2 to about 10 times greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit about 10 to about 100 times greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit about 100 to about 1,000 times greater inhibition of PI3Kα containing one or more mutations described herein compared to inhibition of wild-type PI3Kα. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof may exhibit about 1,000 to about 10,000 times greater inhibition of PI3Kα containing one or more of the mutations described herein compared to inhibition of wild-type PI3Kα.

[0921] Compounds of formula (I) or pharmaceutically acceptable salts thereof and compounds of formula (II) or pharmaceutically acceptable salts thereof are useful for treating diseases that can be treated with PI3Kα inhibitors, such as PI3Kα-associated diseases, e.g., proliferative disorders, e.g., blood cancers and solid tumors (e.g., advanced or metastatic solid tumors).

[0922] In some embodiments, the subject is determined, for example, using regulatory agency approval, for example, FDA approval analysis or kit. PIK3CA It has been confirmed or diagnosed that the subject has cancer (PI3Kα-associated cancer) having dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these. In some embodiments, the subject is PIK3CAThe subject has a tumor positive for dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor positive for the mutations listed in Table 1. The subject PIK3CA The subject may have a tumor(s) that are positive for the gene, the PI3Kα protein, or dysregulation of the expression, activity, or level of any of these (e.g., confirmed as positive using regulatory agency approval, e.g., FDA-approved assays or kits). The subject is a tumor(s) of the subject PIK3CA The subject may have a gene, a PI3Kα protein, or dysregulation of their expression, activity, or level (e.g., if the tumor is thus identified using regulatory agency approval, e.g., an FDA-approved kit or assay). In some embodiments, the subject is suspected of having PI3Kα-associated cancer. In some embodiments, the subject is PIK3CA There is a clinical record indicating the presence of a tumor having dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these (and optionally, the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0923] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt and the compound of formula (II) or its pharmaceutically acceptable salt are useful for preventing diseases defined herein, such as cancer. As used herein, the term 'preventing' means delaying, in whole or in part, the onset, recurrence, or spread of the disease or symptoms described herein.

[0924] The term 'PI3Kα-associated disease' used in this document is PIK3CADysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these (e.g., one or more) (e.g., PIK3CA It refers to a disease associated with or having any type of dysregulation of the expression, activity, or level of a gene, or the PI3Kα protein, or any of the ones described herein. Non-limiting examples of PI3Kα-associated diseases include, for example, proliferative disorders, such as cancer (e.g., PI3Kα-associated cancer).

[0925] The term 'PI3Kα-associated cancer' used in this document is PIK3CA It refers to a cancer associated with or having dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these. Non-limiting examples of PI3Kα-associated cancers are described herein.

[0926] Phrase ' PIK3CA 'Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these' is a genetic mutation [e.g., resulting in the expression of PI3Kα containing a deletion of at least one amino acid compared to wild-type PI3Kα PIK3CA Gene mutations, resulting in the expression of PI3Kα with one or more point mutations compared to wild-type PI3Kα PIK3CA A mutation in the gene resulting in the expression of PI3Kα having at least one inserted amino acid compared to wild-type PI3Kα PIK3CAIt refers to increased expression (e.g., increased levels) of wild-type PI3Kα in mammalian cells due to mutations in genes, gene duplication resulting in increased levels of PI3Kα in cells, or mutations in regulatory sequences (e.g., promoters and / or enhancers) resulting in increased levels of PI3Kα in cells, selective splicing versions of PI3Kα mRNA resulting in PI3Kα having at least one amino acid deletion compared to wild-type PI3Kα, or dysregulation of abnormal cell signaling and / or autocrine / paracrine signaling (e.g., compared to control non-cancerous cells). As another example, PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these does not involve a mutation PIK3CA Encoding PI3Kα that is constitutively active or has increased activity compared to the protein encoded by the gene PIK3CA It may be a mutation of the gene. Non-limiting examples of PI3Kα point mutations / substitutions / insertions / deletions are listed in Table 1.

[0927] The term 'wild type' refers to a nucleic acid (e.g., PIK3CA gene or PI3Kα mRNA) or protein (e.g., PI3Kα) sequence typically found in subjects not suffering from a disease associated with the reference nucleic acid or protein.

[0928] The term 'wild-type PI3Kα' (or 'wild-type PI3Kα') refers to normal PI3Kα nucleic acids found in subjects who do not suffer from a PI3Kα-associated disease, e.g., PI3Kα-associated cancer (and arbitrarily also do not have an increased risk of developing a PI3Kα-associated disease or are not suspected of having one), or found in the cells or tissues of subjects who do not suffer from a PI3Kα-associated disease, e.g., PI3Kα-associated cancer (and arbitrarily also do not have an increased risk of developing a PI3Kα-associated disease or are not suspected of having one) (e.g., PIK3CA or PI3Kα represents mRNA) or protein.

[0929] A method for treating a subject requiring treatment for cancer (e.g., PI3Kα-associated cancer) is provided herein, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, a method for treating a subject requiring treatment for PI3Kα-associated cancer comprises: a) from a sample of the subject PIK3CAA method is provided herein comprising: a) detecting a dysregulation of the expression, activity, or level of a gene, a PI3Kα protein, or any of these; and b) administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for treating cancer in a subject previously determined to have PI3Kα-associated cancer, comprising the step of administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. Some embodiments provide a method for treating cancer in a subject identified or diagnosed with PI3Kα-associated cancer, comprising the step of administering a therapeutically effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0930] A method for treating a subject requiring treatment for cancer (e.g., PI3Kα-associated cancer) is provided herein, comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, a method for treating a subject requiring treatment for PI3Kα-associated cancer comprises: a) from a sample of the subject PIK3CAA method is provided herein comprising: a) detecting a dysregulation of the expression, activity, or level of a gene, a PI3Kα protein, or any of these; and b) administering a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof. Some embodiments provide a method for treating cancer in a subject previously determined to have PI3Kα-associated cancer, comprising the step of administering a therapeutically effective amount of a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject. Some embodiments provide a method for treating cancer in a subject identified or diagnosed with PI3Kα-associated cancer, comprising the step of administering a therapeutically effective amount of a compound of formula (II), a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof to the subject.

[0931] In some embodiments PIK3CA Dysregulation of the expression, activity, or level of the gene, PI3Kα protein, or any of these includes one or more PI3Kα protein substitutions / point mutations / insertions. Non-limiting examples of PI3Kα protein substitutions / insertions / deletions are listed in Table 1.

[0932] In some embodiments, PI3Kα protein substitution / insertion / deletion is E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047 RIt is selected from the group consisting of , H1047Y, G1049R, and combinations thereof. In some embodiments, the PI3Kα protein substitution / insertion / deletion is H1047X, where X is any amino acid other than H. In some embodiments, the PI3Kα protein substitution / insertion / deletion is E542X, where X is any amino acid other than E. In some embodiments, the PI3Kα protein substitution / insertion / deletion is E545X, where X is any amino acid other than E. In some embodiments, the PI3Kα protein substitution / insertion / deletion is H1047R. In some embodiments, the PI3Kα protein substitution / insertion / deletion is E545K.

[0933] In some embodiments PIK3CA Dysregulation of the expression or activity or level of the gene, PI3Kα protein, or any of these includes splice variants of PI3Kα mRNA that produce an expression protein which is a selective splicing variant of PI3Kα in which at least one residue is deleted (compared to the wild-type PI3Kα protein), resulting in constitutive activity of the PI3Kα protein domain.

[0934] In some embodiments PIK3CA Dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these results in the production of a PI3Kα protein having one or more amino acid substitutions compared to the wild-type PI3Kα protein. PIK3CA at least one point mutation within the gene, or resulting in the production of a PI3Kα protein with one or more amino acids inserted or removed PIK3CAThis includes insertions or deletions within a gene. In some cases, the generated mutant PI3Kα protein has increased activity compared to the wild-type PI3Kα protein or a PI3Kα protein that does not contain the same mutation. In some embodiments, the compounds described herein selectively inhibit the generated mutant PI3Kα protein compared to the wild-type PI3Kα protein or a PI3Kα protein that does not contain the same mutation.

[0935] In some embodiments of any of the methods or uses described herein, cancer (e.g., PI3Kα-associated cancer) is selected from blood cancer and solid tumors.

[0936] In some embodiments of any of the methods or uses described herein, cancer (e.g., PI3Kα-associated cancer) is breast cancer (HER2 + and HER2 - Both breast cancers, ER + Selected from breast cancer (including breast cancer and triple-negative breast cancer), uterine cancer (including endometrial cancer), lung cancer (small cell lung cancer [SCLC] and non-small cell lung cancer [NSCLS, including adenocarcinoma and squamous cell lung cancer]), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophageal gastric adenocarcinoma, bladder cancer, head and neck cancer (head and neck squamous cell carcinoma, e.g., oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), renal cancer, pancreatic neuroendocrine neoplasm (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, hepatocellular carcinoma, prostate cancer, malignant peripheral nerve sheath tumor [MPNST], glioblastoma, cholangiocarcinoma, and pancreatic cancer.

[0937] In some embodiments of any of the methods or uses described herein, cancer (e.g., PI3Kα-associated cancer) is breast cancer (HER2+ and HER2 - Both breast cancers, ER + It is selected from breast cancer (including breast cancer and triple-negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell carcinoma (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), renal cancer, pancreatic neuroendocrine neoplasm (pNET), gastric cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma and squamous cell lung carcinoma), and endometrial cancer.

[0938] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer, SCLC, NSCLC, endometrial cancer, esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophageal gastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer.

[0939] In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is breast cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is lung cancer.

[0940] In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is selected from the cancers listed in Table 1.

[0941]

[0942]

[0943] AUnless otherwise noted, the mutations in Table 1 were identified in the cBioPortal database derived from the literature [Cerami et al. The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data. Cancer Discovery. May 2012 2; 401; and Gao et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013)].

[0944] Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075].

[0945] Exemplary sequence of human phosphatidylinositol 4,5-bisphosphate 3-kinase isoform alpha (UniProtKB registration number P42336) (SEQ No. 1)

[0946] MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK

[0947] VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA

[0948] VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP

[0949] NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY

[0950] ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD

[0951] CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD

[0952] IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA

[0953] RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH

[0954] GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV

[0955] SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF

[0956] LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME

[0957] LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV

[0958] RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK

[0959] HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG

[0960] FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII

[0961] FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV

[0962] VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS

[0963] CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE

[0964] RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN

[0965] LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG

[0966] WTTKMDWIFH TIKQHALN

[0967] Additionally, a method for inhibiting PI3Kα activity in cells is provided, comprising the step of contacting cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In some embodiments, contact is made in vitro. In some embodiments, contact is made in vivo. In some embodiments, contact is made in vivo, but the method comprises the step of administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject having cells having abnormal PI3Kα activity. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cells are any cancer described herein. In some embodiments, the cancer cells are PI3Kα-associated cancer cells. As used herein, the term "contact" refers to bringing together the specified moiety in an in vitro system or in vivo system. For example, "contacting" a PI3Kα protein with a compound provided herein includes not only administering the compound provided herein to an individual or subject having a PI3Kα protein, e.g., a human, but also introducing the compound provided herein into a sample containing a cell or purified product containing a PI3Kα protein, e.g.

[0968] Additionally, the present invention provides a method for inhibiting cell proliferation in vitro or in vivo, comprising the step of contacting a cell with an effective amount of a compound of formula (I) defined herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0969] Additionally, the present invention provides a method for increasing apoptosis in vitro or in vivo, comprising the step of contacting cells with an effective amount of a compound of formula (I) as defined herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Additionally, the present invention provides a method for increasing tumor cell apoptosis in a subject, comprising the step of administering to the subject an effective compound of formula (I) or a pharmaceutically acceptable salt thereof in an amount effective for increasing tumor cell apoptosis.

[0970] Additionally, a method for inhibiting PI3Kα activity in cells is provided, comprising the step of contacting cells with a compound of formula (II) or a pharmaceutically acceptable salt thereof. In some embodiments, contact is made in vitro. In some embodiments, contact is made in vivo. In some embodiments, contact is made in vivo, but the method comprises the step of administering an effective amount of the compound of formula (II) or a pharmaceutically acceptable salt thereof to a subject having cells having abnormal PI3Kα activity. In some embodiments, the cells are cancer cells. In some embodiments, the cancer cells are any cancer described herein. In some embodiments, the cancer cells are PI3Kα-associated cancer cells. As used herein, the term "contact" refers to bringing together the specified moiety in an in vitro system or in vivo system. For example, "contacting" a PI3Kα protein with a compound provided herein includes not only administering the compound provided herein to an individual or subject having a PI3Kα protein, such as a human, but also, for example, introducing the compound provided herein into a sample containing a cell or purified product containing a PI3Kα protein.

[0971] Additionally, the present invention provides a method for inhibiting cell proliferation in vitro or in vivo, comprising the step of contacting a cell with an effective amount of a compound of formula (II) defined herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0972] Additionally, the present invention provides a method for increasing apoptosis in vitro or in vivo, comprising the step of contacting cells with an effective amount of a compound of formula (II) defined herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Additionally, the present invention provides a method for increasing tumor cell apoptosis in a subject, comprising the step of administering to the subject an effective compound of formula (II) or a pharmaceutically acceptable salt thereof in an amount effective for increasing tumor cell apoptosis.

[0973] In some embodiments, PI3Kα is human PI3Kα. In some embodiments, PI3Kα is PIK3CA The gene has one or more point mutations. In some embodiments, the point mutations include a substitution at amino acid position 1047 of the human PI3Kα protein. In some embodiments, the substitution is H1047R.

[0974] When used as a pharmaceutical, the compound of formula (I) may be administered in the form of a pharmaceutical composition described herein, including a pharmaceutically acceptable salt thereof.

[0975] Numbered embodiments

[0976] 1. Compound of the following chemical formula (I)

[0977] (I)

[0978] or as a pharmaceutically acceptable salt thereof, in formula (I),

[0979] Z is N or CH, and

[0980] R 1is a quaternary to 10-membered heterocyclile optionally substituted with hydrogen, halogen, cyano, C3-C6 cycloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl; or (i) a C3-C6 cycloalkyl or (ii) a C1-C6 alkyl optionally substituted with a quaternary to 10-membered heterocyclile, and

[0981] R 2 is 1 to 4 independently selected R 2A A C6-C10 aryl arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-membered heteroaryls arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclils arbitrarily substituted with , 1 to 4 independently selected Rs 2A A C4-C10 cycloalkyl optionally substituted with , 1 to 4 independently selected R 2A 4- to 10-membered heterocyclyloxy oxy arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-won heteroaryloxy, -C(=O)NR arbitrarily substituted with A R C A C1-C6 alkoxyalkyl optionally substituted with -C(=O)NR A R C , C1-C6 alkoxy optionally substituted with a C4-C10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, and

[0982] R 2A are each

[0983] (i) Halogen;

[0984] (ii) Cyan;

[0985] (iii) Hydroxyl;

[0986] (iv) -NR A R B ;

[0987] (v) -C(=O)NR A R B ;

[0988] (vi) ;

[0989] (vii) -NHC(=O)R C ;

[0990] (viii) -C(=O)OR D ;

[0991] (ix) -SO2R D ;

[0992] (x) -NHSO2R D ;

[0993] (xi) -SO2NR D R E ;

[0994] (xii) NR A R B -NHC(=O)C1-C6 alkyl arbitrarily substituted with;

[0995] (xiii) C1-C6 haloalkyl;

[0996] (xiv) C1-C6 hydroxyalkyl;

[0997] (xv) Hydroxyl, Cyano, Halogen, -C(=O)NR A R B , -NR A R B , a C1-C6 alkyl optionally substituted with a hydroxyl, and a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclil optionally substituted with a hydroxyl or a C1-C6 alkyl;

[0998] (xvi) hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B4- to 10-membered heterocyclils optionally substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with , and C1-C6 alkoxy or hydroxyl optionally substituted with hydroxyl;

[0999] (xvii) Hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl;

[1000] (xviii) -NR A R B , or a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl;

[1001] (xix) hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or a C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl; and

[1002] (xx) Independently selected from 4- to 10 heterocyclyloxy groups optionally substituted with hydroxyl, cyano, halogen, or C1-C6 alkyl groups optionally substituted with hydroxyl, and

[1003] R A and R B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R A and RB They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[1004] R C are C3-C6 cycloalkyl and -C(=O)NHR, respectively. Y1 , and -NR A R B Independently selected from C1-C6 alkyl or C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 hydroxyalkyl, and

[1005] R D and R E are hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and oxo, respectively, or -NR A R B Independently selected from C1-C6 alkyls arbitrarily substituted with,

[1006] R 3A and R 3B are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R 3A and R 3B They form quaternary to octavalent heterocyclil groups together with the carbon and nitrogen atoms to which they are respectively attached, and

[1007] R 4 is hydrogen, a halogen, a C1-C6 alkyl, or an acrylamido, and

[1008] R 5 -NR 5A R 5B , -NR 5A C(=O)R 5B or -C(=O)NR 5A R 5B And,

[1009] R 5A and R 5Bis independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl, and

[1010] R 6 is hydrogen, a halogen, or a C1-C6 alkyl, and

[1011] X is a bond, CH2, CH(CH3), C(CH3)2 or And,

[1012] W is NR 3B or O and,

[1013] Y is a phenyl, naphthyl, or 5- to 10-membered heteroaryl, wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryls are independently selected from 1 to 3 Rs. Y or It is arbitrarily and independently substituted as, and * is L 1 This indicates that it is connected to the remaining part of the compound of this chemical formula (I),

[1014] R Y are respectively halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -(CH2) n -C(=O)R F , -(CH2) n -NHC(=O)R F , -(CH2) n -NHC(=O)OR F , -C(=O)C(=O)NHR F , -CO2R G , -(CH2) n -SO2NR H R I , -(CH2) n -NHSO2R J , -(CH2) n -S(=O)(=NR H )R J , -(CH2) n -SO2R J , -(CH2) n -C(=O)NR H R I , -(CH2) n-C(=O)NR H OR I and independently selected from C1-C6 haloalkyls optionally substituted with hydroxyl, and

[1015] R F Each is independently selected from C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl optionally substituted with C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and

[1016] R G Each is independently selected from hydrogen, C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and

[1017] R H and R I are hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2) n -C(=O)NH2, -(CH2) n -SO2NH2, -(CH2) n -SO2(C1-C6 alkyl), hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl and -C(=O)NR K1 R K2 Independently selected from C1-C6 alkyls optionally substituted with 1 to 2 independently selected substituents, or R H and R I They form a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and

[1018] R J is a C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, and

[1019] R K1 and R K2Each is independently hydrogen or a C1-C6 alkyl, and

[1020] Ring A is phenyl, 4- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C4-C10 cycloalkyl, and

[1021] L 1 Silver bond, C1-C6 alkoxylene, -(CH2) n -NHC(=O)-, -C(=O)NH-(CH2) n -, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NR G )-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or a C1-C6 alkylene optionally substituted with an oxo, and

[1022] R Y1 ≡ cyano, hydroxyl, halogen, -C(=O)R, respectively. F , -NHC(=O)R F , -CO2R G , -SO2NR H R I , -NHSO2R J , -S(=O)(=NR H )R J , -SO2(C1-C6 alkyl), -C(=O)NR H R I , 4~6 won heteroaryl, R Y2 C1-C6 alkoxy, C1-C6 haloalkyl, R optionally substituted with Y2 Independently selected from C1-C6 alkyl and hydroxyl optionally substituted with , or 4- to 6-membered heterocyclies optionally substituted with C1-C6 alkyl, and

[1023] R Y2 is hydroxyl, -NR H R I , -C(=O)NR H R I or -SO2NR H R I And,

[1024] n is 0, 1, or 2, and

[1025] A compound where z is 0, 1, 2, or 3.

