Methods for treating cancer

Abstract

This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3 kinase (PI3K) isoform alpha (PI3Kα). These compounds are useful for treating a disease in which increased PI3Kα activation contributes to the pathology, symptoms, and / or progression of the disease (e.g., cancer) in a subject.

Description

[0001] Methods for Treating Cancer

[0002] RELATED APPLICATIONS

[0003] This application claims the benefit of priority to U.S. Provisional AppL No. 63 / 615,064, filed on December 27, 2023 and U.S. Provisional AppL No. 63 / 675,810, filed on July 26, 2024, which arehereby incorporated by reference in their entireties.

[0004] SEQUENCE LISTING

[0005] This application contains a Sequence Listing that has been submitted electronically as an XML file named “49366-0056WO3_ST26.SL.XML.” The XML file, created on July 25, 2024, is 2,933 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0006] FIELD

[0007] This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3 -kinase (PI3K) isoform alpha (PI3Kα). These compounds are useful for treating a disease in which increased PI3Kα activation contributes to the pathology, symptoms, and / or progression of the disease (e.g., cancer) in a subject.

[0008] BACKGROUND

[0009] Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Kα), encoded by the PIK3CA gene is a part of the PI3K / AKT / TOR signaling network and is altered in several human cancers.

[0010] Activation of the PI3K pathway occurs in approximately 30-50% human cancers and contributes to resistance to various anti-cancer therapies. (See, Bauer, T.M. et al., Pharmacol. Then 2015, 146, 53-60.) However, development of PI3K inhibitors has been problematic for several reasons, in particular, inability to specifically inhibit signaling by mutant PI3Kα while sparing wild-type PI3Kα, and the related dose-limiting toxicities that prevent sustained PI3K pathway suppression. (See, Hanker et al., Cancer Discovery, April 2019;9: 482-491.) For example, alpelisib is a PI3K inhibitor that is equipotent against wild-type and mutant forms of PI3Kα, which results in dose-limiting toxicities and hyperglycemia. Thus, selectively targeting PI3Kα represents an approach for the treatment of proliferative disorders such as cancer.

[0011] SUMMARY

[0012] Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0013] Z is N or CH; RIis hydrogen, halogen, cyano, C3-C6 cycloalkyl, C1-C6thioalkyl, C1-C6haloalkyl, C1- C6 alkoxy, C1-C6alkoxyalkyl, 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; or C1-C6alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;

[0014] R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A, 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A, C1-C6alkoxyalkyl optionally substituted with - C(=O)NRARC, or C1-C6alkoxy optionally substituted with -C(=O)NRARC, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl; each R2Ais independently selected from:

[0015] (i) halogen;

[0016] (ii) cyano;

[0017] (iii) hydroxyl;

[0018] (iv) -NRARB;

[0019] (v) -C(=O)NRARB;

[0020] (vii) -NHC(=O)Rc;

[0021] (viii) -C(=O)ORD;

[0022] (ix) -SO2RD;

[0023] (x) -NHSO2RD;

[0024] (xi) -SO2NRDRE;

[0025] (xii) -NHC(=O)C1-C6alkyl optionally substituted with NRARB;

[0026] (xiii) C1-C6haloalkyl;

[0027] (xiv) C1-C6hydroxyalkyl;

[0028] (xv) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, -C(=O)NRARB, -NRARB, C1-C6alkyl optionally substituted with hydroxyl; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;

[0029] (xvi) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, - SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl;

[0030] (xvii) C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;

[0031] (xviii) C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl;

[0032] (xix) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; and

[0033] (xx) 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6alkyl optionally substituted with hydroxyl; each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6alkyl optionally substituted with hydroxyl orC1-C6alkoxy, or RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1- C6 alkyl, and -C(=O)C1-C6alkyl; each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl; each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6alkoxy, and C1-C6alkyl optionally substituted with oxo or -NRARB; each R3Aand R3Bis independently selected from hydrogen, C1-C6alkyl, C1-C6alkoxy, and C1-C6haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0034] R4is hydrogen, halogen, C1-C6alkyl, or acrylamido;

[0035] R5is hydrogen, halogen, C1-C6alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR3AR5B;

[0036] R5Aand R5Bare independently selected from hydrogen, C1-C6alkyl, C2-C6 alkenyl, and C1-C6hydroxyalkyl;

[0037] R6is hydrogen, halogen, or C1-C6alkyl;

[0038] X is a bond, CH2, CH(CH3), C(CH3)2, or

[0039] W is NR3Bor O;

[0040] Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5- 10 membered heteroaryl are optionally and independently substituted with 1-3 independently selected RYor wherein * represents the connection of L1to the remainder of the compound of Formula (I); each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, -(CH2)n-C(=O)RF-(CH2)n-NHC(=O)RF, -(CH2)n-NHC(=O)ORF, -C(=O)C(=O)NHRF, -CO2RG, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ, -(CH2)n-SO2RJ, -(CH2)n-C(=O)NRHR1, -(CH2)n-C(=O)NRHR1, and C1-C6haloalkyl optionally substituted with hydroxyl; each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl optionally substituted with C1-C6alkyl; and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RHand RIis independently selected from: hydrogen, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n- SO2NH2, -(CH2)n-SO2(C1-C6alkyl), C1- C6 alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, - SO2(C1-C6alkyl), C1-C6alkoxy, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and - C(=O)NRK1RK2; or RHand RItogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl;

[0041] RJis C1-C6alkyl, C3-C6 cycloalkyl, or C1-C6alkoxy; each RK1and RK2is independently hydrogen or C1-C6alkyl;

[0042] Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;

[0043] L1is a bond, C1-C6alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6alkylene)-, -C(=O)C(=O)NH-, or C1-C6alkylene optionally substituted with oxo; each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2R0, -SO2NRHRI, -NHSO2R2-S(=O)(=NRH)RJ, -SO2(C1-C6alkyl), -C(=O)NRHRI, 4-6 membered heteroaryl, C1-C6alkoxy optionally substituted with RY2, C1-C6haloalkyl, C1-C6alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;

[0044] RY2is hydroxyl, -NRHRr, -C(=O)NRHRI, or -SO2NRHR1; n is 0, 1, or 2; and z is O, 1, 2, or 3.

[0045] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Provided herein is a method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0046] Also provided herein is a method for treating cancer in a subject in need thereof, comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0047] Provided herein is a method of treating a PI3Kα-associated disease in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated disease a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0048] This disclosure also provides a method of treating a PI3Kα-associated disease in a subject, comprising: determining that the cancer in the subject is a PI3Kα-associated disease; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0049] Further provided herein is a method of treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0050] This disclosure also provides a method of treating a PI3Kα-associated cancer in a subject, comprising: determining that the cancer in the subject is a PI3Kα-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein.

[0051] Provided herein is a method of treating a subject, comprising administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a P1K3CA gene, a PI3Kα protein, or expression or activity or level of any of the same.

[0052] This disclosure also provides a method for inhibiting PI3Kα in a mammalian cell, comprising contacting the mammalian cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0053] Other embodiments include those described in the Detailed Description and / or in the claims.

[0054] Additional Definitions

[0055] To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties.

[0056] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation, for example, within experimental variability and / or statistical experimental error, and thus the number or numerical range may vary up to ±10% of the stated number or numerical range.

[0057] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0058] The term “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopically enriched variants of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0059] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. The term "inhibit" or "inhibition of" means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).

[0060] The phrase "therapeutically effective amount" means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat a PI3Kα protein- associated disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, or (iii) delay the onset of one or more symptoms of the particular disease described herein.

[0061] The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.

[0062] As used herein, the term “subject” refer to any animal, including mammals such as primates (e.g., humans), mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and 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.

[0063] As used herein, terms “treat” or “treatment” refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0064] The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0065] The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls.

[0066] The term “hydroxyl” refers to an -OH radical.

[0067] The term “cyano” refers to a -CN radical.

[0068] The term “alkyl” refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, Ci-io indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and / or other substituents as defined herein. The term “alkenyl” refers to an alkyl, in which one or more hydrogen atoms is / are removed such that the alkyl has one or more carbon-carbon double bonds.

[0069] The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen.

[0070] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCHs).

[0071] The term “alkoxyalkyl” refers to an -alkyl-O-alkyl radical (e.g., -CH2CH2OCH3).

[0072] The term “thioalkyl” refers to an -S-alkyl radical (e.g., -SCH3) or an -alkyl-S-alkyl radical (e.g., -CH2CH2SCH3).

[0073] The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with hydroxyl.

[0074] The term “aryl” refers to a 6-20 membered all carbon ring system wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system). Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, 2,3- dihydro-lH-indene, and the like.

[0075] The term “cycloalkyl” as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and / or bridged rings. Non-limiting examples of fused / bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[l.l.l]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, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just 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]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms.

[0076] The term “heteroaryl”, as used herein, refers to a ring system having 5 to 20 ring atoms, such as 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the 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 system is aromatic (but does not have to be a ring which contains a heteroatom, e g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can include monocyclic, bridged, fused, and spiro ring systems, so long as one ring in the system is aromatic. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]yrimidinyl, pyrrolo[2,3-5]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3- c]pyridinyl, pyrazolo[3,4-6]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[6][l,4]dioxine, benzo[d][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[6][l,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of pyridone (e.g., pyrimidone (e.g., , pyridazinone (e.g., , pyrazinone (e.g., ) imidazolone (e.g., ' ), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring).

[0077] The term “heterocyclyl” refers to a saturated or partially unsaturated ring systems with 3- 16 ring atoms (e.g., 3-8 membered monocyclic, 5-12 membered bicyclic, or 10-14 membered tricyclic ring system) having at least one heteroatom selected from O, N, S, Si, and B, wherein one or more ring atoms may be substituted by 1 -3 oxo (forming, e g., a lactam) and one or more N or S atoms may be substituted by 1-2 oxido (forming, e.g., an N-oxide, an S-oxide, or an S,S-dioxide), valence permitting. Heterocyclyl groups can also include one or two imino (=NH) groups, valnce permitting. Heterocyclyl groups include monocyclic, bridged, fused, and spiro ring systems. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2- azabicyclo[1.1.0]butane, 22--aazzaabbiiccyycclloo[[22..11..OOjjppeennttaannee,, 2-azabicyclo[ 1.1. IJpentane, 3- azabicyclo[3.1.OJhexane, 55--aazzaabbiiccyycclloo[[22..11..11 JJhheexxaannee,, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.OJheptane, 7-azabicyclo[2.2.1] heptane, 6- azabicyclo[3.1.1 Jheptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2Joctane, 3- azabicyclo[3.2.1 ] octane, 2-oxabicyclo[l .1.OJbutane, 2-oxabicyclo[2.1.Ojpentane, 2- oxabicyclo[ 1.1. IJpentane, 3-oxabicyclo[3. 1.OJhexane, 5-oxabicyclo[2.1.1 Jhexane, 3- oxabicyclo[3.2. OJheptane, 3-oxabicyclo[4.1.OJheptane, 7-oxabicyclo[2.2.1 Jheptane, 6- oxabicyclo[3.1.1 Jheptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3- oxabicyclo[3.2.1Joctane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2-azaspiro[2.2]pentane, 4-azaspiro[2.5Joctane, 1- azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5Jnonane, 2-azaspiro[4.4Jnonane, 6- azaspiro[2.6Jnonane, l,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4-oxaspiro[2.5] octane, l-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7-oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6- oxaspiro[2.6]nonane, l,7-dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1- oxaspiro[5.5]undecane, 3-oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like.

[0078] An “aralkyl” refers to an aryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6alkyl group, as described herein. Non-limiting examples of an aralkyl group are benzyl, ethylphenyl, methylnaphthyl, and the like.

[0079] A “heteroaralkyl” refers to a heteroaryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6alkyl group, as described herein. Non-limiting examples of an aralkyl group are methylpyridyl, ethylpyrimidinyl, methylimidazolyl, and the like. A “heterocyclyl oxy” refers to an -O-heterocyclyl radical, wherein the heterocyclyl group is as defined herein.

[0080] A “heteroaryloxy” refers to an -O-heteroaryl radical, wherein the heteroaryl group is as defined herein.

[0081] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0082] As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like.

[0083] For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms

[0084] (e.g., [x.x.O] ring systems, in which 0 represents a zero atom bridge single ring atom (spiro-fused ring systems) a contiguous array of ring atoms (bridged ring systems having all bridge lengths

[0085] In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0086] In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety: encompasses the tautomeric form containing the moiety: Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0087] 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, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry (e.g., a “flat” structure) and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. Likewise, unless otherwise indicated, when a disclosed compound is named or depicted by a structure that specifies the stereochemistry (e.g., a structure with “wedge” and / or “dashed” bonds) and has one or more chiral centers, it is understood to represent the indicated stereoisomer of the compound.

[0088] The details of one or more embodiments of this disclosure are set forth in the accompanying drawings and the description below. Other features and advantages of the present disclosure will be apparent from the description and drawings, and from the claims.

[0089] DETAILED DESCRIPTION

[0090] This disclosure provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3 -kinase (PI3K) isoform alpha (PI3Kα). These compounds are useful for treating a disease in which increased PI3Kα activation contributes to the pathology, symptoms, and / or progression of the disease (e.g., cancer) in a subject. Formulae (I) Compounds

[0091] Some embodiments provide a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0092] Z is N or CH; RIis hydrogen, halogen, cyano, C3-C6 cycloalkyl, C1-C6thioalkyl, C1-C6haloalkyl, C1- C6 alkoxy, C1-C6alkoxyalkyl, 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; or C1-C6alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;

[0093] R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A, 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A, C1-C6alkoxyalkyl optionally substituted with - C(=O)NRARC, or C1-C6alkoxy optionally substituted with -C(=O)NRARC, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl; each R2Ais independently selected from:

[0094] (i) halogen;

[0095] (ii) cyano;

[0096] (iii) hydroxyl;

[0097] (iv) -NRARB;

[0098] (v) -C(=O)NRARB;

[0099] 25 (vii) -NHC(=O)Rc;

[0100] (viii) -C(=O)ORD;

[0101] (ix) -SO2RD;

[0102] (x) -NHSO2RD;

[0103] (xi) -SO2NRDRE;

[0104] (xii) -NHC(=O)C1-C6alkyl optionally substituted with NRARB;

[0105] (xiii) C1-C6haloalkyl;

[0106] (xiv) C1-C6hydroxyalkyl;

[0107] (xv) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, -C(=O)NRARB, -NRARB, C1-C6alkyl optionally substituted with hydroxyl; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;

[0108] (xvi) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, - SO2(C1-C6alkyl), -SO2NRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl;

[0109] (xvii) C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;

[0110] (xviii) C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl;

[0111] (xix) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; and

[0112] (xx) 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6alkyl optionally substituted with hydroxyl; each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C 1-C6 alkyl optionally substituted with hydroxyl or C 1-C6 alkoxy, or RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1- C6 alkyl, and -C(=O)C1-C6alkyl; each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl; each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6alkoxy, and C1-C6alkyl optionally substituted with oxo or -NRARB; each R3Aand R3Bis independently selected from hydrogen, C1-C6alkyl, C1-C6alkoxy, and C1-C6haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0113] R4is hydrogen, halogen, C1-C6alkyl, or acrylamido;

[0114] R5is hydrogen, halogen, C1-C6alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;

[0115] R5Aand R5Bare independently selected from hydrogen, C1-C6alkyl, C2-C6 alkenyl, and C1-C6hydroxyalkyl;

[0116] R6is hydrogen, halogen, or C1-C6alkyl;

[0117] X is a bond, CH2, CH(CH3), C(CH3)2, or

[0118] W is NR3Bor O;

[0119] Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5- 10 membered heteroaryl are optionally and independently substituted with 1-3 independently selected RYor wherein * represents the connection of L1to the remainder of the compound of Formula (I); each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, -(CH2)n-C(=O)RF-(CH2)n-NHC(=O)RF-(CH2)n-NHC(=O)ORF, -C(=O)C(=O)NHRF, -CO2R0, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ. -(CH2)n-SO2RJ, -(CH2X-C(=O)NRHRI, -(CH2)n-C(=O)NRHORI, and C1-C6haloalkyl optionally substituted with hydroxyl; each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl optionally substituted with C1-C6alkyl; and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RHand RIis independently selected from: hydrogen, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2ySO2NH2, -(CH2)n-SO2(C1-C6alkyl), C1- C6 alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, - SO2(C1-C6alkyl), C1-C6alkoxy, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and - C(=O)NRK1RK2; or RHand RItogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl;

[0120] RJis C1-C6alkyl, C3-C6 cycloalkyl, or C1-C6alkoxy; each RK1and RK2is independently hydrogen or C1-C6alkyl;

[0121] Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;

[0122] L1is a bond, C1-C6alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6alkylene)-, -C(=O)C(=O)NH-, or C1-C6alkylene optionally substituted with oxo; each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2R0, -SO2NRHRI, -NHSO2R2-S(=O)(=NRH)RJ, -SO2(C1-C6alkyl), -C(=O)NRHRI, 4-6 membered heteroaryl, C1-C6alkoxy optionally substituted with RY2, C1-C6haloalkyl, C1-C6alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;

[0123] RY2is hydroxyl, -NRHRr, -C(=O)NRHRI, or -SO2NRHRI; n is 0, 1, or 2; and z is O, 1, 2, or 3. Some embodiments provide a compound of Formula (IA): or a pharmaceutically acceptable salt thereof, wherein:

[0124] Z is N or CH; RIis hydrogen, cyano, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C1-C6alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl, C1-C6thioalkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6alkoxyalkyl;

[0125] R2is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A, 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A, C1-C6alkoxyalkyl optionally substituted with -C(=O)NRARc, or C1-C6alkoxy optionally substituted with -C(=O)NRARc, 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl; each R2Ais independently selected from:

[0126] (i) halogen,

[0127] (ii) cyano,

[0128] (iii) hydroxyl,

[0129] 20 (iv) -NRARB,

[0130] (v) -C(=O)NRARB,

[0131] (vii) -NHC(=O)Rc,

[0132] (viii) -C(=O)NRDRE,

[0133] (ix) -C(=O)ORF, (x) -SO2RF,

[0134] (xi) -NHSO2RF,

[0135] (xii) -SO2NRFRG,

[0136] (xiii) -NHC(=O)C1-C6alkyl optionally substituted with NRARB,

[0137] (xiv) C1-C6haloalkyl,

[0138] (xv) C1-C6hydroxyalkyl,

[0139] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6alkyl and -NRARB,

[0140] (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRFRG, C1-C6alkyl optionally substituted with C1-C6alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6alkyl optionally substituted with -NRARB,

[0141] (xviii) C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl,

[0142] (xix) C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl, and

[0143] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6alkyl optionally substituted with hydroxyl orC1-C6alkoxy, or RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1- C6 alkyl, and -C(=O)C1-C6alkyl; each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl; each RDand REis independently selected from hydrogen, hydroxyl, C1-C6alkyl, and C1- C6 alkoxy; each R3Aand R3Bis independently selected from hydrogen, C1-C6alkyl, C1-C6alkoxy, and C1-C6haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0144] R4is hydrogen, C1-C6alkyl, or acrylamido;

[0145] R5is hydrogen, C1-C6alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;

[0146] R5Aand R5Bare independently selected from hydrogen, C1-C6alkyl, C2-C6 alkenyl, and C1-C6hydroxyalkyl;

[0147] R6is hydrogen, halogen, or C1-C6alkyl;

[0148] X is a bond, CHj, CH(CH3), C(CH3)2, or

[0149] Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6haloalkyl, C1- C6 alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, -NHC(=O)Rc, -C(=O)NHRY1, -CO2RA, -SO2NRFRG, -NHSO2RF, -S(=O)(=NRF)RG, -SO2(C1-C6alkyl), -C(=O)NRARB, 5-6 membered heteroaryl, heteroaralkyl, and C1-C6alkyl optionally substituted with -CO2RAor 5-6 membered heteroaryl optionally substituted with RY1;

[0150] RY1is -SO2(C1-C6alkyl) or C1-C6alkyl optionally substituted with oxo; and each RFand RGis independently selected from hydrogen, phenyl, and C1-C6alkyl optionally substituted with oxo or -NRARB.

[0151] Some embodiments, provide a compound of Formula (IB): or a pharmaceutically acceptable salt thereof, wherein: Z is N or CH; R1is hydrogen, halogen, cyano, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C1-C6alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl, C1-C6thioalkyl, C1-C6haloalkyl, C1-C6alkoxy, or C1-C6alkoxyalkyl;

[0152] R2is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, 4-10 membered cycloalkyl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A, 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A, C1-C6alkoxyalkyl optionally substituted with -C(=O)NRARc, or C1-C6alkoxy optionally substituted with -C(=O)NRARc, 4-10 membered cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl; each R2Ais independently selected from:

[0153] (i) halogen,

[0154] (ii) cyano,

[0155] (iii) hydroxyl,

[0156] (iv) -NRARB,

[0157] (v) -C(=O)NRARB,

[0158] (vii) -NHC(=O)Rc,

[0159] (viii) -C(=O)NRDRE,

[0160] (ix) -C(=O)ORF,

[0161] (x) -SO2RF,

[0162] (xi) -NHSO2RF,

[0163] (xii) -SO2NRFRG,

[0164] (xiii) -NHC(=O)C1-C6alkyl optionally substituted with NRARB,

[0165] (xiv) C1-C6haloalkyl,

[0166] (xv) C1-C6hydroxyalkyl,

[0167] (xvi) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6alkyl and -NRARB, (xvii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRFRG, C1-C6alkyl optionally substituted with C1-C6alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6alkyl optionally substituted with -NRARB,

[0168] (xviii) C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl,

[0169] (xix) C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl, and

[0170] (xx) C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6alkyl optionally substituted with hydroxyl orC1-C6alkoxy, or RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1- C6 alkyl, and -C(=O)C1-C6alkyl; each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl; each RDand REis independently selected from hydrogen, hydroxyl, C1-C6alkyl, and C1- C6 alkoxy; each R3Aand R3Bis independently selected from hydrogen, C1-C6alkyl, C1-C6alkoxy, and C1-C6haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0171] R4is hydrogen, halogen, C1-C6alkyl, or acrylamido;

[0172] R3is hydrogen, halogen, C1-C6alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR3AR3B;

[0173] R3Aand R3Bare independently selected from hydrogen, C1-C6alkyl, C2-C6 alkenyl, and C1-C6hydroxyalkyl;

[0174] R6is hydrogen, halogen, or C1-C6alkyl; X is a bond, CH2, CH(CH3), C(CH3)2, or

[0175] W is NR3Bor O;

[0176] Y is phenyl optionally substituted with 1-3 independently selected RY, naphthyl optionally substituted with 1-3 independently selected RY, or 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY; each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6haloalkyl optionally substituted with hydroxyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, - NHC(=O)Rc, -C(=O)NHRY1, -CO2RA, -SO2NRFRG, -NHSO2RF-S(=O)(=NRF)RG, -SO2(C1-C6alkyl), -C(=O)NRARB, 4-6 membered heteroaryl, heteroaralkyl, 4-6 membered heterocyclyl optionally substituted with RY1, and C1-C6alkyl optionally substituted with -CO2RAor 4-6 membered heteroaryl optionally substituted with RY1;

[0177] RY1is -SO2(C1-C6alkyl) or C1-C6alkyl optionally substituted with oxo; and each RFand RGis independently selected from hydrogen, phenyl, and C1-C6alkyl optionally substituted with oxo or -NRARB.

[0178] In some embodiments, Z is CH.

[0179] In some embodiments, Z is N.

[0180] In some embodiments, R1is hydrogen.

[0181] In some embodiments, R1is halogen. In some embodiments, R1is I, Br, C1, or F. In some embodiments, R1is Cl or F. In some embodiments, R1is F. In some embodiments, R1is Cl.

[0182] In some embodiments, R1is cyano.

[0183] In some embodiments, R1is C3-C6 cycloalkyl. In some embodiments, R1is cyclopropyl or cyclobutyl.

[0184] In some embodiments, R1is 4-10 membered heterocyclyl optionally substituted with C1- C6 alkyl. In some embodiments, R1is 4-10 membered heterocyclyl. In some embodiments, R1is 4-10 membered heterocyclyl substituted with C1-C6alkyl.

[0185] In some embodiments, R1is 5-8 membered heterocyclyl.

[0186] In some embodiments, the heterocyclyl of R1is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyranyl, octahydrocyclopenta[b]pyranyl, 2-oxabicyclo[2.1.1]hexanyl, 2- oxabicyclo[3.1.1]heptanyl, or morpholinyl. In some embodiments, the heterocyclyl of R1is octahydrocyclopenta[c]pyranyl. In some embodiments, the heterocyclyl of R1is octahydrocyclopenta[b]pyranyl. In some embodiments, the heterocyclyl of R1is 2- oxabicyclo[2.1. I]hexanyl. In some embodiments, the heterocyclyl of R1is 2- oxabicyclo[3.1.1 ]heptanyl .

[0187] In some embodiments, R1is C1-C6alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl. In some embodiments, R1is C1-C6alkyl substituted with with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl. In some embodiments, R1is C1-C3 alkyl substituted with with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl In some embodiments, R1is C1-C6alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R1is C1-C6alkyl substituted with 4-10 membered heterocyclyl. In some embodiments, R1is C1-C6alkyl. In some embodiments, R1is methyl, ethyl, or isopropyl. In some embodiments, R1is methyl.

[0188] In some embodiments, R1is C1-C6thioalkyl. In some embodiments, R1is C1-C3 thioalkyl. In some embodiments, R1is thiomethyl, thioethyl, or thiopropyl. In some embodiments, R1is methyl-thiomethyl, methyl-thioethyl, or ethyl -thiomethyl. In some embodiments, R1is thiomethyl.

[0189] In some embodiments, R1is C1-C6haloalkyl. In some embodiments, R1is C1-C3 haloalkyl. In some embodiments, R1is C1-C3 fluoroalkyl. In some embodiments, R1is CF3. In some embodiments, R1is CHF2.

[0190] In some embodiments, R1is C1-C6alkoxy. In some embodiments, R1is C1-C3 alkoxy. In some embodiments, R1is -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R1is -OCH3.

[0191] In some embodiments, R1is C1-C6alkoxyalkyl. In some embodiments, R1is C1-C3 alkoxyalkyl. In some embodiments, R1is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R1is -CH2OCH3.

[0192] In some embodiments, R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is C6-C10 aryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is C6-C10 aryl substituted with 1 R2A. In some embodiments, R2is C6-C10 aryl substituted with 2 independently selected R2A. In some embodiments, R2is C6-C10 aryl optionally substituted with 3 independently selected R2A. In some embodiments, R2is C6-C10 aryl.

[0193] In some embodiments, R2is phenyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is phenyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is phenyl substituted with 1 R2A. In some embodiments, R2is phenyl substituted with 2 independently selected R2AIn some embodiments, R2is phenyl optionally substituted with 3 independently selected R2A. In some embodiments, R2is phenyl.

[0194] In some embodiments, R2is 2,3 -dihydro- IH-indenyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 2,3-dihydro-lH-indenyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 2,3-dihydro-lH-indenyl substituted with 1 R2A. In some embodiments, R2is 2,3-dihydro-lH-indenyl substituted with 2 independently selected R2A. In some embodiments, R2is 2,3-dihydro-lH-indenyl optionally substituted with 3 independently selected R2A. In some embodiments, R2is 2,3-dihydro-lH- indenyl.

[0195] In some embodiments, R2is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 5-10 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 5-10 membered heteroaryl substituted with 1 R2A. In some embodiments, R2is 5-10 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2is 5-10 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2is 5-10 membered heteroaryl.

[0196] In some embodiments, R2is 6 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 6 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 6 membered heteroaryl substituted with 1 R2A. In some embodiments, R2is 6 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2is 6 membered heteroaryl optionally substituted with 3 independently selected R2AIn some embodiments, R2is 6 membered heteroaryl.

[0197] In some embodiments, R2is 9 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 9 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 9 membered heteroaryl substituted with 1 R2A. In some embodiments, R2is 9 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2is 9 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2is 9 membered heteroaryl.

[0198] In some embodiments, the heteroaryl of R2is pyridinyl, pyrimidinyl, pyridazinyl, indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, azaisoindoline, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzoisoxazolyl, benzisothiazolyl, quinolinyl, 6,7- dihydro-5H-cyclopenta[c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, chromanyl, 3,4- dihydro-2H-112-quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 6,7-dihydro-5H- cyclopenta[c]pyridinyl, 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 isoquinolinyl. In some embodiments, the heteroaryl of R2is pyridinyl or pyrimidinyl. In some embodiments, the heteroaryl of R2is pyridinyl. In some embodiments, the heteroaryl of R2is indole, indazole, azaindole, azaindazole, indoline, azaindoline, isoindoline, or azaisoindoline. In some embodiments, the heteroaryl of R2is 6,7- dihydro-5H-cyclopenta[c]pyridinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, chromanyl, 3,4- dihydro-2H-112-quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 6,7-dihydro-5H- cyclopenta[c]pyridinyl, 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, or 5,6,7,8-tetrahydroquinazolinyl. In some embodiments, the heteroaryl of R2is 6,7-dihydro-5H- cyclopenta[c]pyridinyl. In some embodiments, the heteroaryl of R2is 6,7-dihydro-5H- cy cl opentafb] pyridinyl. In some embodiments, the heteroaryl of R2is chromanyl. In some embodiments, the heteroaryl of R2is 3,4-dihydro-2H-quinolinyl, 5,6,7,8-tetrahydroquinazolinyl, or 6,7-dihydro-5H-cyclopenta[c]pyridinyl. In some embodiments, the heteroaryl of R2is 3,4- dihydro-2H-112-quinolinyl. In some embodiments, the heteroaryl of R2is 5,6,7,8- tetrahydroquinazolinyl. In some embodiments, the heteroaryl of R2is 6,7-dihydro-5H- cyclopenta[c]pyridinyl. In some embodiments, the heteroaryl of R2is 4-dihydro-2H-pyrano[2,3- bjpyridinyl. In some embodiments, the heteroaryl of R2is 3,4-dihydro-2H-pyrano[2,3-c]pyridinyl, or 5,6,7,8-tetrahydroquinazolinyl, In some embodiments, the heteroaryl of R2is 3,4-dihydro-2H- pyrano[3,2-b]pyridinyL In some embodiments, the heteroaryl of R2is 7,8-dihydro-6H-pyrano[3,2- djpyrimidinyl, In some embodiments, the heteroaryl of R2is 5,6,7,8-tetrahydroquinazolinyl.

[0199] In some embodiments, R2is 5-10 membered heteroaryloxy optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 5-10 membered heteroaryloxy substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 5-10 membered heteroaryloxy substituted with 1 R2A. In some embodiments, R2is 5-10 membered heteroaryloxy substituted with 2 independently selected R2A. In some embodiments, R2is 5-10 membered heteroaryloxy optionally substituted with 3 independently selected R2A. In some embodiments, R2is 5-10 membered heteroaryloxy.

[0200] In some embodiments, R2is 6 membered heteroaryloxy optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 6 membered heteroaryloxy substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 6 membered heteroaryloxy substituted with 1 R2A. In some embodiments, R2is 6 membered heteroaryloxy substituted with 2 independently selected R2A. In some embodiments, R2is 6 membered heteroaryloxy optionally substituted with 3 independently selected R2A. In some embodiments, R2is 6 membered heteroaryloxy.

[0201] In some embodiments, R2is 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 4-10 membered heterocyclyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 4-10 membered heterocyclyl substituted with 1 R2A. In some embodiments, R2is 4-10 membered heterocyclyl substituted with 2 independently selected R2AIn some embodiments, R2is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2is 4-10 membered heterocyclyl.

[0202] In some embodiments, R2is 4-10 membered bicyclic ether optionally substituted with 1 or 2 independently selected R2AIn sone embodiments, R2is 4-10 membered bridging bicyclic ether optionally substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 4-10 membered fused bicyclic ether optionally substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 4-10 membered spirocyclic ether optionally substituted with 1 or 2 independently selected R2A. In some embodiments, R2is an unsubstituted 4-10 membered bridging bicyclic ether. In some embodiments, R2is an unsubstituted 4-10 membered fused bicyclic ether. In some embodiments, R2is an unsubstituted 4-10 membered spirocyclic ether. In some embodiments, R2is 4-10 membered bridging bicyclic ether substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 4-10 membered fused bicyclic ether substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 4-10 membered spirocyclic ether substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyl substituted with 1 R2A. In some embodiments, R2is 5-8 membered heterocyclyl substituted with 2 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyl.

[0203] In some embodiments, the heterocyclyl of R2is piperidinyl, piperazinyl, octahydrocyclopenta[c]pyranyl, octahydrocyclopenta[b]pyranyl, 2-oxabicyclo[2.1.1]hexanyl, 2- oxabicyclo[3.1.1]heptanyl, or morpholinyl. In some embodiments, the heterocyclyl of R2is octahydrocyclopenta[c]pyranyl. In some embodiments, the heterocyclyl of R2is octahydrocyclopenta[b]pyranyl. In some embodiments, the heterocyclyl of R2is 2- oxabicyclo[2.1.1]hexanyl. In some embodiments, the heterocyclyl of R2is 2- oxabicyclo[3.1.1]heptanyl. In some embodiments, R2is 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 4-10 membered heterocyclyloxy substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 4-10 membered heterocyclyloxy substituted with 1 R2A. In some embodiments, R2is 4-10 membered heterocyclyloxy substituted with 2 independently selected R2A. In some embodiments, R2is 4-10 membered heterocyclyloxy optionally substituted with 3 independently selected R2A. In some embodiments, R2is 4-10 membered heterocyclyloxy.

[0204] In some embodiments, R2is 5-8 membered heterocyclyloxy optionally substituted with 1- 4 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyloxy substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyloxy substituted with 1 R2A. In some embodiments, R2is 5-8 membered heterocyclyloxy substituted with 2 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyloxy optionally substituted with 3 independently selected R2A. In some embodiments, R2is 5-8 membered heterocyclyloxy.

[0205] In some embodiments, R2is C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is C4-C10 cycloalkyl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is C4-C10 cycloalkyl substituted with 1 R2A. In some embodiments, R2is C4-C10 cycloalkyl substituted with 2 independently selected R2A. In some embodiments, R2is C4-C10 cycloalkyl optionally substituted with 3 independently selected R2A. In some embodiments, R2is C4-C10 cycloalkyl.

[0206] In some embodiments, R2is C5-C7 cycloalkyl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is C5-C7 cycloalkyl substituted with 1 or 2 independently selected R2AIn some embodiments, R2is C5-C7 cycloalkyl substituted with 1 R2A. In some embodiments, R2is C5-C7 cycloalkyl substituted with 2 independently selected R2A. In some embodiments, R2is C5-C7 cycloalkyl optionally substituted with 3 independently selected R2A. In some embodiments, R2is C5-C7 cycloalkyl.

[0207] In some embodiments, the cycloalkyl of R2is cyclopentyl, [l.l.ljbicyclopentyl, octahydro- IH-indenyl, bicyclo[2.1.1]hexanyl, bicyclo[3.1.0]hexanyl, spiro[2.4]heptanyl, or cyclohexyl. In some embodiments, the cycloalkyl of R2is octahydro-lH-indenyl. In some embodiments, the cycloalkyl of R2is bicyclo[2.1.1]hexanyl. In some embodiments, the cycloalkyl of R2is bicyclo[3.1.OJhexanyl.

[0208] In some embodiments, R2is C1-C6alkoxy optionally substituted with -C(=O)NRARc, C4- C10 cycloalkyl, or phenyl. In some embodiments, R2is C1-C6alkoxy substituted with - C(=O)NRARc, C4-C10 cycloalkyl, or phenyl. In some embodiments, R2is C1-C6alkoxy substituted with -C(=O)NRARc. In some embodiments, R2is C1-C6alkoxy substituted with C4- C10 cycloalkyl. In some embodiments, R2is C1-C6alkoxy substituted with C4-C6 cycloalkyl. In some embodiments, R2is C1-C6alkoxy substituted with phenyl. In some embodiments, R2is C1- C6 alkoxy. In some embodiments, R2is C1-C3 alkoxy. In some embodiments, R2is -OCH3 or - OCH2CH3.

[0209] In some embodiments, R2is C1-C6alkoxyalkyl optionally substituted with -C(=O)NRARC. In some embodiments, R2is C1-C6alkoxyalkyl substituted with -C(=O)NRARc. In some embodiments, R2is C3-C6 alkoxyalkyl substituted with -C(=O)NRARc. In some embodiments, R2is C1-C6alkoxyalkyl. In some embodiments, R2is-CIhOCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R2is -CH2OCH3.

[0210] In some embodiments, R2is

[0211] .

[0212] In some embodiments, R2is

[0213] , In some embodiments, R2is

[0214]

[0215] In some embodiments, 1, 2, 3, or 4 of R2Aare independently halogen. In some embodiments, 1, 2, or 3 of R2Aare independently fluoro or chloro. In some embodiments, 1 or 2 of R2Aare independently fluoro or chloro. In some embodiments, 1 R2Ais fluoro or chloro.

[0216] In some embodiments, 1, 2, 3, or 4 of R2Aare independently cyano. In some embodiments, 1 or 2 of R2Aare cyano. In some embodiments, 1 R2Ais cyano.

[0217] In some embodiments, 1, 2, 3, or 4 of R2Aare independently hydroxyl, In some embodiments, 1 or 2 of R2Aare hydroxyl. In some embodiments, 1 R2Ais hydroxyl.

[0218] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -NRARB. In some embodiments, 1 or 2 of R2Aare independently -NRARB. In some embodiments, 1 R2Ais -NRARB.

[0219] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -C(=O)NRARB. In some embodiments, 1 or 2 of R2Aare independently -C(=O)NRARB. In some embodiments, 1 R2Ais -C(=O)NRARB. In some embodiments, 1, 2, 3, or 4 of R2Aare independently In some embodiments, 1 or 2 of R2Aare independently In some embodiments, 1 R2Ais

[0220] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -NHC(=O)Rc. In some embodiments, 1 or 2 of R2Aare independently -NHC(=O)Rc. In some embodiments, 1, 2, 3, or 4 of R2Aare independently -C(=O)ORD. In some embodiments, 1 or 2 of R2Aare independently - C(=O)ORD. In some embodiments, 1 R2Ais -C(=O)ORD.

[0221] In some embodiments, 1, 2, 3, or 4 of R^ are independently -SO2RD. In some embodiments, 1 or 2 of R2Aare independently -SO2RD. In some embodiments, 1 R2Ais -SO2RD.

[0222] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -NHSO2RD. In some embodiments, 1 or 2 of R2Aare independently -NHSO2RD. In some embodiments, 1 R ,2: Ais -NHSO2RD.

[0223] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -SO2NRDRE. In some embodiments, 1 or 2 of R2Aare independently -SO2NRDRE. In some embodiments, 1 R2Ais -SO2NRDRE.

[0224] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -NHC(=O)C1-C6alkyl optionally substituted with NRARB. In some embodiments, 1, 2, or 3 of R2Aare independently -NHC(=O)C1-C6alkyl substituted with NRARB. In some embodiments, 1, 2, or 3 of R2Aare independently -NHC(=O)C1-C6alkyl. In some embodiments, 1 or 2 of R2Aare independently -NHC(=O)C1-C6alkyl optionally substituted with NRARB. In some embodiments, 1 or 2 of R2Aare independently -NHC(=O)C1-C6alkyl substituted with NRARB. In some embodiments, 1 or 2 of R2Aare independently -NHC(=O)C1-C6alkyl. In some embodiments, 1 R2Ais -NHC(=O)C1- C6 alkyl optionally substituted with NRARB.

[0225] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6haloalkyl. In some embodiments, 1 or 2 of R2Aare independently C1-C3 haloalkyl. In some embodiments, 1 or 2 of R2Aare trifluoromethyl. In some embodiments, 1 R2Ais C1-C6haloalkyl. In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6hydroxyalkyl. In some embodiments, 1 or 2 of R2Aare independently C1-C3 hydroxyalkyl. In some embodiments, 1 R2Ais C1-C3 hydroxyalkyl.

[0226] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, -C(=O)NRARB, -NRARB, C1-C6alkyl optionally substituted with hydroxyl; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl. In some embodiments, 1, 2, 3, or 4 of R2Aare independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6alkyl, halogen, -C(=O)NRARB, -NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl. In some embodiments, 1, 2, 3, or 4 of R2Aare independently 5-10 membered heteroaryl. In some embodiments, 1 R2Ais 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, -C(=O)NRARB, -NRARB, C1-C6alkyl optionally substituted with hydroxyl; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl.

[0227] In some embodiments, 1 of R2Ais 5-6 membered heteroaryl optionally substituted with 1- 3 substituents independently selected from hydroxyl, cyano, C1-C6alkyl, halogen, -C(=O)NRARB, -NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl. In some embodiments, 1 of R2Ais 5-6 membered heteroaryl substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6alkyl, halogen, -C(=O)NRARB, -NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl. In some embodiments, 1 of R2Ais 5-6 membered heteroaryl.

[0228] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, - C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl. In some embodiments, 1 of R2Ais 4- 10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), - SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl. In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl, and C1-C6alkyl. In some embodiments, 1 of R2Ais 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl, and C1-C6alkyl.

[0229] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2<C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, - NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl substituted with C1-C6alkoxy or hydroxyl. In some embodiments, 1 of R2Ais 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, - NRARB, -NHC(=O)C1-C6alkyl substituted with -NRARB, and C1-C6alkyl substituted with C1- C6 alkoxy or hydroxyl.

[0230] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl substituted with 1 substituent independently selected from hydroxyl, cyano, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2<C1-C6alkyl), -SO2NRE, C1-C6alkyl, -C(=O)NRARB, -NRARB, or -NHC(=O)C1-C6alkyl. In some embodiments, 1 of R2Ais 4-10 membered heterocyclyl substituted with 1 substituent independently selected from hydroxyl, cyano, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRE, C1-C6alkyl, -C(=O)NRARB, -NRARB, or -NHC(=O)C1-C6alkyl.

[0231] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl. In some embodiments, 1 of R2Ais 4-10 membered heterocyclyl.

[0232] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R2Aare independently C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl. In some embodiments, 1 R2Ais C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl .

[0233] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.

[0234] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.

[0235] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl.

[0236] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl. In some embodiments, 1, 2, or 3 of R2Aare independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of R2Aare methyl. In some embodiments, 1 or 2 of R2Aare independently C1-C6alkyl. In some embodiments, 1 or 2 of R2Aare independently C1-C3 alkyl. In some embodiments, 1 or 2 of R2Aare methyl.

[0237] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R2Aare independently C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl. In some embodiments, 1 R2Ais C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl . In some embodiments, 1 , 2, 3, or 4 of R2Aare independently C1-C6 alkoxy substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[0238] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy substituted with -NRARBor 4-10 membered heterocyclyl substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[0239] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy substituted with -NRARBor 4-10 membered heterocyclyl.

[0240] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy.

[0241] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl. In some embodiments, 1 or 2 of R2Aare independently C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl. In some embodiments, 1 R2Ais C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl.

[0242] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl.

[0243] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl substituted with C1- C6 alkyl.

[0244] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl.

[0245] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R2Aare independently C3-C6 cycloalkyl.

[0246] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyloxy. In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyloxy substituted with hydroxyl, cyano, halogen, or C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, 1 or 2 of R2Aare independently 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6alkyl optionally substituted with hydroxyl. In some embodiments, 1 R2Ais 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6alkyl optionally substituted with hydroxyl.

[0247] In some embodiments, R2is substituted with 1 R2A. In some embodiments, R2is substituted with 2 independently selected R2A. In some embodiments, R2is substituted with 3 independently selected R2A. In some embodiments, R2is substituted with 4 independently selected R2A.

[0248] In some embodiments, R2is piperidinyl substituted with 1-2 independently selected R2A. In some embodiments, R2is piperidinyl substituted with 2-4 independently selected R2A. In some embodiments, R2is morpholinyl substituted with 2-4 independently selected R2A. In some embodiments, R2is morpholinyl. In some embodiments, R2is piperazinyl substituted with 1-2 independently selected R2A

[0249] In some embodiments, R2is phenyl substituted with 1-2 independently selected R2A. In some embodiments, R2is pyridinyl substituted with 1-2 independently selected R2A.

[0250] In some embodiments, R2is indolyl substituted with 1-2 independently selected R2A. In some embodiments, R2is indazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2is 7-azaindolyl substituted with 1-2 independently selected R2A. In some embodiments, R2is 7-azaindazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2is l,2-dihydro-3H-indazol-3-one substituted with 1-2 independently selected R2A. In some embodiments, R2is isoindolinyl substituted with 1-2 independently selected R2A. In some embodiments, R2is isoindolinyl. In some embodiments, R2is 2-indolinone substituted with 1-2 independently selected R2A. In some embodiments, R2is benzimidazolyl substituted with 1-2 independently selected R2A. In some embodiments, R2is imidazopyridinyl substituted with 1-2 independently selected R2A. In some embodiments, R2is l,3-dihydro-2H-benzo[d]imidazol-2- onyl substituted with 1-2 independently selected R2A. In some embodiments, R2is [l,2,4]triazolo[l,5-a]pyridine substituted with 1-2 independently selected R2A.

[0251] In some embodiments, one R2Ais C1-C6alkyl, C1-C6haloalkyl, C1-C6hydroxyalkyl, cyano, or hydroxyl, and the other R2Aare independently selected from C1-C6haloalkyl, C1-C6hydroxyalkyl, cyano, hydroxyl, halogen, -NRARB, -C(=O)NRARB, -NHC(=O)Rc, -C(=O)ORD, -SO2RD, -NHSO2RD, -SO2NRDRE, -NHC(=O)C1-C6alkyl optionally substituted withNRARB, 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from C1-C6alkyl and -NRARB, 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkyl optionally substituted with C1- C6 alkoxy, -C(=O)NRARB, or -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl, C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl, and C3-C6 cycloalkyl optionally substituted with 4-10 membered heterocyclyl optionally substituted with C1- C6 alkyl.

[0252] In some embodiments, each R2Ais 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.

[0253] In some embodiments, 1, 2, or 3 R2Aare independently selected from halogen, methyl, ethyl, -NH2, -NHCH3, -N((CH3)2-C(=O)NH2, -C(=O)NHClfc, -C(=O)N(CH3)2, -C(=0)NH0H, -SO2NH2, -SO2NHCH3, -SO2N(CH_3)2, cyclopropyl, cyclobutyl, trifluoromethyl, 2,2,2- trifluoroethyl, and acetyl.

[0254] In some embodiments, 1 or 2 R2Aare 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.

[0255] In some embodiments, each R2Ais independently selected from:

[0256] (i) halogen;

[0257] (ii) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, or -C(=N)ORD;

[0258] (iii) methyl;

[0259] (iv) C1-C2 haloalkyl; (v) 4-6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, -C(=O)NRARB, -C(=O)C1-C6alkyl, -NRARB, and C1-C6alkyl optionally substituted with hydroxyl; and

[0260] (vi) 5-6 membered heteroaryl optionally substituted with halogen, cyano, C1-C6alkyl optionally substituted with hydroxyl, hydroxyl, -C(=O)NRARB, -NRARB, or 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl.

[0261] In some embodiments, 1 or 2 R2Aare independently selected from:

[0262] (i) halogen;

[0263] (ii) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, or

[0264] -C(=N)ORD;

[0265] (iii) methyl;

[0266] (iv) C1-C2 haloalkyl;

[0267] (v) 4-6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, -C(=O)NRARB, -C(=O)C1-C6alkyl, -NRARB, and C1-C6alkyl optionally substituted with hydroxyl; and

[0268] (vi) 5-6 membered heteroaryl optionally substituted with halogen, cyano, C1-C6alkyl optionally substituted with hydroxyl, hydroxyl, -C(=O)NRARB, -NRARB, or 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl.

[0269] In some embodiments, 1 R2Ais:

[0270] (i) halogen;

[0271] (ii) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, or

[0272] -C(=N)ORD;

[0273] (iii) methyl;

[0274] (iv) C1-C2 haloalkyl;

[0275] (v) 4-6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, -C(=O)NRARB, -C(=O)C1-C6alkyl, -NRARB, and C1-C6alkyl optionally substituted with hydroxyl; or

[0276] (vi) 5-6 membered heteroaryl optionally substituted with halogen, cyano, C1-C6alkyl optionally substituted with hydroxyl, hydroxyl, -C(=O)NRARB, -NRARB, or 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl.

[0277] In some embodiments, X is a bond. In some embodiments, X is CH2.

[0278] In some embodiments, X is CH(CH3).

[0279] In some embodiments, X is C(CH3)2.

[0280] In some embodiments,

[0281] In some embodiments, W is O.

[0282] In some embodiments, R3Ais hydrogen.

[0283] In some embodiments, R3Ais C1-C6alkyl. In some embodiments, R3Ais methyl or ethyl. In some embodiments, R3Ais methyl.

[0284] In some embodiments, R3Ais C1-C6alkoxy. In some embodiments, R3Ais C1-C3 alkoxy. In some embodiments, R3Ais -OCH3, -OCH2CH3, or-OCH2CH2CH3. In some embodiments, R3Ais -OCH3.

[0285] In some embodiments, R3Ais C1-C6haloalkyl. In some embodiments, R3Ais C1-C3 haloalkyl. In some embodiments, R3Ais C1-C3 fluoroalkyl. In some embodiments, R3Ais CF3. In some embodiments, R3Ais CHF2.

[0286] In some embodiments, W is NR3B.

[0287] In some embodiments, one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis C1- C6 alkyl. In some embodiments, one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis methyl. In some embodiments, each of R3Aand R3Bis hydrogen. In some embodiments, each of R3Aand R3Bis an independently selected C1-C6alkyl. In some embodiments, each of R3Aand R3Bis methyl.

[0288] In some embodiments, one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis C1- C6 alkoxy. In some embodiments, one of R3Aand R3Bis C1-C6alkyl and the other of R3Aand R3Bis C1-C6alkoxy. In some embodiments, R3Ais C1-C6alkoxy. In some embodiments, R3Ais C1- C3 alkoxy. In some embodiments, R3Ais -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R3Ais -OCH3.