[1026] 2. A compound of Embodiment 1, wherein Z is CH.

[1027] 3. A compound of Embodiment 1, wherein Z is N.

[1028] 4. In any one of embodiments 1 to 3, R 1 A compound that is hydrogen.

[1029] 5. In any one of embodiments 1 to 3, R 1 It is a halogen compound.

[1030] 6. In any one of embodiments 1 to 3, R 1 Cyanoin, a compound.

[1031] 7. In any one of embodiments 1 to 3, R 1 A compound that is a C3-C6 cycloalkyl.

[1032] 8. In any one of embodiments 1 to 3, R 1 A compound that is a C1-C6 alkyl or 4- to 10-membered heterocyclile optionally substituted with a C3-C6 cycloalkyl.

[1033] 9. In any one of embodiments 1 to 3 or 8, R 1 A compound that is a C1-C6 alkyl or 4- to 10-membered heterocyclile substituted with a C3-C6 cycloalkyl.

[1034] 10. In any one of embodiments 1 to 3 or 8, R 1 A compound that is a C1-C6 alkyl.

[1035] 11. In any one of embodiments 1 to 3, 8 or 10, R 1 It is methyl, a compound.

[1036] 12. In any one of embodiments 1 to 3, R 1A compound that is a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl group.

[1037] 13. In any one of embodiments 1 to 3, R 1 A compound that is a C1-C6 thioalkyl.

[1038] 14. In any one of embodiments 1 to 3, R 1 A compound that is a C1-C6 haloalkyl.

[1039] 15. In any one of embodiments 1 to 3, R 1 C1-C6 alkoxyne, a compound.

[1040] 16. In any one of embodiments 1 to 3, R 1 A compound that is a C1-C6 alkoxyalkyl.

[1041] 17. In any one of embodiments 1 to 16, R 2 is 1 to 4 independently selected R 2A A C6-C10 aryl compound arbitrarily substituted with

[1042] 18. In any one of embodiments 1 to 16 or 17, R 2 is 1 to 4 independently selected R 2A A C6-C10 aryl compound arbitrarily substituted with

[1043] 19. In any one of embodiments 1 to 16 or 17, R 2 is a C6-C10 aryl compound.

[1044] 20. In any one of embodiments 1 to 18, R 2 is 1 to 4 independently selected R 2A A compound of phenyl phosphate arbitrarily substituted with .

[1045] 21. In any one of embodiments 1 to 18 or 20, R 2 is 1 to 4 independently selected R 2AA compound of phenyl substituted with

[1046] 22. In any one of embodiments 1 to 16 or 20, R 2 is phenyl, a compound.

[1047] 23. In any one of embodiments 1 to 16, R 2 is 1 to 4 independently selected R 2A A compound that is a 5- to 10-membered heteroaryl arbitrarily substituted with .

[1048] 24. In any one of embodiments 1 to 16, R 2 is 1 to 4 independently selected R 2A A compound that is a 5- to 10-membered heteroaryl substituted with .

[1049] 25. In any one of embodiments 1 to 16, R 2 is a compound that is a 5- to 10-won heteroaryl.

[1050] 26. In any one of embodiments 1 to 16, R 2 is 1 to 3 independently selected R 2A A compound that is a 4- to 10-membered heterocyclile arbitrarily substituted with .

[1051] 27. In any one of embodiments 1 to 16, R 2 is 1 to 3 independently selected R 2A A compound that is a 4- to 10-membered heterocyclile substituted with .

[1052] 28. In any one of embodiments 1 to 16, R 2 is a compound that is a 4- to 10-membered heterocyclile.

[1053] 29. In any one of embodiments 1 to 16, R 2 is 1 to 3 independently selected R 2A A compound that is a C4-C10 cycloalkyl alkyl arbitrarily substituted with

[1054] 30. In any one of embodiments 1 to 16, R 2 is 1 to 3 independently selected R 2A A compound that is a C4-C10 cycloalkyl substituted with

[1055] 31. In any one of embodiments 1 to 16, R 2 is a compound that is a C4-C10 cycloalkyl.

[1056] 32. In any one of embodiments 1 to 16, R 2 is 1 to 4 independently selected R 2A 4- to 10-membered heterocyclyloxyne compounds arbitrarily substituted with .

[1057] 33. In any one of embodiments 1 to 16, R 2 is 1 to 4 independently selected R 2A 4- to 10-membered heterocyclyloxyne substituted with , compound.

[1058] 34. In any one of embodiments 1 to 16, R 2 is a 4- to 10-won heterocyclyloxyne compound.

[1059] 35. In any one of embodiments 1 to 16, R 2 is 1 to 4 independently selected R 2A 5- to 10-membered heteroaryloxyne arbitrarily substituted with , a compound.

[1060] 36. In any one of embodiments 1 to 16, R 2 is 1 to 4 independently selected R 2A 5- to 10-membered heteroaryloxyne substituted with, compound.

[1061] 37. In any one of embodiments 1 to 16, R 2 is a 5-10 won heteroaryloxyin, compound.

[1062] 38. In any one of embodiments 1 to 16, R 2 is -C(=O)NRA R C , C4-C10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl or C1-C6 alkoxyne optionally substituted with phenyl, compound.

[1063] 39. In any one of embodiments 1 to 16 or 38, R 2 is -C(=O)NR A R C , C4-C10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl or C1-C6 alkoxyne substituted with phenyl, compound.

[1064] 40. In any one of embodiments 1 to 16 or 38, R 2 is a C1-C6 alkoxyne, a compound.

[1065] 41. In any one of embodiments 1 to 16, R 2 is -C(=O)NR A R C A compound that is a C1-C6 alkoxyalkyl alkyl arbitrarily substituted with .

[1066] 42. In any one of embodiments 1 to 16, R 2 is -C(=O)NR A R C A compound that is a C1-C6 alkoxyalkyl substituted with

[1067] 43. In any one of embodiments 1 to 16, R 2 is a compound that is a C1-C6 alkoxyalkyl.

[1068] 44. In any one of embodiments 1 to 43, 1, 2, 3, or 4 Rs 2A is a compound that is independently a halogen.

[1069] 45. In any one of embodiments 1 to 44, 1, 2, 3, or 4 Rs 2A is independently cyanoin, a compound.

[1070] 46. ​​In any one of embodiments 1 to 45, 1, 2, 3, or 4 Rs 2A A compound that is independently hydroxyl.

[1071] 47. In any one of embodiments 1 to 46, 1, 2, 3, or 4 Rs 2A is independently -NR A R B Phosphorus, compound.

[1072] 48. In any one of embodiments 1 to 47, 1, 2, 3, or 4 Rs 2A is independently -C(=O)NR A R B Phosphorus, compound.

[1073] 49. In any one of embodiments 1 to 48, 1, 2, 3, or 4 Rs 2A is independently Phosphorus, compound.

[1074] 50. In any one of embodiments 1 to 49, 1, 2, 3, or 4 Rs 2A is independently -NHC(=O)R C Phosphorus, compound.

[1075] 51. In any one of embodiments 1 to 50, 1, 2, 3, or 4 Rs 2A -C(=O)OR independently D Phosphorus, compound.

[1076] 52. In any one of embodiments 1 to 51, 1, 2, 3, or 4 Rs 2A is independently -SO2R D Phosphorus, compound.

[1077] 53. In any one of embodiments 1 to 52, 1, 2, 3, or 4 Rs 2A is independently -NHSO2R D Phosphorus, compound.

[1078] 54. In any one of embodiments 1 to 53, 1, 2, 3, or 4 Rs 2A is independently -SO2NR D R E Phosphorus, compound.

[1079] 55. In any one of embodiments 1 to 54, 1, 2, 3, or 4 Rs 2A is independently NR A R B A compound that is an -NHC(=O)C1-C6 alkyl alkyl arbitrarily substituted with .

[1080] 56. In any one of embodiments 1 to 55, 1, 2, 3, or 4 Rs 2A is independently NR A R B A compound that is a -NHC(=O)C1-C6 alkyl substituted with

[1081] 57. In any one of embodiments 1 to 56, 1, 2, 3, or 4 Rs 2A is a compound that is independently a C1-C6 haloalkyl.

[1082] 58. In any one of embodiments 1 to 57, 1, 2, 3, or 4 Rs 2A is a compound that is independently a C1-C6 hydroxyalkyl.

[1083] 59. In any one of embodiments 1 to 58, 1, 2, 3, or 4 Rs 2A is independently a C1-C6 alkyl, halogen, or -C(=O)NR optionally substituted with hydroxyl, cyano, or hydroxyl. A R B , -NR A R B A compound that is a 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from 4- to 10-membered heterocyclils optionally substituted with hydroxyl or C1-C6 alkyl groups.

[1084] 60. In any one of embodiments 1 to 59, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, cyano, C1-C6 alkyl, halogen, -C(=O)NR A R B , -NR A R B A compound that is a 5- to 10-membered heteroaryl substituted with 1 to 3 substituents independently selected from 4- to 10-membered heterocyclies optionally substituted with hydroxyl or C1-C6 alkyl groups.

[1085] 61. In any one of embodiments 1 to 60, 1, 2, 3, or 4 Rs 2A is a compound that is independently a 5- to 10-membered heteroaryl.

[1086] 62. In any one of embodiments 1 to 61, 1, 2, 3, or 4 Rs 2A are independently hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B A compound that is a 4- to 10-membered heterocyclile optionally substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl optionally substituted with -NHC(=O)C1-C6 alkyl and C1-C6 alkoxy or hydroxyl optionally substituted with C1-C6 alkyl.

[1087] 63. In any one of embodiments 1 to 62, 1, 2, 3, or 4 Rs 2A are independently hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NRA R B , -NR A R B , -NR A R B A compound that is a 4- to 10-membered heterocyclile substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl optionally substituted with hydroxyl.

[1088] 64. In any one of embodiments 1 to 63, 1, 2, 3, or 4 Rs 2A are independently hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B A compound that is a 4- to 10-membered heterocyclile substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl substituted with , C1-C6 alkoxy or hydroxyl substituted C1-C6 alkyl.

[1089] 65. In any one of embodiments 1 to 64, 1, 2, 3, or 4 Rs 2A are independently hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NHC(=O)C1-C6 alkyl and a compound that is a 4- to 10-membered heterocyclile substituted with 1 to 3 substituents independently selected from C1-C6 alkyl.

[1090] 66. In any one of embodiments 1 to 62, 1, 2, 3, or 4 Rs 2A A compound that is independently a 4- to 10-membered heterocyclile.

[1091] 67. In any one of embodiments 1 to 66, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or a compound that is a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl.

[1092] 68. In any one of embodiments 1 to 67, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy, and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or a compound that is a C1-C6 alkyl substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl.

[1093] 69. In any one of embodiments 1 to 68, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy, and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR AR B or a compound that is a C1-C6 alkyl substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile substituted with a -C(=O)C3-C6 cycloalkyl.

[1094] 70. In any one of embodiments 1 to 69, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, oxo, -NR A R B , -C(=O)NR A R B A compound that is a C1-C6 alkyl substituted with 1 to 3 substituents independently selected from 4- to 10-membered heterocyclils.

[1095] 71. In any one of embodiments 1 to 67, 1, 2, 3, or 4 Rs 2A is a compound that is independently a C1-C6 alkyl.

[1096] 72. In any one of embodiments 1 to 71, 1, 2, 3, or 4 Rs 2A is independently -NR A R B A compound of a C1-C6 alkoxyne, optionally substituted with a 4- to 10-membered heterocycline optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[1097] 73. In any one of embodiments 1 to 72, 1, 2, 3, or 4 Rs 2A is independently -NR A R B A compound of a C1-C6 alkoxyne substituted with a 4- to 10-membered heterocycline optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[1098] 74. In any one of embodiments 1 to 73, 1, 2, 3, or 4 Rs 2A is independently -NR A RB A compound of a C1-C6 alkoxyne substituted with a 4- to 10-membered heterocyclile substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[1099] 75. In any one of embodiments 1 to 73, 1, 2, 3, or 4 Rs 2A is independently -NR A R B A compound of a C1-C6 alkoxyne substituted with a 4- to 10-membered heterocyclile.

[1100] 76. In any one of embodiments 1 to 72, 1, 2, 3, or 4 Rs 2A is an independently C1-C6 alkoxyne, a compound.

[1101] 77. In any one of embodiments 1 to 76, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D , or a compound that is a C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl.

[1102] 78. In any one of embodiments 1 to 77, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D A compound that is a C3-C6 cycloalkyl substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl.

[1103] 79. In any one of embodiments 1 to 78, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D, or a compound which is a C3-C6 cycloalkyl substituted with a 4- to 10-membered heterocyclile substituted with a C1-C6 alkyl.

[1104] 80. In any one of embodiments 1 to 79, 1, 2, 3, or 4 Rs 2A is independently hydroxyl, -C(=O)NR A R B , -C(=N)OR D or a compound that is a C3-C6 cycloalkyl substituted with a 4- to 10-membered heterocyclile.

[1105] 81. In any one of embodiments 1 to 77, 1, 2, 3, or 4 Rs 2A is a compound that is independently a C3-C6 cycloalkyl.

[1106] 82. A compound in any one of embodiments 1 to 81, wherein X is a bond.

[1107] 83. A compound in any one of embodiments 1 to 81, wherein X is CH2.

[1108] 84. A compound in any one of embodiments 1 to 81, wherein X is CH(CH3).

[1109] 85. A compound in any one of embodiments 1 to 81, wherein X is C(CH3)2.

[1110] 86. In any one of embodiments 1 to 81, X is Phosphorus, compound.

[1111] 87. A compound in any one of embodiments 1 to 86, wherein W is O.

[1112] 88. In any one of embodiments 1 to 87, R 3A is a compound that is hydrogen.

[1113] 89. In any one of embodiments 1 to 87, R 3A is a compound that is a C1-C6 alkyl.

[1114] 90. In any one of embodiments 1 to 87 or 89, R 3A is a methyl compound.

[1115] 91. In any one of embodiments 1 to 87, R 3A is a C1-C6 alkoxyne, a compound.

[1116] 92. In any one of embodiments 1 to 87, R 3A is a compound that is a C1-C6 haloalkyl.

[1117] 93. In any one of embodiments 1 to 86, W is NR 3B Phosphorus, compound.

[1118] 94. In any one of embodiments 1 to 86 or 93, R 3A and R 3B One of them is hydrogen and R 3A and R 3B The remaining one is a compound that is a C1-C6 alkyl.

[1119] 95. In any one of embodiments 1 to 86 or 93, R 3A and R 3B One of them is hydrogen and R 3A and R 3B The remaining one is methyl, a compound.

[1120] 96. In any one of embodiments 1 to 86 or 93, R 3A and R 3B are compounds that are hydrogen, respectively.

[1121] 97. In any one of embodiments 1 to 86 or 93, R 3A and R 3B Compounds, each being an independently selected C1-C6 alkyl.

[1122] 98. In any one of embodiments 1 to 86, 93 or 97, R 3A and R 3B are methyl, a compound, respectively.

[1123] 99. In any one of embodiments 1 to 86 or 93, R 3A and R 3B One of them is hydrogen and R 3A and R 3B The remaining one is a C1-C6 alkoxyne, a compound.

[1124] 100. In any one of embodiments 1 to 86 or 93, R 3A and R 3B One of them is a C1-C6 alkyl and R 3A and R 3B The remaining one is a C1-C6 alkoxyne, a compound.

[1125] 101. In any one of embodiments 1 to 86 or 93, R 3A and R 3B are C1-C6 alkoxyne compounds, respectively.

[1126] 102. In any one of embodiments 1 to 86 or 93, R 3A and R 3B One of them is hydrogen and R 3A and R 3B A compound in which the remaining one is a C1-C6 haloalkyl.

[1127] 103. In any one of embodiments 1 to 86 or 93, R 3A and R 3B One of them is a C1-C6 alkyl and R 3A and R 3B A compound in which the remaining one is a C1-C6 haloalkyl.

[1128] 104. In any one of embodiments 1 to 86 or 93, R 3A and R 3B Compounds, each being a C1-C6 haloalkyl.

[1129] 105. In any one of embodiments 1 to 86 or 93, R 3A and R 3BA compound in which they each form a 4- to 8-membered heterocyclile group together with the carbon and nitrogen atoms to which they are attached.

[1130] 106. A compound in any one of embodiments 1 to 105, wherein Y is an unsubstituted phenyl.

[1131] 107. A compound in any one of embodiments 1 to 105, wherein Y is unsubstituted naphthyl.

[1132] 108. A compound in any one of embodiments 1 to 105, wherein Y is an unsubstituted 5- to 10-membered heteroaryl.

[1133] 109. In any one of embodiments 1 to 105, Y is one to three independently selected Rs Y A compound of phenyl phosphate arbitrarily substituted with .

[1134] 110. In any one of embodiments 1 to 105, Y is one to three independently selected Rs Y A compound of naphthyl arbitrarily substituted with .

[1135] 111. In any one of embodiments 1 to 105, Y is one to three independently selected Rs Y A compound that is a 5- to 10-membered heteroaryl arbitrarily substituted with .

[1136] 112. In any one of embodiments 1 to 105 or 109 to 111, 1, 2, or 3 Rs Y is a compound that is independently a halogen.

[1137] 113. In any one of embodiments 1 to 105 or 109 to 111, 1, 2, or 3 Rs Y is a compound that is hydroxyl.

[1138] 114. In any one of embodiments 1 to 105 or 109 to 113, 1, 2, or 3 Rs Y is cyanoin, a compound.

[1139] 115. In any one of embodiments 1 to 105 or 109 to 114, 1, 2, or 3 Rs Y is a compound that is a C1-C6 alkyl.

[1140] 116. In any one of embodiments 1 to 105 or 109 to 115, 1, 2, or 3 Rs Y A compound that is an independently optionally substituted C1-C6 haloalkyl.

[1141] 117. In any one of embodiments 1 to 105 or 109 to 116, 1, 2, or 3 Rs Y is an independently C1-C6 alkoxyne, a compound.

[1142] 118. In any one of embodiments 1 to 105 or 109 to 117, 1, 2, or 3 Rs Y is an independently C1-C6 haloalkoxy, compound.

[1143] 119. In any one of embodiments 1 to 105 or 109 to 118, 1, 2, or 3 Rs Y is a compound that is independently a C1-C6 hydroxyalkyl.

[1144] 120. In any one of embodiments 1 to 105 or 109 to 119, 1, 2, or 3 Rs Y -(CH2) independently n -NHC(=O)R F Phosphorus, compound.

[1145] 121. In any one of embodiments 1 to 105 or 109 to 120, 1, 2, or 3 Rs Y -(CH2) independently n -C(=O)R F Phosphorus, compound.

[1146] 122. In any one of embodiments 1 to 105 or 109 to 121, 1, 2, or 3 Rs Y is independently -CO2R G Phosphorus, compound.

[1147] 123. In any one of embodiments 1 to 105 or 109 to 122, 1, 2, or 3 Rs Y -(CH2) independently n -SO2NR H R I Phosphorus, compound.

[1148] 124. In any one of embodiments 1 to 105 or 109 to 123, 1, 2, or 3 Rs Y -(CH2) independently n -NHSO2R J Phosphorus, compound.

[1149] 125. In any one of embodiments 1 to 105 or 109 to 124, 1, 2, or 3 Rs Y -(CH2) independently n -S(=O)(=NR H )R J Phosphorus, compound.

[1150] 126. In any one of embodiments 1 to 105 or 109 to 125, 1, 2, or 3 Rs Y -(CH2) independently n -SO2R J Phosphorus, compound.

[1151] 127. In any one of embodiments 1 to 105 or 109 to 126, 1, 2, or 3 Rs Y -(CH2) independently n -C(=O)NR H R I Phosphorus, compound.

[1152] 128. In any one of embodiments 1 to 105 or 109 to 126, 1, 2, or 3 RsY -(CH2) independently n -C(=O)NR H OR I Phosphorus, compound.

[1153] 129. In any one of embodiments 1 to 105 or 109 to 127, 1, 2, or 3 Rs Y is a compound that is independently a C1-C6 alkyl.

[1154] 130. In any one of embodiments 1 to 105, Y is A phenyl substituted with , where * is L 1 A compound that indicates being connected to the rest of the compound of this chemical formula (I).

[1155] 131. In any one of embodiments 1 to 105, Y is Naphthyl substituted with, where * is L 1 A compound that indicates being connected to the rest of the compound of this chemical formula (I).

[1156] 132. In any one of embodiments 1 to 105, Y is A 5- to 10-membered heteroaryl substituted with , where * is L 1 A compound that indicates being connected to the rest of the compound of this chemical formula (I).

[1157] 133. In any one of embodiments 1 to 105 or 130 to 132, L 1 A compound that is a bond.

[1158] 134. In any one of embodiments 1 to 105 or 130 to 132, L 1 is a compound that is a C1-C6 alkoxylene.

[1159] 135. In any one of embodiments 1 to 105 or 130 to 132, L 1 -(CH2) n -NHC(=O)-, compound.

[1160] 136. In any one of embodiments 1 to 105 or 130 to 132, L 1 -C(=O)NH-(CH2) n - Phosphorus, compound.

[1161] 137. In any one of embodiments 1 to 105 or 130 to 132, L 1 A compound that is -CO2-.

[1162] 138. In any one of embodiments 1 to 105 or 130 to 132, L 1 A compound containing -SO2-.

[1163] 139. In any one of embodiments 1 to 105 or 130 to 132, L 1 A compound that is -NHSO2- or -SO2NH-.

[1164] 140. In any one of embodiments 1 to 105 or 130 to 132, L 1 -S(=O)(=NR G )-phosphorus, compound.

[1165] 141. In any one of embodiments 1 to 105 or 130 to 132, L 1 A compound with -SO2(C1-C6 alkylene)-phosphorus.

[1166] 142. In any one of embodiments 1 to 105 or 130 to 132, L 1 A compound that is -C(=O)C(=O)NH-.

[1167] 143. In any one of embodiments 1 to 105 or 130 to 132, L 1 A compound that is a C1-C6 alkylene arbitrarily substituted with an oxo.

[1168] 144. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is independently cyano, a compound.

[1169] 145. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 A compound that is independently hydroxyl.

[1170] 146. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is a compound that is independently a halogen.

[1171] 147. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is independently -C(=O)R F Phosphorus, compound.

[1172] 148. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is independently -NHC(=O)R F Phosphorus, compound.

[1173] 149. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is independently -CO2R G Phosphorus, compound.

[1174] 150. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is independently -SO2NR H R I Phosphorus, compound.

[1175] 151. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is independently -NHSO2R J Phosphorus, compound.

[1176] 152. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is independently -S(=O)(=NR H )R F Phosphorus, compound.

[1177] 153. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 A compound that is independently -SO2(C1-C6 alkyl).

[1178] 154. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is independently -C(=O)NR H R I Phosphorus, compound.

[1179] 155. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 A compound that is independently a 4- to 6-membered heteroaryl.

[1180] 156. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 R independently Y2 A C1-C6 alkoxy compound arbitrarily substituted with .

[1181] 157. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 is a compound that is independently a C1-C6 haloalkyl.

[1182] 158. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 R independently Y2 A compound that is a C1-C6 alkyl alkyl arbitrarily substituted with .

[1183] 159. In any one of embodiments 1 to 105 or 130 to 143, 1, 2, or 3 Rs Y1 A compound that is a quaternary to 6-membered heterocyclile independently optionally substituted with a hydroxyl or C1-C6 alkyl.

[1184] 160. A compound in any one of embodiments 1 to 105 or 130 to 159, wherein ring A is phenyl.

[1185] 161. A compound in any one of embodiments 1 to 105 or 130 to 159, wherein ring A is a quaternaryl to 10aryl heteroaryl.

[1186] 162. A compound in any one of embodiments 1 to 105 or 130 to 159, wherein ring A is a 4- to 10-membered heterocyclile.

[1187] 163. A compound in any one of embodiments 1 to 105 or 130 to 159, wherein ring A is a C4-C10 cycloalkyl.

[1188] 164. In any one of embodiments 1 to 163, R 4 is a compound that is hydrogen.

[1189] 165. In any one of embodiments 1 to 163, R 4 is a halogen, a compound.

[1190] 166. In any one of embodiments 1 to 163, R 4 is a compound that is a C1-C6 alkyl.

[1191] 167. In any one of embodiments 1 to 163, R 4 is acrylamidoin, a compound.

[1192] 168. In any one of embodiments 1 to 167, R 5 is a compound that is hydrogen.

[1193] 169. In any one of embodiments 1 to 167, R 5 is a halogen, a compound.

[1194] 170. In any one of embodiments 1 to 167, R 5 is a compound that is a C1-C6 alkyl.

[1195] 171. In any one of embodiments 1 to 167, R 5 is cyanoin, a compound.

[1196] 172. In any one of embodiments 1 to 167, R 5 is -NR 5A R 5B Phosphorus, compound.

[1197] 173. In any one of embodiments 1 to 167, R 5 is -C(=O)NR 5A R 5B Phosphorus, compound.

[1198] 174. In any one of embodiments 1 to 167, R 5 is -NR 5A C(=O)R 5B Phosphorus, compound.

[1199] 175. In any one of embodiments 1 to 167 or 172 to 174, R 5A and R 5B One of them is hydrogen and R 5A and R 5B A compound in which the remaining one is a C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.

[1200] 176. In any one of embodiments 1 to 167 or 172 to 174, R 5A and R 5B One of them is a C1-C6 alkyl and R 5A and R 5B A compound in which the remaining one is a C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl.

[1201] 177. In any one of embodiments 1 to 167 or 172 to 174, R 5A and R 5B are compounds that are hydrogen, respectively.

[1202] 178. In any one of embodiments 1 to 167 or 172 to 174, R 5A and R 5B Compounds, each being an independently selected C1-C6 alkyl.

[1203] 179. In any one of embodiments 1 to 178, R 6 is a compound that is hydrogen.

[1204] 180. In any one of embodiments 1 to 178, R 6 is a halogen, a compound.

[1205] 181. In any one of embodiments 1 to 178, R 6 is a compound that is a C1-C6 alkyl.

[1206] 182. In any one of embodiments 1 to 181, R A and R B A compound independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

[1207] 183. In any one of embodiments 1 to 182, R A and R B One of them is hydrogen and R A and R B A compound in which the remaining one is a hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or a C1-C6 alkyl optionally substituted with a hydroxyl or C1-C6 alkoxy.

[1208] 184. In any one of embodiments 1 to 182, R A and RB One of them is hydrogen and R A and R B A compound in which the remaining one is a hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or a C1-C6 alkyl substituted with a hydroxyl or C1-C6 alkoxy.

[1209] 185. In any one of embodiments 1 to 182, R A and R B One of them is hydrogen and R A and R B A compound in which the remaining one is a hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6 alkyl.

[1210] 186. In any one of embodiments 1 to 182, R A and R B A compound that forms a 4- to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, or -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached.

[1211] 187. In any one of embodiments 1 to 182 or 186, R A and R B A compound that forms a 4- to 10-membered heterocyclile substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, or -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached.

[1212] 188. In any one of embodiments 1 to 182 or 186, R A and R B A compound that forms a 4- to 10-membered heterocyclile together with the nitrogen atoms to which they are attached.

[1213] 189. In any one of embodiments 1 to 188, R C Each independently consists of C3-C6 cycloalkyl, -C(=O)NHRY1 , or -NR A R B A compound that is a C1-C6 alkyl substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl or a C1-C6 hydroxyalkyl.

[1214] 190. In any one of embodiments 1 to 188, R C Each independently consists of C3-C6 cycloalkyl, -C(=O)NHR Y1 , or -NR A R B A compound that is a C1-C6 alkyl substituted with a 4- to 10-membered heterocyclile substituted with a C1-C6 alkyl or a C1-C6 hydroxyalkyl.

[1215] 191 In any one of embodiments 1 to 188, R C Each independently consists of C3-C6 cycloalkyl, -C(=O)NHR Y1 , or -NR A R B A compound that is a C1-C6 alkyl substituted with a 4- to 10-membered heterocyclile.

[1216] 192. In any one of embodiments 1 to 188, R C Each independently consists of C3-C6 cycloalkyl, -C(=O)NHR Y1 or a compound that is a C1-C6 alkyl.

[1217] 193. In any one of embodiments 1 to 192, R D are, respectively, hydrogen, hydroxyl, or C1-C6 alkoxygen, compounds.

[1218] 194. In any one of embodiments 1 to 192, R D Compounds, each being a C1-C6 alkyl optionally substituted with phenyl or oxo.

[1219] 195. In any one of embodiments 1 to 194, R Eare, respectively, hydrogen, hydroxyl, or C1-C6 alkoxygen, compounds.

[1220] 196. In any one of embodiments 1 to 194, R E Compounds, each being a C1-C6 alkyl optionally substituted with phenyl or oxo.

[1221] 197. In any one of embodiments 1 to 196, R F A compound in which is a C1-C6 alkyl optionally substituted with a hydroxyl or -SO2(C1-C6 alkyl).

[1222] 198. In any one of embodiments 1 to 196, R F Compounds that are each a C3-C6 cycloalkyl, a 5- to 6-membered heteroaryl, or a 4- to 6-membered heterocyclyl.

[1223] 199. In any one of embodiments 1 to 198, R G Compounds, each being hydrogen, a C3-C6 cycloalkyl, or a C1-C6 alkyl optionally substituted with a hydroxyl or -SO2(C1-C6 alkyl).

[1224] 200. In any one of embodiments 1 to 198, R G Compounds that are each a 5- to 6-membered heteroaryl or a 4- to 6-membered heterocyclil.

[1225] 201. In any one of embodiments 1 to 200, R H and R I One of them is hydrogen, and R H and R I The remaining one of them is hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl, and -C(=O)NR K1 R K2 A compound that is a C1-C6 alkyl optionally substituted with a C1-C6 alkyl optionally substituted with one or two independently selected substituents.

[1226] 202. In any one of embodiments 1 to 200, R H and R I One of them is hydrogen and R H and R I A compound in which the remaining one is a C1-C6 alkoxy, C3-C6 cycloalkyl, or C2-C6 alkeneyl.

[1227] 203. In any one of embodiments 1 to 200, R H and R I are compounds that are hydrogen, respectively.

[1228] 204. In any one of embodiments 1 to 200, R H and R I are, respectively, hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl, and -C(=O)NR K1 R K2 A compound that is an independently selected C1-C6 alkyl, optionally substituted with one or two independently selected substituents, and optionally substituted with a C1-C6 alkyl.

[1229] 205. In any one of embodiments 1 to 200, R H and R I One of them is hydrogen and R H and R I The remaining one is -(CH2) n -C(=O)NH2, -(CH2) n -SO2NH2 or -(CH2) n -SO2(C1-C6 alkyl) compound.

[1230] 206. In any one of embodiments 1 to 200, R H and R I A compound that forms a 4- to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached.

[1231] 207. In any one of embodiments 1 to 206, R J is a compound that is a C1-C6 alkyl.

[1232] 208. In any one of embodiments 1 to 206, R J is a C1-C6 alkoxyne, a compound.

[1233] 209. In any one of embodiments 1 to 206, R J is a compound that is a C3-C6 cycloalkyl.

[1234] 210. A compound selected from the group consisting of the compounds of Table A or their pharmaceutically acceptable salts and the compounds of Table B or their pharmaceutically acceptable salts.

[1235] 211. A pharmaceutical composition comprising any one of embodiments 1 to 210, a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[1236] 212. A method for treating a subject requiring cancer treatment, comprising the step of administering to the subject a therapeutically effective amount of any one of the compounds of Embodiments 1 to 210, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 211.

[1237] 213. As a method of treating a subject requiring cancer treatment, (a) cancer is PIK3CA A method comprising: (a) determining that there is a dysregulation of the expression, activity, or level of a gene, PI3Kα protein, or any of these; and (b) administering to a subject a therapeutically effective amount of any one of the compounds of Examples 1 to 210, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Example 211.

[1238] 214. A method for treating PI3Kα-associated cancer in a subject, comprising the step of administering a therapeutically effective amount of any one of the compounds of Embodiments 1 to 210, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 211 to a subject confirmed or diagnosed to have PI3Kα-associated cancer.

[1239] 215. A method for inhibiting mutant PI3Kα activity in mammalian cells, comprising the step of contacting mammalian cells with an effective amount of any one of the compounds in Examples 1 to 210 or a pharmaceutically acceptable salt thereof.

[1240] Examples

[1241] Example 1: Preparation of Compound

[1242] A general method for preparing the compound of formula (I) is described in an exemplary manner and is intended to be illustrative rather than limiting. Therefore, it will be understood that conditions such as solvent selection, reaction temperature, volume, and reaction time may be changed as long as the desired compound is consistently produced. It will also be understood that many of the reagents provided in the following examples may be replaced with other suitable reagents. For example, refer to the literature [Smith & March, Advanced Organic Chemistry, 7th Ed. (2013)]. Such changes and modifications, including but not limited to those relating to the chemical structures, substituents, derivatives, intermediates, synthesis, formulations, and / or methods of use provided herein, may be made without departing from the spirit and scope of the invention.

[1243] The starting materials used for synthesis are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, and VWR Scientific. Nuclear Magnetic Resonance (NMR) analysis was performed using a Bruker AVANCE III HD (300 or 400) MHz spectrometer or a Bruker AVANCE NEO 400 MHz spectrometer with a suitable deuteration solvent. LCMS spectra were obtained on a Shimadzu LCMS-2020 by electrospray ionization in cation detection mode using a 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA detector, and LCMS 2020 MS detector.

[1244] Intermediate manufacturing:

[1245] Intermediate: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile

[1246]

[1247] Step 1: Synthesis of 5-bromo-3-chloro-7-methylquinoline-2(1H)-one.