[0289] In some embodiments, one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis C 1- C6 haloalkyl. In some embodiments, one of R3Aand R3Bis C1-C6alkyl and the other of R3Aand R3Bis C1-C6haloalkyl. In some embodiments, R3Ais C1-C6haloalkyl. In some embodiments, R3Ais C1-C3 haloalkyl. In some embodiments, R3Ais C1-C3 fluoroalkyl. In some embodiments, R3Ais CF3. In some embodiments, R3Ais CHF2. In some embodiments, R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group. In some embodiments, R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 5-6 membered heterocyclyl group.

[0290] In some embodiments, Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5-10 membered heteroaryl are optionally and independently substituted with 1-3 independently selected RY.

[0291] In some embodiments, Y is phenyl optionally substituted with RY, naphthyl substituted with RY, or 5-10 membered heteroaryl substituted with RY.

[0292] In some embodiments, Y is phenyl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is phenyl substituted with 1 or 2 independently selected RY. In some embodiments, Y is phenyl substituted with 1 RY. In some embodiments, Y is phenyl substituted with 2 independently selected RY. In some embodiments, Y is phenyl optionally substituted with 3 independently selected RY. In some embodiments, Y is phenyl.

[0293] In some embodiments, Y is naphthyl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is naphthyl substituted with 1 or 2 independently selected RY. In some embodiments, Y is naphthyl substituted with 1 RY. In some embodiments, Y is naphthyl substituted with 2 independently selected RY. In some embodiments, Y is naphthyl optionally substituted with 3 independently selected R\ In some embodiments, Y is naphthyl.

[0294] In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 or 2 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl substituted with 1 RY. In some embodiments, Y is 5-10 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl optionally substituted with 3 independently selected RY. In some embodiments, Y is 5-10 membered heteroaryl.

[0295] In some embodiments, Y is 6 membered heteroaryl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is 6 membered heteroaryl substituted with 1 or 2 independently selected RY. In some embodiments, Y is 6 membered heteroaryl substituted with 1 RY. In some embodiments, Y is 6 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 6 membered heteroaryl optionally substituted with 3 independently selected RY. In some embodiments, Y is 6 membered heteroaryl. In some embodiments, the 6 membered heteroaryl of Y is pyridyl (e.g., 3-pyridyl).

[0296] In some embodiments, Y is 9 membered heteroaryl optionally substituted with 1-3 independently selected RY. In some embodiments, Y is 9 membered heteroaryl substituted with 1 or 2 independently selected RY. In some embodiments, Y is 9 membered heteroaryl substituted with 1 RY. In some embodiments, Y is 9 membered heteroaryl substituted with 2 independently selected RY. In some embodiments, Y is 9 membered heteroaryl optionally substituted with 3 independently selected R\ In some embodiments, Y is 9 membered heteroaryl.

[0297] In some embodiments, 1, 2, or 3 of RYis independently halogen. In some embodiments, 1, 2, or 3 of RYis independently chloro or fluoro. In some embodiments, 1 or 2 of RYis independently chloro or fluoro.

[0298] In some embodiments, 1, 2, or 3 of RYis hydroxyl. In some embodiments, 1 or 2 of RYis hydroxyl.

[0299] In some embodiments, 1, 2, or 3 of RYis cyano. In some embodiments, 1 or 2 of RYis cyano.

[0300] In some embodiments, 1, 2, or 3 of RYis independently C1-C6alkyl. In some embodiments, 1 or 2 of RYis independently C1-C6alkyl. In some embodiments, 1 or 2 of RYis independently C1-C3 alkyl.

[0301] In some embodiments, 1, 2, or 3 of RYis independently unsubstituted C1-C6haloalkyl. In some embodiments, 1 or 2 of RYis independently unsubstituted C1-C3 haloalkyl. In some embodiments, 1 or 2 of RYis trifluoromethyl.

[0302] In some embodiments, 1, 2, or 3 of RYis independently C1-C6haloalkyl substituted with hydroxyl. In some embodiments, 1 or 2 of RYis independently C1-C3 haloalkyl substituted with hydroxyl.

[0303] In some embodiments, 1, 2, or 3 of RYis independently C1-C6alkoxy. In some embodiments, 1 or 2 of RYis independently C1-C3 alkoxy. In some embodiments, 1 or 2 of RYis methoxy.

[0304] In some embodiments, 1, 2, or 3 of RYis independently C1-C6haloalkoxy. In some embodiments, 1 or 2 of RYis independently C1-C3 haloalkoxy. In some embodiments, 1 or 2 of RYis trifluoromethoxy. In some embodiments, 1, 2, or 3 of RYis independently C1-C6hydroxyalkyl. In some embodiments, 1 or 2 of RYis independently C1-C3 hydroxyalkyl. In some embodiments, 1 or 2 of RYis independently mono-hydroxyl C1-C3 alkyl. In some embodiments, 1 or 2 of RYis independently di-hydroxyl C2-C3 alkyl.

[0305] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-C(=O)RF, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-C(=0)RF, where n is 1.

[0306] In some embodiments, 1, 2, or 3 of RYis independently -C(=O)RF. In some embodiments,

[0307] 1 or 2 of RYis independently -C(=O)RF. In some embodiments, 1 of RYis

[0308] -C(=O)RF. In some embodiments, Y is substituted with 1 RY, and RYis -C(=O)RF.

[0309] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-NHC(=0)RF, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-NHC(=O)RFwhere n is 1.

[0310] In some embodiments, 1, 2, or 3 of RYis independently -NHC(=O)RF. In some embodiments, 1 or 2 of RYis independently -NHC(=O)RF. In some embodiments, 1 of RYis -NHC(=O)RFIn some embodiments, Y is substituted with 1 RY, and RYis -NHC(=O)RF.

[0311] In some embodiments, 1, 2, or 3 of RYis independently -C(=O)C(=O)NHRF. In some embodiments, 1 or 2 of RYis independently -C(=O)C(=O)NHRF. In some embodiments, 1 of RYis -C(=O)C(=O)NHRF. In some embodiments, Y is substituted with 1 RY, and RYis -C(=O)C(=O)NHRF.

[0312] In some embodiments, 1, 2, or 3 of RYis independently -CO2R0. In some embodiments, 1 or 2 of RYis independently -CO2R0. In some embodiments, 1 of RYis -CO2R0. In some embodiments, Y is substituted with 1 RY, and RYis -CO2RG. In some embodiments, Y is substituted with 1 RY, and RYis -CO2H.

[0313] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-SO2NRHR1, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-SO2NRHR1, where n is 1.

[0314] In some embodiments, 1, 2, or 3 of RYis independently -SO2NRIIRI. In some embodiments, 1 or 2 of RYis independently -SO2NRHRI. In some embodiments, 1 of RYis - SO2NRHRT. In some embodiments, Y is substituted with 1 RY, and RYis -SO2NRHRI.

[0315] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-NHSO2RJ, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-NHSO2RJ, where n is 1. In some embodiments, 1, 2, or 3 of RYis independently -NHSO2RJ. In some embodiments, 1 or 2 of RYis independently -NHSO2R1. In some embodiments, 1 of RYis -NHSO2RJ. In some embodiments, Y is substituted with 1 RY, and RYis -NHSO2R1.

[0316] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-S(=O)(=NRH)RJ, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-S(=O)(=NRH)RJ, where n is 1.

[0317] In some embodiments, 1, 2, or 3 of RYis independently -S(=O)(=NRH)RJ. In some embodiments, 1 or 2 of RYis independently -S(=O)(=NRH)RJ. In some embodiments, 1 of RYis -S(=O)(=NRH)RJ. In some embodiments, Y is substituted with 1 RY, and RYis -S(=O)(=NRH)RJ.

[0318] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-SO2R1, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-SO2RJ, where n is 1.

[0319] In some embodiments, 1, 2, or 3 of RYis independently -SO2RJ. In some embodiments, 1 or 2 of RYis independently -SO2RJ. In some embodiments, 1 of RYis -SO2R1. In some embodiments, 1, 2, or 3 of RYis independently -SO2(C1-C6alkyl). In some embodiments, 1 or 2 of RYis -SO2CH3. In some embodiments, 1 of RYis -SO2CH3. In some embodiments, Y is substituted with 1 RY, and RYis -SO2CH3.

[0320] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-C(=O)NRHRI, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-C(=O)NRHRI, where n is 1.

[0321] In some embodiments, 1, 2, or 3 of RYis independently -C(=O)NRHRI. In some embodiments, 1 or 2 of RYis independently -C(=O)NRHRI. In some embodiments, 1 of RYis - C(=O)NRHRI. In some embodiments, Y is substituted with 1 RY, and RYis -C(=O)NRHRI.

[0322] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-C(=O)NRHORI, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-C(=O)NRHORI, where n is 1.

[0323] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-C(=O)NRHOR1. In some embodiments, 1 or 2 of RYis independently -(CH2)n-C(=O)NRHORI. In some embodiments, 1 of RYis -(CH2)n-C(=O)NRIIORI. In some embodiments, Y is substituted with 1 RY, and RYis -(CH2)n-C(=O)NRHORI.

[0324] In some embodiments, each RYis independently selected from: halogen, -CO2H, -SO2NH2, -SO2CH3, -C(=O)NH2, -C(=O)NHRH, -(CH2)n-C(=O)NHORI, and -(CH2)n-S(=O)(=NH)RJ.

[0325] In some embodiments, 1 or 2 RYis independently selected from: halogen, -CO2H, -

[0326] 30 SO2NH2, -SO2CH3, -C(=O)NH2, -C(=O)NHRH, -(CH2)n-C(=O)NHORI, and -(CH2)n- S(=O)(=NH)RJ. In some embodiments, 1 RYis halogen, -CO2H, -SO2NH2, -SO2CH3, -C(=0)NH2, - C(=O)NHRH, -(CH2)n-C(=O)NHOR1, or -(CH2)n-S(=O)(=NH)RJ.

[0327] In some embodiments, Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5-10 membered heteroaryl are optionally and independently substituted with wherein * represents the connection of L1to the remainder of the compound of Formula (I).

[0328] In some embodiments, Y is phenyl and the phenyl is substituted with wherein * represents the connection of L1to the remainder of the compound of Formula (I).

[0329] In some embodiments, Y is naphthyl and the naphthyl is substituted with wherein * represents the connection of L1to the remainder of the compound of Formula (I).

[0330] In some embodiments, Y is 5-10 membered heteroaryl and the 5-10 membered heteroaryl is substituted with wherein * represents the connection of L1to the remainder of the compound of Formula (I).

[0331] In some embodiments, Ring A is phenyl.

[0332] In some embodiments, Ring A is 4-10 membered heteroaryl. In some embodiments, Ring A is 9-10 membered heteroaryl. In some embodiments, Ring A is 4-6 membered heteroaryl.

[0333] In some embodiments, Ring A is 4-10 membered heterocyclyL In some embodiments, Ring A is 9-10 membered heterocyclyL In some embodiments, Ring A is 4-6 membered heterocyclyL

[0334] In some embodiments, Ring A is C4-C10 cycloalkyl. In some embodiments, Ring A is C9- C10 cycloalkyl. In some embodiments, Ring A is C4-C6 cycloalkyl.

[0335] In some embodiments, L1is a bond.

[0336] In some embodiments, L1is C1-C6alkoxylene. In some embodiments, L1is -(CH2)n-NHC(=O)-.

[0337] In some embodiments, L1is -C(=O)NH-(CH2)n-.

[0338] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0339] In some embodiments, L1is -CO2-.

[0340] In some embodiments, L1is -SO2-.

[0341] In some embodiments, L1is -NHSO2-.

[0342] In some embodiments, L1is -SO2NH-.

[0343] In some embodiments, L1is -S(=O)(=NRG)-.

[0344] In some embodiments, L1is -SO2( C1-C6alkylene)-.

[0345] In some embodiments, L1is -C(=O)C(=O)NH-.

[0346] In some embodiments, L1is C1-C6alkylene optionally substituted with oxo. In some embodiments, L1is unsubstituted C1-C6alkylene. In some embodiments, L1is C1-C6alkylene substituted with oxo.

[0347] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3.

[0348] In some embodiments, 1, 2, or 3 of RY1is independently halogen. In some embodiments, 1, 2, or 3 of RY1is independently chloro or fluoro. In some embodiments, 1 or 2 of RY1is independently chloro or fluoro.

[0349] In some embodiments, 1, 2, or 3 of RY1is hydroxyl. In some embodiments, 1 or 2 of RY1is hydroxyl.

[0350] In some embodiments, 1, 2, or 3 of RY1is cyano. In some embodiments, 1 or 2 of RY1is cyano.

[0351] In some embodiments, 1, 2, or 3 of RY1is independently C1-C6alkyl. In some embodiments, 1 or 2 of RY1is independently C1-C6alkyl. In some embodiments, 1 or 2 of RY1is independently C1-C3 alkyl.

[0352] In some embodiments, 1, 2, or 3 of RY1is independently C1-C6alkyl substituted with RY2. In some embodiments, 1 or 2 of RY1is independently C1-C6alkyl substituted with RY2. In some embodiments, 1 or 2 of RY1is independently C1-C3 alkyl substituted with RY2. In some embodiments, 1, 2, or 3 of RY1is independently unsubstituted C1-C6haloalkyl. In some embodiments, 1 or 2 of RY1is independently unsubstituted C1-C3 haloalkyl. In some embodiments, 1 or 2 of RY1is trifluoromethyl.

[0353] In some embodiments, 1, 2, or 3 of RY1is independently C1-C6alkoxy substituted with RY2. In some embodiments, 1 or 2 of RY1is independently C1-C3 alkoxy substituted with RY2. In some embodiments, 1 or 2 of RY1is methoxy substituted with RY2.

[0354] In some embodiments, RY2is hydroxyl.

[0355] In some embodiments, RY2is -NRHR1.

[0356] In some embodiments, RY2is -C(=O)NRHRI.

[0357] In some embodiments, RY2is -SO2NRHRI.

[0358] In some embodiments, 1, 2, or 3 of RY1is independently C1-C6alkoxy. In some embodiments, 1 or 2 of RY1is independently C1-C3 alkoxy. In some embodiments, 1 or 2 of RY1is methoxy.

[0359] In some embodiments, 1, 2, or 3 of RY1is independently -C(=O)RF. In some embodiments,

[0360] 1 or 2 of RY1is independently -C(=O)RF. In some embodiments, 1 of RY1is

[0361] -C(=O)RF. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -C(=O)RF.

[0362] In some embodiments, 1, 2, or 3 of RY1is independently -NHC(=O)RF. In some embodiments, 1 or 2 of RY1is independently -NHC(=O)RF. In some embodiments, 1 of RY1is -NHC(=O)RF. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -NHC(=O)RF.

[0363] In some embodiments, 1, 2, or 3 of RY1is independently -CO2R0. In some embodiments, 1 or 2 of RY1is independently -CO2RG. In some embodiments, 1 of RY1is -COIRG. In some embodiments, Y is substituted with 1 RY1, and RY1is -CO2RG. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -CO2H.

[0364] In some embodiments, 1, 2, or 3 of RY1is independently -SO2NRHRI. In some embodiments, 1 or 2 of RY1is independently -SO2NRIIRI. In some embodiments, 1 of RY1is -SO2NRHR1. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -SO2NRHR1.

[0365] In some embodiments, 1, 2, or 3 of RY1is independently -NHSO2R1. In some embodiments, 1 or 2 of RY1is independently -NHSO2R1. In some embodiments, 1 of RY1is - NHSOiR1. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -NHSO2R1.

[0366] In some embodiments, 1, 2, or 3 of RY1is independently -S(=O)(=NRH)RJ. In some embodiments, 1 or 2 of RY1is independently -S(=O)(=NRH)RJ. In some embodiments, 1 of RY1 is -S(=O)(=NRH)RJ. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -

[0367] S(=O)(=NRH)RJ.

[0368] In some embodiments, 1, 2, or 3 of RY1is independently -SO2(C1-C6alkyl). In some embodiments, 1 or 2 of RY1is -SO2CH3. In some embodiments, 1 of RYis -SO2CH3. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -SO2CH3.

[0369] In some embodiments, 1, 2, or 3 of RY1is independently -C(=O)NRHRI. In some embodiments, 1 or 2 of RY1is independently -C(=O)NRHRI. In some embodiments, 1 of RY1is -C(=O)NRHRI. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -C(=O)NRHRI.

[0370] In some embodiments, 1, 2, or 3 of RY1is independently 4-6 membered heteroaryl. In some embodiments, 1 of RY1is 4-6 membered heteroaryl. In some embodiments, Ring A is substituted with 1 RY1, and RY1is 4-6 membered heteroaryl.

[0371] In some embodiments, 1, 2, or 3 of RY1is independently 5-6 membered heteroaryl. In some embodiments, 1 of RY1is 5-6 membered heteroaryl. In some embodiments, Ring A is substituted with 1 RY1, and RY1is 5-6 membered heteroaryl.

[0372] In some embodiments, 1, 2, or 3 of RY1is independently 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl. In some embodiments, 1, 2, or 3 of RY1is independently 4-6 membered heterocyclyl substituted with hydroxyl or C1-C6alkyl. In some embodiments, 1, 2, or 3 of RY1is independently 4-6 membered heterocyclyl.

[0373] In some embodiments, each RY1is independently selected from: hydroxyl, cyano, - SO2NH2, -C(=O)RF, -C(=O)NH2, C1-C3 alkoxy optionally substituted with hydroxyl, and C1-C3 alkyl optionally substituted with hydroxyl.

[0374] In some embodiments, 1 or 2 RY1is independently selected from: hydroxyl, cyano, - SO2NH2, -C(=O)RF, -C(=O)NH2, C1-C3 alkoxy optionally substituted with hydroxyl, and C1-C3 alkyl optionally substituted with hydroxyl.

[0375] In some embodiments, 1 RY1is hydroxyl, cyano, -SO2NH2, -C(=O)RF, -C(=O)NH2, C1-C3 alkoxy optionally substituted with hydroxyl, and C 1-C3 alkyl optionally substituted with hydroxyl.

[0376] In some embodiments, 1, 2, or 3 of RYis independently heteroaralkyl. In some embodiments, 1 of RYis independently heteroaralkyl.

[0377] In some embodiments, 1, 2, or 3 of RYis independently 4-6 membered heterocyclyl optionally substituted with RY1. In some embodiments, 1 of RYis 4-6 membered heterocyclyl. In some embodiments, 1 of RYis 4-6 membered heterocyclyl substituted with RY1. In some embodiments, Y is substituted with 1 RY, and RYis 4-6 membered heterocyclyl substituted with

[0378] RY1, where RY1is hydroxyl. In some embodiments, RYis In some embodiments, RY

[0379] In some embodiments, Y is selected from the group consisting of: In some embodiments, Y is selected from the group consisting of:

[0380] In some embodiments, Y is selected from the group consisting of:

[0381] In some embodiments, Y is selected from the group consisting of: In some embodiments, 1, 2, or 3 of RYis independently C1-C6alkyl optionally substituted with -CO2RAor 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RYis independently C 1-C6 alkyl substituted with -COzRAor 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RYis independently C1-C6alkyl substituted with -CO2RAor 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1, 2, or 3 of RYis independently C1-C6alkyl substituted with -CO2RAor 5-6 membered heteroaryl. In some embodiments, Y is substituted with 1 RY, and RYis C1-C6alkyl substituted with -CO2RA. In some embodiments, Y is substituted with 1 RY, and RYis C1-C6alkyl substituted with -CO2H.

[0382] In some embodiments, 1 or 2 of RYis independently C1-C6alkyl optionally substituted with -CO2RAor 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6alkyl substituted with -CO2RAor 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6alkyl substituted with -CO2RAor 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6alkyl substituted with -CO2RAor 5-6 membered heteroaryl.

[0383] In some embodiments, 1 or 2 of RYis independently C1-C6alkyl substituted with -CO2RA. In some embodiments, 1 or 2 of RYis independently C1-C6alkyl substituted 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6alkyl substituted with 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6alkyl substituted with 5-6 membered heteroaryl.

[0384] In some embodiments, 1, 2, or 3 of RYis independently C1-C6alkyl. In some embodiments, 1 or 2 of RYis independently C1-C3 alkyl. In some embodiments, 1, 2, or 3 of RYis methyl. In some embodiments, RY1is -SO2(C1-C6alkyl). In some embodiments, RY1is - SO2CH3.

[0385] In some embodiments, RY1is C1-C6alkyl optionally substituted with oxo. In some embodiments, RY1is C1-C6alkyl substituted with oxo. In some embodiments, RY1is acetyl, 1- oxoethyl, or 1-oxopropyL In some embodiments, RY1is C1-C6alkyl. In some embodiments, RY1is methyl. In some embodiments, R4is hydrogen.

[0386] In some embodiments, R4is halogen. In some embodiments, R4is fluoro or chloro. In some embodiments, R4is fluoro. In some embodiments, R4is chloro. In some embodiments, R4is C1-C6alkyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl.

[0387] In some embodiments, R4is acrylamido.

[0388] In some embodiments, R5is hydrogen. In some embodiments, R5is C1-C6alkyl. In some embodiments, R3is methyl or ethyl. In some embodiments, R3is methyl.

[0389] In some embodiments, R3is halogen. In some embodiments, R3is fluoro or chloro. In some embodiments, R3is fluoro. In some embodiments, R5is chloro.

[0390] In some embodiments, R5is cyano.

[0391] In some embodiments, R3is -NR3AR3B.

[0392] In some embodiments, R5is -NR5AC(=O)R5B.

[0393] In some embodiments, R5is -C(=O)NR5AR5B.

[0394] In some embodiments, one of R5Aand R3Bis hydrogen and the other of R5Aand R3Bis C1- C6 alkyl, C2-C6 alkenyl, or C1-C6hydroxyalkyl. In some embodiments, one of R5Aand R3Bis C1-C6alkyl and the other of R3Aand R3Bis C1-C6alkyl, C2-C6 alkenyl, or C1-C6hydroxyalkyl. In some embodiments, each of R5Aand R3Bis hydrogen. In some embodiments, each of R5Aand R3Bis an independently selected C1-C6alkyl. In some embodiments, each of R3Aand R3Bis methyl. In some embodiments, the C1-C6hydroxyalkyl of R3Aand R3Bis hydroxymethyl, 1- hydroxyethyl, 2-hydroxyethyl, dihydroxypropyl or dihydroxybutyl.

[0395] In some embodiments, R3is acrylamido.

[0396] In some embodiments, R6is hydrogen.

[0397] In some embodiments, R6is halogen. In some embodiments, R6is fluoro. In some embodiments, R6is chloro.

[0398] In some embodiments, R6is C1-C6alkyl. In some embodiments, R6is methyl.

[0399] In some embodiments, each of RAand RBare independently selected from hydrogen, hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6alkyl optionally substituted with hydroxyl or C1-C6alkoxy.

[0400] In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6alkyl optionally substituted with hydroxyl or C1-C6alkoxy. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6alkyl substituted with hydroxyl or C1-C6alkoxy.

[0401] In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6alkyl.

[0402] In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C 1- C6 alkoxy. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C3-C6 cycloalkyl . In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C2-C6 alkenyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl optionally substituted with hydroxyl or C1-C6alkoxy. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl substituted with C1-C6alkoxy.

[0403] In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6alkyl. In some embodiments, each of RAand RBare hydrogen. In some embodiments, each of RAand RBare an independently selected C1-C6alkyl optionally substituted with hydroxyl or C1-C6alkoxy. In some embodiments, each ofRAand RBare an independently selected C1-C6alkyl. In some embodiments, each of RAand RBare methyl.

[0404] In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, hydroxyl, and-C(=O)C1-C6alkyl.

[0405] In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, hydroxyl, and -C(=O)C1-C6alkyl.

[0406] In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with halogen, C1-C6alkyl, hydroxyl, or -C(=O)C1-C6alkyl. In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substitutents independently selected from fluoro, hydroxyl, methyl, and acetyl. In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl. In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 4-6 membered heterocyclyl.

[0407] In some embodiments, each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6alkyl substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl. In some embodiments, each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl substituted with -NRARBor with 4-10 membered heterocyclyl substituted with C1-C6alkyl or with C1-C6hydroxylalkyl. In some embodiments, each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl substituted with -NRARBor with 4-10 membered heterocyclyl. In some embodiments, each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl.

[0408] In some embodiments, each Rcis independently C3-C6 cycloalkyl. In some embodiments, each Rcis independently -C(=O)NHRY1. In some embodiments, each Rcis independently C1-C6alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl. In some embodiments, each Rcis independently C1-C6alkyl substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl.

[0409] In some embodiments, each RDis independently selected from hydrogen, hydroxyl, phenyl, C1-C6alkoxy, and C1-C6alkyl optionally substituted with oxo or -NRARB.

[0410] In some embodiments, RDis hydrogen.

[0411] In some embodiments, RDis hydroxyl.

[0412] In some embodiments, RDis phenyl.

[0413] In some embodiments, RDis C1-C6alkoxy.

[0414] In some embodiments, RDis C1-C6alkyl optionally substituted with oxo or -NRARB. In some embodiments, RDis unsubstituted C1-C6alkyl. In some embodiments, RDis C1-C6alkyl substituted with oxo or -NRARB. In some embodiments, RGis C1-C6alkyl substituted with -NRARB.