[1248] In a three-necked flask equipped with a stirring bar, a condenser, and a nitrogen inlet, ethyl-2-chloroacetate (32 mL, 42 mmol) and 3-amino-5-bromo-4-tolualdehyde (3 g, 14 mmol) were charged in tetrahydrofuran (32 mL). The solution was cooled to -78 °C, and a 1.3 M THF solution of lithium bis(trimethylsilyl)azanide (3 equivalents, 393 mmol) was added in portions under a nitrogen atmosphere. The mixture was heated to room temperature until the reaction was considered complete. The mixture was poured into ice and water, the resulting slurry was extracted with ethyl acetate (2 x 30 mL), the suspension was washed with water (2 x 30 mL), and the solid was dried by vacuum concentration using ethyl acetate (50 mL). The slurry was resuspended in ethyl acetate (30 mL) and heated to 50 °C in a water bath. The solid was cooled under sonication, filtered using MTBE, and the cake was transferred and rinsed to obtain the title compound as a white solid (1.7 g, 44%). MS: 273.1 m / z (M+H + ). 1 H NMR (400 MHz, DMSO) δ 12.49 (s, 1H), 8.17 (s, 1H), 7.42 (s, 1H), 7.14 (s, 1H), 2.38 (s, 3H).

[1249] Step 2: Synthesis of 5-acetyl-3-chloro-7-methylquinoline-2(1H)-one.

[1250] 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (537 mg, 0.1 equivalent, 734 μmol) and tributyl(1-ethoxythenyl)stanneine (2.98 mL, 1.2 equivalent, 8.81 mmol) were charged into a suspension of 5-bromo-3-chloro-7-methyl-2-quinolinol (2 g, 7.34 mmol) in 1,4-dioxane (120 mL, 1.41 mol). Nitrogen was introduced into the suspension for 3 minutes, and the reaction mixture was heated to 110 °C in a heating block for 2 hours. The unrefined reaction mixture was filtered, the filtrate was concentrated, and the resulting solid was resuspended in MTBE / heptane (1:1, 100 mL). The resulting thin slurry was concentrated to approximately 40 mL under vacuum, and the obtained solid was filtered using heptane to separate and rinse the solid, yielding the intermediate 3-chloro-5-(1-ethoxyvinyl)-7-methylquinoline-2(1H)-one (1.4 g, 72%). MS: 264.1 m / z (M+H + ).

[1251] The intermediate 3-chloro-5-(1-ethoxyvinyl)-7-methylquinoline-2(1H)-one (1.4 g, 5.3 mmol) was resuspended in THF (30 mL) and a 3 N HCl aqueous solution (30 mL, 90 mmol) was added. The slurry was stirred at room temperature until the reaction was considered complete (about 1 hour). The solvent was concentrated, and the aqueous residue was extracted with ethyl acetate (2 x 200 mL). The resulting slurry was concentrated to about 100 mL, and a solution of potassium fluoride (1.28 g, 22 mmol) in water (100 mL) was added. The slurry was stirred at room temperature for 1 hour. The layer was allowed to settle, and the organic layer containing the slurry was separated and washed with water (2 x 50 mL). The solvent was vacuum concentrated and dried, then ethyl acetate (3 x 100 mL) was added, and the water was removed by evaporation through azeotropic distillation. Ethyl acetate (30 mL) was added to the resulting solid, and the mixture was heated in a water bath to 60 °C until a homogeneous slurry was obtained. The solid was cooled to room temperature under sonication and filtered, and the cake was washed with ethyl acetate to obtain the title compound as a light brown solid (1.2 g, 69%). MS: 236.1 m / z (M+H + ). 1 H NMR (400 MHz, DMSO) δ 12.44 (s, 1H), 8.71 (s, 1H), 7.71 (s, 1H), 7.33 (s, 1H), 2.61 (s, 3H), 2.45 (s, 3H).

[1252] Step 3: 5-acetyl-3-chloro-7-methylquinoline-2-yl trifluoromethanesulfonate.

[1253] A suspension of 5-acetyl-3-chloro-7-methylquinoline-2(1H)-one (0.3 g, 1.27 mmol) and pyridine (309 μL, 3.82 mmol) in DCM (12 mL) was loaded into a 40 mL vial equipped with a stirring rod and a diaphragm cap. The mixture was cooled to 0 °C, and trifluoro(trifluoromethyloxysulfonyl)methane (641 μL, 3 equivalents, 3.82 mmol) was loaded aliquot through a needle. After the addition was complete, the initial slurry was dissolved. The reaction mixture was stirred for an additional 10 minutes, and the reaction mixture was poured into an ice / saturated NaHCO3 mixture. The mixture was poured into a separatory funnel, and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL), the organic layers were combined, dried with sodium sulfate, filtered, and concentrated and dried to obtain the title product as a light purple solid (460 g, 98% yield). MS: 367.1 m / z (M+H + ). 1 H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 2.77 (s, 3H), 2.63 (s, 3H).

[1254] Step 4: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile.

[1255] 1-[3-chloro-7-methyl-2-(trifluoromethyloxy)-5-quinolyl]-1-ethanol (1 g, 2.45 mmol), zinc bis(cyanide) (345 mg, 1.2 equivalents, 2.94 mmol), tetrakis(triphenylphosphine)palladium (0) (283 mg, 0.1 equivalents, 245 μmol) and dimethylformamide (15 mL, 194 mmol) were loaded into a 40 mL vial equipped with a stirring rod and a diaphragm cap. Nitrogen was introduced into the mixture for 3 minutes, the vial was sealed, and the mixture was heated to 90 °C for 1 hour. The reaction mixture was cooled to room temperature and stirred for 1 hour. The obtained solid was filtered, washed with MTBE (10 mL), and air-dried to obtain the title compound as a light brown solid (556 mg, 92%). MS: 245.1 m / z (M+H + ). 1 H NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 2.77 (s, 3H), 2.63 (s, 3H).

[1256] Intermediate: 6-chloro-3-hydroxypyridine-2-sulfonamide

[1257]

[1258] Step 1 - Synthesis of 2-(benzylthio)-6-chloro-3-fluoropyridine:

[1259] BnSH (8.49 mL, 72.30 mmol, 1.2 equivalents) was added dropwise at 0 °C to a solution of KOH (4.11 g, 73.25 mmol, 1.2 equivalents) in EtOH (50 mL). After addition, 2,6-dichloro-3-fluoropyridine (10 g, 60.25 mmol, 1 equivalent) in EtOH (50 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 hours. Then, the reaction of the mixture was terminated with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The unrefined product was purified by silica gel chromatography (solvent gradient: 100% petroleum ether) to obtain the title compound (14 g, 91%) as a pink oil, and this 13 It was further confirmed by C-NMR (2D-NMR). 1 H NMR (400 MHz, CDCl3) δ 7.48 - 7.44 (m, 2H), 7.37 - 7.29 (m, 2H), 7.29 - 7.24 (m, 1H), 7.22 - 7.17 (m, 1H), 7.02 - 6.98 (m, 1H), 4.44 (s, 2H).

[1260] Step 2 - Synthesis of 6-chloro-3-fluoropyridine-2-sulfonamide:

[1261] AcOH (36.10 mL, 630.61 mmol, 8 equivalents) was added at 0 °C to a solution of 2-benzylsulfanyl-6-chloro-3-fluoropyridine (20 g, 78.83 mmol, 1 equivalent) in water (20 mL) and acetonitrile (200 mL). After addition, NCS (42.10 g, 315.30 mmol, 4 equivalents) was slowly added at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 hours. Water (50 mL) was added to the mixture, followed by extraction with DCM (3 x 100 mL). The combined organic layer was washed with brine (100 mL x 3) and dried with Na2SO4. The organic mixture was then 0 in ammonium hydroxide (80 mL, 623.19 mmol, 29 wt%, 8 equivalents) in THF (80 mL). o It was added at C. After addition, the reaction mixture was stirred at 0 °C for 10 minutes. Then, the reaction was terminated with water (100 mL) and the mixture was extracted with EtOAc (100 mL x 3). The combined organic layer was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The crude product was softened with DCM (50 mL), filtered, and the filter cake was vacuum concentrated to obtain the title compound (11 g, 66%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.14 - 8.09 (m, 1H), 7.97 (s, 2H), 7.92 - 7.88 (m, 1H).

[1262] Step 3 - Synthesis of 6-chloro-3-hydroxypyridine-2-sulfonamide:

[1263] KOH (26.64 g, 474.80 mmol, 10 equivalents) was added at room temperature to a solution of 6-chloro-3-fluoro-pyridine-2-sulfonamide (10 g, 47.48 mmol, 1 equivalent) in water (250 mL). After addition, the reaction mixture was stirred at 110 °C for 5 hours. After cooling to 0 °C, the pH was adjusted to approximately 4–5 using concentrated HCl (12 M). The mixture was DCM:i After extraction with -PrOH=3:1 (100 mL x 5), the combined organic layer was washed with brine (200 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated. The unrefined product was purified by silica gel chromatography (solvent gradient: 0–30% EtOAc in petroleum ether) to obtain the title compound (2.9 g, 29%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.23 (s, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.35 (s, 2H).

[1264] Example 1: ( R )-2-((1-(3-(isoindoline-2-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoic acid(compound 1)

[1265]

[1266] Step 1 - Synthesis of 3-(benzyloxy)-5-bromo-7-methylquinoline:

[1267] Aqueous NaOH (748 mg, 18.68 mmol, dissolved in 2 mL H2O) was added to a mixture of 2-amino-6-bromo-4-methylbenzaldehyde (2.0 g, 9.36 mmol) (prepared according to the procedure of WO202192525) and 2-benzyloxyacetaldehyde (1.68 g, 11.20 mmol, 1.56 mL) in EtOH (40 mL). The reaction vessel was sealed and stirred at 110 °C for 30 minutes under microwave. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to obtain the title compound (2.53 g, 83%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 2.4 Hz, 1H), 7.79 (s, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.46 - 7.40 (m, 2H), 7.34 - 7.28 (m, 1H), 5.33 (s, 2H), 2.47 (s, 3H). MS: m / z 328.0 (M+H + ).

[1268] Step 2 - Synthesis of 1-(3-(benzyloxy)-7-methylquinoline-5-yl)ethane-1-one:

[1269] A mixture of 3-(benzyloxy)-5-bromo-7-methylquinoline (2.53 g, 7.71 mmol), tributyl(1-ethoxyvinyl)stanneine (5.57 g, 15.42 mmol), and Pd(dppf)Cl2 (305 mg, 416 umol) in dioxane (20 mL) was stirred at 90 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, the reaction of the mixture was terminated with 50 mL of 10% KF aqueous solution and stirred for 30 minutes. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain an unpurified product (2.55 g) as a yellow solid. The crude product was dissolved in dioxane (20 mL), and then 1 M HCl (10 mL) was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filter cake was vacuum dried to obtain the title compound (1.34 g, 60%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 2.8 Hz, 1H), 8.61 (d, J = 2.8 Hz, 1H), 8.14 (s, 1H), 7.98 (s, 1H), 7.57 - 7.51 (m, 2H), 7.47 - 7.33 (m, 3H), 5.24 (s, 2H), 2.73 (s, 3H), 2.54 (s, 3H). MS: m / z 292.2 (M+H+ ).

[1270] Step 3 - Synthesis of 1-(3-(benzyloxy)-7-methylquinoline-5-yl)ethane-1-amine:

[1271] NaBH3CN (808 mg, 12.87 mmol) was added to a solution of 1-(3-(benzyloxy)-7-methylquinoline-5-yl)ethane-1-one (1.25 g, 4.29 mmol), NH4OAc (4.96 g, 64.35 mmol), and AcOH (257 mg, 4.29 mmol, 236 μL) in MeOH (40 mL). The reaction mixture was heated at 60 °C for 16 hours under an N2 atmosphere. It was heated to [temperature]. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL). The mixture was washed with saturated NaHCO3 solution (50 mL x 3) and brine (100 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated to obtain the title compound (1.15 g, unrefined) as a yellow solid requiring no further purification. MS: m / z 293.2 (M+H + ).

[1272] Step 4 - Synthesis of methyl 2-((1-(3-(benzyloxy)-7-methylquinoline-5-yl)ethyl)amino)benzoate:

[1273] A mixture of methyl 2-iodobenzoate (909 mg, 3.47 mmol), 1-(3-(benzyloxy)-7-methylquinoline-5-yl)ethane-1-amine (676 mg, 5.30 mmol), Pd2(dba)3 (113 mg, 123 μmol), Xantphos (143 mg, 247 μmol), and Cs2CO3 (2.26 g, 6.61 mmol) in dioxane (10 mL) under an N2 atmosphere. The mixture was heated to 110 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–20% EtOAc in petroleum ether) to obtain the title compound (820 mg, 83%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.70 (d, J= 2.4 Hz, 1H), 8.27 (d, J = 6.0 Hz, 1H), 8.05 (d, J = 2.4 Hz, 1H), 7.88 - 7.79 (m, 1H), 7.64 (s, 1H), 7.54 (d, J = 7.2 Hz, 2H), 7.43 - 7.31 (m, 4H), 7.22 - 7.16 (m, 1H), 6.59 - 6.51 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.50 - 5.41 (m, 1H), 5.39 - 5.30 (m, 2H), 3.85 (s, 3H), 2.37 (s, 3H), 1.54 (d, J = 6.8 Hz, 3H). MS: m / z 427.2 (M+H + ).

[1274] Step 5 - Synthesis of methyl 2-((1-(3-hydroxy-7-methylquinoline-5-yl)ethyl)amino)benzoate:

[1275] Carbon-supported Pd(OH)2 (400 mg, 20% Pd, 50% wet with water) was added to a solution of methyl 2-((1-(3-(benzyloxy)-7-methylquinoline-5-yl)ethyl)amino)benzoate (815 mg, 1.91 mmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 1 hour under an H2 atmosphere (15 psi). The reaction mixture was filtered through diatomite, and the filtrate was vacuum concentrated to obtain the title compound (160 mg, 25%) as a yellow solid requiring no further purification. MS: m / z 337.2 (M+H + ).

[1276] Step 6 - Synthesis of methyl 2-((1-(7-methyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate:

[1277] Pyridine (115 μL, 1.43 mmol) and Tf2O (201 mg, 713 μmol, 118 μL) were added to a solution of methyl 2-((1-(3-hydroxy-7-methylquinoline-5-yl)ethyl)amino)benzoate (160 mg, 476 μmol) in DCM (4 mL). The reactants were 0 oThe mixture was stirred at C for 1 hour. The reaction mixture was diluted with 20 mL of DCM, washed with 1 M HCl (10 mL), the organic layer was washed with NaHCO3 (10 mL x 2), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain the title compound (198 mg, 89%) as a yellow solid requiring no further purification. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 9.06 (s, 1H), 9.02 (s, 1H), 8.26 (d, J = 6.4 Hz, 1H), 7.92 - 7.78 (m, 2H), 7.56 (s, 1H), 7.26 - 7.16 (m, 1H), 6.64 - 6.52 (m, 1H), 6.43 (d, J = 8.4 Hz, 1H), 5.64 - 5.46 (m, 1H), 3.86 (s, 3H), 2.49 (s, 3H),1.59 (d, J = 6.4 Hz, 3H). MS: m / z 469.1 (M+H + ).

[1278] Step 7 - Synthesis of methyl 2-((1-(3-(isoindolin-2-yl)-7-methylquinolin-5-yl)ethyl)amino)benzoate:

[1279] A mixture of methyl 2-((1-(7-methyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate (198 mg, 423 μmol), isoindoline (76 mg, 634 μmol), Pd2(dba)3 (38 mg, 42 μmol), Xantphos (49 mg, 85 μmol), and Cs2CO3 (413 mg, 1.27 mmol) in dioxane (4 mL). The mixture was heated to 110 °C for 8 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–50% EtOAc in petroleum ether) to obtain the title compound (76 mg, 41%) as a white solid. MS: m / z 438.1 (M+H + ).

[1280] Step 8 - Synthesis of 2-((1-(3-(isoindolin-2-yl)-7-methylquinolin-5-yl)ethyl)amino)benzoic acid:

[1281] LiOH (42 mg, 1.75 mmol, dissolved in 0.2 mL H2O) was added to a solution of methyl 2-((1-(3-(isoindoline-2-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoate (76 mg, 174 μmol) in MeOH (2 mL) and THF (0.2 mL). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (45%–75% acetonitrile / 0.225% formic acid in water) to obtain the title compound (50 mg, 68%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.66 (d, J = 2.4 Hz, 1H), 8.59 - 8.49 (m, 1H), 7.84 - 7.75 (m, 1H), 7.56 (s, 1H), 7.49 - 7.40 (m, 3H), 7.38 - 7.32 (m, 2H), 7.29 (d, J = 1.2 Hz, 1H), 7.21 - 7.12 (m, 1H), 6.54 - 6.48 (m, 1H), 6.44 (d, J = 8.4 Hz, 1H), 5.48 - 5.31 (m, 1H), 4.87 - 4.75 (m, 4H), 2.37 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H). MS: m / z 424.2 (M+H + ).

[1282] Step 9 - ( R )-2-((1-(3-(isoindoline-2-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoic acid and ( S Synthesis of )-2-((1-(3-(isoindolin-2-yl)-7-methylquinolin-5-yl)ethyl)amino)benzoic acid:

[1283] 2-((1-(3-(isoindoline-2-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoic acid (50 mg, 118 μmol) was separated using chiral SFC [DAICEL CHIRALPAK AD (250 mm*30 mm, 10 µm); supercritical CO2 / EtOH+0.1 % NH3·H2O=60 / 40; 70 mL / min] ( R )-2-((1-(3-(isoindolin-2-yl)-7-methylquinolin-5-yl)ethyl)amino)benzoic acid (4 mg, 1st peak) and ( S )-2-((1-(3-(isoindoline-2-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoic acid (5 mg, 2nd peak) Both were obtained as white solids. The absolute stereoconfiguration was arbitrarily assigned to each enantiomer. (1st peak): 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.76 (s, 1H), 8.66 (d, J = 2.4 Hz, 1H), 8.58 - 8.47 (m, 1H), 7.85 - 7.76 (m, 1H), 7.56 (s, 1H), 7.47 - 7.40 (m, 3H), 7.38 - 7.33 (m, 2H), 7.29 (s, 1H), 7.20 - 7.13 (m, 1H), 6.56 - 6.49 (m, 1H), 6.45 (d, J = 8.4 Hz, 1H), 5.47 - 5.34 (m, 1H), 4.88 - 4.73 (m, 4H), 2.37 (s, 3H), 1.64 (d, J = 6.4 Hz, 3H). MS: m / z 424.1 (M+H + ).

[1284] Example 2: 2-((1-(7-methyl-3-(tetrahydro-2 H -pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid(compound 2)

[1285]

[1286] Step 1 - Methyl 2-((1-(3-(3,6-dihydro-2 H Synthesis of -pyran-4-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoate:

[1287] methyl 2-((1-(7-methyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate (270 mg, 576 μmol), 2-(3,6-dihydro- 2H A mixture of -pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabololene (242 mg, 1.15 mmol), Pd(PPh3)4 (66 mg, 58 μmol), and K2CO3 (239 mg, 1.41 mmol). The mixture was stirred at 110 °C for 8 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–33% EtOAc in petroleum ether) to obtain the title compound (231 mg, 98%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 9.09 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.87 - 7.79 (m, 1H), 7.69 (s, 1H), 7.40 (d, J = 1.2 Hz, 1H), 7.25 - 7.14 (m, 1H), 6.65 - 6.52 (m, 2H), 6.47 (d, J = 8.4 Hz, 1H), 5.63 - 5.51 (m, 1H), 4.30 (d, J = 2.8 Hz, 2H), 3.91 - 3.87 (m, 2H), 3.86 (s, 3H), 2.68 - 2.58 (m, 2H), 2.43 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m / z 403.1 (M+H + ).

[1288] Step 2 - Methyl 2-((1-(7-methyl-3-(tetrahydro-2 H Synthesis of -pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoate:

[1289] Methyl 2-((1-(3-(3,6-dihydro-2) in MeOH (10 mL) H Carbon-supported Pd(OH)2 (115 mg, 20% Pd, 50% wet with water) was added to a solution of pyran-4-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoate (231 mg, 547 μmol). The reaction mixture was stirred at room temperature for 1 hour under an H2 atmosphere (15 psi). The reaction mixture was filtered through diatomite, and the filtrate was vacuum concentrated to obtain the title compound (196 mg, 83%) as a yellow solid requiring no further purification. MS: m / z 405.1 (M+H + ).

[1290] Step 3 - 2-((1-(7-methyl-3-(tetrahydro-2 H Synthesis of -pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid:

[1291] Methyl 2-((1-(7-methyl-3-(tetrahydro-2) in MeOH (4 mL) and THF (0.4 mL) H LiOH (99 mg, 2.35 mmol, dissolved in H2O) was added to a solution of pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoate (196 mg, 470 μmol). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (25%–55% acetonitrile / 0.225% formic acid in water) to obtain the title compound (84 mg, 45%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.79 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.55 (s, 1H), 8.45 (d, J = 1.2 Hz, 1H), 7.84 - 7.76 (m, 1H), 7.66 (s, 1H), 7.38 (d, J= 1.2 Hz, 1H), 7.20 - 7.10 (m, 1H), 6.56 - 6.47 (m, 1H), 6.41 (d, J = 8.4 Hz, 1H), 5.54 - 5.44 (m, 1H), 4.04 - 3.97 (m, 2H), 3.54 - 3.45 (m, 2H), 3.09 - 2.99 (m, 1H), 2.42 (s, 3H), 1.92 - 1.79 (m, 4H), 1.59 (d, J = 6.4 Hz, 3H). MS: m / z 391.1 (M+H + ).

[1292] Examples 3A and 3B: ( R )-2-((1-(7-methyl-3-(tetrahydro-2 H -Pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid(compound 3) & ( S )-2-((1-(7-methyl-3-(tetrahydro-2 H -Pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid (compound 4):

[1293]

[1294] Step 1 - ( R )-2-((1-(7-methyl-3-(tetrahydro-2 H -pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid & ( S )-2-((1-(7-methyl-3-(tetrahydro-2 H Synthesis of -pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid:

[1295] 2-((1-(7-methyl-3-(tetrahydro-2 H -Pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid (80 mg, 197.78 μmol) was separated using chiral SFC [DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 µm); supercritical CO2 / EtOH+0.1 % NH3·H2O=60 / 40; 70 mL / min] ( R )-2-((1-(7-methyl-3-(tetrahydro-2 H -pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid (21 mg, 1st peak) and ( S )-2-((1-(7-methyl-3-(tetrahydro-2 H-pyran-4-yl)quinoline-5-yl)ethyl)amino)benzoic acid (16 mg, 2nd peak) Both were obtained as white solids. The absolute stereoconfiguration was arbitrarily assigned to each enantiomer. Example 3A (1st peak): 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.80 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.57 - 8.40 (m, 2H), 7.88 - 7.74 (m, 1H), 7.67 (s, 1H), 7.38 (s, 1H), 7.22 - 7.11 (m, 1H), 6.60 - 6.47 (m, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.49 (s, 1H), 4.09 - 3.93 (m, 2H), 3.58 - 3.44 (m, 2H), 3.10 - 2.97 (m, 1H), 2.42 (s, 3H), 1.91 - 1.77 (m, 4H), 1.59 (d, J = 6.8 Hz, 3H). MS: m / z 391.1 (M+H + ). Example 3B (Peak 2): 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.77 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.58 - 8.37 (m, 2H), 7.86 - 7.76 (m, 1H), 7.67 (s, 1H), 7.38 (s, 1H), 7.21 - 7.09 (m, 1H), 6.58 - 6.47 (m, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.49 (s, 1H), 4.06 - 3.94 (m, 2H), 3.56 - 3.42 (m, 2H), 3.10 - 2.99 (m, 1H), 2.42 (s, 3H), 1.93 - 1.78 (m, 4H), 1.59 (d, J = 6.8 Hz, 3H). MS: m / z 391.1 (M+H + ).

[1296] Example 4: 2-((1-(3-(4-fluorophenyl)-7-methylquinoline-5-yl)ethyl)amino)benzoic acid (compound 5)

[1297]

[1298] Step 1 - Synthesis of methyl 2-((1-(3-(4-fluorophenyl)-7-methylquinoline-5-yl)ethyl)amino)benzoate:

[1299] A mixture of methyl 2-((1-(7-methyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate (139 mg, 297 μmol), (4-fluorophenyl)boronic acid (83 mg, 593 μmol), Pd(PPh3)4 (34 mg, 30 μmol) and K2CO3 (123 mg, 890 mmol) in dioxane (3 mL) and H2O (0.1 mL). The mixture was stirred at 110 °C for 2 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–33% EtOAc in petroleum ether) to obtain the title compound (122 mg, 99%) as a white solid. MS: m / z 415.1 (M+H + ).

[1300] Step 2 - Synthesis of 2-((1-(3-(4-fluorophenyl)-7-methylquinoline-5-yl)ethyl)amino)benzoic acid:

[1301] LiOH (35 mg, 1.47 mmol, dissolved in 0.4 mL H2O) was added to a solution of methyl 2-((1-(3-(4-fluorophenyl)-7-methylquinoline-5-yl)ethyl)amino)benzoate (122 mg, 294 μmol) in MeOH (4 mL) and THF (0.4 mL). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (50%–80% acetonitrile / 0.225% formic acid in water) to obtain the title compound (21 mg, 18%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.78 (s, 1H), 9.21 (d, J= 2.0 Hz, 1H), 8.87 (d, J = 1.6 Hz, 1H), 8.50 (s, 1H), 8.03 - 7.95 (m, 2H), 7.86 - 7.79 (m, 1H), 7.74 (s, 1H), 7.46 - 7.36 (m, 3H), 7.22 - 7.12 (m, 1H), 6.57 - 6.44 (m, 2H), 5.73 - 5.59 (m, 1H), 2.45 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). MS: m / z 401.2 (M+H + ).

[1302] Example 5: 2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid (compound 6)

[1303]

[1304] Step 1 - Synthesis of 3-(benzyloxy)-5-bromo-2,7-dimethylquinoline:

[1305] NaOH (206 mg, 5.14 mmol) was added to a solution of 2-amino-6-bromo-4-methyl-benzaldehyde (550 mg, 2.54 mmol) and 1-benzyloxypropan-2-one (506 mg, 3.08 mmol) in EtOH (15 mL) and H2O (1 mL). The reaction vessel was sealed and stirred at 110 °C under microwave for 30 minutes. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified as a yellow solid by silica gel chromatography (880 mg, 78%). 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.72 (s, 2H), 7.66 (s, 1H), 7.59 - 7.53 (m, 2H), 7.47 - 7.41 (m, 2H), 7.39 - 7.35 (m, 1H), 5.34 (s, 2H), 2.61 (s, 3H), 2.46 (s, 3H). MS: m / z 342.0 (M+H + ).

[1306] Step 2 - Synthesis of 1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethane-1-one:

[1307] A mixture of 3-(benzyloxy)-5-bromo-2,7-dimethylquinoline (880 mg, 2.38 mmol), tributyl(1-ethoxyvinyl)stanneine (1.72 g, 4.77 mmol), and Pd(dppf)Cl2 (174 mg, 238 umol) in dioxane (10 mL) was stirred at 90 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, the reaction of the mixture was terminated with 30 mL of 10% KF aqueous solution and stirred for 30 minutes. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain an unpurified product (790 mg) as a yellow solid. The crude product was dissolved in dioxane (10 mL), and then aqueous HCl (1 M, 40 mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filter cake was vacuum dried to obtain the title compound (560 mg, 69%) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.56 (s, 1H), 8.08 (d, J = 1.6 Hz, 1H), 7.91 (s, 1H), 7.59 - 7.52 (m, 2H), 7.47 - 7.40 (m, 2H), 7.39 - 7.35 (m, 1H), 5.24 (s, 2H), 2.72 (s, 3H), 2.58 (s, 3H), 2.53 (s, 3H). MS: m / z 306.1 (M+H + ).

[1308] Step 3 - Synthesis of 1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethane-1-amine:

[1309] NaBH3CN (808 mg, 5.01 mmol) was added to a solution of 1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethane-1-one (560 mg, 1.67 mmol), NH4OAc (1.93 g, 25.05 mmol), and AcOH (100 mg, 1.67 mmol, 96 μL) in MeOH (10 mL). The reaction mixture was heated at 60 °C for 16 hours under an N2 atmosphere. It was heated to [temperature]. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL). The mixture was washed with a saturated NaHCO3 solution (50 mL) and brine (50 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was vacuum concentrated to obtain the title compound (960 mg, unpurified) as a yellow solid requiring no further purification. MS: m / z 307.1 (M+H + ).

[1310] Step 4 - Synthesis of methyl 2-((1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1311] A mixture of methyl 2-iodobenzoate (638 mg, 2.44 mmol), 1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethane-1-amine (676 mg, 5.30 mmol), Pd2(dba)3 (84 mg, 92 μmol), Xantphos (188 mg, 324 μmol), and Cs2CO3 (1.58 g, 4.87 mmol) in dioxane (2 mL). The mixture was stirred at 110 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–20% EtOAc in petroleum ether) to obtain the title compound (330 mg, 40%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.25 (d, J= 6.0 Hz, 1H), 7.92 (s, 1H), 7.84 - 7.80 (m, 1H), 7.56 - 7.51 (m, 4H), 7.43 - 7.39 (m, 2H), 7.36 - 7.32 (m, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.21 - 7.15 (m, 1H), 6.60 - 6.49 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.38 - 5.30 (m, 2H), 3.85 (s, 3H), 2.58 (s, 3H), 2.36 (s, 3H), 1.52 (d, J = 6.4 Hz, 3H). MS: m / z 441.3 (M+H + ).

[1312] Step 5 - Synthesis of methyl 2-((1-(3-hydroxy-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1313] Carbon-supported Pd(OH)2 (200 mg, 20% Pd, 50% wet with water) was added to a solution of methyl 2-((1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (330 mg, 749 μmol) in MeOH (10 mL). The reaction mixture was stirred at room temperature for 1 hour under an H2 atmosphere (15 psi). The reaction mixture was filtered through diatomite, and the filtrate was vacuum concentrated to obtain the title compound (209 mg, 80%) as a yellow solid requiring no further purification. MS: m / z 351.2 (M+H + ).

[1314] Step 6 - Synthesis of methyl 2-((1-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate:

[1315] Tf2O (252 mg, 895 μmol) was added to a solution of methyl 2-((1-(3-hydroxy-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (209 mg, 596 μmol) and pyridine (144 μL, 1.79 mmol) in DCM (4 mL). The reaction mixture was stirred at 0 °C for 1 hour. The reaction mixture was diluted with DCM (30 mL), washed with 1 M HCl (10 mL), the organic layer was washed with NaHCO3 (10 mL x 2), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain the title compound (280 mg, 97%) as a yellow solid requiring no further purification. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.79 (s, 1H), 8.23 ​​(d, J = 6.0 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.74 (s, 1H), 7.49 (s, 1H), 7.23 - 7.17 (m, 1H), 6.60 - 6.54 (m, 1H), 6.46 (d, J = 8.4 Hz, 1H), 5.56 - 5.42 (m, 1H), 3.85 (s, 3H), 3.31 (s, 3H), 2.70 (s, 3H), 1.59 (d, J = 6.4 Hz, 3H). MS: m / z 483.2 (M+H + ).

[1316] Step 7 - Synthesis of methyl 2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoate:

[1317] A mixture of methyl 2-((1-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate (280 mg, 746 μmol), isoindoline (133 mg, 1.12 mmol), Pd2(dba)3 (68 mg, 75 μmol), Xantphos (86 mg, 149 μmol), and Cs2CO3 (729 mg, 2.24 mmol) in dioxane (4 mL). The mixture was stirred at 110 °C for 3 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–33% EtOAc in petroleum ether) to obtain the title compound (187 mg, 56%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.25 (d, J = 6.0 Hz, 1H), 8.15 - 7.98 (m, 1H), 7.90 - 7.77 (m, 2H), 7.52 (s, 1H), 7.42 - 7.36 (m, 2H), 7.34 - 7.29 (m, 2H), 7.27 (s, 1H), 6.57 - 6.44 (m, 2H), 5.50 - 5.36 (m, 1H), 4.86 - 4.62 (m, 4H), 3.83 (s, 3H), 2.80 (s, 3H), 2.37 (s, 3H), 1.63 (d, J = 6.4 Hz, 3H). MS: m / z 452.3 (M+H + ).

[1318] Step 8 - Synthesis of 2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid:

[1319] LiOH monohydrate (42 mg, 997 μmol, dissolved in 0.2 mL H2O) was added to a solution of methyl 2-((1-(3-(isoindoline-2-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (90 mg, 199 μmol) in MeOH (2 mL) and THF (0.2 mL). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (35%–65% acetonitrile / 0.225% formic acid in water) to obtain the title compound (60 mg, 69%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.70 (s, 1H), 8.44 (s, 1H), 7.88 - 7.72 (m, 2H), 7.51 (s, 1H), 7.42 - 7.37 (m, 2H), 7.34 - 7.29 (m, 2H), 7.27 (s, 1H), 7.22 - 7.16 (m, 1H), 6.57 - 6.45 (m, 2H), 5.45 - 5.35 (m, 1H), 4.78 - 4.68 (m, 4H), 2.80 (s, 3H), 2.38 (s, 3H), 1.62 (d, J = 6.8 Hz, 3H). MS: m / z 438.3 (M+H + ).

[1320] Example 6: ( S )-2-((1-(3-(isoindoline-2-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid(compound 7)

[1321]

[1322] Step 1 - ( R )-2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid & ( S Synthesis of )-2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid:

[1323] 2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid (50 mg, 114 µmol) was separated using chiral SFC [DAICEL CHIRALPAK AD (250 mm*30 mm, 10 µm); supercritical CO2 / EtOH+0.1 % NH3·H2O=60 / 40; 60 mL / min] ( R )-2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid (5 mg, 1st peak) and ( S )-2-((1-(3-(isoindoline-2-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid (6 mg, 2nd peak) Both were obtained as white solids. The absolute stereoconfiguration was arbitrarily assigned to each enantiomer. Example 6 (2nd peak): 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.72 (s, 1H), 8.42 (d, J = 6.0 Hz, 1H), 7.84 - 7.75 (m, 2H), 7.51 (s, 1H), 7.44 - 7.36 (m, 2H), 7.34 - 7.29 (m, 2H), 7.27 (s, 1H), 7.22 - 7.16 (m, 1H), 6.55 - 6.46 (m, 2H), 5.48 - 5.34 (m, 1H), 4.79 - 4.67 (m, 4H), 2.80 (s, 3H), 2.38 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m / z 438.1 (M+H + ).

[1324] Example 7A: 2-((1-(2,7-dimethyl-3-(tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (compound 79)

[1325]

[1326] Step 1 - Methyl 2-((1-(3-(5,6-dihydro-2 H Synthesis of -pyran-3-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1327] Methyl 2-((1-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate (310 mg, 643 μmol), 2-(5,6-dihydro-2) in dioxane (5 mL) H A mixture of -pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabololene (202 mg, 964 μmol), Pd2(dba)3 (59 mg, 64 μmol), Xantphos (74 mg, 129 μmol), and Cs2CO3 (628 mg, 1.93 mmol). The mixture was stirred at 110 °C for 3 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–33% EtOAc in petroleum ether) to obtain the title compound (200 mg, 75%) as a white solid. MS: m / z 417.2 (M+H + ).

[1328] Step 2 - Methyl 2-((1-(2,7-dimethyl-3-(tetrahydro-2 H Synthesis of -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoate:

[1329] Methyl 2-((1-(3-(5,6-dihydro-2) in MeOH (10 mL) H Carbon-supported Pd(OH)2 (100 mg, 20% Pd, 50% wet with water) was added to a solution of pyran-3-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (200 mg, 480 μmol). The reaction mixture was stirred at room temperature for 4 hours under an H2 atmosphere (15 psi). The reaction mixture was filtered through diatomite, and the filtrate was concentrated to obtain the title compound (100 mg, 50%) as a yellow solid requiring no further purification. MS: m / z 419.3 (M+H + ).