[0415] In some embodiments, each REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6alkoxy, and C1-C6alkyl optionally substituted with oxo or -NRARB.

[0416] In some embodiments, REis hydrogen.

[0417] In some embodiments, REis hydroxyl. In some embodiments, REis phenyl.

[0418] In some embodiments, REis C1-C6alkoxy.

[0419] In some embodiments, REis C1-C6alkyl optionally substituted with oxo or -NRARB. In some embodiments, REis unsubstituted C1-C6alkyl. In some embodiments, REis C1-C6alkyl substituted with oxo or -NRARB. In some embodiments, REis C1-C6alkyl substituted with -NRARB.

[0420] In some embodiments, one of RDand REis hydrogen and the other of RDand REis hydroxyl, C1-C6alkyl, or C1-C6alkoxy. In some embodiments, one of R° and REis hydrogen and the other of RDand REis hydroxyl. In some embodiments, one of RDand REis hydrogen and the other of RDand REis C1-C6alkyl. In some embodiments, one of RDand REis hydrogen and the other of RDand REis C1-C6alkoxy. In some embodiments, one of RDand REis hydrogen and the other of RDand REis hydroxyl, methyl, or methoxy. In some embodiments, each of RDand REis hydrogen. In some embodiments, each of RDand REis an independently selected C1-C6alkyl. In some embodiments, each of RDand REis methyl.

[0421] In some embodiments, each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6alkyl optionally substituted with hydroxyl or-SO2(C1-C6alkyl).

[0422] In some embodiments, RFis C3-C6 cycloalkyl.

[0423] In some embodiments, RFis 5-6 membered heteroaryl.

[0424] In some embodiments, RFis 4-6 membered heterocyclyl optionally substituted with C1-C6alkyl. In some embodiments, RFis 4-6 membered heterocyclyl. In some embodiments, RFis 4-6 membered heterocyclyl substituted with C1-C6alkyl.

[0425] In some embodiments, RFis C1-C6alkyl optionally substituted with hydroxyl or-SO2(C1- C6 alkyl). In some embodiments, RFis unsubstituted C1-C6alkyl. In some embodiments, RFis C1-C6alkyl substituted with hydroxyl or -SO2(C1-C6alkyl). In some embodiments, RFis C1-C6alkyl substituted with hydroxyl. In some embodiments, RFis C1-C6alkyl substituted with -SO2(C1-C6alkyl).

[0426] In some embodiments, each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl).

[0427] In some embodiments, RGis hydrogen. In some embodiments, RGis C3-C6 cycloalkyl.

[0428] In some embodiments, RGis 5-6 membered heteroaryl.

[0429] In some embodiments, RGis 4-6 membered heterocyclyl.

[0430] In some embodiments, RGis C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1- C6 alkyl). In some embodiments, RGis unsubstituted C1-C6alkyl. In some embodiments, RGis C1-C6alkyl substituted with hydroxyl or-SO2(C1-C6alkyl). In some embodiments, RGis C1-C6alkyl substituted with hydroxyl. In some embodiments, RGis C1-C6alkyl substituted with -SO2(C1-C6alkyl).

[0431] In some embodiments, each RHand R1is independently selected from: hydrogen, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, -(CH2)n- SO2(C1-C6alkyl), C1-C6alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, -SO2(C1-C6alkyl), C1-C6alkoxy, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and -C(=O)NRK1RK2.

[0432] In some embodiments, RHis hydrogen.

[0433] In some embodiments, RHis C1-C6alkoxy.

[0434] In some embodiments, RHis C3-C6 cycloalkyl.

[0435] In some embodiments, RHis C2-C6 alkenyl.

[0436] In some embodiments, RHis -(CH2)n-C(=O)NH2.

[0437] In some embodiments, RHis -(CH2)n-SO2NH2.

[0438] In some embodiments, RHis -(CH2)n-SC)2(C1-C6alkyl).

[0439] In some embodiments, RHis C1-C6alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, -SO2(C1-C6alkyl), C1-C6alkoxy, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and -C(=O)NRK1RK2. In some embodiments, RHis unsubstituted C1-C6alkyl. In some embodiments, RHis C1-C6alkyl substituted with hydroxyl or -SO2(C1-C6alkyl). In some embodiments, Rnis C1-C6alkyl substituted with hydroxyl. In some embodiments, RHis C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, RHis C1-C6alkyl substituted with C1-C6alkoxy. In some embodiments, RHis C1-C6alkyl substituted with 5-6 membered heteroaryl. In some embodiments, RHis C1-C6alkyl substituted with C3-C6 cycloalkyl. In some embodiments, RHis C1-C6alkyl substituted with -C(=O)NRK1RK2.

[0440] In some embodiments, both RK1and RK2are hydrogen.

[0441] In some embodiments, both RK1and RK2are C1-C6alkyl. In some embodiments, one of RK1and RK2is hydrogen and the other of RK1and RK2is C1- C6 alkyl.

[0442] In some embodiments, R1is hydrogen.

[0443] In some embodiments, R1is C1-C6alkoxy.

[0444] In some embodiments, R1is C3-C6 cycloalkyl.

[0445] In some embodiments, R1is C2-C6 alkenyl.

[0446] In some embodiments, R1is -(CH2)n-C(=O)NH2.

[0447] In some embodiments, R1is -(CH2)n-SO2NH2.

[0448] In some embodiments, R1is -(CH2)n-SO2(C1-C6alkyl).

[0449] In some embodiments, R1is C1-C6alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, -SO2(C1-C6alkyl), C1-C6alkoxy, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and -C(=O)NRK1RK2. In some embodiments, R1is unsubstituted C1- C6 alkyl. In some embodiments, R1is C1-C6alkyl substituted with hydroxyl or -SO2(C1-C6alkyl). In some embodiments, R1is C1-C6alkyl substituted with hydroxyl. In some embodiments, RIis C1-C6alkyl substituted with -SO2(C1-C6alkyl). In some embodiments, R1is C1-C6alkyl substituted with C1-C6alkoxy. In some embodiments, RIis C1-C6alkyl substituted with 5-6 membered heteroaryl. In some embodiments, R1is C1-C6alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R1is C1-C6alkyl substituted with -C(=O)NRK1RK2.

[0450] In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is phenyl or C1-C6alkyl optionally substituted with oxo or-NRARB. In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is phenyl or C1-C6alkyl substituted with oxo or -NRARB. In some embodiments, one of RHand RIis hydrogen and the other of RHand RIis phenyl or C 1-C6 alkyl. In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is phenyl. In some embodiments, one of Rnand R1is hydrogen and the other of RIIand R1is C1- C6 alkyl optionally substituted with oxo or -NRARB. In some embodiments, one of RHand RIis hydrogen and the other of RHand R1is C1-C6alkyl substituted with oxo or -NRARB. In some embodiments, each of RHand R1is hydrogen. In some embodiments, each of RHand R1is an independently selected C1-C6alkyl. In some embodiments, each of RHand RIis methyl.

[0451] In some embodiments, each of RHand R1is hydrogen. In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is C1-C6alkoxy, C3-C6 cycloalkyl, or C2-C6 alkenyl.

[0452] In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is C1-C6alkyl optionally substituted with hydroxyl, -SO2(C1-C6alkyl), or C1-C6alkoxy.

[0453] In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is -(CH2)n- C(=O)NH2, -(CH2)n-SO2NH2, or -(CH2)n-SO2(C1-C6alkyl).

[0454] In some embodiments, RHand R1together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl. In some embodiments, RHand R1together with the nitrogen atom to which they are attached form an unsubstituted 4-10 membered heterocyclyl. In some embodiments, RHand R1together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl. In some embodiments, RHand R1together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1 substituent independently selected from halogen, C1-C6alkyl, and -C(=O)C1- C6 alkyl. In some embodiments, RHand R1together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 2 substituents independentiy selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl.

[0455] In some embodiments, RJis C1-C6alkyl, C3-C6 cycloalkyl, or C1-C6alkoxy.

[0456] In some embodiments, RJis C1-C6alkyl. In some embodiments, RJis C1-C3 alkyl.

[0457] In some embodiments, RJis C3-C6 cycloalkyl.

[0458] In some embodiments, RJis C1-C6alkoxy.

[0459] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-Al): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-Bl): or a pharmaceutically acceptable salt thereof.

[0460] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A2): or a pharmaceutically acceptable salt thereof.

[0461] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A3): or a pharmaceutically acceptable salt thereof.

[0462] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B2): or a pharmaceutically acceptable salt thereof.

[0463] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A5): or a pharmaceutically acceptable salt thereof.

[0464] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B3): or a pharmaceutically acceptable salt thereof.

[0465] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A5): or a pharmaceutically acceptable salt thereof.

[0466] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B4): or a pharmaceutically acceptable salt thereof.

[0467] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A6): or a pharmaceutically acceptable salt thereof.

[0468] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A6a): or a pharmaceutically acceptable salt thereof.

[0469] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B5):

[0470] or a pharmaceutically acceptable salt thereof.

[0471] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B5a): or a pharmaceutically acceptable salt thereof.

[0472] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A7): or a pharmaceutically acceptable salt thereof.

[0473] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A7a):

[0474] or a pharmaceutically acceptable salt thereof.

[0475] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A8): or a pharmaceutically acceptable salt thereof.

[0476] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B6): or a pharmaceutically acceptable salt thereof.

[0477] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A9): or a pharmaceutically acceptable salt thereof.

[0478] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B7): or a pharmaceutically acceptable salt thereof.

[0479] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A10): or a pharmaceutically acceptable salt thereof.

[0480] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-Al 1): or a pharmaceutically acceptable salt thereof.

[0481] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A12): or a pharmaceutically acceptable salt thereof.

[0482] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A13): or a pharmaceutically acceptable salt thereof.

[0483] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A14): or a pharmaceutically acceptable salt thereof.

[0484] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A15): or a pharmaceutically acceptable salt thereof.

[0485] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B8): or a pharmaceutically acceptable salt thereof.

[0486] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B9): or a pharmaceutically acceptable salt thereof.

[0487] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (LB10): or a pharmaceutically acceptable salt thereof.

[0488] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-Bl 1): or a pharmaceutically acceptable salt thereof.

[0489] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (LB12): or a pharmaceutically acceptable salt thereof.

[0490] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A16): or a pharmaceutically acceptable salt thereof.

[0491] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A17): or a pharmaceutically acceptable salt thereof.

[0492] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A18): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A19): or a pharmaceutically acceptable salt thereof.

[0493] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A20): or a pharmaceutically acceptable salt thereof.

[0494] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A20a): or a pharmaceutically acceptable salt thereof.

[0495] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A20b): or a pharmaceutically acceptable salt thereof.

[0496] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A21):

[0497] 5 or a pharmaceutically acceptable salt thereof.

[0498] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A21a): or a pharmaceutically acceptable salt thereof.

[0499] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A22): or a pharmaceutically acceptable salt thereof.

[0500] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A23): or a pharmaceutically acceptable salt thereof.

[0501] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A24): or a pharmaceutically acceptable salt thereof, wherein Ring B is C6 aryl or C5-C6 heteroaryl optionally substituted with 1-2 independently selected RY.

[0502] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A25): or a pharmaceutically acceptable salt thereof, wherein Ring B is C6 aryl or C5-C6 heteroaryl optionally substituted with 1-2 independently selected RY.

[0503] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A26): or a pharmaceutically acceptable salt thereof.

[0504] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A26a): or a pharmaceutically acceptable salt thereof.

[0505] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A27): or a pharmaceutically acceptable salt thereof.

[0506] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A28): or a pharmaceutically acceptable salt thereof.

[0507] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A29): or a pharmaceutically acceptable salt thereof.

[0508] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A30): or a pharmaceutically acceptable salt thereof.

[0509] In some embodiments, the compound of Formula (1), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A31): or a pharmaceutically acceptable salt thereof.

[0510] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B13): or a pharmaceutically acceptable salt thereof.

[0511] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B14): or a pharmaceutically acceptable salt thereof.

[0512] Also provided herein are compounds of Formula (II), or a pharmaceutically acceptable salt thereof, wherein:

[0513] Z1, Z2, and Z3are each independently N or CH, wherein one or two of Z1, Z2, and Z3is N;

[0514] Z is N or CH;

[0515] R2is phenyl optionally substituted with 1-4 independently selected R2A, 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A, 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2AC1-C6alkoxyalkyl optionally substituted with - C(=O)NRARc, or C1-C6alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl; each R2Ais independently selected from:

[0516] (i) halogen;

[0517] (ii) cyano;

[0518] (iii) hydroxyl;

[0519] (iv) -NRARB;

[0520] (v) -C(=O)NRARB;

[0521] (vii) -NHC(=O)Rc;

[0522] (viii) -C(=O)ORD;

[0523] (ix) -SO2RD;

[0524] (x) -NHSO2RD;

[0525] (xi) -SO2NRDRE;

[0526] (xii) -NHC(=O)C1-C6alkyl optionally substituted with NRARB;

[0527] (xiii) C1-C6haloalkyl;

[0528] (xiv) C1-C6hydroxyalkyl;

[0529] (xv) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6alkyl optionally substituted with hydroxyl, halogen, - C(=O)NRARB, -NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;

[0530] (xvi) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, - SO2(C1-C6alkyl), -SO2NRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl;

[0531] (xvii) C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;

[0532] (xviii) C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl; and

[0533] (xix) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6alkyl optionally substituted with hydroxyl orC1-C6alkoxy, or RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1- C6 alkyl, and -C(=O)C1-C6alkyl; each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6 hydroxylalkyl; each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6alkoxy, and C1-C6alkyl optionally substituted with oxo or -NRARB; each R3Aand R3Bis independently selected from hydrogen, C1-C6alkyl, C1-C6alkoxy, and C1-C6haloalkyl; or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0534] R4is hydrogen, halogen, C1-C6alkyl, or acrylamido;

[0535] R5is hydrogen, halogen, C1-C6alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;

[0536] R5Aand R5Bare independently selected from hydrogen, C1-C6alkyl, C2-C6 alkenyl, and C1-C6hydroxyalkyl;

[0537] R6is hydrogen, halogen, or C1-C6alkyl;

[0538] X is a bond, CH2, CH(CH3), C(CH3)2,

[0539] W is NR3Bor O;

[0540] Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5- 10 membered heteroaryl are optionally and independently substituted with 1-3 independently selected RYor wherein * represents the connection of L1to the remainder of the compound of Formula (I); each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, -(CH2)n-C(=O)RF, -(CH2)n-NHC(=O)RF, -(CH2)n-NHC(=O)ORF, -CO2RG, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ, -(CH2)n-SO2RJ, -(CH2)n-C(=O)NRHR1, -( CH2)nC(=O)NRHR,1and C1-C6haloalkyl optionally substituted with hydroxyl; each RFis independently selected from: 03-06 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RHand R1is independently selected from: hydrogen, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, C1-C6alkyl optionally substituted with hydroxyl, -SO2(C1-C6alkyl), or C1-C6alkoxy, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, and -(CH2)n-SO2(C 1-C6 alkyl), or RHand R1together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl;

[0541] RJis C1-C6alkyl, C3-C6 cycloalkyl, or C1-C6alkoxy;

[0542] Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;

[0543] L1is a bond, C1-C6alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -802(C1-C6alkylene)-, -C(=O)C(=O)NH-, or C1-C6alkylene optionally substituted with oxo; each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2RG, -SO2NRHRI, -NHSO2RJ, -S(=O)(=NRH)RJ, -802( C1-C6alkyl), -C(=O)NRHRI, 4-6 membered heteroaryl, C1-C6alkoxy optionally substituted with RY2, C1-C6 haloalkyl, C1-C6alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;

[0544] RY2is hydroxyl, -NRHRI, -C(=O)NRHRI, or -SO2NRHRI; n is 0, 1, or 2; and z is O, 1, 2, or 3.

[0545] Z, R2, R2A, R3A, R3B, R4, R5, R5A, R5B, R6, RA, RB, RC, RD, RE, RF, RG, RH, R1, RJ, X, W, Y, RY, RY1, RY2, Ring A, L1, n, and z are further defined as disclosed above in Formula (I).

[0546] In some embodiments, Z1is N.

[0547] In some embodiments, Z1is CH.

[0548] In some embodiments, Z2is N.

[0549] In some embodiments, Z2is CH.

[0550] In some embodiments, Z3is N.

[0551] In some embodiments, Z3is CH

[0552] Provided herein are compounds of Formula (II- A), or a pharmaceutically acceptable salt thereof: wherein:

[0553] R2, R3A, R4, R5, R6, X, W, Y, are defined as disclosed above in Formula (I).

[0554] Provided herein are compounds of Formula (II-B), or a pharmaceutically acceptable salt thereof: wherein: R2, R3A, R4, R5, R6, X, W, Y, are defined as disclosed above in Formula (I).

[0555] Provided herein are compounds of Formula (II-D), or a pharmaceutically acceptable salt thereof: wherein:

[0556] R2, R3A, R4, R5, R6, X, W, Y, are defined as disclosed above in Formula (I).

[0557] Provided herein are compounds of Formula (II-D), or a pharmaceutically acceptable salt thereof: wherein:

[0558] R2, R3A, R4, R5, R6, X, W, Y, are defined as disclosed above in Formula (I).

[0559] Provided herein are compounds of Formula (II-E), or a pharmaceutically acceptable salt thereof: wherein:

[0560] R2, R3A, R4, R5, R6, X, W, Y, are defined as disclosed above in Formula (I). Provided herein are compounds of Formula (II-F), or a pharmaceutically acceptable salt thereof: wherein:

[0561] R2, R3A, R4, R5, R6, X, W, Y, are defined as disclosed above in Formula (I).

[0562] Non-Limiting Exemplary Compounds

[0563] In some embodiments, the compound is selected from the group consisting of the compounds in Examples 1-668 (e.g., Compound 1, Compound 2, or Compound 620), or a pharmaceutically acceptable salt thereof.

[0564] In some embodiments, the compound is selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof. Stereochemistry shown for the compounds in Table A has been arbitrarily assigned.

[0565] Table A

[0566]

[0567] In some embodiments, the compound is selected from the group consisting of the compounds in Table B, or a pharmaceutically acceptable salt thereof. Stereochemistry shown for the compounds in Table B has been arbitrarily assigned. Table B

[0568] Pharmaceutical Compositions

[0569] 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.

[0570] 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. Methods of Treatment

[0571] A “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 inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a PI3Kα inhibitor can be selective for PI3Ku over one or more other kinases. In some embodiments, a PI3Kα inhibitor can be selective for a PI3Kα having one or more mutations.

[0572] The ability of test compounds to act as inhibitors of PI3Kα may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3Kα inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labeling the compound prior to binding, isolating the compound / kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radioligands.

[0573] Potency of a PI3Kα inhibitor as provided herein can be determined by ECso value. A compound with a lower ECso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ECso value.

[0574] Potency of a PI3Kα inhibitor as provided herein can also be determined by ICso value. A compound with a lower ICso value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher ICso value. In some embodiments, the substantially similar conditions comprise determining a PI3Kα-dependent phosphorylation level, in vitro or in vivo.

[0575] The selectivity between wild type PI3Kα and PI3Kα containing one or more mutations as described herein can also be measured using in vitro assays such as surface plasmon resonance and fluorence-based binding assays, and cellular assays such as the levels of pAKT, a biomarker of PI3Kα activity, and / or proliferation assays where cell proliferation is dependent on mutant PI3Kα kinase activity.

[0576] In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of PI3Kα. For example, the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3Kα. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a PI3Kα kinase including one or more mutations, for example, the mutations in Table 1.

[0577] In some embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα over another kinase or non- kinase target.

[0578] In some embodiments, the compounds of Formula (II), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα. For example, a compound of Formula (II), or a pharmaceutically acceptable salt thereof, can selectively target PI3Kα over another kinase or non- kinase target.

[0579] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, (or a compound of Formula (II), or a pharmaceutically acceptable salt thereof) can exhibit greater inhibition of PI3Kα containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1) relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kot. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10,000-fold greater inhibition of PI3Kα having a combination of mutations described herein relative to inhibition of wild type PI3Kα.

[0580] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10,000-fold greater inhibition of PI3Kα containing one or more mutations as described herein relative to inhibition of wild type PI3Kα.

[0581] Compounds of Formula (I), or pharmaceutically acceptable salts thereof, and compounds of Formula (II), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a PI3Kα inhibitor, such as PI3Kα-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).

[0582] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (a PI3Kα-associated cancer), for example, as determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit. In some embodiments, the subject has a tumor that is positive for a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1. The subject can be a subject with a tumor(s) that is positive for a dysregulation of a P1K3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a PI3Kα -associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).

[0583] In certain embodiments, compounds of Formula (I), or pharmaceutically acceptable salt thereof, and compounds of Formula (II), or a pharmaceutically acceptable salt thereof, are useful for preventing diseases as defined herein such as cancer. The term “preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease as described herein, or a symptom thereof. The term “PI3Kα-associated disease” as used herein refers to diseases associated with or having a dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a PIK3CA gene, or a PI3Kα protein, or the expression or activity or level of any of the same described herein). Non- limiting examples of a PI3Kα-associated disease include, for example, proliferative disorders such as cancer (e.g., PI3Kα-associated cancer).

[0584] The term “PI3Kα-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3Kα-associated cancer are described herein.

[0585] The phrase “dysregulation of a PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a PIK3CA gene that results in the expression of a PI3Kα that includes a deletion of at least one amino acid as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with one or more point mutations as compared to a wild type PI3Kα, a mutation in a PIK3CA gene that results in the expression of PI3Kα with at least one inserted amino acid as compared to a wild type PI3Kα, a gene duplication that results in an increased level of PI3Kα in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of PI3Kα in a cell), an alternative spliced version of PI3Kα mRNA that results in PI3Kα having a deletion of at least one amino acid in the PI3Kα as compared to the wild type PI3Kα), or increased expression (e.g., increased levels) of a wild type PI3Kα in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., as compared to a control non- cancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity, or level of any of the same, can be a mutation in a PIK3CA gene that encodes a PI3Kα that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation. Non-limiting examples of PI3Kα point mutations / substitutions / insertions / deletions are described in Table 1.

[0586] The term “wild type” describes a nucleic acid (e.g., a PIK3CA gene or a PI3Kα mRNA) or protein (e.g., a PI3Kα) sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein.

[0587] The term “wild type PI3Kα” or “wild-type PI3Kα” describes a normal PI3Kct nucleic acid (e g., a.PIK3CA or PI3Kα mRNA) or protein that is found in a subject that does not have a PI3Kα- associated disease, e g., a PI3Kα -associated cancer (and optionally also does not have an increased risk of developing a PI3Kα -associated disease and / or is not suspected of having a PI3Kα- associated disease), or is found in a cell or tissue from a subject that does not have a PI3Kα- associated disease, e.g., a PI3Kα -associated cancer (and optionally also does not have an increased risk of developing a PI3Kα -associated disease and / or is not suspected of having a PI3Kα- associated disease).

[0588] Provided herein is a method of treating cancer (e.g., a PI3Kα-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3Kα-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same in a sample from the subj ect; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments provide a method of treating cancer in a subject identified or diagnosed with a PI3Kα-associated cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0589] Provided herein is a method of treating cancer (e.g., a PI3Kα-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3Kα-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of PIK3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same in a sample from the subj ect; and b) administering a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Kα-associated cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments provide a method of treating cancer in a subject identified or diagnosed with a PI3Kα-associated cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0590] In some embodiments, the dysregulation of a PIK.3CA gene, a PI3Kα protein, or the expression or activity or level of any of the same includes one or more a PI3Kα protein substitutions / point mutations / insertions. Non-limiting examples of PI3Kα protein substitutions / insertions / deletions are described in Table 1.

[0591] In some embodiments, the PI3Kα protein substitution / insertion / deletion is selected from the group consisting of E542A, E542G, E542K, E542Q, E542V, E545A, E545D, E545G, E545K, E545Q, M1043I, M1043L, M1043T, M1043V, H1047L, H1047Q, H1047R, 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 PI3Ku 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.

[0592] In some embodiments, the dysregulation of a.PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, includes a splice variation in a PI3Kα mRNA which results in an expressed protein that is an alternatively spliced variant of PI3Kα having at least one residue deleted (as compared to the wild type PI3Kα protein) resulting in a constitutive activity of a PI3Kα protein domain.

[0593] In some embodiments, the dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same, includes at least one point mutation in a PIK3CA gene that results in the production of a PBKa protein that has one or more amino acid substitutions or insertions or deletions in a P1K.3CA gene that results in the production of a PI3Kα protein that has one or more amino acids inserted or removed, as compared to the wild type PI3Kα protein. In some cases, the resulting mutant PI3Kα protein has increased activity, as compared to a wild type PI3Kα protein or a PI3Kα protein not including the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Kα protein relative to a wild type PI3Kα protein or a PI3Kα protein not including the same mutation.

[0594] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from a hematological cancer and a solid tumor.