[1330] Step 3 - 2-((1-(2,7-dimethyl-3-(tetrahydro-2 H Synthesis of -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid:

[1331] Methyl 2-((1-(2,7-dimethyl-3-(tetrahydro-2) in MeOH (0.3 mL) and THF (3 mL) H LiOH (29 mg, 1.19 mmol, dissolved in 0.3 mL H2O) was added to a mixture of pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoate (50 mg, 119 μmol). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (20%–50% acetonitrile / 0.225% formic acid in water) to obtain the title compound (10 mg, 21%) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.74 (s, 1H), 8.51 - 8.38 (m, 1H), 8.36 - 8.30 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 7.38 - 7.28 (m, 1H), 7.24 - 7.13 (m, 1H), 6.56 - 6.44 (m, 2H), 5.51 - 5.35 (m, 1H), 3.95 - 3.81 (m, 2H), 3.48 - 3.34 (m, 2H), 3.14 - 3.01 (m, 1H), 2.68 (s, 3H), 2.41 (s, 3H), 1.99 - 1.89 (m, 1H), 1.87 - 1.77 (m, 1H), 1.76 - 1.65 (m, 2H), 1.60 (d, J = 6.4 Hz, 3H). MS: m / z 405.1 (M+H + ).

[1332] Example 7B: 2-((1-(2,7-dimethyl-3-(tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid: 2-((( R )-1-(2,7-dimethyl-3-(( R )-tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid; 2-((( R )-1-(2,7-dimethyl-3-(( S )-tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid; 2-((( S )-1-(2,7-dimethyl-3-(( R )-tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid; and 2-((( S )-1-(2,7-dimethyl-3-(( S )-tetrahydro-2 H -Pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (compounds 8A~8D)

[1333]

[1334] 2-((1-(2,7-dimethyl-3-(tetrahydro-2 H -Pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (60 mg, 148 μmol) was separated using chiral SFC [DAICEL CHIRALCEL OD (250 mm*30 mm, 10 µm); supercritical CO2 / EtOH+0.1 % NH3·H2O=60 / 40; 70 mL / min] to 2-((( R )-1-(2,7-dimethyl-3-(( R )-tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid and 2-((( R )-1-(2,7-dimethyl-3-(( S )-tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (20 mg, peaks 2 and 4, unseparable), 2-((( S )-1-(2,7-dimethyl-3-(( R )-tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (4 mg, 1st peak) and 2-((( S )-1-(2,7-dimethyl-3-(( S )-tetrahydro-2 H-pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (7 mg, Peak 3) was obtained as a white solid. The mixture of Peaks 2 and 4 (20 mg, 48 μmol) was separated using chiral SFC [DAICEL CHIRALCEL IG (250 mm * 30 mm, 10 μm); supercritical CO2 / EtOH + 0.1 % NH3·H2O = 65 / 35; 70 mL / min] to obtain 2-((( R )-1-(2,7-dimethyl-3-(( R )-tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (4 mg, 2nd peak) and 2-((( R )-1-(2,7-dimethyl-3-(( S )-tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (5 mg, 4th peak) was obtained. The absolute stereoconfiguration was arbitrarily assigned to each enantiomer. (The retention times of these four peaks are aligned according to this method. OJ_3_EtOH_DEA_5_40_25ML_6MIN).

[1335] Peak 2 (Compound 8A): 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.76 (s, 1H), 8.67 - 8.27 (m, 2H), 7.80 (d, J = 7.2 Hz, 1H), 7.57 (s, 1H), 7.34 (s, 1H), 7.23 - 7.12 (m, 1H), 6.58 - 6.41 (m, 2H), 5.44 - 5.40 (m, 1H), 3.89 - 3.87 (m, 1H), 3.45 - 3.40 (m, 2H), 3.09 - 3.05 (m, 1H), 2.68 (s, 3H), 2.41 (s, 3H), 1.96 - 1.91 (m, 1H), 1.85 - 1.78 (m, 1H), 1.74 - 1.66 (m, 2H), 1.60 (d, J= 6.0 Hz, 3H), 1.58 - 1.57 (m, 1H). MS: m / z 405.1 (M+H + ). Peak 4 (Compound 8B): 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.46 (s, 1H), 8.33 (s, 1H), 7.87 - 7.76 (m, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 7.25 - 7.11 (m, 1H), 6.58 - 6.42 (m, 2H), 5.51 - 5.36 (m, 1H), 3.95 - 3.84 (m, 2H), 3.48 - 3.42 (m, 2H), 3.12 - 3.02 (m, 1H), 2.68 (s, 3H), 2.41 (s, 3H), 1.97 - 1.89 (m, 1H), 1.89 - 1.79 (m, 1H), 1.75 - 1.65 (m, 2H), 1.60 (d, J = 6.4 Hz, 3H). MS: m / z 405.1 (M+H + ). Peak 1 (Compound 8C): 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.46 (s, 1H), 8.34 (s, 1H), 7.88 - 7.74 (m, 1H), 7.56 (s, 1H), 7.34 (s, 1H), 7.24 - 7.09 (m, 1H), 6.61 - 6.41 (m, 2H), 5.47 - 5.32 (m, 1H), 3.96 - 3.79 (m, 2H), 3.47 - 3.40 (m, 2H), 3.13 - 3.00 (m, 1H), 2.68 (s, 3H), 2.41 (s, 3H), 2.00 - 1.89 (m, 1H), 1.87 - 1.77 (m, 1H), 1.77 - 1.64 (m, 2H), 1.60 (d, J = 6.4 Hz, 3H). MS: m / z 405.1 (M+H + ). Peak 3 (Compound 8D): 1 ¹H NMR (400 MHz, DMSO- d6) δ 8.53 (s, 1H), 8.33 (s, 1H), 7.91 - 7.72 (m, 1H), 7.56 (s, 1H), 7.32 (s, 1H), 7.23 - 7.09 (m, 1H), 6.62 - 6.38 (m, 2H), 5.44 (s, 1H), 3.96 - 3.84 (m, 2H), 3.47 - 3.43 (m, 2H), 3.11 - 3.04 (m, 1H), 2.68 (s, 3H), 2.40 (s, 3H), 1.98 - 1.89 (m, 1H), 1.89 - 1.79 (m, 1H), 1.75 - 1.66 (m, 2H), 1.60 (d, J = 6.4 Hz, 3H). MS: m / z 405.0 (M+H + ).

[1336] Example 8: 2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethyl)amino)benzoic acid (compound 9)

[1337]

[1338] Step 1 - N Synthesis of -(2-bromo-4-methyl-6-nitrophenyl)-2-oxopropanamide:

[1339] DMF (54 mg, 738 μmol) and oxalyl chloride (721 mg, 5.7 mmol) were added to a solution of 2-oxopropanoic acid (0.5 g, 5.68 mmol) in THF (5 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour under an N2 atmosphere. Then, 2-bromo-4-methyl-6-nitroaniline (0.7 g, 3 mmol) and TEA (919 mg, 9.09 mmol) dissolved in THF (10 mL) were added to the mixture. The mixture was stirred at room temperature for 2 hours. The reaction of the mixture was terminated with H2O (20 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to obtain the title compound (600 mg, 66%) as a yellow solid. 1¹H NMR (400 MHz, DMSO- d 6) δ 10.63 (s, 1H), 7.96 (s, 1H), 7.88 (d, J = 1.2 Hz, 1H), 2.43 (s, 3H), 2.41 (s, 3H).

[1340] Step 2 - Synthesis of 8-Bromo-3,6-Dimethylquinoxalin-2-ol:

[1341] In AcOH (6 mL) N Fe (557 mg, 10 mmol, powder) was added to a solution of -(2-bromo-4-methyl-6-nitro-phenyl)-2-oxo-propanamide (0.6 g, 2 mmol). The mixture was stirred at 100 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, the solution was filtered and vacuum concentrated. The residue was dissolved in H2O (20 mL) and stirred for 10 minutes. The suspension was filtered, and the filter cake was vacuum dried to obtain the title compound (350 mg, 70%) as a yellow solid requiring no further purification. 1 H NMR (400 MHz, DMSO- d 6) δ 7.63 (s, 1H), 7.54 (s, 1H), 2.42 (s, 3H), 2.37 (s, 3H).

[1342] Step 3 - Synthesis of 5-Bromo-3-chloro-2,7-dimethylquinoxaline:

[1343] Solution of 8-bromo-3,6-dimethyl-quinoxalin-2-ol (0.35 g, 1.38 mmol) in POCl3 (2 mL, 21 mmol). The mixture was stirred at 120 °C for 5 hours. After cooling to room temperature, the POCl3 was removed under vacuum, DCM (50 mL) was added, and the mixture was washed with saturated aqueous NaHCO3 (50 mL). The organic layer was dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain an unpurified product (72 g, 99%) as a white solid requiring no further purification. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.07 (d, J= 1.6 Hz, 1H), 7.86 (s, 1H), 2.77 (s, 3H), 2.54 (s, 3H).

[1344] Step 4 - Synthesis of 5-Bromo-3-(isoindolin-2-yl)-2,7-dimethylquinoxaline:

[1345] K2CO3 (718 mg, 5.2 mmol) was added to a solution of 5-bromo-3-chloro-2,7-dimethyl-quinoxaline (0.47 g, 1.73 mmol) and isoindoline (412 mg, 3.46 mmol) in MeCN (5 mL). The reaction mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with 1 M HCl (20 mL) and brine (20 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain the title compound (600 mg, 97%) as a yellow solid requiring no further purification. 1 H NMR (400 MHz, DMSO- d 6) δ 7.75 (d, J = 1.6 Hz, 1H), 7.58 (s, 1H), 7.47 -7.43 (m, 2H), 7.37 - 7.31 (m, 2H), 5.21 (s, 4H), 2.94 (s, 3H), 2.43 (s, 3H). MS: m / z 354.0 (M+H + ).

[1346] Step 5 - Synthesis of 1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethane-1-one:

[1347] A mixture of 5-bromo-3-(isoindolin-2-yl)-2,7-dimethylquinoxaline (880 mg, 2.48 mmol), tributyl(1-ethoxyvinyl)stanneine (2.24 g, 6.21 mmol), and Pd(dppf)Cl2 (182 mg, 0.25 mmol) in dioxane (10 mL) was degassed and purged with N2 three times. The reaction mixture was stirred at 90 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, HCl (1 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 hours. 50 mL of 10% KF aqueous solution was added to the reaction mixture and stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (60 mL x 3). The combined organic layer was washed with brine (60 mL), dried with anhydrous Na2SO4, filtered, and concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–50% EtOAc in petroleum ether) to obtain the title compound (200 mg, 28%) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 7.78 - 7.76 ( m , 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.47 - 7.43 ( m , 2H), 7.36 - 7.32 ( m , 2H), 5.22 (s, 4H), 2.96 (s, 3H), 2.93 (s, 3H), 2.45 (s, 3H).

[1348] Step 6 - Synthesis of 1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethane-1-amine:

[1349] NaBH3CN (101 mg, 1.61 mmol) was added to a solution of 1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethane-1-one (170 mg, 0.53 mmol) and NH4OAc (619 mg, 8.03 mmol) in MeOH (4 mL). The reaction mixture was heated to 60 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain the title compound (160 mg, 94%) as a yellow oil that does not require further purification. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.50 - 7.47 (m, 2H), 7.46 -7.42 (m, 2H), 7.35 - 7.30 (m, 2H), 5.23 - 5.12 (m, 4H), 4.97 - 4.92 (m, 1H), 2.91 (s, 3H), 2.44 (s, 3H), 1.49 (d, J = 6.8 Hz, 3H). MS: m / z 319.1 (M+H + ).

[1350] Step 7 - Synthesis of tert-butyl 2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethyl)amino)benzoate:

[1351] A mixture of 1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethane-1-amine (160 mg, 502 μmol), tert-butyl 2-iodobenzoate (229 mg, 753 μmol), Pd2(dba)3 (46 mg, 50 μmol), Xantphos (58 mg, 100 μmol), and Cs2CO3 (491 mg, 1.51 mmol) in dioxane (4 mL). The mixture was heated to 100 °C for 4 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–30% EtOAc in petroleum ether) to obtain the title compound (100 mg, 40%) as a yellow oil. MS: m / z 495.2 (M+H + ).

[1352] Step 8 - Synthesis of 2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethyl)amino)benzoic acid:

[1353] TFA (0.5 mL, 6.9 mmol) was added to a mixture of tert-butyl 2-((1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethyl)amino)benzoate (100 mg, 202 μmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by reverse-phase chromatography (53%–83% acetonitrile / 0.225% formic acid in water) to obtain the title compound (52 mg, 11%) as a yellow solid. 1 H NMR (400 MHz, DMSO- d 6) δ 12.65 (s, 1H), 8.53 (s, 1H), 7.79 - 7.75 (m, 1H), 7.50 - 7.40 (m, 3H), 7.37 - 7.28 (m, 3H), 7.18 - 7.11 (m, 1H), 6.56 - 6.41 (m, 2H), 5.63 - 5.56 (m, 1H), 5.32 - 5.14 (m, 4H), 2.94 (s, 3H), 2.36 (s, 3H), 1.65 (d, J= 6.8 Hz, 3H). MS: m / z 439.2 (M+H + ).

[1354] Example 11A: 2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid (compound 10)

[1355]

[1356] Step 1 - Synthesis of methyl 2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1357] A mixture of methyl 2-((1-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate (150 mg, 311 μmol), (3-fluorophenyl)boronic acid (87 mg, 622 μmol), Pd(PPh3)4 (36 mg, 31 μmol) and K2CO3 (129 mg, 933 μmol) in dioxane (3 mL) and H2O (0.1 mL). The mixture was stirred at 100 °C for 2 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to obtain the title compound (106 mg, 80%) as a yellow solid. MS: m / z 429.1 (M+H + ).

[1358] Step 2 - Synthesis of 2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1359] KOH (26 mg, 467 μmol, dissolved in 0.2 mL H2O) was added to a solution of methyl 2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (20 mg, 47 μmol) in EtOH (0.2 mL). The mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (32%–62% acetonitrile / 0.225% formic acid in water) to obtain the title compound (15 mg, 78%) as a white solid. 1 ¹H NMR (400 MHz, DMSO-d 6) δ 8.58 - 8.41 (m, 2H), 7.85 - 7.77 (m, 1H), 7.66 (s, 1H), 7.60 - 7.51 (m, 1H), 7.48 - 7.42 (m, 1H), 7.41 - 7.34 (m, 2H), 7.33 - 7.24 (m, 1H), 7.18 - 7.08 (m, 1H), 6.55 - 6.46 (m, 1H), 6.40 (d, J = 8.0 Hz, 1H), 5.56 - 5.39 (m, 1H), 2.59 (s, 3H), 2.43 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H). MS: m / z 414.9 (M+H + ).

[1360] Example 11B: ( R )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid and ( S )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid (compound 10A and compound 10B)

[1361]

[1362] Step 1 - Methyl ( R )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate & methyl ( S Synthesis of )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1363] Methyl 2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (100 mg, 233 μmol) was separated using chiral SFC [DAICEL CHIRALCEL OD (250 mm*30 mm, 10 µm); supercritical CO2 / EtOH+0.1 % NH3·H2O=75 / 25; 70 mL / min] to methyl ( R )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (40 mg, 1st peak) and methyl ( S)-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (40 mg, 2nd peak) Both were obtained as white solids. The absolute stereoconfiguration was arbitrarily assigned to each enantiomer. MS: m / z 429.1 (M+H + ).

[1364] Step 2A - ( R Synthesis of )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1365] Methyl (in 0.4 mL of EtOH) R KOH (52 mg, 934 μmol, dissolved in 0.4 mL H2O) was added to a solution of )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (40 mg, 93 μmol). The mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (37%–67% acetonitrile / 0.225% formic acid in water) to obtain the title compound (11 mg, 28%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.63 - 8.51 (m, 1H), 8.46 (s, 1H), 7.84 - 7.77 (m, 1H), 7.66 (s, 1H), 7.60 - 7.50 (m, 1H), 7.45 (d, J = 9.6 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.33 - 7.25 (m, 1H), 7.17 - 7.07 (m, 1H), 6.55 - 6.45 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.49 - 5.43 (m, 1H), 2.59 (s, 3H), 2.43 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H). MS: m / z 415.0 (M+H + ).

[1366] Step 2B - ( S Synthesis of )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1367] Methyl (in 0.4 mL of EtOH) S KOH (52 mg, 934 μmol, dissolved in 0.4 mL H2O) was added to a solution of )-2-((1-(3-(3-fluorophenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (40 mg, 93 μmol). The mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (37%–67% acetonitrile / 0.225% formic acid in water) to obtain the title compound (16 mg, 41%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.62 - 8.50 (m, 1H), 8.46 (s, 1H), 7.83 - 7.77 (m, 1H), 7.66 (s, 1H), 7.61 - 7.50 (m, 1H), 7.45 (d, J = 9.6 Hz, 1H), 7.41 - 7.34 (m, 2H), 7.33 - 7.24 (m, 1H), 7.18 - 7.07 (m, 1H), 6.56 - 6.44 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.50 - 5.44 (m, 1H), 2.59 (s, 3H), 2.43 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H). MS: m / z 415.0 (M+H + ).

[1368] Example 12A: 2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid (Compound 11)

[1369]

[1370] Step 1 - Synthesis of methyl 2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1371] A mixture of methyl 2-((1-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate (150 mg, 311 μmol), 2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (152 mg, 622 μmol) (prepared according to the procedure of WO2019211463), Pd(PPh3)4 (36 mg, 31 μmol), and K2CO3 (129 mg, 933 μmol) in dioxane (3 mL) and H2O (0.1 mL). The mixture was stirred at 100 °C for 2 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to obtain the title compound (126 mg, 85%) as a yellow solid. MS: m / z 452.2 (M+H + ).

[1372] Step 2 - Synthesis of 2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1373] KOH (31 mg, 554 μmol, dissolved in 0.4 mL H2O) was added to a solution of methyl 2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (25 mg, 55 μmol) in EtOH (0.4 mL). The mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (23%–53% acetonitrile / 0.225% formic acid in water) to obtain the title compound (15 mg, 62%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d6) δ 8.61 - 8.47 (m, 3H), 7.86 - 7.77 (m, 1H), 7.67 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.34 - 7.28 (m, 1H), 7.18 - 7.08 (m, 1H), 6.55 - 6.46 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.57 - 5.38 (m, 1H), 2.60 (s, 3H), 2.44 (s, 3H), 2.23 - 2.13 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.02 - 0.97 (m, 4H). MS: m / z 438.1 (M+H + ).