[0595] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer (including both HER2+and HER2' breast cancer, ER+breast cancer, and triple negative breast cancer), uterine cancer (including endometrial cancer), lung cancer (including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLS, including adenocarcinoma lung cancer and squamous cell lung carcinoma)), esophageal squamous cell carcinoma, ovarian cancer, colorectal cancer, esophagastric adenocarcinoma, bladder cancer, head and neck cancer (including head and neck squamous cell cancers such as oropharyngeal squamous cell carcinoma), thyroid cancer, glioma, cervical cancer, lymphangioma, meningioma, melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach 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.

[0596] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Kα-associated cancer) is selected from breast cancer (including both HER2+and HER2" breast cancer, ER+breast cancer, and triple negative breast cancer), colon cancer, rectal cancer, colorectal cancer, ovarian cancer, lymphangioma, meningioma, head and neck squamous cell cancer (including oropharyngeal squamous cell carcinoma), melanoma (including uveal melanoma), kidney cancer, pancreatic neuroendocine neoplasms (pNETs), stomach cancer, esophageal cancer, acute myeloid leukemia, relapsed and refractory multiple myeloma, pancreatic cancer, lung cancer (including adenocarcinoma lung cancer and squamous cell lung carcinoma), and endometrial cancer.

[0597] 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, esophagastric adenocarcinoma, bladder cancer, head and neck cancer, thyroid cancer, glioma, and cervical cancer. 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.

[0598] In some embodiments of any of the methods or uses described herein, the PI3Kα-associated cancer is selected from the cancers described in Table 1.

[0599] Table 1. PI3Kα Protein Amino Acid Substitutions / InsertionsZDeletionsA

[0600] AUnless noted otherwise, the mutations of Table 1 are found in cBioPortal database derived from Cerami et al. The eBio 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, pll (2013). Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Cameiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(ll): 1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075.

[0601] Exemplary Sequence of Human Phosphatidylinositol 4,5-bisphosphate 3 -kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1) MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGF A IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IWIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNGETSTKSLWVI NSALRIKILC ATYVNVNIRD

[0602] IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH

[0603] GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSWKFPDMS VIEEHANWSV

[0604] SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLK HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEH FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYKAYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN

[0605] Also provided is a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3K<x activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3Kα-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3Kα protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3Kα protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Kα protein.

[0606] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0607] Further provided herein is a method of increase cell death, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject, comprising administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[0608] Also provided is a method for inhibiting PI3Kα activity in a cell, comprising contacting the cell with a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3Kα activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is a PI3Kα-associated cancer cell. As used herein, the term "contacting” refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a PI3Kα protein with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having a PI3Kα protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Kα protein.

[0609] Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[0610] Further provided herein is a method of increase cell death, in vitro or in vivo, comprising contacting a cell with an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject, comprising administering to the subject an effective compound of Formula (II), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[0611] In some mebodiments, the PI3Kα is human PI3Kα. In some embodiments, the PI3Kα has one or more point mutations in the PIK3CA gene. In some embodiments, the point rotations include a substitution at amino acid position 1047 of a human PI3Kα protein. In some embodiments, the substitution is H1047R. When employed as pharmaceuticals, the compounds of Formula (I), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein.

[0612] NUMBERED EMBODIMENTS

[0613] 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0614] Z is N or CH;

[0615] R1is hydrogen, halogen, cyano, C3-C6 cycloalkyl, C1-C6thioalkyl, C1-C6haloalkyl, C1- C6 alkoxy, C1-C6alkoxyalkyl, 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; or C1-C6alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;

[0616] R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A, 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A, C1-C6alkoxyalkyl optionally substituted with - C(=O)NRARC, or C1-C6alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl; each R2Ais independently selected from:

[0617] (i) halogen;

[0618] (ii) cyano;

[0619] (iii) hydroxyl;

[0620] (iv) -NRARB; (v) -C(=O)NRARB;

[0621] (vii) -NHC(=0)Rc;

[0622] (viii) -C(=0)0RD;

[0623] (ix) -SO2RD;

[0624] (x) -NHS02RD;

[0625] (xi) -SO2NRDRE;

[0626] (xii) -NHC(=O)C1-C6alkyl optionally substituted with NRARB;

[0627] (xiii) C1-C6haloalkyl;

[0628] (xiv) C1-C6hydroxyalkyl;

[0629] (xv) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, -C(=O)NRARB, -NRARB, C1-C6alkyl optionally substituted with hydroxyl; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;

[0630] (xvi) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, - SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl;

[0631] (xvii) C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;

[0632] (xviii) C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl;

[0633] (xix) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; and

[0634] (xx) 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6alkyl optionally substituted with hydroxyl; each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C1-C6alkyl optionally substituted with hydroxyl orC1-C6alkoxy, or RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1- C6 alkyl, and -C(=O)C1-C6alkyl; each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl; each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6alkoxy, and C1-C6alkyl optionally substituted with oxo or -NRARB; each R3Aand R3Bis independently selected from hydrogen, C1-C6alkyl, C1-C6alkoxy, and C1-C6haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0635] R4is hydrogen, halogen, C1-C6alkyl, or acrylamido;

[0636] R3is hydrogen, halogen, C1-C6alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR3AR3B;

[0637] R3Aand R3Bare independently selected from hydrogen, C1-C6alkyl, C2-C6 alkenyl, and C1-C6hydroxyalkyl;

[0638] R6is hydrogen, halogen, or C1-C6alkyl;

[0639] X is a bond,

[0640] W is NR3Bor O;

[0641] Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5- 10 membered heteroaryl are optionally and independently substituted with 1-3 independently selected RYor wherein * represents the connection of L1to the remainder of the compound of Formula (I); each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, -(CH2)n-C(=O)R1', -(CH2)n-NHC(=O)R1', -(CH2)n-NHC(=O)ORF, -C(=O)C(=O)NHRF, -CO2RG, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ, -(CH2)n-SO2RJ, -(CH2)n-C(=O)NRHRI, -(CH2)n-C(=O)NRHOR1, and C1-C6haloalkyl optionally substituted with hydroxyl; each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl optionally substituted with C1-C6alkyl; and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C 1-C6 alkyl); each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RHand R1is independently selected from: hydrogen, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2-(CH2)n-SO2(C1-C6alkyl), C1- C6 alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, - SO2(C1-C6alkyl), C1-C6alkoxy, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and - C(=O)NRK1RK2; or RHand R1together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl;

[0642] RJis C1-C6alkyl, C3-C6 cycloalkyl, or C1-C6alkoxy; each RK1and RK2is independently hydrogen or C1-C6alkyl;

[0643] Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;

[0644] L1is a bond, C1-C6alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6alkylene)-, -C(=O)C(=O)NH-, or C1-C6alkylene optionally substituted with oxo; each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2RG, -SO2NRHRI, -NHSO2R1, -S(=O)(=NRH)RJ, -SO2<C1-C6alkyl), -C(=O)NRIIRI, 4-6 membered heteroaryl, C1-C6alkoxy optionally substituted with RY2, C1-C6haloalkyl, C1-C6alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;

[0645] RY2is hydroxyl, -NRHR1, -C(=O)NRHRI, or -SO2NRHR1; n is 0, 1, or 2; and z is O, 1, 2, or 3.

[0646] 2. The compound of Embodiment 1, wherein Z is CH. 3. The compound of Embodiment 1, wherein Z is N.

[0647] 4. The compound of any one of Embodiments 1-3, wherein R1is hydrogen.

[0648] 5. The compound of any one of Embodiments 1-3, wherein R1is halogen.

[0649] 6. The compound of any one of Embodiments 1-3, wherein R1cyano.

[0650] 7. The compound of any one of Embodiments 1-3, wherein R1is C3-C6 cycloalkyl.

[0651] 8. The compound of any one of Embodiments 1-3, wherein R1is C1-C6alkyl optionally substituted with C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.

[0652] 9. The compound of any one of Embodiments 1-3 or 8, wherein R1is C1-C6alkyl substituted with C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.

[0653] 10. The compound of any one of Embodiments 1-3 or 8, wherein R1is C1-C6alkyl

[0654] 11. The compound of any one of Embodiments 1-3, 8, or 10, wherein R1is methyl.

[0655] 12. The compound of any one of Embodiments 1-3, wherein R1is 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl.

[0656] 13. The compound of any one of Embodiments 1-3, wherein R1is C1-C6thioalkyl.

[0657] 14. The compound of any one of Embodiments 1-3, wherein R1is C1-C6haloalkyl.

[0658] 15. The compound of any one of Embodiments 1-3, wherein R1is C1-C6alkoxy.

[0659] 16. The compound of any one of Embodiments 1-3, wherein R1is C1-C6alkoxyalkyl.

[0660] 17. The compound of any one of Embodiments 1-16, wherein R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A.

[0661] 18. The compound of any one of Embodiments 1-16 or 17, wherein R2is C6-C10 aryl substituted with 1-4 independently selected R2A.

[0662] 19. The compound of any one of Embodiments 1-16 or 17, wherein R2is C6-C10 aryl.

[0663] 20. The compound of any one of Embodiments 1-18, wherein R2is phenyl optionally substituted with 1-4 independently selected R2A.

[0664] 21. The compound of any one of Embodiments 1-18 or 20, wherein R2is phenyl substituted with 1-4 independently selected R2A.

[0665] 22. The compound of any one of Embodiments 1-16 or 20, wherein R2is phenyl.

[0666] 23. The compound of any one of Embodiments 1-16, wherein R2is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A.

[0667] 24. The compound of any one of Embodiments 1-16, wherein R2is 5-10 membered heteroaryl substituted with 1-4 independently selected R2A. 25. The compound of any one of Embodiments 1-16, wherein R2is 5-10 membered heteroaryl.

[0668] 26. The compound of any one of Embodiments 1-16, wherein R2is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A.

[0669] 27. The compound of any one of Embodiments 1-16, wherein R2is 4-10 membered heterocyclyl substituted with 1-3 independently selected R2A.

[0670] 28. The compound of any one of Embodiments 1-16, wherein R2is 4-10 membered heterocyclyl.

[0671] 29. The compound of any one of Embodiments 1-16, wherein R2is C4-C10 cycloalkyl optionally substituted with 1-3 independently selected R2A.

[0672] 30. The compound of any one of Embodiments 1-16, wherein R2is C4-C10 cycloalkyl substituted with 1-3 independently selected R2A.

[0673] 31. The compound of any one of Embodiments 1-16, wherein R2is C4-C10 cycloalkyl.

[0674] 32. The compound of any one of Embodiments 1-16, wherein R2is 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A.

[0675] 33. The compound of any one of Embodiments 1-16, wherein R2is 4-10 membered heterocyclyloxy substituted with 1-4 independently selected R2A.

[0676] 34. The compound of any one of Embodiments 1-16, wherein R2is 4-10 membered heterocyclyloxy.

[0677] 35. The compound of any one of Embodiments 1-16, wherein R2is 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A.

[0678] 36. The compound of any one of Embodiments 1-16, wherein R2is 5-10 heteroaryloxy substituted with 1-4 independently selected R2A.

[0679] 37. The compound of any one of Embodiments 1-16, wherein R2is 5-10 heteroaryloxy.

[0680] 38. The compound of any one of Embodiments 1-16, wherein R2is C1-C6alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5- 10 membered heteroaryl, or phenyl.

[0681] 39. The compound of any one of Embodiments 1-16 or 38, wherein R2is C1-C6alkoxy substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl.

[0682] 40. The compound of any one ofEmbodiments 1-16 or 38, whereinR2is C1-C6alkoxy. 41. The compound of any one of Embodiments 1-16, R2is C1-C6alkoxyalkyl optionally substituted with -C(=O)NRARc.

[0683] 42. The compound of any one of Embodiments 1-16, R2is C1-C6alkoxyalkyl substituted with -C(=O)NRARc.

[0684] 43. The compound of any one of Embodiments 1-16, R2is C1-C6alkoxyalkyl.

[0685] 44. The compound of any one of Embodiments 1-43, wherein 1, 2, 3, or 4 of R2Aare independently halogen.

[0686] 45. The compound of any one of Embodiments 1-44, wherein 1, 2, 3, or 4 of R2Aare independently cyano.

[0687] 46. The compound of any one of Embodiments 1-45, wherein 1, 2, 3, or 4 of R2Aare independently hydroxyl.

[0688] 47. The compound of any one of Embodiments 1-46, wherein 1, 2, 3, or 4 of R2Aare independently -NRARB.

[0689] 48. The compound of any one of Embodiments 1-47, wherein 1, 2, 3, or 4 of R2Aare independently -C(=O)NRARB.

[0690] 49. The compound of any one of Embodiments 1-48, wherein 1, 2, 3, or 4 of R2Aare independently

[0691] 50. The compound of any one of Embodiments 1-49, wherein 1, 2, 3, or 4 of R2Aare independently -NHC(=O)Rc.

[0692] 51. The compound of any one of Embodiments 1-50, wherein 1, 2, 3, or 4 of R2Aare independently -C(=O)ORD.

[0693] 52. The compound of any one of Embodiments 1-51, wherein 1, 2, 3, or 4 of R2Aare independently -SO2RD.

[0694] 53. The compound of any one of Embodiments 1-52, wherein 1, 2, 3, or 4 of R2Aare independently -NHSO2RD.

[0695] 54. The compound of any one of Embodiments 1-53, wherein 1, 2, 3, or 4 of R2Aare independently -SO2NRDRE.

[0696] 55. The compound of any one of Embodiments 1-54, wherein 1, 2, 3, or 4 of R2Aare independently -NHC(=O)C1-C6alkyl optionally substituted with NRARB. 56. The compound of any one of Embodiments 1-55, wherein 1, 2, 3, or 4 of R2Aare independently -NHC(=O)C1-C6alkyl substituted with NRARB.

[0697] 57. The compound of any one of Embodiments 1-56, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6haloalkyl.

[0698] 58. The compound of any one of Embodiments 1-57, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6hydroxy alkyl.

[0699] 59. The compound of any one of Embodiments 1-58, wherein 1, 2, 3, or 4 of R2Aare independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6alkyl optionally substituted with hydroxyl, halogen, -C(=O)NRARB, -NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl.

[0700] 60. The compound of any one of Embodiments 1-59, wherein 1, 2, 3, or 4 of R2Aare independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6alkyl, halogen, -C(=O)NRARB, -NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl.

[0701] 61. The compound of any one of Embodiments 1-60, wherein 1, 2, 3, or 4 of R2Aare independently 5-10 membered heteroaryl.

[0702] 62. The compound of any one of Embodiments 1-61, wherein 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, - SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl.

[0703] 63. The compound of any one of Embodiments 1-62, wherein 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C 1 -C6 haloalkyl, -C(=O)C 1 -C6 alkyl, -SO2(C 1 -C6 alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl. 64. The compound of any one of Embodiments 1-63, wherein 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl substituted with - NRARB, and C1-C6alkyl substituted with C1-C6alkoxy or hydroxyl.

[0704] 65. The compound of any one of Embodiments 1-64, wherein 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, -SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl, and C1-C6alkyl.

[0705] 66. The compound of any one of Embodiments 1-62, wherein 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl.

[0706] 67. The compound of any one of Embodiments 1-66, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl.

[0707] 68. The compound of any one of Embodiments 1-67, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or - C(=O)C3-C6 cycloalkyl.

[0708] 69. The compound of any one of Embodiments 1-68, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl .

[0709] 70. The compound of any one of Embodiments 1-69, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, and 4-10 membered heterocyclyl.

[0710] 71. The compound of any one of Embodiments 1-67, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkyl.

[0711] 72. The compound of any one of Embodiments 1-71, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl. 73. The compound of any one of Embodiments 1-72, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[0712] 74. The compound of any one of Embodiments 1-73, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy substituted with -NRARBor 4-10 membered heterocyclyl substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl.

[0713] 75. The compound of any one of Embodiments 1-73, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy substituted with -NRARBor 4-10 membered heterocyclyl.

[0714] 76. The compound of any one of Embodiments 1-72, wherein 1, 2, 3, or 4 of R2Aare independently C1-C6alkoxy.

[0715] 77. The compound of any one of Embodiments 1-76, wherein 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, - C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl.

[0716] 78. The compound of any one of Embodiments 1-77, wherein 1, 2, 3, or 4 of R 22AAare independently C3-C6 cycloalkyl substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl.

[0717] 79. The compound of any one of Embodiments 1-78, wherein 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl substituted with C1-C6alkyl.

[0718] 80. The compound of any one of Embodiments 1-79, wherein 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl.

[0719] 81. The compound of any one of Embodiments 1-77, wherein 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkyl.

[0720] 82. The compound of any one of Embodiments 1-81, wherein X is a bond.

[0721] 83. The compound of any one of Embodiments 1-81, wherein X is CH2.

[0722] 84. The compound of any one of Embodiments 1-81, wherein X is CH(CH3).

[0723] 85. The compound of any one of Embodiments 1-81, wherein X is C(CH3)2.

[0724] 86. The compound of any one of Embodiments 1-81, wherein X is

[0725] 87. The compound of any one of Embodiments 1-86, wherein W is O. 88. The compound of any one of Embodiments 1-87, wherein R3Ais hydrogen.

[0726] 89. The compound of any one of Embodiments 1-87, wherein R3Ais C1-C6alkyl.

[0727] 90. The compound of any one of Embodiments 1-87 or 89, wherein R3Ais methyl.

[0728] 91. The compound of any one of Embodiments 1-87, wherein R3Ais C1-C6alkoxy.

[0729] 92. The compound of any one of Embodiments 1-87, wherein R3Ais C1-C6haloalkyl.

[0730] 93. The compound of any one of Embodiments 1-86, wherein W is NR3B.

[0731] 94. The compound of any one of Embodiments 1-86 or 93, wherein one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis C1-C6alkyl.

[0732] 95. The compound of any one of Embodiments 1-86 or 93, wherein one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis methyl.

[0733] 96. The compound of any one of Embodiments 1-86 or 93, wherein each of R3Aand R3Bis hydrogen.

[0734] 97. The compound of any one of Embodiments 1-86 or 93, wherein each of R3Aand R3Bis an independently selected C1-C6alkyl.

[0735] 98. The compound of any one of Embodiments 1-86, 93, or 97, wherein each of R3Aand R3Bis methyl.

[0736] 99. The compound of any one of Embodiments 1-86 or 93, wherein one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis C1-C6alkoxy.

[0737] 100. The compound of any one of Embodiments 1-86 or 93, wherein one of R3Aand R3Bis C1-C6alkyl and the other of R3Aand R3Bis C1-C6alkoxy.

[0738] 101. The compound of any one of Embodiments 1-86 or 93, wherein each of R3Aand R3Bis C1-C6alkoxy.

[0739] 102. The compound of any one of Embodiments 1-86 or 93, wherein one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis C1-C6haloalkyl.

[0740] 103. The compound of any one of Embodiments 1-86 or 93, wherein one of R3Aand R3Bis C1-C6alkyl and the other of R3Aand R3Bis C1-C6haloalkyl.

[0741] 104. The compound of any one of Embodiments 1-86 or 93, wherein each of R3Aand R3Bis C1-C6haloalkyl.

[0742] 105. The compound of any one of Embodiments 1-86 or 93, wherein R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group. 106. The compound of any one of Embodiments 1-105, wherein Y is unsubstituted phenyl.

[0743] 107. The compound of any one of Embodiments 1-105, wherein Y is unsubstituted napthyl.

[0744] 108. The compound of any one of Embodiments 1-105, wherein Y is unsubstituted 5-10 membered heteroaryl.

[0745] 109. The compound of any one of Embodiments 1-105, wherein Y is phenyl optionally substituted with 1-3 independently selected RY.

[0746] 110. The compound of any one of Embodiments 1-105, wherein Y is naphthyl optionally substituted with 1-3 independently selected RY.

[0747] 111. The compound of any one of Embodiments 1-105, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY.

[0748] 112. The compound of any one of Embodiments 1-105 or 109-111, wherein 1, 2, or 3 of RYis independently halogen.

[0749] 113. The compound of any one of Embodiments 1-105 or 109-111, wherein 1, 2, or 3 of RYis hydroxyl.

[0750] 114. The compound of any one of Embodiments 1-105 or 109-113, wherein 1, 2, or 3 of

[0751] RYis cyano.

[0752] 115. The compound of any one of Embodiments 1-105 or 109-114, wherein 1, 2, or 3 of

[0753] RYis C1-C6alkyl.

[0754] 116. The compound of any one of Embodiments 1-105 or 109-115, wherein 1, 2, or 3 of RYis independently C1-C6haloalkyl optionally substituted with hydroxyl.

[0755] 117. The compound of any one of Embodiments 1-105 or 109-116, wherein 1, 2, or 3 of RYis independently C1-C6alkoxy.

[0756] 118. The compound of any one of Embodiments 1-105 or 109-117, wherein 1, 2, or 3 of RYis independently C1-C6haloalkoxy.

[0757] 119. The compound of any one of Embodiments 1-105 or 109-118, wherein 1, 2, or 3 of RYis independently C1-C6hydroxyalkyl.

[0758] 120. The compound of any one of Embodiments 1-105 or 109-119, wherein 1, 2, or 3 of RYis independently -(CH2)n-NHC(=O)RF. 121. The compound of any one of Embodiments 1-105 or 109-120, wherein 1, 2, or 3 of RYis independently -(CH2)n-C(=O)RF.

[0759] 122. The compound of any one of Embodiments 1-105 or 109-121, wherein 1, 2, or 3 of RYis independently -CO2RG.

[0760] 123. The compound of any one of Embodiments 1-105 or 109-122, wherein 1, 2, or 3 of RYis independently -(CH2)n-SO2NRHR1.

[0761] 124. The compound of any one of Embodiments 1-105 or 109-123, wherein 1, 2, or 3 of RYis independently -(CH2)n-NHSO2RJ.

[0762] 125. The compound of any one of Embodiments 1-105 or 109-124, wherein 1, 2, or 3 of RYis independently -(CH2)n-S(=O)(=NRH)RJ.

[0763] 126. The compound of any one of Embodiments 1-105 or 109-125, wherein 1, 2, or 3 of RYis independently -CH2)n-SO2R1.

[0764] 127. The compound of any one of Embodiments 1-105 or 109-126, wherein 1, 2, or 3 of RYis independently -(CH2)n-C(=O)NRHRI.

[0765] 128. The compound of any one of Embodiments 1-105 or 109-126, wherein 1, 2, or 3 of RYis independently -(CH2)n-C(=O)NRHORI.

[0766] 129. The compound of any one of Embodiments 1-105 or 109-127, wherein 1, 2, or 3 of RYis independently C1-C6alkyl.

[0767] 130. The compound of any one of Embodiments 1-105, wherein Y is phenyl substituted with wherein * represents the connection of L1to the remainder of the compound of Formula (I).

[0768] 131. The compound of any one of Embodiments 1-105, wherein Y is naphthyl substituted with wherein * represents the connection of L1to the remainder of the compound of Formula (I). 132. The compound of any one of Embodiments 1-105, wherein Y is 5-10 membered

[0769] * heteroaryl substituted with wherein * represents the connection of

[0770] L1to the remainder of the compound of Formula (I).

[0771] 133. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is a bond.

[0772] 134. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is C1-C6alkoxylene.

[0773] 135. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is -

[0774] (CH2)n-NHC(=O)-.

[0775] 136. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is - C(=O)NH-(CH2)n-.

[0776] 137. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is -CO2-

[0777] 138. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is -SO2-

[0778] 139. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is - NHSO2- or -SO2NH-.

[0779] 140. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is

[0780] -S(=O)(=NRG)-.

[0781] 141. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is - SO2(C1-C6alkylene)-.

[0782] 142. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is -C(=O)C(=O)NH-.

[0783] 143. The compound of any one of Embodiments 1-105 or 130-132, wherein L1is C1-C6alkylene optionally substituted with oxo.

[0784] 144. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently cyano.

[0785] 145. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently hydroxyl. 146. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently halogen.

[0786] 147. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently -C(=O)RF.

[0787] 148. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently -NHC(=O)RF.

[0788] 149. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently -COaRG.

[0789] 150. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently -SO2NRHRI.

[0790] 151. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently -NHSO2RJ.

[0791] 152. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently -S(=O)(=NRH)RF.

[0792] 153. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently -SO2(C1-C6alkyl).

[0793] 154. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently -C(=O)NRHRI.

[0794] 155. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently 4-6 membered heteroaryl.

[0795] 156. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently C1-C6alkoxy optionally substituted with RY2.

[0796] 157. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently C1-C6haloalkyl.

[0797] 158. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently C1-C6alkyl optionally substituted with RY2.

[0798] 159. The compound of any one of Embodiments 1-105 or 130-143, wherein 1, 2, or 3 of RY1is independently 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl.

[0799] 160. The compound of any one of Embodiments 1-105 or 130-159, wherein Ring A is phenyl. 161. The compound of any one of Embodiments 1-105 or 130-159, wherein Ring A is

[0800] 4-10 membered heteroaryl.

[0801] 162. The compound of any one of Embodiments 1-105 or 130-159, wherein Ring A is

[0802] 4-10 membered heterocyclyl.

[0803] 163. The compound of any one of Embodiments 1-105 or 130-159, wherein Ring A is C4-C10 cycloalkyl.

[0804] 164. The compound of any one of Embodiments 1-163, wherein R4is hydrogen.