[1374] Example 12B: ( R )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid and ( S )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid (compound 11A and compound 11B)

[1375]

[1376] Step 1 - Methyl ( R )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate & methyl ( S Synthesis of )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1377] Methyl 2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (100 mg, 221 μmol) was separated using chiral SFC [DAICEL CHIRALCEL OD (250 mm*30 mm, 10 µm); supercritical CO2 / EtOH+0.1 % NH3·H2O=60 / 40; 70 mL / min] to methyl ( R )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (40 mg, 1st peak) and methyl ( S)-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (40 mg, 2nd peak) Both were obtained as white solids. The absolute stereoconfiguration was arbitrarily assigned to each enantiomer. MS: m / z 452.2 (M+H + ).

[1378] Step 2A - ( R Synthesis of )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1379] Methyl (in MeOH (0.1 mL) and THF (1 mL) R LiOH (21 mg, 886 μmol, dissolved in 0.1 mL H2O) was added to a solution of )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (40 mg, 89 μmol). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (21%–51% acetonitrile / 0.225% formic acid in water) to obtain the title compound (16 mg, 42%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.70 - 8.46 (m, 3H), 7.83 - 7.77 (m, 1H), 7.67 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.34 - 7.27 (m, 1H), 7.19 - 7.04 (m, 1H), 6.55 - 6.46 (m, 1H), 6.40 (d, J = 8.4 Hz, 1H), 5.60 - 5.34 (m, 1H), 2.60 (s, 3H), 2.44 (s, 3H), 2.23 - 2.14 (m, 1H), 1.57 (d, J = 6.8 Hz, 3H), 1.04 - 0.96 (m, 4H). MS: m / z 438.1 (M+H + ).

[1380] Step 2B - ( S Synthesis of )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1381] Methyl (in MeOH (0.1 mL) and THF (1 mL) S LiOH (21 mg, 886 μmol, dissolved in 0.1 mL H2O) was added to a solution of )-2-((1-(3-(2-cyclopropylpyridine-4-yl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (40 mg, 89 μmol). The mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (21%–51% acetonitrile / 0.225% formic acid in water) to obtain the title compound (14 mg, 37%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.66 - 8.47 (m, 3H), 7.83 - 7.77 (m, 1H), 7.67 (s, 1H), 7.48 (s, 1H), 7.37 (s, 1H), 7.34 - 7.28 (m, 1H), 7.18 - 7.06 (m, 1H), 6.59 - 6.45 (m, 1H), 6.39 (d, J = 8.4 Hz, 1H), 5.57 - 5.41 (m, 1H), 2.60 (s, 3H), 2.44 (s, 3H), 2.23 - 2.14 (m, 1H), 1.57 (d, J = 6.4 Hz, 3H), 1.02 - 0.96 (m, 4H). MS: m / z 438.1 (M+H + ).

[1382] Example 13: Methyl 2-((1-(3-(3-(difluoromethyl)phenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (Compound 29)

[1383]

[1384] Step 1 - Synthesis of methyl 2-((1-(3-(3-(difluoromethyl)phenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1385] A mixture of methyl 2-((1-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinoline-5-yl)ethyl)amino)benzoate (150 mg, 311 μmol), (3-(difluoromethyl)phenyl)boronic acid (107 mg, 622 μmol), Pd(PPh3)4 (36 mg, 31 μmol) and K2CO3 (129 mg, 933 μmol) in dioxane (3 mL) and H2O (0.1 mL). The mixture was stirred at 100 °C for 2 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to obtain the title compound (100 mg, 70%) as a white solid. MS: m / z 461.1 (M+H + ).

[1386] Step 2 - Synthesis of 2-((1-(3-(3-(difluoromethyl)phenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1387] KOH (24 mg, 434 μmol, dissolved in 0.2 mL H2O) was added to a solution of methyl 2-((1-(3-(3-(difluoromethyl)phenyl)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (20 mg, 43 μmol) in EtOH (0.2 mL). The reaction mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (30%–60% acetonitrile / 0.225% formic acid in water) to obtain the title compound (15 mg, 77%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.52 - 8.38 (m, 2H), 7.84 - 7.78 (m, 1H), 7.77 - 7.70 (m, 2H), 7.69 - 7.65 (m, 3H), 7.36 (s, 1H), 7.27 - 6.96 (m, 2H), 6.60 - 6.47 (m, 1H), 6.41 (d, J= 8.0 Hz, 1H), 5.55 - 5.43 (m, 1H), 2.58 (s, 3H), 2.43 (s, 3H), 1.57 (d, J = 6.8 Hz, 3H). MS: m / z 447.0 (M+H + ).

[1388] Example 14: 2-((1-(2-cyano-7-methyl-3-(tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (compound 30)

[1389]

[1390] Step 1 - Synthesis of 3-(benzyloxy)-5-bromo-7-methylquinoline 1-oxide:

[1391] 3-(benzyloxy)-5-bromo-7-methylquinoline (2.5 g, 7.61 mmol) and in DCM (25 mL) m A mixture of -CPBA (3.09 g, 15.24 mmol, 85% purity) was stirred at room temperature for 16 hours. The reaction mixture was terminated at room temperature with saturated aqueous Na2S2O3 (20 mL) and then extracted with DCM (30 mL). The organic layer was washed with NaHCO3 (20 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain the title compound (2.53 g, unpurified) as a black solid requiring no further purification. MS: m / z 344.1 (M+H + ).

[1392] Step 2 - Synthesis of 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbonitrile:

[1393] A mixture of 3-(benzyloxy)-5-bromo-7-methylquinoline 1-oxide (2.10 g, 6.10 mmol), TEA (1.23 g, 12.20 mmol), CCl4 (1.88 g, 12.20 mmol), TMSCN (726 mg, 7.32 mmol), and diethyl phosphonate (1.69 g, 12.20 mmol) in CHCl3 (40 mL) was stirred at room temperature under an N2 atmosphere for 16 hours. The reaction mixture was diluted with DCM (20 mL). The mixture was washed with NaHCO3 (30 mL x 2) and brine (30 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to obtain the title compound (1.3 g, 60%) as a yellow solid. MS: m / z 353.0 (M+H + ).

[1394] Step 3 - Synthesis of 5-(1-ethoxyvinyl)-3-hydroxy-7-methylquinoline-2-carbonitrile:

[1395] A mixture of tributyl(1-ethoxyvinyl)stanneine (1.84 g, 5.10 mmol), 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbonitrile (900 mg, 2.55 mmol), and Pd(dppf)Cl2 (186 mg, 255 μmol) in dioxane (10 mL) was stirred at 100 °C for 16 hours under an N2 atmosphere. After cooling to room temperature, the reaction of the mixture was terminated with 30 mL of 10% KF aqueous solution and stirred for 30 minutes. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–33% EtOAc in petroleum ether) to obtain the title compound (400 mg, 62%) as a yellow solid. . 1 ¹H NMR (400 MHz, DMSO- d6) δ 11.55 (s, 1H), 7.97 (s, 1H), 7.75 (s, 1H), 7.50 (s, 1H), 4.63 - 4.52 (m, 1H), 4.46 - 4.33 (m, 1H), 3.98 (q, J = 6.8 Hz, 2H), 2.48 - 2.44 (m, 3H), 1.36 (t, J = 6.8 Hz, 3H). MS: m / z 255.1 (M+H + ).

[1396] Step 4 - Synthesis of 5-acetyl-2-cyano-7-methylquinoline-3-yl trifluoromethanesulfonate:

[1397] A mixture of 5-(1-ethoxyvinyl)-3-hydroxy-7-methylquinoline-2-carbonitrile (100 mg, 393 μmol), pyridine (93 mg, 1.18 mmol), and Tf2O (166 mg, 590 μmol) in 4 mL of DCM was stirred at 0 °C for 1 hour. The mixture was added to 5 mL of HCl (1 M) and stirred at room temperature for 0.5 hours. The mixture was alkalized to pH 7 with saturated aqueous NaHCO3. The mixture was then extracted with 2 mL of DCM (15 mL). The combined organic layer was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain the title compound (128 mg, unpurified) as a yellow solid requiring no further purification. MS: m / z 359.0 (M+H + ).

[1398] Step 5 - 5-acetyl-3-(5,6-dihydro-2 H Synthesis of -pyran-3-yl)-7-methylquinoline-2-carbonitrile:

[1399] 5-acetyl-2-cyano-7-methylquinoline-3-yl trifluoromethanesulfonate (128 mg, 357 μmol), 2-(5,6-dihydro-2) in dioxane (2 mL) and H2O (0.2 mL) HA mixture of -pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxabololene (113 mg, 536 μmol), Pd(PPh3)4 (41 mg, 36 μmol), and K2CO3 (148 mg, 1.07 mmol). The mixture was stirred at 100 °C for 2 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to obtain the title compound (73 mg, 70%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.98 (s, 1H), 8.34 (s, 1H), 8.12 (s, 1H), 6.36 - 6.24 (m, 1H), 4.41 - 4.38 (m, 2H), 3.86 - 3.81 (m, 2H), 2.76 (s, 3H), 2.62 (s, 3H), 2.35 - 2.31 (m, 2H). MS: m / z 293.4 (M+H + ).

[1400] Step 6 - 5-(1-aminoethyl)-3-(5,6-dihydro-2 H Synthesis of -pyran-3-yl)-7-methylquinoline-2-carbonitrile:

[1401] 5-acetyl-3-(5,6-dihydro-2) in MeOH (1 mL) HA mixture of -pyran-3-yl)-7-methylquinoline-2-carbonitrile (65 mg, 222 μmol), NH4OAc (257 mg, 3.34 mmol), and AcOH (13 mg, 222 μmol) was stirred at room temperature for 1 hour. Then, NaBH3CN (42 mg, 667 μmol) was added to the reaction mixture. After addition, the reaction mixture was stirred at 60 °C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL). The mixture was washed with saturated NaHCO3 solution (10 mL x 3) and brine (10 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain the title compound (63 mg, unpurified) as a yellow solid requiring no further purification. MS: m / z 294.2 (M+H + ).

[1402] Step 7 - tert-butyl 2-((1-(2-cyano-3-(5,6-dihydro-2 H Synthesis of -pyran-3-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoate:

[1403] 5-(1-aminoethyl)-3-(5,6-dihydro-2) in dioxane (2 mL) H A mixture of -pyran-3-yl)-7-methylquinoline-2-carbonitrile (63 mg, 215 μmol), tert-butyl 2-iodobenzoate (98 mg, 322 μmol), Cs2CO3 (210 mg, 644 μmol), Pd2(dba)3 (20 mg, 21 μmol), and Xantphos (25 mg, 43 μmol), and the reaction mixture was stirred at 100 °C for 2 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–20% EtOAc in petroleum ether) to obtain the title compound (50 mg, 50%) as a yellow solid. MS: m / z 470.3 (M+H + ).

[1404] Step 8 - tert-butyl 2-((1-(2-cyano-7-methyl-3-(tetrahydro-2 H Synthesis of -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoate:

[1405] tert-butyl 2-((1-(2-cyano-3-(5,6-dihydro-2) in MeOH (1 mL) H Carbon-supported Pd(OH)2 (16 mg, 20% Pd, 50% wet with water) was added to a solution of pyran-3-yl)-7-methylquinoline-5-yl)ethyl)amino)benzoate (50 mg, 106 μmol). The reaction mixture was stirred at room temperature for 1 hour under an H2 atmosphere (15 psi). The reaction mixture was filtered through diatomite, and the filtrate was vacuum concentrated to obtain the title compound (49 mg, unpurified) as a yellow solid requiring no further purification. MS: m / z 472.3 (M+H + ).

[1406] Step 9 - 2-((1-(2-cyano-7-methyl-3-(tetrahydro-2 H Synthesis of -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid:

[1407] tert-butyl 2-((1-(2-cyano-7-methyl-3-(tetrahydro-2) in DCM (2 mL) H TFA (154 mg, 1.36 mmol) was added to a solution of pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoate (13 mg, 28 μmol). The reaction mixture was stirred at 40 °C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (56%–86% acetonitrile / 0.225% formic acid in water) to obtain the title compound (2.9 mg, 25%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d6) δ 12.78 (s, 1H), 8.76 (s, 1H), 8.62 - 8.40 (m, 1H), 7.91 - 7.71 (m, 2H), 7.60 - 7.57 (m, 1H), 7.26 - 7.10 (m, 1H), 6.57 - 6.53 (m, 1H), 6.50 - 6.41 (m, 1H), 5.68 - 5.46 (m, 1H), 4.02 - 3.85 (m, 2H), 3.57 - 3.43 (m, 3H), 2.48 - 2.45 (m, 3H), 2.13 - 1.91 (m, 2H), 1.78 - 1.67 (m, 2H), 1.61 (d, J = 5.6 Hz, 3H). MS: m / z 416.3 (M+H + ).

[1408] Example 15: 2-((1-(2-carbamoil-7-methyl-3-(tetrahydro-2 H -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid (compound 31)

[1409]

[1410] Step 1 - tert-butyl 2-((1-(2-carbamoil-7-methyl-3-(tetrahydro-2 H Synthesis of -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoate:

[1411] tert-butyl 2-((1-(2-cyano-7-methyl-3-(tetrahydro-2) in THF (2 mL) and H2O (0.5 mL) HH2O2 (96 mg, 848 μmol, 30% in water) and NaOH (14 mg, 339 μmol) were added to a solution of pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoate (40 mg, 85 μmol). After addition, the reaction mixture was stirred at room temperature for 16 hours. The reaction was terminated with a saturated aqueous Na2S2O3 solution (5 mL) and stirred for 30 minutes. The mixture was extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated. The unrefined residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to obtain the title compound (38 mg, 64%) as a white solid. MS: m / z 490.1 (M+H + ).

[1412] Step 2 - 2-((1-(2-carbamoil-7-methyl-3-(tetrahydro-2 H Synthesis of -pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoic acid:

[1413] In DCM (1 mL), tert-butyl 2-((1-(2-carbamoil-7-methyl-3-(tetrahydro-2 H TFA (0.3 mL, 37.9 mmol) was added to a solution of pyran-3-yl)quinoline-5-yl)ethyl)amino)benzoate (38 mg, 78 μmol). The reaction mixture was stirred at room temperature for 16 hours. The mixture was concentrated, and the residue was purified by reverse-phase chromatography (45%–75% acetonitrile / 0.225% formic acid in water) to obtain the title compound (4.9 mg, 14%) as a yellow solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.77 (s, 1H), 8.57 (d, J = 5.6 Hz, 1H), 8.05 (s, 1H), 7.85 - 7.79 (m, 1H), 7.72 - 7.65 (m, 2H), 7.45 (d, J= 8.0 Hz, 1H), 7.25 - 7.12 (m, 1H), 6.56 - 6.44 (m, 2H), 5.58 - 5.44 (m, 1H), 3.98 - 3.84 (m, 2H), 3.40 - 3.88 (m, 3H), 2.46 - 2.44 (m, 3H), 2.06 - 1.78 (m, 2H), 1.69 - 1.59 (m, 5H). MS: m / z 434.2 (M+H + ).

[1414] Example 16: 2-((1-(3-(cyclopropylmethoxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid (Compound 32)

[1415]

[1416] Step 1 - Synthesis of methyl 2-((1-(3-(cyclopropylmethoxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate:

[1417] A mixture of methyl 2-((1-(3-hydroxy-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (120 mg, 342 μmol), bromomethylcyclopropane (120 mg, 888 μmol), and Cs2CO3 (335 mg, 1.03 mmol) in DMF (3 mL) was stirred at 80 °C for 2 hours. After cooling to room temperature, the reaction mixture was terminated with water (15 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (30 mL x 3) and brine (30 mL), dried with anhydrous Na2SO4, filtered, and vacuum concentrated to obtain the title compound (120 mg, unpurified) as a yellow solid requiring no further purification. MS: m / z 405.1 (M+H + ).

[1418] Step 2 - Synthesis of 2-((1-(3-(cyclopropylmethoxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1419] KOH (194 mg, 3.46 mmol, dissolved in 1 mL H2O) was added to a solution of methyl 2-((1-(3-(cyclopropylmethoxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (120 mg, 297 μmol) in EtOH (1 mL). The reaction mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (26%–56% acetonitrile / 0.225% formic acid in water) to obtain the title compound (100 mg, 86%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 8.54 - 8.34 (m, 1H), 7.82 - 7.74 (m, 2H), 7.53 (s, 1H), 7.28 (d, J = 1.2 Hz, 1H), 7.19 - 7.11 (m, 1H), 6.54 - 6.47 (m, 1H), 6.42 (d, J = 8.4 Hz, 1H), 5.50 - 5.29 (m, 1H), 3.99 (d, J = 6.8 Hz, 2H), 2.54 (s, 3H), 2.37 (s, 3H), 1.57 (d, J = 6.4 Hz, 3H), 1.34 - 1.22 (m, 1H), 0.65 - 0.55 (m, 2H), 0.45 - 0.34 (m, 2H). MS: m / z 391.1 (M+H + ).

[1420] Example 17: 2-((1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid (compound 33)

[1421]

[1422] Step 1 - Synthesis of 2-((1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoic acid:

[1423] KOH (127 mg, 2.27 mmol, dissolved in 1 mL H2O) was added to a solution of methyl 2-((1-(3-(benzyloxy)-2,7-dimethylquinoline-5-yl)ethyl)amino)benzoate (100 mg, 227 μmol) in EtOH (1 mL). The reaction mixture was stirred at 100 °C for 2 hours. After cooling to room temperature, the reaction mixture was adjusted to pH 6 with formic acid. The reaction mixture was concentrated, and the residue was purified by reverse-phase chromatography (50%–80% acetonitrile / 0.225% formic acid in water) to obtain the title compound (65 mg, 66%) as a white solid. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 12.80 (s, 1H), 8.55 - 8.41 (m, 1H), 7.91 (s, 1H), 7.83 - 7.78 (m, 1H), 7.57 - 7.51 (m, 3H), 7.45 - 7.38 (m, 2H), 7.37 - 7.30 (m, 1H), 7.27 (d, J = 1.2 Hz, 1H), 7.17 - 7.09 (m, 1H), 6.55 - 6.48 (m, 1H), 6.37 (d, J = 8.4 Hz, 1H), 5.40 - 5.29 (m, 3H), 2.58 (s, 3H), 2.36 (s, 3H), 1.51 (d, J = 6.8 Hz, 3...