[0805] 165. The compound of any one of Embodiments 1-163, wherein R4is halogen.

[0806] 166. The compound of any one of Embodiments 1-163, wherein R4is C1-C6alkyl.

[0807] 167. The compound of any one of Embodiments 1-163, wherein R4is acrylamido.

[0808] 168. The compound of any one of Embodiments 1-167, wherein R5is hydrogen.

[0809] 169. The compound of any one of Embodiments 1-167, wherein R3is halogen.

[0810] 170. The compound of any one of Embodiments 1-167, wherein R3is C1-C6alkyl.

[0811] 171. The compound of any one of Embodiments 1-167, wherein R3is cyano.

[0812] 172. The compound of any one of Embodiments 1-167, wherein R3is -NR5AR5B.

[0813] 173. The compound of any one of Embodiments 1-167, wherein R5is

[0814] -C(=O)NR3AR3B.

[0815] 174. The compound of any one of Embodiments 1-167, wherein R3is -NR5AC(=O)R5B.

[0816] 175. The compound of any one of Embodiments 1-167 or 172-174, wherein one of R5Aand R3Bis hydrogen and the other of R3Aand R3Bis C1-C6alkyl, C2-C6 alkenyl, or C1-C6hydroxy alkyl.

[0817] 176. The compound of any one of Embodiments 1-167 or 172-174, wherein one of R5Aand R3Bis C1-C6alkyl and the other of R3Aand R3Bis C1-C6alkyl, C2-C6 alkenyl, or C1-C6hydroxy alkyl.

[0818] 177. The compound of any one of Embodiments 1-167 or 172-174, wherein each of R5Aand R3Bis hydrogen.

[0819] 178. The compound of any one of Embodiments 1-167 or 172-174, wherein each of R5Aand R3Bis an independently selected C1-C6alkyl.

[0820] 179. The compound of any one of Embodiments 1-178, wherein R6is hydrogen.

[0821] 180. The compound of any one of Embodiments 1-178, wherein R6is halogen.

[0822] 181. The compound of any one of Embodiments 1-178, wherein R6is C1-C6alkyl. 182. The compound of any one of Embodiments 1-181, wherein each of RAand RBare independently selected from hydrogen, hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6alkyl optionally substituted with hydroxyl or C1-C6alkoxy.

[0823] 183. The compound of any one of Embodiments 1-182, wherein one of RAand RBis hydrogen and the other of RAand RBis hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6alkyl optionally substituted with hydroxyl or C1-C6alkoxy.

[0824] 184. The compound of any one of Embodiments 1-182, wherein one of RAand RBis hydrogen and the other of RAand RBis hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6alkyl substituted with hydroxyl or C1-C6alkoxy.

[0825] 185. The compound of any one of Embodiments 1-182, wherein one of RAand RBis hydrogen and the other of RAand RBis hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, or C1-C6alkyl.

[0826] 186. The compound of any one of Embodiments 1-182, wherein RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, or -C(=O)C1-C6alkyl.

[0827] 187. The compound of any one of Embodiments 1-182 or 186, wherein RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, or-C(=O)C1- C6 alkyl.

[0828] 188. The compound of any one of Embodiments 1-182 or 186, wherein RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl.

[0829] 189. The compound of any one of Embodiments 1-188, wherein each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl.

[0830] 190. The compound of any one of Embodiments 1-188, wherein each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl substituted with -NRARBor with 4-10 membered heterocyclyl substituted with C1-C6alkyl or with C1-C6hydroxylalkyl. 191. The compound of any one of Embodiments 1-188, wherein each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl substituted with -NRARBor with 4-10 membered heterocyclyL

[0831] 192. The compound of any one of Embodiments 1-188, wherein each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6alkyl.

[0832] 193. The compound of any one of Embodiments 1-192, wherein each RDis hydrogen, hydroxyl, or C1-C6alkoxy.

[0833] 194. The compound of any one of Embodiments 1-192, wherein each RDis phenyl or C1-C6alkyl optionally substituted with oxo.

[0834] 195. The compound of any one of Embodiments 1-194, wherein each REis hydrogen, hydroxyl, or C1-C6alkoxy.

[0835] 196. The compound of any one of Embodiments 1-194, wherein each REis phenyl or C1-C6alkyl optionally substituted with oxo.

[0836] 197. The compound of any one of Embodiments 1-196, wherein each RFis C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl).

[0837] 198. The compound of any one of Embodiments 1-196, wherein each RFis C3-C6 cycloalkyl, 5-6 membered heteroaryl, or 4-6 membered heterocyclyL

[0838] 199. The compound of any one of Embodiments 1-198, wherein each RGis hydrogen, C3-C6 cycloalkyl, or C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl).

[0839] 200. The compound of any one of Embodiments 1-198, wherein each RGis 5-6 membered heteroaryl or 4-6 membered heterocyclyL

[0840] 201. The compound of any one of Embodiments 1-200, wherein one of RHand R1is hydrogen and the other of RHand R1is C1-C6alkyl optionally substituted with C1-C6alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, -SO2(C1-C6alkyl), C1-C6alkoxy, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and -C(=O)NRK1RK2.

[0841] 202. The compound of any one of Embodiments 1-200, wherein one of RHand R1is hydrogen and the other of RHand R1is C1-C6alkoxy, C3-C6 cycloalkyl, or C2-C6 alkenyl.

[0842] 203. The compound of any one of Embodiments 1-200, wherein each of RHand R1is hydrogen.

[0843] 204. The compound of any one of Embodiments 1-200, wherein each of RHand R1is an independently selected C1-C6alkyl optionally substituted with C1-C6alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, -SO2(C1-C6alkyl), C1-C6alkoxy, 5- 6 membered heteroaryl, C3-C6 cycloalkyl, and -C(=O)NRK1RK2.

[0844] 205. The compound of any one of Embodiments 1-200, wherein one of RHand R1is hydrogen and the other of RHand R1is -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, or -(CH2)n-SO2(C1- C6 alkyl).

[0845] 206. The compound of any one of Embodiments 1-200, wherein RHand R1together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl. 207. The compound of any one of Embodiments 1-206, wherein RJis C1-C6alkyl.

[0846] 208. The compound of any one of Embodiments 1-206, wherein RJis C1-C6alkoxy.

[0847] 209. The compound of any one of Embodiments 1-206, wherein RJis C3-C6 cycloalkyl.

[0848] 210. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof and the compounds in Table B, or a pharmaceutically acceptable salt thereof.

[0849] 211. A pharmaceutical composition comprising a compound of any one of Embodiments 1-210, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0850] 212. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1- 210, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 211.

[0851] 213. A method for treating cancer in a subject in need thereof, the method comprising

[0852] (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Embodiments 1-210, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 211.

[0853] 214. A method of treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of Embodiments 1-210 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Embodiment 211. 215. A method for inhibiting mutant PI3Kα activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Embodiments 1-210, or a pharmaceutically acceptable salt thereof.

[0854] EXAMPLES

[0855] Example 1: Compound Preparation

[0856] The general methods for the preparation of the compounds of Formula (I) have been described in an illustrative manner and is intended to be description, rather than of limitation. Thus, it will be appreciated that conditions such as choice of solvent, temperature of reaction, volumes, reaction time may vary while still producing the desired compounds. In addition, it will be appreciated that many of the reagents provided in the following examples may be substituted with other suitable reagents. See, e.g., Smith & March, Advanced Organic Chemistry, 7th Ed. (2013). Such changes and modifications, including without limitation, those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods of use provided herein, may be made without departing from the spirit and scope thereof.

[0857] The starting materials used for the syntheses are either synthesized or obtained from commercial sources, such as, but not limited to, Sigma-Aldrich, Fluka, Acros Organics, Alfa Aesar, Enamine, Strem, VWR Scientific, and the like. Nuclear Magnetic Resonance (NMR) analysis was conducted using a Broker A VANCE in HD (300 or 400) MHz spectrometer or Broker AVANCE NEO 400 MHz spectrometer with an appropriate deuterated solvent. LCMS spectra were obtained on a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector.

[0858] Intermediate Preparation:

[0859] Intermediate: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile

[0860] Step 1: Synthesis of 5-bromo-3-chloro-7-methylquinolin-2(lH)-one. In a three necked flask provided with a stir 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) in tetrahydrofuran (32 mL) were charged. The solution was cooled at -78 °C, and 1.3 M THF solution of lithium bis(trimethylsilyl)azanide (3 eq., 393 mmol) was added portion wise under nitrogen atmosphere. The reaction was allowed to warm up to room temperature until deemed complete. The mixture was poured into ice / water and the resulting slurry was extracted with ethyl acetate (2 x 30 mL) and the suspension was washed with water (2 x 30 mL) and concentrated under vacuum using ethyl acetate (50 mL) to dry the solids by azeotropic distillation. The slurry was resuspended in ethyl acetate (30 mL) and heated to 50 °C in a water bath. The solids were cooled while sonicating and filtered using MTBE to transfer and rinse the cake to give the title compound as a white solid (1.7 g, 44%). MS: 273.1 m / z (M+H+).1H 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).

[0861] Step 2: Synthesis of 5-acetyl-3-chloro-7-methylquinolin-2(lH)-one.

[0862] To a suspension of 5-bromo-3-chloro-7-methyl-2-quinolinol (2 g, 7.34 mmol) inl,4- dioxane (120 mL, 1.41 mol), l,r-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (537 mg, 0.1 eq., 734 μmol) and tributyl(l-ethoxyethenyl)stannane (2.98 mL, 1.2 eq., 8.81 mmol) were charged. The suspension was sparged with nitrogen for 3 min and the reaction was heated in a heating block to 110 °C for 2 h. The crude reaction mixture was filtered, the filtrate concentrated, and the resulting solids resuspended in MTBE / heptane (1:1, 100 mL). The resulting thin slurry was concentrated under vacuum to aprox 40 mL and the solids obtained were filtered using heptane to transfer and rinse the solids to give the intermediate 3-chloro-5-(l-ethoxyvinyl)-7- methylquinolin-2(lH)-one (1.4 g, 72%). MS: 264.1 m / z (M+H+).

[0863] The intermediate 3-chloro-5-(l-ethoxyvinyl)-7-methylquinolin-2(lH)-one (1.4 g, 5.3 mmol) was resuspended in THF (30 mL) and a 3N aqueous HC1 solution (30 mL, 90 mmol) was charged. The slurry was stirred at room temperature until the reaction was deemed complete (~ Ih). The solvent was concentrated, and the aqueous residue was extracted with ethyl acetate (2 x 200 mL). The resulting slurry was concentrated to ~ 100 mL and a solution of potassium fluoride (1.28 g, 22 mmol) in water (100 mL) was charged. The slurry was stirred at room temperature for 1 h. The layers were allowed to settle and the organic layer containing the slurry was separated and washed with water (2 x 50 mL). The solvent was concentrated to dryness under vacuum, then ethyl acetate (3 x 100 mL) was charged and evaporated to remove water by azeotropic distillation. To the resulting solids, ethyl acetate (30 mL) was charged and the mixture heated to 60 °C in a water bath until a homogeneous slurry was obtained. The solids were cooled to room temp while sonicating and were filtered using ethyl acetate to wash the cake to give the title compound as a light brown solid. (1.2 g, 69%). MS: 236.1 m / z (M+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).

[0864] Step 3: 5-acetyl-3-chloro-7-methylquinolin-2-yl trifluoromethanesulfonate.

[0865] In a 40 mL vial provided with a stir bar and a septum cap, a suspension of 5 -acetyl -3- chloro-7-methylquinolin-2(lH)-one (0.3 g, 1.27 mmol) and pyridine (309 uL, 3.82 mmol) in DCM (12 mL) was charged. The mixture was cooled to 0 °C and trifluoro(trifluoromesyloxysulfonyl)methane (641 μL, 3 eq., 3.82 mmol) was charged portion wise via needle. The initial slurry dissolved after the addition was completed. The reaction was stirred for another 10 min and the reaction was poured over an ice / sat NaHCO2mixture. The mixture was poured into a separatory funnel, and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL) and the organic layers combined, dried over sodium sulfate, filtered and concentrated to dryness to give the title product as a light purple solid (460 g, 98% yield). MS: 367.1 m / z (M+H+).1H NMR (400 MHz, CDC13) 59.52 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 2.77 (s, 3H), 2.63 (s, 3H).

[0866] Step 4: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile.

[0867] In a 40 mL vial provided with a stir bar and a septum cap, l-[3-chloro-7-methyl-2- (trifluoromesyloxy)-5-quinolyl]-l -ethanone (1 g, 2.45 mmol), zinc bis(cyanide) (345 mg, 1.2 eq., 2.94 mmol), Tetrakis(triphenylphosphine)palladium(0) (283 mg, 0.1 eq., 245 μmol) and dimethylformamide (15 mL, 194 mmol) were charged. The mixture was sparged with nitrogen for 3 min and the vial was capped and heated to 90 °C for 1 h. The reaction was cooled to room temperature and stirred for 1 h. The solids obtained were filtered and washed with MTBE ( 10 mL) and air dried to give the title compound as a light brown solid (556 mg, 92%). MS: 245.1 m / z (M+H+).1H NMR (400 MHz, DMSO) 59.29 (s, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 2.77 (s, 3H), 2.63 (s, 3H).

[0868] Intermediate: 6-chloro-3-hydroxypyridine-2-sulfonamide Stepl - Synthesis of 2-(benzylthio)-6-chloro-3-fluoropyridine:

[0869] To a solution of KOH (4.11 g, 73.25 mmol, 1.2 eq) in EtOH (50 mL) was added dropwise BnSH (8.49 mL, 72.30 mmol, 1.2 eq) at 0 °C. After addition, 2, 6-dichloro-3 -fluoro-pyridine (10 g, 60.25 mmol, 1 eq) in EtOH (50 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 16 h. Then the mixture was quenched with water (100 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by silica gel chromatography (solvent gradient: 100% petroleum ether) to give the title compound (14 g, 91%) as pink oil, which was further confirmed by13C-NMR (2D-NMR).1H NMR (400 MHz, CDCh) 57.48 - 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).

[0870] Step 2 - Synthesis of 6-chloro-3-fluoropyridine-2-sulfonamide:

[0871] To a solution of 2-benzylsulfanyl-6-chloro-3 -fluoro-pyridine (20 g, 78.83 mmol, 1 eq) in water (20 mL) and acetonitrile (200 mL) was added AcOH (36.10 mL, 630.61 mmol, 8 eq) at 0 °C. After addition, thenNCS (42.10 g, 315.30 mmol, 4 eq) was added slowly at 0 °C. The resulting mixture was stirred at 0 °C for 0.5 h. The mixture was added water (50 mL), then extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (100 mL x 3) and dried over Na2SO4. The organic mixture was added to ammonium hydroxide (80 mL, 623.19 mmol, 29 wt%, 8 eq) in THF (80 mL) at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 10 min. Then the mixture was quenched with water (100 mL), extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude product was triturated with DCM (50 mL), then filtered and the filter cake was concentrated in vacuo to give the title compound (11 g, 66%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.14 - 8.09 (m, 1H), 7.97 (s, 2H), 7.92 - 7.88 (m, 1H).

[0872] Step 3 - Synthesis of 6-chloro-3-hydroxypyridine-2-sulfonamide:

[0873] To a solution of 6-chloro-3-fluoro-pyridine-2-sulfonamide (10 g, 47.48 mmol, 1 eq) in water (250 mL) was added KOH (26.64 g, 474.80 mmol, 10 eq) at room temperature. After the addition, the reaction mixture was stirred at 110 °C for 5 h. After cooling to 0 °C, the pH was adjusted to ~ 4 - 5 with concentrated HC1 (12M). The mixture was extracted with DCM: z-PrOH = 3:1 (100 mL x 5), then the combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (2.9 g, 29%) as a white solid.1H 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).

[0874] Example 1: (R)-2-((l-(3-(isoindolin-2-yl)-7-methylquinolin-5-yl)ethyl)amino)benzoic acid (Compound 1)

[0875] Step 1 - Synthesis of 3-(benzyloxy)-5-bromo-7-methylquinoline:

[0876] To a mixture of 2-amino-6-bromo-4-methylbenzaldehyde (2.0 g, 9.36 mmol) (prepared according to the procedure in WO202192525) and 2-benzyloxyacetaldehyde (1.68 g, 11.20 mmol, 1.56 mL) in EtOH (40 mL) was added aqueous NaOH (748 mg, 18.68 mmol, dissolved in 2 mL H2O). The reaction vessel was sealed and stirred at 110 °C under microwave for 30 min. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give 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+).

[0877] Step 2 - Synthesis of l-(3-(benzyloxy)-7-methylquinolin-5-yl)ethan-l-one:

[0878] A mixture of 3-(benzyloxy)-5-bromo-7-methylquinoline (2.53 g, 7.71 mmol), tributyl(l- ethoxyvinyl)stannane (5.57 g, 15.42 mmol), Pd(dppf)Ch (305 mg, 416 umol) in dioxane (20 mL) was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, the mixture was quenched with 50 mL of 10% KF aqueous solution and stirred for 30 min. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product (2.55 g) as a yellow solid. The crude product was dissolved in dioxane (20 mL), then added IM HC1 (10 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was filtered and the filter cake was dried in vacuo to give the title compound (1.34 g, 60%) as a yellow solid.1H 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+).

[0879] Step 3 - Synthesis of l-(3-(benzyloxy)-7-methylquinolin-5-yl)ethan-l-amine:

[0880] To a solution of l-(3-(benzyloxy)-7-methylquinolin-5-yl)ethan-l-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) was added NaBH3CN (808 mg, 12.87 mmol). The reaction was heated to 60 °C for 16 h under Nz atmosphere. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL). The mixture was washed with saturated NaHCO3solution (50 mL x 3), brine (100 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated to give the title compound (1.15 g, crude) as a yellow solid that required no further purification. MS: m / z 293.2 (M+H+).

[0881] Step 4 - Synthesis of methyl 2-((l-(3-(benzyloxy)-7-methylquinolin-5- yl)ethyl)amino)benzoate:

[0882] A mixture of methyl 2-iodobenzoate (909 mg, 3.47 mmol), 1 -(3 -(benzyloxy )-7- methylquinolin-5-yl)ethan-l -amine (676 mg, 5.30 mmol), Pdz(dba)3 (113 mg, 123 μmol), Xantphos (143 mg, 247 μmol) and CszCO3(2.26 g, 6.61 mmol) in dioxane (10 mL) under Nz atmosphere. The mixture was heated to 110 °C for 16 h under Nz atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petrolaim ether) to give the title compound (820 mg, 83%) as a white solid,1H NMR (400 MHz, DMSO-d6) 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+).

[0883] Step 55 - Synthesis of methyl 2-((l-(3-hydroxy-7-methylquinolin-5- yl)ethyl)amino)benzoate:

[0884] To a solution of methyl 2-((l-(3-(benzyloxy)-7-methylquinolin-5-yl)ethyl)amino)benzoate (815 mg, 1.91 mmol) in MeOH (10 mL) was added Pd(OH)2on carbon (400 mg, 20% Pd, 50% wet with water). The reaction was stirred at room temperature for 1 h under H2atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give the title compound (160 mg, 25%) as a yellow solid that required no further purification. MS: m / z 337.2 (M+H+).

[0885] Step 6 - Synthesis ooff methyl 2-((l-(7-methyl-3-

[0886] (((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)ethyl)amino)benzoate:

[0887] To a solution of methyl 2-((l-(3-hydroxy-7-methylquinolin-5-yl)ethyl)amino)benzoate (160 mg, 476 μmol) in DCM (4 mL) was added pyridine (115 μL, 1.43 mmol) and TfzO (201 mg, 713 μmol, 118 μL). The reaction was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM 20 mL and washed with IM HC1 (10 mL), and then the organic layer was washed with NaHCO3(10 mL x 2), dried over anhydrous Na2SO4 and filtered and concentrated in vacuo to give the title compound (198 mg, 89%) as a yellow solid that required no further purification.1H NMR (400 MHz, DMSO-d6) 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+).

[0888] Step 7 - Synthesis of methyl 2-((l-(3-(isoindolin-2-yl)-7-methylquinolin-5- yl)ethyl)amino)benzoate:

[0889] A mixture of methyl 2-((l-(7-methyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-5- yl)ethyl)amino)benzoate (198 mg, 423 μmol), isoindoline (76 mg, 634 μmol), Pdi(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 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (76 mg, 41%) as a white solid. MS: m / z 438.1 (M+H+).

[0890] Step 8 - Synthesis of 2-((l-(3-(isoindolin-2-yl)-7-methylquinolin-5- yl)ethyl)amino)benzoic acid:

[0891] A solution of methyl 2-((l-(3-(isoindolin-2-yl)-7-methylquinolin-5- yl)ethyl)amino)benzoate (76 mg, 174 μmol) in MeOH (2 mL) and THF (0.2 mL) was added LiOH (42 mg, 1.75 mmol, dissolved in 0.2 mL H2O). The mixture was stirred at 60 °C for 16 h. 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 (acetonitrile 45% - 75% / 0.225% formic acid in water) to give the title compound (50 mg, 68%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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+).

[0892] Step 99 - Synthesis of (R)-2-((l-(3-(isoindolin-2-yl)-7-methylquinolin-5- yl)ethyl)amino)benzoic acid and (S)-2-((l-(3-(isoindolin-2-yl)-7-methylquinolin-5- yl)ethyl)amino)benzoic acid: 2-((l-(3-(isoindolin-2-yl)-7-methylquinolin-5-yl)ethyl)amino)benzoic acid (50 mg, 118 μmol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm *30mm,10um); Supercritical CO2 / EtOH + 0.1% NH3- H2O = 60 / 40; 70 mL / min) to afford (R )2-((l-(3- (isoindolin-2-yl)-7-methylquinolin-5-yl)ethyl)amino)benzoic acid (4 mg, first peak) and (S)-2-((l- (3-(isoindolin-2-yl)-7-methylquinolin-5-yl)ethyl)amino)benzoic acid (5 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer, (first peak):1H NMR (400 MHz, DMSOd6) 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+).

[0893] Example 22:: 2-((l-(7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5- yl)ethyl)amino)benzoic acid (Compound 2)

[0894] Step 1 - Synthesis of methyl 2-((l-(3-(3,6-dihydro-2H-pyran-4-yl)-7-methylquinolin- 5-yl)ethyl)amino)benzoate:

[0895] A mixture of methyl 2-((l-(7-methyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-5- yl)ethyl)amino)benzoate (270 mg, 576 μmol), 2-(3,6-dihydro-2Z / -pyran-4-yl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (242 mg, 1.15 mmol), Pd(PPhs)4 (66 mg, 58 μmol) and K2CO3 (239 mg, 1.41 mmol) in dioxane (4 mL) and H2O (0.1 mL). The mixture was stirred at 110 °C for 8 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 33% EtOAc in petroleum ether) to give the title compound (231 mg, 98%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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+).

[0896] Step 2 - Synthesis of methyl 2-((l-(7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5- yl)ethyl)amino)benzoate:

[0897] To a solution of methyl 2-((l-(3-(3,6-dihydro-2H -pyran-4-yl)-7-methylquinolin-5- yl)ethyl)amino)benzoate (231 mg, 547 μmol) in MeOH (10 mL) was added Pd(OH)2 on carbon (115 mg, 20% Pd, 50% wet with water). The reaction was stirred at room temperature for 1 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give the title compound (196 mg, 83%) as a yellow solid that required no further purification. MS: m / z 405.1 (M+H+).

[0898] Step 3 - Synthesis of 2-((l-(7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5- yl)ethyl)amino)benzoic acid:

[0899] A solution of methyl 2-((l-(7-methyl-3-(tetrahydro-2 / H pyran-4-yl)quinolin-5- yl)ethyl)amino)benzoate (196 mg, 470 μmol) in MeOH (4 mL) and THF (0.4 mL) was added LiOH (99 mg, 2.35 mmol, dissolved in H2O). The mixture was stirred at 60 °C for 16 h. 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 (acetonitrile 25% - 55% / 0.225% formic acid in water) to give the title compound (84 mg, 45%) as a white solid.1H NMR (400 MHz, DMSOd6) 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+). Example 3A and Example 3B: (R)-2-((l-(7-methyl-3-(tetrahydro-2H-pyran-4- yl)quinolin-5-yl)ethyl)amino)benzoic acid (Compound 3) & (S)-2-((l-(7-methyl-3- (tetrahydro-2H-pyran-4-yl)quinolin-5-yl)ethyl)amino) benzoic acid (Compound 4):

[0900] Step 1 - Synthesis of (R)-2-((l-(7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5- yl)ethyl)amino)benzoic acid & (S)-2-((l-(7-methyl-3-(tetrahydro-2 / Z-pyran-4-yl)quinoIin-5- yl)ethyl)amino)benzoic acid:

[0901] 2-((l -(7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5-yl)ethyl)amino)benzoic acid (80 mg, 197.78 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OJ (250mm*30mm,10um); Supercritical CO2 / EtOH+O.1% NH3.H2O = 60 / 40; 70 mL / min) to afford (R)-2-((l-(7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5-yl)ethyl)amino)benzoic acid (21 mg, first peak) and (S)-2-((l-(7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5- yl)ethyl)amino)benzoic acid (16 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Example 3 A (first peak):1H NMR (400 MHz, DMSO-d6) 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

[0902] - 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 (second peak):1H NMR (400 MHz, DMSO-d6) 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

[0903] - 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+).

[0904] Example 4: 2-((l-(3-(4-fluorophenyl)-7-methylquinolin-5-yl)ethyl)amino)benzoic acid (Compound 5)

[0905] Step 1 - Synthesis of methyl 2-((l-(3-(4-fluorophenyl)-7-methylquinolin-5- yl)ethyl)amino)benzoate:

[0906] A mixture of methyl 2-((l-(7-methyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-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 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 33% EtOAc in petroleum ether) to give the title compound (122 mg, 99%) as a white solid. MS: m / z 415.1 (M+H+).

[0907] Step 2 - Synthesis of 2-((l-(3-(4-fluorophenyl)-7-methylquinolin-5- yl)ethyl)amino)benzoic acid:

[0908] A solution of methyl 2-((l-(3-(4-fluorophenyl)-7-methylquinolin-5- yl)ethyl)amino)benzoate (122 mg, 294 μmol) in MeOH (4 mL) and THE (0.4 mL) was added LiOH (35 mg, 1.47 mmol, dissolved in 0.4 mL H2O). The mixture was stirred at 60 °C for 16 h. 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 (acetonitrile 50% - 80% / 0.225% formic acid in water) to give the title compound (21 mg, 18%) as a white solid.1HNMR(400 MHz, DMSO-d6) 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+).

[0909] Example 5: 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)cthyl)amino)benzoic acid (Compound 6)

[0910] Step 1 - Synthesis of 3-(benzyloxy)-5-bromo-2,7-dimethylquinoline:

[0911] 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) was added NaOH (206 mg, 5.14 mmol). The reaction vessel was sealed and stirred at 110 °C under microwave for 30 min. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (880 mg, 78%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 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+).

[0912] Step 2 - Synthesis of l-(3-(benzyloxy)-2,7-diniethylquinolin-5-yl)ethan-l-one:

[0913] A mixture of 3-(benzyloxy)-5-bromo-2,7-dimethylquinoline (880 mg, 2.38 mmol), tributyl (1 -ethoxyvinyl )stannane (1.72 g, 4.77 mmol), Pd(dppf)C12 (174 mg, 238 umol) in dioxane (10 mL) was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, the mixture was quenched with 30 mL of 10% KF aqueous solution and stirred for 30 min. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give a crude product (790 mg) as a yellow solid. The crude product was dissolved in dioxane (10 mL), then added aqueous HC1 (IM, 40 mL). The mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the filter cake was dried in vacuo to give the title compound (560 mg, 69%) as a yellow solid.]H NMR (400 MHz, DMSO-d6) 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+).

[0914] Step 3 - Synthesis of l-(3-(benzyloxy)-2,7-diniethylquinolin-5-yl)ethan-l-aniine:

[0915] To a solution of l-(3-(benzyloxy)-2,7-dimethylquinolin-5-yl)ethan-l-one (560 mg, 1.67 mmol), NHtOAc (1.93 g, 25.05 mmol) and AcOH (100 mg, 1.67 mmol, 96 μL) in MeOH (10 mL) was added NaBH3CN (808 mg, 5.01 mmol). The reaction was heated to 60 °C for 16 h under N2atmosphere. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL). The mixture was washed with saturated NaHCO3solution (50 mL) and brine (50 mL), dried over anhydrous Na2SO2and filtered. The filtrate was concentrated in vacuo to give the title compound (960 mg, crude) as a yellow solid that required no further purification. MS: m / z 307.1 (M+H+).

[0916] Step 4 - Synthesis of methyl 2-((l-(3-(benzyloxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate:

[0917] A mixture of methyl 2-iodobenzoate (638 mg, 2.44 mmol), l-(3-(benzyloxy)-2,7- dimethylquinolin-5-yl)ethan-l -amine (676 mg, 5.30 mmol), Pdi(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 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (330 mg, 40%) as a white solid,1H NMR (400 MHz, DMSO-d6) 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+).

[0918] Step 55 - Synthesis of methyl 2-((l-(3-hydroxy-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate:

[0919] To a solution of methyl 2-((l-(3-(benzyloxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (330 mg, 749 μmol) in MeOH (10 mL) was added Pd(OH)2on carbon (200 mg, 20% Pd, 50% wet with water). The reaction was stirred at room temperature for 1 h under H2atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give the title compound (209 mg, 80%) as a yellow solid that required no further purification. MS: m / z 351.2 (M+H+).

[0920] Step 66 - Synthesis ooff methyl 2-((l-(2,7-dimethyl-3-

[0921] (((trifluoromethyl)sulfonyl)oxy)quinolin-5-yl)ethyl)amino)benzoate:

[0922] To a solution of methyl 2-((l-(3-hydroxy-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoate (209 mg, 596 μmol), pyridine (144 μL, 1.79 mmol) in DCM (4 mL) was added TfiO (252 mg, 895 μmol). The reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM (30 mL) and washed with IM HC1 (10 mL), and then the organic layer was washed with NaHCO3(10 mL x 2), dried over anhydrous Na2SO4 and filtered and concentrated in vacuo to give the title compound (280 mg, 97%) as a yellow solid that required no further purification.1H NMR (400 MHz, DMSO-d6) 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+).

[0923] Step 7 - Synthesis of methyl 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate:

[0924] A mixture of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-5- yl)ethyl)amino)benzoate (280 mg, 746 μmol), isoindoline (133 mg, 1.12 mmol), Pdz(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 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 33% EtOAc in Petroleum ether) to give the title compound (187 mg, 56%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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+).

[0925] Step 8 - Synthesis of 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid:

[0926] To a solution of methyl 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (90 mg, 199 μmol) in MeOH (2 mL) and THF (0.2 mL) was added LiOH monohydrate (42 mg, 997 μmol, dissolved in 0.2 mL H2O). The mixture was stirred at 60 °C for 16 h. 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 (acetonitrile 35% - 65% / 0.225% formic acid in water) to give the title compound (60 mg, 69%) as a white solid. NMR (400 MHz, DMSOd6) 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+). Example 66:: (S)-2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid (Compound 7)

[0927] Step 11 - Synthesis of (R)-2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid & (S)-2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid:

[0928] 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid (50 mg, 114 umol) wwaass separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm*30mm, lOum); Supercritical CO2 / EtOH + 0.1% NH3. H2O = 60 / 40; 60 mL / min) to afford (R)-2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid (5 mg, first peak) and (S)-2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid (6 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. Example 6 (second peak):1HNMR (400 MHz, DMSO-d6) 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+).

[0929] Example 7A: 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)benzoic acid (Compound 79) Step 1 - Synthesis of methyl 2-((l-(3-(5,6-dihydro-2H-pyran-3-yl)-2,7- dimethylquinolin-5-yl)ethyl)amino)benzoate:

[0930] A mixture of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-5- yl)ethyl)amino)benzoate (310 mg, 643 μmol), 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane (202 mg, 964 μmol), Pdi(dba)3 (59 mg, 64 μmol), Xantphos (74 mg, 129 μmol) and CS2CO3 (628 mg, 1.93 mmol) in dioxane (5 mL). The mixture was stirred at 110 °C for 3 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 33% EtOAc in petroleum ether) to give the title compound (200 mg, 75%) as a white solid. MS: m / z 417.2 (M+H+).

[0931] Step 2 - Synthesis of methyl 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3- yl)quinolin-5-yl)ethyl)amino)benzoate:

[0932] To a solution of methyl 2-((l-(3-(5,6-dihydro-2H-pyran-3-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (200 mg, 480 μmol) in MeOH (10 mL) was added wet Pd(OH)2 on carbon (100 mg, 20% Pd, 50% wet with water). The reaction was stirred at room temperature for 4 h under H2atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated to afford the title compound (100 mg, 50%) as a yellow solid that required no further purification. MS: m / z 419.3 (M+H+).

[0933] Step 3 - Synthesis of 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)benzoic acid:

[0934] A mixture of methyl 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)benzoate (50 mg, 119 μmol) in MeOH (0.3 mL) and THF (3 mL) was added LiOH (29 mg, 1.19 mmol, dissolved in 0.3 mL H2O). The mixture was stirred at 60 °C for 16 h. 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 (acetonitrile 20% - 50% / 0.225% formic acid in water) to give the title compound (10 mg, 21%) as a yellow solid.1HNMR (400 MHz, DMSO-d6) 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+).

[0935] Example 7B: 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)benzoic acid: 2-(((R)-l-(2,7-dimethyl-3-(R )-tetrahydro-2H-pyran-3- yl)quinolin-5-yl)ethyl)amino)benzoic acid; 2-((R )-l-(2,7-dimethyl-3-((S)-tetrahydro-2H- pyran-3-yl)quinolin-5-yl)ethyl)amino)benzoic acid; 2-(((S)-l-(2,7-dimethyl-3-((lt)- tetrahydro-2H-pyran-3-yl)quinolin-5-yl)ethyl)amino)benzoic acid; and 2-(((S)-l-(2,7- dimethyl-3-((S)-tetrahydro-2H-pyran-3-yl)quinolin-5-yl)ethyl)amino)benzoic acid

[0936] (Compounds 8A-8D)

[0937] 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5-yl)ethyl)amino)benzoic acid (60 mg, 148 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250mm*30mm,10um); Supercritical CO2 / EtOH+O.1% NH3.H2O = 60 / 40; 70 mL / min) to afford

[0938] 2-(((R)-l-(2,7-dimethyl-3-((R)-tetrahydro-2H-pyran-3-yl)quinolin-5-yl)ethyl)amino)benzoic acid and 2-(((R)-l-(2,7-dimethyl-3-((S)-tetrahydro-2H-pyran-3-yl)quinolin-5-yl)ethyl)amino)benzoic acid (20 mg, peak 2 and peak 4, inseparable), 2-(((S)-l-(2,7-dimethyl-3-((R)-tetrahydro-2H-pyran-

[0939] 3-yl)quinolin-5-yl)ethyl)amino)benzoic acid (4 mg, first peak) and 2-(((S)-l-(2,7-dimethyl-3-((S)- tetrahydro-2H-pyran-3-yl)quinolin-5-yl)ethyl)amino)benzoic acid (7 mg, third peak) both as white solid. The mixture of peak 2 and peak 4 (20 mg, 48 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL IG (250mm*30mm, lOum); Supercritical CO2 / EtOH+0.1% NH3.H2O = 65 / 35; 70 mL / min) to afford 2-(((R)-l-(2,7-dimethyl-3-((R)-tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)benzoic acid (4 mg, second peak) and 2-(((R)-l-(2,7-dimethyl-3-((S)-tetrahydro- 2H-pyran-3-yl)quinolin-5-yl)ethyl)amino)benzoic acid (5 mg, fourth peak). Absolute configuration was arbitrarily assigned to each enantiomer. (The retention times of these four peaks are sorted according to this method: OJ_3_EtOH_DEA_5_40_25ML_6MIN). Second peak (Compound 8A):1HNMR (400 MHz, DMSOd6) 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+). Fourth peak (Compound 8B):1H NMR (400 MHz, DMSO-d6) 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+). First peak (Compound 8C):1H NMR (400 MHz, DMSO-d6) 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+). Third peak (Compound 8D):]H NMR (400 MHz, DMSOd6) 5 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+).

[0940] Example 88:: 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5- yl)ethyl)amino)benzoic acid (Compound 9)

[0941] Step 1 - Synthesis of N -(2-bromo-4-methyl-6-nitrophenyl)-2-oxopropanamide:

[0942] To a solution of 2-oxopropanoic acid (0.5 g, 5.68 mmol) in THF (5 mL) was added DMF (54 mg, 738 μmol) and oxalyl chloride (721 mg, 5.7 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h under N2 atmosphere. Then 2-bromo-4-methyl-6-nitro-aniline (0.7 g, 3 mmol) dissolved in THF (10 mL) and TEA (919 mg, 9.09 mmol) was added to the mixture. The mixture was stirred at room temperature for 2 h. The mixture was quenched with H2O (20 mL), extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (600 mg, 66%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 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).

[0943] Step 2 - Synthesis of 8-bromo-3, 6-dimethylquinoxalin-2-ol:

[0944] To a solution of N-(2-bromo-4-methyl-6-nitro-phenyl)-2-oxo-propanamide (0.6 g, 2 mmol) in AcOH (6 mL) was added Fe (557 mg, 10 mmol, powder). The mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the solution was filtered and concentrated in vacuo. The residue was dissolved in H2O (20 mL) and stirred for 10 min. The suspension solution was filtered and the filter cake was dried in vacuo to give the title compound (350 mg, 70%) as a yellow solid that required no further purification.1H NMR (400MHz, DMSO-d6) δ 7.63 (s, 1H), 7.54 (s, 1H), 2.42 (s, 3H), 2.37 (s, 3H).

[0945] Step 3 - Synthesis of 5-bromo-3-chloro-2, 7-dimethylquinoxaline:

[0946] A solution of 8-bromo-3,6-dimethyl-quinoxalin-2-ol (0.35 g, 1.38 mmol) in POCb (2 mL, 21 mmol). The mixture was stirred at 120 °C for 5 h. After cooling to room temperature, POCh was removed in vacuo, DCM (50 mL) was added, and the mixture was washed with sat. aq. NaHCCb (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (72 g, 99%) as a white solid that required no further purification. ‘H NMR (400 MHz, DMSOd6) 58.07 (d, J= 1.6 Hz, 1H), 7.86 (s, 1H), 2.77 (s, 3H), 2.54 (s, 3H).

[0947] Step 4 - Synthesis of 5-bromo-3-(isoindolin-2-yl)-2, 7-dimethylquinoxaline:

[0948] To a solution of 5-bromo-3-chloro-2,7-dimethyl-quinoxaline (0.47g, 1.73 mmol) and isoindoline (412 mg, 3.46 mmol) in MeCN (5 mL) was added K2CO3 (718 mg, 5.2 mmol). The reaction mixture was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction was diluted with water (20 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with IM HC1 (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (600 mg, 97%) as a yellow solid that required no further purification.1H NMR (400MHz, DMSO-d6) 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+). Step 5 - Synthesis of 1-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethan-1-one:

[0949] A mixture of 5-bromo-3-(isoindolin-2-yl)-2,7-dimethylquinoxaline (880 mg, 2.48 mmol), tributyl(l -ethoxy vinyl)stannane (2.24 g, 6.21 mmol) and Pd(dppf)C12 (182 mg, 0.25 mmol) in dioxane (10 mL) was degassed and purged with N2 for 3 times. The reaction mixture was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, HC1 (1 mL, 1 M) was added. The mixture was stirred at room temperature for 0.5 h. The reaction mixture was added 50 mL 10% KF aqueous solution, stirred at room temperature for 2 h. The mixture was extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (200 mg, 28%) as a yellow solid.1H NMR (400MHz, DMSOd6) 5 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).

[0950] Step 6 - Synthesis of l-(3-(isoindolin-2-yl)-2, 7-dimethylquinoxalin-5-yl)ethan-l- amine:

[0951] To a solution of l-(3-(isoindolin-2-yl)-2, 7-dimethylquinoxalin-5-yl)ethan-l-one (170 mg, 0.53 mmol), NHiOAc (619 mg, 8.03 mmol) in MeOH (4 mL), NaBH3CN (101 mg, 1.61 mmol) was added. The reaction was heated to 60 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was diluted with water (20 mL), extracted with EtOAc (30 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (160 mg, 94%) as yellow oil that required no further purification.1H NMR (400 MHz, DMSO-d6) 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+).

[0952] Step 7 - Synthesis of tert-butyl 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5- yl)ethyl)amino)benzoate:

[0953] A mixture of l-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5-yl)ethan-l-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 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (100 mg, 40%) as yellow oil. MS: m / z 495.2 (M+H+).

[0954] Step 88 - Synthesis of 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5- yl)ethyl)amino)benzoic acid:

[0955] To a mixture of tert-butyl 2-((l-(3-(isoindolin-2-yl)-2,7-dimethylquinoxalin-5- yl)ethyl)amino)benzoate (100 mg, 202 umol) in DCM (3 mL) was added TFA (0.5 mL, 6.9 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 53% - 83% / 0.225% formic acid in water) to give the title compound (52 mg, 11%) as a yellow solid.1H NMR (400MHz, DMSOd6) 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+H1).

[0956] Example 1111 AA:: 2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid (Compound 10)

[0957] Step 1 - Synthesis of methyl 2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate:

[0958] A mixture of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-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 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (106 mg, 80%) as a yellow solid. MS: m / z 429.1 (M+H+). Step 22 - Synthesis of 2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid:

[0959] A solution of methyl 2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (20 mg, 47 μmol) in EtOH (0.2 mL) was added KOH (26 mg, 467 μmol, dissolved in 0.2 mL H2O). The mixture was stirred at 100 °C for 2 h. 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 (acetonitrile 32% - 62% / 0.225% formic acid in water) to give the title compound (15 mg, 78%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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+).

[0960] Example 1111BB:: (R)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid and (S)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid (Compound 10A and Compound 10B)

[0961] Step 1 - Synthesis of methyl (R)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate & methyl (S)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate: methyl 2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoate (100 mg, 233 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250mm*30mm,10um); Supercritical CO2 / EtOH+0.1% NH3.H2O = 75 / 25; 70 mL / min) to afford methyl (R)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoate (40 mg, first peak) and methyl (S)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (40 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m / z 429.1 (M+H~). Step 2A - Synthesis of (R)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid:

[0962] A solution of methyl (R)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (40 mg, 93 μmol) in EtOH (0.4 mL) was added KOH (52 mg, 934 μmol, dissolved in 0.4 mL H2O). The mixture was stirred at 100 °C for 2 h. 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 (acetonitrile 37% - 67% / 0.225% formic acid in water) to give the title compound (11 mg, 28%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.63 - 8.51 (m, 1H), 8.46 (s, 1H), 7.84 - 7.77 (m, 1H), 7.66 (s, 1H),

[0963] 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+).

[0964] Step 2B - Synthesis of (5)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid:

[0965] A solution of methyl (S)-2-((l-(3-(3-fluorophenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (40 mg, 93 μmol) in EtOH (0.4 mL) was added KOH (52 mg, 934 μmol, dissolved in 0.4 mL H2O). The mixture was stirred at 100 °C for 2 h. 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 (acetonitrile 37% - 67% / 0.225% formic acid in water) to give the title compound (16 mg, 41%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.62 - 8.50 (m, 1H), 8.46 (s, 1H), 7.83 - 7.77 (m, 1H), 7.66 (s, 1H),

[0966] 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+).

[0967] Example 12A: 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid (Compound 11)

[0968]

[0969] Step 1 - Synthesis of methyl 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7- dimethylquinolin-5-yl)ethyl)amino)benzoate:

[0970] A mixture of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-5- yl)ethyl)amino)benzoate (150 mg, 311 μmol), 2-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (152 mg, 622 μmol) (prepared according to the procedure in 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 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (126 mg, 85%) as a yellow solid. MS: m / z 452.2 (M+H+).

[0971] Step 2 - Synthesis of 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid:

[0972] To a solution of methyl 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (25 mg, 55 μmol) in EtOH (0.4 mL) was added KOH (31 mg, 554 μmol, dissolved in 0.4 mL H2O). The mixture was stirred at 100 °C for 2 h. 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 (acetonitrile 23% - 53% / 0.225% formic acid in water) to give the title compound (15 mg, 62%) as a white solid.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+).

[0973] Example 12B: R )-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic aacciidd aanndd (S)-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7- dimethylquinolin-5-yl)ethyl)amino)benzoic acid (Compound 11A and 11B)

[0974]

[0975] Step 1 - Synthesis of methyl (R)-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7- dimethylquinolin-5-yl)ethyl)amino)benzoate & methyl (S)-2-((l-(3-(2-cydopropylpyridin-4- yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoate: methyl 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino) benzoate (100 mg, 221 μmol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250mm*30mm,10um); Supercritical CO2 / EtOH+O.1% NH3.H2O = 60 / 40; 70 mL / min) to afford methyl (R)-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoate (40 mg, first peak) and methyl (S)-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (40 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m / z 452.2 (M+H~).

[0976] Step 2A - Synthesis of R )-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin- 5-yl)ethyl)amino)benzoic acid:

[0977] A solution of methyl (R)-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (40 mg, 89 μmol) in MeOH (0.1 mL) and THF (1 mL) was added LiOH (21 mg, 886 μmol, dissolved in 0.1 mL H2O). The mixture was stirred at 60 °C for 16 h. 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 (acetonitrile 21% - 51% / 0.225% formic acid in water) to give the title compound (16 mg, 42%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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+).

[0978] Step 2B - Synthesis of (SS-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin- 5-yl)ethyl)amino)benzoic acid: A solution of methyl (S)-2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (40 mg, 89 μmol) in MeOH (0.1 mL) and THF (1 mL) was added LiOH (21 mg, 886 μmol, dissolved in 0.1 mL H2O).The mixture was stirred at 60 °C for 16 h. 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 (acetonitrile 21% - 51% / 0.225% formic acid in water) to give the title compound (14 mg, 37%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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+).

[0979] Example 13: methyl 2-((l-(3-(3-(difluoromethyl)phenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (Compound 29)

[0980] Step 11 - Synthesis ooff methyl 2-((l-(3-(3-(difluoromethyl)phenyl)-2,7- dimethylquinolin-5-yl)ethyl)amino)benzoate:

[0981] A mixture of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-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 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (100 mg, 70%) as a white solid. MS: m / z 461.1 (M+H+).

[0982] Step 2 - Synthesis of 2-((l-(3-(3-(difluoromethyl)phenyl)-2,7-dimethylquinolm-5- yl)ethyl)amino)benzoic acid:

[0983] A solution of methyl 2-((l-(3-(3-(difluoromethyl)phenyl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (20 mg, 43 μmol) in EtOH (0.2 mL) was added KOH (24 mg, 434 μmol, dissolved in 0.2 mL H2O). The reaction mixture was stirred at 100 °C for 2 h. 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 (acetonitrile 30% - 60% / 0.225% formic acid in water) to give the title compound (15 mg, 77%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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+H4).

[0984] Example 1144:: 2-((l-(2-cyano-7-methyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)benzoic acid (Compound 30)

[0985] Step 1 - Synthesis of 3-(benzyloxy)-5-bromo-7-methylquinoline 1 -oxide:

[0986] A mixture of 3-(benzyloxy)-5-bromo-7-methylquinoline (2.5 g, 7.61 mmol) and m-CPBA (3.09 g, 15.24 mmol, 85% purity) in DCM (25 mL) was stirred at room temperature for 16 h. The reaction mixture was quenched with sat. aq. Na2S2O3(20 mL) at room temperature, and then extracted with DCM (30 mL). The organic layer was washed with NaHCO3(20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (2.53 g, crud6) as a black solid that required no further purification. MS: m / z 344.1 (M+H+).

[0987] Step 2 - Synthesis of 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbonitrile:

[0988] A mixture of 3-(benzyloxy)-5-bromo-7-methylquinoline 1 -oxide (2.10 g, 6.10 mmol), TEA (1.23 g, 12.20 mmol), CC14(1.88 g, 12.20 mmol), TMSCN (726 mg, 7.32 mmol) and diethyl phosphonate (1.69 g, 12.20 mmol) in CHCh (40 mL) was stirred at room temperature for 16 h under N2 atmosphere. The reaction mixture was diluted with DCM (20 mL). The mixture was washed with NaHCO3(30 mL x 2), brine (30 mL), dried over anhydrous Na2SO3, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (1.3 g, 60%) as a yellow solid. MS: m / z 353.0 (M+H+).

[0989] Step 3 - Synthesis of 5-(l-ethoxyvinyl)-3-hydroxy-7-niethylquinoline-2-carbonitrile:

[0990] A mixture of tributyl(l-ethoxyvinyl)stannane (1.84 g, 5.10 mmol), 3 -(benzyl oxy )-5- bromo-7-methylquinoline-2-carbonitrile (900 mg, 2.55 mmol), Pd(dppf)Ch (186 mg, 255 μmol) in dioxane (10 mL) was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the mixture was quenched with 30 mL of 10% KF aqueous solution and stirred for 30 min. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 33% EtOAc in petroleum ether) to give the title compound (400 mg, 62%) as a yellow solid.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+H1).

[0991] Step 4 Synthesis of 5-acetyl-2-cyano-7-methylquinolin-3-yl trifluoromethanesulfonate:

[0992] A mixture of 5-(l-ethoxyvinyl)-3-hydroxy-7-methylquinoline-2-carbonitrile (100 mg, 393 μmol), pyridine (93 mg, 1.18 mmol), Tf2O (166 mg, 590 μmol) in DCM (4 mL) was stirred at 0 °C for 1 h. The mixture was added to HC1 (5 mL, IM), and then stirred at room temperature for 0.5 h. The mixture was basified with sat. aq. NaHCOi to pH 7. Then the mixture was extracted with DCM (15 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (128 mg, crude) as a yellow solid that required no further purification. MS: m / z 359.0 (M+H+).