Claims

Claim 1 Compound of the following chemical formula (I) (I) or a pharmaceutically acceptable salt thereof, wherein in the above formula (I), Z is N or CH, and R 1 is a quaternary to 10-membered heterocyclile optionally substituted with hydrogen, halogen, cyano, C3-C6 cycloalkyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl; or is a C1-C6 alkyl optionally substituted with (i) a C3-C6 cycloalkyl or (ii) a quaternary to 10-membered heterocyclile, and R 2 is 1 to 4 independently selected R 2A A C6-C10 aryl arbitrarily substituted with , 1 to 4 independently selected R 2A 5- to 10-membered heteroaryls arbitrarily substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclils arbitrarily substituted with , 1 to 4 independently selected Rs 2A A C4-C10 cycloalkyl optionally substituted with , 1 to 4 independently selected Rs 2A 4- to 10-membered heterocyclyloxy oxy arbitrarily substituted with , 1 to 4 independently selected Rs 2A 5- to 10-member heteroaryloxy, -C(=O)NR arbitrarily substituted with A R C C1-C6 alkoxyalkyl alkyls optionally substituted with -C(=O)NR A R C , C1-C6 alkoxy optionally substituted with a C4-C10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, and R 2A Each is (i) halogen; (ii) cyano; (iii) hydroxyl; (iv) -NR A R B ;(v) -C(=O)NR A R B ;(vi) ;(vii) -NHC(=O)R C ;(viii) -C(=O)OR D ;(ix) -SO2R D ;(x) -NHSO2R D ;(xi) -SO2NR D R E ;(xii) NR A R B -NHC(=O)C1-C6 alkyl arbitrarily substituted with; (xiii) C1-C6 haloalkyl; (xiv) C1-C6 hydroxyalkyl; (xv) hydroxyl, cyano, halogen, -C(=O)NR A R B , -NR A R B , C1-C6 alkyl optionally substituted with hydroxyl, and 5- to 10-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from 4- to 10-membered heterocyclies optionally substituted with hydroxyl or C1-C6 alkyl; (xvi) hydroxyl, cyano, halogen, C1-C6 haloalkyl, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NR D R E , C1-C6 alkoxy, -C(=O)NR A R B , -NR A R B , -NR A R B 4- to 10-membered heterocyclils optionally substituted with 1 to 3 substituents independently selected from -NHC(=O)C1-C6 alkyl optionally substituted with -NHC(=O)C1-C6 alkyl and C1-C6 alkoxy or hydroxyl optionally substituted with C1-C6 alkyl; (xvii) hydroxyl, oxo, -NR A R B , -C(=O)NR A R B , C1-C6 alkoxy and hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NR A R B or a C1-C6 alkyl optionally substituted with 1 to 3 substituents independently selected from a 4- to 10-membered heterocyclile optionally substituted with a -C(=O)C3-C6 cycloalkyl; (xviii) -NR A R B , or a C1-C6 alkoxy optionally substituted with a 4- to 10-membered heterocyclyl optionally substituted with a C1-C6 alkyl, aralkyl, heteroaralkyl or -C(=O)C3-C6 cycloalkyl; (xix) hydroxyl, -C(=O)NR A R B , -C(=NH)OR D , or C3-C6 cycloalkyl optionally substituted with a 4- to 10-membered heterocyclyl optionally substituted with a C1-C6 alkyl; and (xx) independently selected from 4- to 10-membered heterocyclyloxy optionally substituted with a hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with a hydroxyl, and R A and R B is independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy, or R A and R B is formed a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and R C are C3-C6 cycloalkyl and -C(=O)NHR, respectively. Y1 , and -NR A R B R is independently selected from C1-C6 alkyl or C1-C6 alkyl optionally substituted with a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 hydroxyalkyl, and R D and R E are hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and oxo, respectively, or -NR A R B Independently selected from C1-C6 alkyls arbitrarily substituted with , and R 3A and R 3B are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R 3A and R 3B They form quaternary to octavalent heterocyclil groups together with the carbon and nitrogen atoms to which they are respectively attached, and R 4 is hydrogen, a halogen, a C1-C6 alkyl, or an acrylamido, and R 5 -NR 5A R 5B , -NR 5A C(=O)R 5B or -C(=O)NR 5A R 5B and, R 5A and R 5B is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl, and R 6 is hydrogen, a halogen, or a C1-C6 alkyl, and X is a bond, CH2, CH(CH3), C(CH3)2 or and W is NR 3B or O, and Y is a phenyl, naphthyl, or 5- to 10-membered heteroaryl, wherein the phenyl, naphthyl, and 5- to 10-membered heteroaryl are independently selected 1 to 3 Rs Y or It is replaced arbitrarily and independently, and * is L 1 This indicates that it is connected to the remaining part of the compound of the above chemical formula (I), and R Y are respectively halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -(CH2) n -C(=O)R F , -(CH2) n -NHC(=O)R F , -(CH2) n -NHC(=O)OR F , -C(=O)C(=O)NHR F , -CO2R G , -(CH2) n -SO2NR H R I , -(CH2) n -NHSO2R J , -(CH2) n -S(=O)(=NR H )R J , -(CH2) n -SO2R J , -(CH2) n -C(=O)NR H R I , -(CH2) n -C(=O)NR H OR I and independently selected from C1-C6 haloalkyls optionally substituted with hydroxyl, and R F Each is independently selected from C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl optionally substituted with C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and R G Each is independently selected from hydrogen, C3-C6 cycloalkyl, 5-6 member heteroaryl, 4-6 member heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl), and R H and R I are hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2) n -C(=O)NH2, -(CH2) n -SO2NH2, -(CH2) n -SO2(C1-C6 alkyl), hydroxyl, -SO2(C1-C6 alkyl), C1-C6 alkoxy, 5- to 6-membered heteroaryl, C3-C6 cycloalkyl and -C(=O)NR K1 R K2 Independently selected from C1-C6 alkyls optionally substituted with 1 to 2 independently selected substituents, or R H and R I is formed a quaternary to 10-membered heterocyclile optionally substituted with 1 to 2 substituents independently selected from halogens, C1-C6 alkyls, and -C(=O)C1-C6 alkyls, together with the nitrogen atoms to which they are attached, and R J is a C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy, and R K1 and R K2 is independently hydrogen or a C1-C6 alkyl, ring A is a phenyl, a 4- to 10-membered heteroaryl, a 4- to 10-membered heterocyclyl, or a C4-C10 cycloalkyl, and L 1 Silver bond, C1-C6 alkoxylene, -(CH2) n -NHC(=O)-, -C(=O)NH-(CH2) n -, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NR G )-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or a C1-C6 alkylene optionally substituted with an oxo, and R Y1 ≡ cyano, hydroxyl, halogen, -C(=O)R, respectively. F , -NHC(=O)R F , -CO2R G , -SO2NR H R I , -NHSO2R J , -S(=O)(=NR H )R J , -SO2(C1-C6 alkyl), -C(=O)NR H R I , 4~6 won heteroaryl, R Y2 C1-C6 alkoxy, C1-C6 haloalkyl, R optionally substituted with Y2 Independently selected from C1-C6 alkyl and hydroxyl optionally substituted with or 4- to 6-membered heterocyclies optionally substituted with C1-C6 alkyl, and R Y2 is hydroxyl, -NR H R I , -C(=O)NR H R I or -SO2NR H R I A compound in which n is 0, 1 or 2, and z is 0, 1, 2 or 3. Claim 2 In paragraph 1, Z is a compound that is CH. Claim 3 In paragraph 1, Z is a compound of which is N. Claim 4 In any one of paragraphs 1 to 3, R 1 A compound that is hydrogen. Claim 5 In any one of paragraphs 1 to 3, R 1 It is a halogen, a compound. Claim 6 In any one of paragraphs 1 to 3, R 1 Cyanoin, a compound. Claim 7 In any one of paragraphs 1 to 3, R 1 A compound that is a C3-C6 cycloalkyl. Claim 8 In any one of paragraphs 1 to 3, R 1 A compound that is a C1-C6 alkyl or 4- to 10-membered heterocyclile optionally substituted with a C3-C6 cycloalkyl. Claim 9 In any one of paragraphs 1 through 3 or paragraph 8, R 1 A compound that is a C1-C6 alkyl. Claim 10 In any one of paragraphs 1 through 3, paragraph 8, or paragraph 9, R 1 It is methyl, a compound. Claim 11 In any one of paragraphs 1 to 3, R 1 A compound that is a 4- to 10-membered heterocyclile optionally substituted with a C1-C6 alkyl group. Claim 12 In any one of paragraphs 1 to 3, R 1 A compound that is a C1-C6 thioalkyl. Claim 13 In any one of paragraphs 1 to 3, R 1 A compound that is a C1-C6 haloalkyl. Claim 14 In any one of paragraphs 1 to 3, R 1 C1-C6 alkoxyne, a compound. Claim 15 In any one of paragraphs 1 to 3, R 1 A compound that is a C1-C6 alkoxyalkyl. Claim 16 In any one of paragraphs 1 through 15, R 2 is 1 to 4 independently selected R 2A A C6-C10 aryl compound arbitrarily substituted with Claim 17 In any one of paragraphs 1 through 15, R 2 is 1 to 4 independently selected R 2A A compound of phenyl phosphate arbitrarily substituted with . Claim 18 In any one of paragraphs 1 through 15, R 2 is 1 to 4 independently selected R 2A A compound that is a 5- to 10-membered heteroaryl arbitrarily substituted with . Claim 19 In any one of paragraphs 1 through 15, R 2 is 1 to 3 independently selected R 2A A compound that is a 4- to 10-membered heterocyclile arbitrarily substituted with . Claim 20 In any one of paragraphs 1 through 15, R 2 is 1 to 3 independently selected R 2A A compound that is a 4- to 10-membered heterocyclile substituted with . Claim 21 In any one of paragraphs 1 through 15, R 2 is a compound that is a 4- to 10-membered heterocyclile. Claim 22 In any one of paragraphs 1 through 15, R 2 is 1 to 3 independently selected R 2A A compound that is a C4-C10 cycloalkyl alkyl arbitrarily substituted with Claim 23 In any one of paragraphs 1 through 15, R 2 is 1 to 4 independently selected R 2A 4- to 10-membered heterocyclyloxyne compounds arbitrarily substituted with . Claim 24 In any one of paragraphs 1 through 15, R 2 is 1 to 4 independently selected R 2A 5- to 10-membered heteroaryloxyne arbitrarily substituted with , a compound. Claim 25 In any one of paragraphs 1 through 15, R 2 is -C(=O)NR A R C , C4-C10 cycloalkyl, 4- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl or C1-C6 alkoxyne optionally substituted with phenyl, compound. Claim 26 In any one of paragraphs 1 through 15, R 2 is -C(=O)NR A R C A compound that is a C1-C6 alkoxyalkyl arbitrarily substituted with Claim 27 In any one of paragraphs 1 through 26, R 2A are respectively (i) halogen; (ii) hydroxyl, -C(=O)NR A R B or -C(=N)OR D C3-C6 cycloalkyl arbitrarily substituted with; (iii) methyl; (iv) C1-C2 haloalkyl; (v) halogen, hydroxyl, -C(=O)NR A R B , -C(=O)C1-C6 alkyl, -NR A R B and optionally substituted with 1 to 3 substituents independently selected from C1-C6 alkyl optionally substituted with hydroxyl; and (vi) C1-C6 alkyl, hydroxyl, -C(=O)NR optionally substituted with halogen, cyano, or hydroxyl A R B , -NR A R B A compound independently selected from , or 5-6 member heteroaryls optionally substituted with 4- to 10 member heterocyclies optionally substituted with hydroxyl or C1-C6 alkyl. Claim 28 A compound in any one of paragraphs 1 to 27, wherein X is a bond. Claim 29 A compound in any one of paragraphs 1 to 27, wherein X is CH2. Claim 30 A compound in any one of paragraphs 1 to 27, wherein X is CH(CH3). Claim 31 A compound in any one of paragraphs 1 to 27, wherein X is C(CH3)2. Claim 32 In any one of paragraphs 1 through 27, X is Phosphorus, compound. Claim 33 A compound in any one of paragraphs 1 to 32, wherein W is O. Claim 34 In any one of paragraphs 1 through 33, R 3A is a compound that is hydrogen. Claim 35 In any one of paragraphs 1 through 33, R 3A is a compound that is a C1-C6 alkyl. Claim 36 In any one of paragraphs 1 through 33, R 3A is a C1-C6 alkoxyne, a compound. Claim 37 In any one of paragraphs 1 through 33, R 3A is a compound that is a C1-C6 haloalkyl. Claim 38 In any one of paragraphs 1 through 32, W is NR 3B Phosphorus, compound. Claim 39 In any one of paragraphs 1 through 32 or paragraph 38, R 3B is a compound that is hydrogen. Claim 40 In any one of paragraphs 1 through 32 or paragraph 38, R 3B is a methyl compound. Claim 41 A compound according to any one of claims 1 to 40, wherein Y is an unsubstituted 5- to 10-membered heteroaryl. Claim 42 In any one of claims 1 to 40, Y is 1 to 3 independently selected R Y A compound of phenyl phosphate arbitrarily substituted with . Claim 43 In any one of claims 1 to 40, Y is 1 to 3 independently selected R Y A compound of naphthyl arbitrarily substituted with . Claim 44 In any one of claims 1 to 40, Y is 1 to 3 independently selected R Y A compound that is a 5- to 10-membered heteroaryl arbitrarily substituted with . Claim 45 In any one of paragraphs 1 through 40 or paragraphs 42 through 44, R Y are halogen, -CO2H, -SO2NH2, -SO2CH3, -C(=O)NH2, and -C(=O)NHR, respectively. H , -(CH2) n -C(=O)NHOR I and -(CH2) n -S(=O)(=NH)R J A compound independently selected from. Claim 46 In any one of paragraphs 1 through 40, Y is A phenyl substituted with , where * is L 1 A compound that indicates that this is connected to the remaining part of the compound of the above chemical formula (I). Claim 47 In any one of paragraphs 1 through 40, Y is Naphthyl substituted with, where * is L 1 A compound that indicates that this is connected to the remaining part of the compound of the above chemical formula (I). Claim 48 In any one of paragraphs 1 through 40, Y is A 5- to 10-membered heteroaryl substituted with , where * is L 1 A compound that indicates that this is connected to the remaining part of the compound of the above chemical formula (I). Claim 49 In any one of paragraphs 1 through 40 or paragraphs 46 through 48, R Y1 ≠ hydroxyl, cyano, -SO2NH2, -C(=O)R, respectively. F , -C(=O)NH2, a compound independently selected from C1-C3 alkoxy optionally substituted with hydroxyl and C1-C3 alkyl optionally substituted with hydroxyl. Claim 50 In any one of paragraphs 1 through 49, R 4 is a compound that is hydrogen. Claim 51 In any one of paragraphs 1 through 49, R 4 is a halogen, a compound. Claim 52 In any one of paragraphs 1 through 49, R 4 is a compound that is a C1-C6 alkyl. Claim 53 In any one of paragraphs 1 through 49, R 4 is acrylamidoin, a compound. Claim 54 In any one of paragraphs 1 through 53, R 5 is a compound that is hydrogen. Claim 55 In any one of paragraphs 1 through 53, R 5 is a halogen, a compound. Claim 56 In any one of paragraphs 1 through 53, R 5 is a compound that is a C1-C6 alkyl. Claim 57 In any one of paragraphs 1 through 53, R 5 is cyanoin, a compound. Claim 58 In any one of paragraphs 1 through 53, R 5 is -NR 5A R 5B Phosphorus, compound. Claim 59 In any one of paragraphs 1 through 53, R 5 is -C(=O)NR 5A R 5B Phosphorus, compound. Claim 60 In any one of paragraphs 1 through 53, R 5 is -NR 5A C(=O)R 5B Phosphorus, compound. Claim 61 In any one of paragraphs 1 through 60, R 6 is a compound that is hydrogen. Claim 62 In any one of paragraphs 1 through 60, R 6 is a halogen, a compound. Claim 63 In any one of paragraphs 1 through 60, R 6 is a compound that is a C1-C6 alkyl. Claim 64 In any one of paragraphs 1 through 50, R 4 is hydrogen, and R 5 is methyl, and R 6 is a compound that is hydrogen. Claim 65 In any one of paragraphs 1 through 50, R 4 is hydrogen, and R 5 is chloro, and R 6 is a compound that is hydrogen. Claim 66 In paragraph 64 or 65, R 1 Methyl or cyanoin, a compound. Claim 67 A compound selected from the group consisting of the compounds in Table A or a pharmaceutically acceptable salt thereof. Claim 68 A pharmaceutical composition comprising a compound of any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Claim 69 A method for treating a subject requiring cancer treatment, comprising the step of administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 67, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68. Claim 70 As a method for treating a subject requiring cancer treatment, (a) said cancer PIK3CA A method comprising: (a) determining that the expression or activity or level of a gene, PI3Kα protein, or any of these is associated with a dysregulation; and (b) administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 67, a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 68. Claim 71 A method for treating PI3Kα-associated cancer in a subject, comprising the step of administering a therapeutically effective amount of a compound of any one of claims 1 to 67, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 68 to a subject confirmed or diagnosed to have PI3Kα-associated cancer. Claim 72 A method for inhibiting mutant PI3Kα activity in mammalian cells, comprising the step of contacting said mammalian cells with an effective amount of a compound of any one of claims 1 to 67 or a pharmaceutically acceptable salt thereof.

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