[0993] Step 5 - Synthesis of 5-acetyl-3-(5,6-dihydro-2H-pyran-3-yl)-7-methylquinoline-2- carbonitrile:

[0994] A mixture of 5-acetyl-2-cyano-7-methylquinolin-3-yl trifluoromethanesulfonate (128 mg, 357 μmol), 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (113 mg, 536 μmol), Pd(PPh3)4 (41 mg, 36 μmol) and K2CO3 (148 mg, 1.07 mmol) in dioxane (2 mL) and H2O (0.2 mL). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (73 mg, 70%) as a white solid. NMR (400 MHz, DMSO-d6) 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+).

[0995] Step 6 - Synthesis of 5-(l-aminoethyl)-3-(5,6-dihydro-2H-pyran-3-yl)-7- methylquinoline-2-carbonitrile:

[0996] A mixture of 5-acetyl-3-(5,6-dihydro-2H-pyran-3-yl)-7-methylquinoline-2-carbonitrile (65 mg, 222 μmol), NHtOAc (257 mg, 3.34 mmol) and AcOH (13 mg, 222 μmol) in MeOH (1 mL) was stirred at room temperature for 1 h. Then NaBFhCN (42 mg, 667 μmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with DCM (20 mL). The mixture was washed with saturated NaHCO3solution (10 mL x 3), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (63 mg, crude) as a yellow solid that required no further purification. MS: m / z 294.2 (M+H+).

[0997] Step 7 - Synthesis of tert-butyl 2-((l-(2-cyano-3-(5,6-dihydro-2H-pyran-3-yl)-7- methylquinolin-5-yl)ethyl)amino)benzoate:

[0998] A mixture of 5-(l-aminoethyl)-3-(5,6-dihydro-2H-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) in dioxane (2 mL), the reaction mixture was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give the title compound (50 mg, 50%) as a yellow solid. MS: m / z 470.3 (M+H+).

[0999] Step 8 - Synthesis of tert-butyl 2-((l-(2-cyano-7-methyl-3-(tetrahydro-2H-pyran-3- yl)quinolin-5-yl)ethyl)amino)benzoate:

[1000] To a solution of tert-butyl 2-((l-(2-cyano-3-(5,6-dihydro-2H-pyran-3-yl)-7- methylquinolin-5-yl)ethyl)amino)benzoate (50 mg, 106 μmol) in MeOH (1 mL) was added Pd(OH)2 on carbon (16 mg, 20% Pd, 50% wet with water). The reaction was stirred at room temperature for 1 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give the title compound (49 mg, crude) as a yellow solid that required no further purification. MS: m / z 472.3 (M+H+). Step 9 - Synthesis of 2-((l-(2-cyano-7-methyl-3-(tetrahydro-2H-pyran-3-yl)quinolin- 5-yl)ethyl)amino)benzoic acid:

[1001] To a solution of tert-butyl 2-((l-(2-cyano-7-methyl-3-(tetrahydro-2H-pyran-3-yl)quinolin- 5-yl)ethyl)amino)benzoate (13 mg, 28 μmol) in DCM (2 mL) was added TEA (154 mg, 1.36 mmol). The reaction mixture was stirred at 40 °C for 2 h. After cooling to room temperature, the reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 56% - 86% / 0.225% formic acid in water) to give the title compound (2.9 mg, 25%) as a white solid. 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+).

[1002] Example 15: 2-((l-(2-carbamoyl-7-methyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino) benzoic acid (Compound 31)

[1003] Step 1 - Synthesis of tert-butyl 2-((l-(2-carbamoyl-7-methyl-3-(tetrahydro-2H-pyran- 3-yl)quinolin-5-yl)ethyl)amino)benzoate:

[1004] To a solution of tert-butyl 2-((l-(2-cyano-7-methyl-3-(tetrahydro-2H-pyran-3-yl)quinolin- 5-yl)ethyl)amino)benzoate (40 mg, 85 μmol) in THE (2 mL) and H2O (0.5 mL) was added H2O2 (96 mg, 848 μmol, 30% in water) and NaOH (14 mg, 339 μmol). After the addition, the reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with sat. aq. Na2S20a solution (5 mL) and stirred for 30 min. The mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (38 mg, 64%) as a white solid. MS: m / z 490.1 (M+H+). Step 2 - Synthesis of 2-((l-(2-carbamoyl-7-methyl-3-(tetrahydro-2H-pyran-3- yl)quinolin-5-yl)ethyl)amino)bcnzoic acid:

[1005] To a solution of tert-butyl 2-((l-(2-carbamoyl-7-methyl-3-(tetrahydro-2H-pyran-3- yl)quinolin-5-yl)ethyl)amino)benzoate (38 mg, 78 umol) in DCM (1 mL) was added TFA (0.3 mL, 37.9 mmol). The reaction mixture was stirred at room temperature for 16 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 45% - 75% / 0.225% formic acid in water) to give the title compound (4.9 mg, 14%) as a yellow solid. 'HNMR (400 MHz, DMSO-d6) 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+).

[1006] Example 16: 2-((l-(3-(cyclopropylmethoxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid (Compound 32)

[1007] Step 1 - Synthesis of methyl 2-((l-(3-(cyclopropylmethoxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate:

[1008] A mixture of methyl 2-((l-(3-hydroxy-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoate (120 mg, 342 μmol), bromomethylcyclopropane (120 mg, 888 μmol), CS2CO3 (335 mg, 1.03 mmol) in DMF (3 mL) was stirred at 80 °C for 2 h. After cooling to room temperature, the reaction mixture was quenched with water (15 mL), extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (30 mL x 3) and brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (120 mg, crude) as a yellow solid that required no further purification. MS: m / z 405.1 (M+H+).

[1009] Step 2 - Synthesis of 2-((l-(3-(cyclopropylmethoxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid: To a solution of methyl 2-((l-(3-(cyclopropylmethoxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (120 mg, 297 μmol) in EtOH (1 mL) was added KOH (194 mg, 3.46 mmol, dissolved in 1 mL H2O). The reaction mixture was stirred at 100 °C for 2 h. 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 (acetonitrile 26% - 56% / 0.225% formic acid in water) to give the title compound (100 mg, 86%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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+).

[1010] Example 17: 2-((l-(3-(benzyloxy)-2,7-dimethylquinolin-5-yl)ethyl)amino)benzoic acid (Compound 33)

[1011] Step 11 - Synthesis of 2-((l-(3-(benzyloxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid:

[1012] To aa solution of methyl 2-((l-(3-(benzyloxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (100 mg, 227 μmol) in EtOH (1 mL) was added KOH (127 mg, 2.27 mmol, dissolved in 1 mL H2O). The reaction mixture was stirred at 100 °C for 2 h. 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 (acetonitrile 50% - 80% / 0.225% formic acid in water) to give the title compound (65 mg, 66%) as a white solid.1H NMR (400 MHz, DMSO-d6) 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, 3H). MS: m / z 427.2 (M+H+). Example 18: 2-((l-(3-(l-(2,2-difluoroethyl)piperidin-3-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino) benzoic acid (Compound 34)

[1013] Step 1 - Synthesis of tert-butyl 5-(5-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)-2,7- dimethylquinolin-3-yl)-3,6-dihydropyridine-l(2H)- carboxylate:

[1014] A mixture of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy)quinolin-5- yl)ethyl)amino)benzoate (200 mg, 415 μmol), tert-butyl 5-(4,4,5,5-tetramethyl-l,3,2- di oxab oral an-2-yl)-3,6-dihydropyri dine- l(227)-carb oxy late (192 mg, 622 μmol), Pd(PPh3)4 (48 mg, 42 μmol) and K2CO3 (172 mg, 1.24 mmol) in dioxane (2 mL) and H2O (0.2 mL). The mixture was heated to 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was quenched with water (5 mL), diluted with EtOAc (20 mL). The mixture was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 15% EtOAc in petroleum ether) to give the title compound (200 mg, 95%) as a white solid.1H NMR (400 MHz, DMSO-d6) 58.36 (s, 1H), 8.23 (d, J= 6.0 Hz, 1H), 7.83 - 7.79 (m, 1H), 7.60 (s, 1H), 7.32 (s, 1H), 7.22 - 7.16 (m, 1H), 6.57 - 6.51 (m, 1H), 6.41 (d, J= 8.4 Hz, 1H), 5.91 - 5.87 (m, 1H), 5.48 - 5.44 (m, 1H), 4.09 - 4.06 (m, 2H), 3.85 (s, 3H), 3.57 - 3.52 (m, 2H), 2.62 (s, 3H), 2.40 (s, 3H), 2.30 - 2.26 (m, 2H), 1.58 (d, J= 6.8 Hz, 3H), 1.07 (s, 9H). MS: m / z 516.3 (M+H+).

[1015] Step 2 - Synthesis of tert-butyl 3-(5-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)-2,7- dimethylquinolin-3-yl)piperidine-l-carboxylate:

[1016] To a solution of tert-butyl 5-(5-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)-2,7- dimethylquinolin-3-yl)-3,6-dihydropyridine-l(2H)-carboxylate (200 mg, 388 μmol) in MeOH (2 mL) was added Pd(OH)2 on carbon (60 mg, 20% Pd, 50% wet with water). The reaction was stirred at room temperature for 1 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to give the title compound (138 mg, crude) as a yellow solid that required no further purification.1H NMR (400 MHz, DMSO--d6) δ 8.35 (s, 1H), 8.23 (d, J= 6.0 Hz, 1H), 7.83 - 7.81 (m, J= 8.0 Hz, 1H), 7.58 (s, 1H), 7.38 - 7.28 (m, 1H), 7.27 - 7.18 (m, 1H), 6.60 - 6.45 (m, 2H), 5.57 - 5.38 (m, 1H), 4.14 - 4.07 (m, 1H), 4.05 - 3.96 (m, 2H), 3.86 - 3.81 (m, 3H), 2.90 - 2.86 (m, 1H), 2.84 - 2.76 (m, 1H), 2.70 (s, 3H), 2.40 (s, 3H), 1.93 - 1.88 (m, 2H), 1.80 - 1.71 (m, 1H), 1.61 (d, J = 6.8 Hz, 3H), 1.52 - 1.48 (m, 1H), 1.42 (s, 9H). MS: m / z 518.3 (M+H+).

[1017] Step 3 - Synthesis of methyl 2-((l-(2,7-diinethyl-3-(piperidin-3-yl)quinolin-5- yl)ethyl)amino)benzoate hydrochloride:

[1018] To a solution of tert-butyl 3-(5-(l-((2-(methoxycarbonyl)phenyl)amino)ethyl)-2,7- dimethylquinolin-3-yl)piperidine-l -carboxylate (138 mg, 267 μmol) in DCM (2 mL) was added HC1 (2 mL, 4M in EtOAc). After the addition, the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give the title compound (120 mg, crude) as a yellow solid that required no further purification. MS: m / z 418.3 (M+H+).

[1019] Step 4 - Synthesis of methyl 2-((l-(3-(l-(2,2-difluoroethyl)piperidin-3-yl)-2,7- dimethylquinolin-5-yl)ethyl)amino)benzoate:

[1020] A mixture of methyl 2-((l-(2,7-dimethyl-3-(piperidin-3-yl)quinolin-5- yl)ethyl)amino)benzoate hydrochloride (120 mg, 263 μmol), 2,2-difluoroethyl trifluoromethanesulfonate (85 mg, 395 μmol) and TEA (110 μL, 790 μmol) in DCM (2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 50 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was quenched by addition water (10 mL) and diluted with DCM (15 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4 and filtered. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 36% EtOAc in petroleum ether) to give the title compound (66 mg, 52%) as a white solid.]H NMR (400 MHz, DMSO--d6) δ 8.41 - 8.30 (m, 1H), 8.20 (d, J= 6.0 Hz, 1H), 7.83 - 7.80 (m, 1H), 7.57 (s, 1H), 7.37 - 7.30 (m, 1H), 7.29 - 7.20 (m, 1H), 6.61 - 6.49 (m, 2H), 6.35 - 5.98 (m, 1H), 5.49 - 5.38 (m, 1H), 3.86 - 3.77 (m, 3H), 3.10 - 3.01 (m, 1H), 2.97 - 2.86 (m, 2H), 2.81 - 2.72 (m, 2H), 2.67 (s, 3H), 2.41 (s, 3H), 2.27 - 2.23 (m, 2H), 1.84 - 1.77 (m, 1H), 1.76 - 1.65 (m, 2H), 1.62 (d, J = 6.8 Hz, 3H), 1.52 - 1.46 (m, 1H). MS: m / z 482.2 (M+H+).

[1021] Step 5 - 2-((l-(3-(l-(2^-difluoroethyl)piperidin-3-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoic acid:

[1022] A solution of methyl 2-((l-(3-(l-(2,2-difluoroethyl)piperidin-3-yl)-2,7-dimethylquinolin- 5-yl)ethyl)amino)benzoate (66 mg, 137 μmol) in EtOH (0.5 mL) was added KOH (19 mg, 342 μmol, dissolved in 0.5 mL H2O). The mixture was stirred at 100 °C for 1 h. 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 (acetonitrile 15 - 45% 10.225% formic acid in water) to give the title compound (2.2 mg, 2%) as a white solid. NMR (400 MHz, DMSO-d6) δ 12.75 (s, 1H), 8.47 - 8.38 (m, 1H), 8.34 (s, 1H), 7.85 - 7.77 (m, 1H), 7.57 (s, 1H), 7.36 - 7.29 (m, 1H), 7.26 - 7.15 (m, 1H), 6.58 - 6.46 (m, 2H), 6.34 - 6.00 (m, 1H), 5.48 - 5.35 (m, 1H), 3.10 - 3.00 (m, 1H), 2.95 - 2.88 (m, 2H), 2.80 - 2.70 (m, 2H), 2.67 (s, 3H), 2.41 (s, 3H), 2.32 - 2.20 (m, 2H), 1.83 - 1.79 (m, 1H), 1.76 - 1.63 (m, 2H), 1.61 (d, J= 6.8 Hz, 3H), 1.57 - 1.47 (m, 1H). MS: m / z 468.3 (M+H+).

[1023] Example 1199:: 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)-5-fluorobenzoic acid (Compound 35)

[1024] Step 1 - Synthesis of methyl 2-((l-(3-(henzyloxy)-2,7-dimethylquinolin-5- yl)ethyl)amino)-5-fluorobenzoate:

[1025] A mixture of l-(3-benzyloxy-2,7-dimethyl-5-quinolyl)ethanamine (2 g, 6.53 mmol), methyl 2-bromo-5-fluoro-benzoate (2.28 g, 9.79 mmol), Pd2(dba)3(597 mg, 652 μmol), Xantphos (755 mg, 1.31 mmol) and CS2CO3 (6.38 g, 19.58 mmol) in dioxane (40 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 110 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give the title compound (1.1 g, 35%) as a white solid. MS: m / z 459.1 (M+H+).

[1026] Step 2 - Synthesis of methyl 5-fluoro-2-((l-(3-hydroxy-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate: To a solution of methyl 2-((l-(3-(benzyloxy)-2,7-dimethylquinolin-5-yl)ethyl)amino)-5- fluorobenzoate (900 mg, 1.96 mmol) in MeOH (30 mL) was added wet Pd on carbon (835 mg, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for lh under H2atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated to afford the title compound (600 mg, 83%) as white solid that required no further purification. MS: m / z 369.1 (M+H+).

[1027] Step 3 - Synthesis of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy) quinolin-5-yl)ethyl)amino)-5-fluorobenzoate:

[1028] To a solution of 5-fluoro-2-((l-(3-hydroxy-2,7-dimethylquinolin-5- yl)ethyl)amino)benzoate (250 mg, 678 μmol) in DCM (5 mL) was added pyridine (161 mg, 2.04 mmol) and TfaO (287 mg, 1.02 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM (30 mL) and washed with IM HC1 (10 mL), and then the organic layer was washed with NaHCO3(10 mL x 2), dried over anhydrous Na2SO4 and filtered and concentrated in vacuo to give the title compound (340 mg, 84%) as a white solid that required no further purification. MS: m / z 501.3 (M+H+).

[1029] Step 4 - Synthesis of methyl 2-((l-(3-(5,6-dihydro-2H-pyran-3-yl)-2,7- dimethylquinolin-5-yl)ethyl)amino)-5-fluorobenzoate:

[1030] A mixture of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy) quinolin-5- yl)ethyl)amino)-5-fluorobenzoate (340 mg, 679 μmol), 2-(3,6-dihydro-2H-pyran-5-yl)-4, 4,5,5- tetramethyl-l,3,2-dioxaborolane (171 mg, 815 μmol), Pd(PPhs)4 (78 mg, 67 μmol), K2CO3 (281 mg, 2.04 mmol) in dioxane (5 mL) and H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (270 mg, 86%) as a white solid. MS: m / z 435.1 (M+H+).

[1031] Step 5 - Synthesis of methyl 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3- yl)quinolin-5-yl)ethyl)amino)-5-fluorobenzoate:

[1032] To aa solution of methyl methyl 2-((l-(3-(5,6-dihydro-2H-pyran-3-yl)-2,7- dimethylquinolin-5-yl)ethyl)amino)-5-fluorobenzoate (270 mg, 621 μmol) in MeOH (20 mL) was added wet Pd on carbon (264 mg, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 1.5 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated to afford the title compound (210 mg, 62%) as white solid that required no further purification. MS: m / z 437.1 (M+H+).

[1033] Step 6 - Synthesis of 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)-5-fluorobenzoic acid:

[1034] To a solution of methyl 2-((l-(2,7-dimethyl-3-(tetrahydro-2H-pyran-3-yl)quinolin-5- yl)ethyl)amino)-5-fluorobenzoate (30 mg, 68 μmol) in EtOH (1 mL) was added KOH (38 mg, 687 μmol, dissolved in 1 mL H2O). The mixture was stirred at 100 °C for 2 h. 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 (acetonitrile 19 - 49% 10.225% formic acid in water) to afford the title compound (4.22 mg, 14%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 8.33 (s, 1H), 8.23 (s, 1H), 7.57 (s, 1H), 7.54 - 7.49 (m, 1H), 7.33 - 7.29 (m, 1H), 7.17 - 7.10 (m, 1H), 6.52 - 6.44 (m, 1H), 5.48 - 5.37 (m, 1H), 3.95 - 3.85 (m, 2H), 3.45 - 3.37 (m, 2H), 3.12 - 3.03 (m, 1H), 2.68 (s, 3H), 2.42 - 2.39 (m, 3H), 1.99 - 1.90 (m, 1H), 1.88 - 1.78 (m, 1H), 1.75 - 1.66 (m, 2H), 1.60 (d, J= 6.4 Hz, 3H). MS: m / z 423.1 (M+H+).

[1035] Example 2200:: 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)-5-fluorobenzoic acid (Compound 36)

[1036] Step 11 - Synthesis ooff methyl 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7- dimethylquinolin-5-yl)ethyl)amino)-5-fluorobenzoate:

[1037] A mixture of methyl 2-((l-(2,7-dimethyl-3-(((trifluoromethyl)sulfonyl)oxy) quinolin-5- yl)ethyl)amino)-5-fluorobenzoate (40 mg, 80 μmol), 2-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (39 mg, 160 μmol), Pd(PPh3)4 (9 mg, 8 μmol), K2CO3 (33 mg, 240 μmol) in dioxane (2 mL) and H2O (0.2 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give the title compound (11 mg, 29%) as a white solid. MS: m / z 470.1 (M+H+).

[1038] Step 2 - Synthesis of 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)-5-fluorobenzoic acid

[1039] A solution of methyl 2-((l-(3-(2-cyclopropylpyridin-4-yl)-2,7-dimethylquinolin-5- yl)ethyl)amino)-5-fluorobenzoate (11 mg, 23 μmol) and LiOH (6 mg, 251 μmol) in THE (1 mL), MeOH (0.1 mL) and H2O (0.1 mL) was stirred at 60 °C for 2 h. 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 (acetonitrile 29 - 49% / 0.225% formic acid in water) to afford the title compound (4 mg, 38%) as a white solid.1H NMR (400 MHz, DMSO-t / s) 5 8.52 - 8.49 (m, 2H), 7.67 (s, 1H), 7.55 - 7.50 (m, 1H), 7.50 - 7.48 (m, 1H), 7.36 (d, J= 1.2 Hz, 1H), 7.34 - 7.31 (m, 1H), 7.08 - 7.01 (m, 1H), 6.41 - 6.36 (m, 1H), 5.48 - 5.44 (m, 1H), 2.60 (s, 3H), 2.43 (s, 3H), 2.23 - 2.17 (m, 1H), 1.56 (d, J = 6.4 Hz, 3H), 1.01 - 0.97 (m, 4H). MS: m / z 456.1 (M+H+).

[1040] Example 2211:: 2-((l-(2,7-dimethyl-3-((tetrahydro-2H-pyran-4-yl)oxy)quinolin-5- yl)ethyl)amino) benzoic acid (Compound 37)

[1041] Step 1 - Synthesis of methyl 2-((l-(2,7-dimethyl-3-((tetrahydro-2H-pyran-4- yl)oxy)quinolin-5-yl)ethyl)amino)benzoate:

[1042] To a solution of methyl 2-((l-(3-hydroxy-2,7-dimethylquinolin-5-yl)ethyl)amino) benzoate (140 mg, 399 μmol) and 4-bromotetrahydropyran (131 mg, 799 μmol) in DMF (8 mL) was added K2CO3 (165 mg, 1.20 mmol). The mixture was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (40 mg, 22%) as a white solid. MS: m / z 435.2 (M+H+).

[1043] Step 2 - Synthesis of 2-((l-(2,7-dimethyl-3-((tetrahydro-2H-pyran-4-yl)oxy) quinoline- 5-yl)ethyl)amino)benzoic acid:

[1044] To a solution of methyl 2-((l-(2,7-dimethyl-3-((tetrahydro-2H-pyran-4-yl)oxy) quinolin- 5-yl)ethyl)amino)benzoate (40 mg, 92 μmol) in EtOH (1 mL) was added KOH (51 mg, 920 μmol, dissolved in 1 mL H2O). The mixture was stirred at 100 °C for 2 h. The solution was adjusted to pH 6 with formic acid. The crude residue was purified by reverse phase chromatography (acetonitrile 23-53% / 0.225% formic acid in water) to afford the title compound (8.2 mg, 21%) as a white solid.1H NMR (400MHz, DMSO-d6) δ 12.73 (s, 1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.82 - 7.78 (m, 1H), 7.55 (s, 1H), 7.32 (d, J= 1.2 Hz, 1H), 7.23 - 7.17 (m, 1H), 6.55 - 6.49 (m, 2H), 5.43 - 5.39 (m, 1H), 4.84 - 4.76 (m, 1H), 3.88 - 3.79 (m, 2H), 3.56 - 3.43 (m, 2H), 2.53 (s, 3H), 2.39 (s, 3H), 2.03 - 1.92 (m, 2H), 1.70 - 1.62 (m, 2H), 1.58 (d, J= 6.4 Hz, 3H). MS: m / z 421.1 (M+H+).

[1045] Example 22: (R)-2-((l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4- yl)quinolin-5-yl)ethyl)amino)benzoic acid (Compound 38)

[1046] Step 1 - Synthesis of 5-bromo-7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinoline:

[1047] To a solution of 2-(tetrahydro-2H-pyran-4-yl)acetaldehyde (5.03 g, 39.24 mmol) and 2- amino-6-bromo-4-methyl-benzaldehyde (7 g, 32.70 mmol) in n-BuOH (100 mL) and H2O (10 mL) was added NaOH (2.62 g, 65.40 mmol). The reaction mixture was stirred at 110 °C for 1 h. After cooling to room temperature, the mixture was adjusted pH to 5 with HC1 (IM), then was added water (50 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 16% EtOAc in petroleum ether) to give the title compound (9.6 g, 96%) as yellow oil.1H NMR (400 MHz, DMSO--d6) δ 8.90 (d, J= 2.0 Hz, 1H), 8.16 (d, J= 1.6 Hz, 1H), 7.83 (s, 2H), 4.05 - 3.96 (m, 2H), 3.55 - 3.45 (m, 2H), 3.16 - 3.03 (m, 1H), 2.51 (s, 3H), 1.88 - 1.76 (m, 4H). MS: m / z 305.9 (M+H+).

[1048] Step 2 - Synthesis of 5-bromo-2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran- 4-yl)quinoline:

[1049] A mixture of 5-bromo-7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinoline (2 g, 6.53 mmol), bis(difluoromethylsulfonyloxy)zinc (4.28 g, 13.06 mmol) in DCM (2 mL) and H2O (0.6 mL) was added TFA (744 mg, 6.53 mmol) and 2-hydroperoxy-2-methyl-propane (1.77 g, 19.60 mmol). The reaction mixture was stirred at room temperature for 16 h under N2 atmosphere. The mixture was quenched with sat. aq. NaHCOi (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (160 mg, 7%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.96 (s, 1H), 7.92 (s, 1H), 7.47 - 7.17 (m, 1H), 4.06 - 3.96 (m, 2H), 3.56 - 3.47 (m, 2H), 3.46 - 3.37 (m, 1H), 2.53 (s, 3H), 2.04 - 1.70 (m, 4H). MS: m / z 356.0 (M+H+).

[1050] Step 3 - Synthesis of 2-(difluoromethyl)-5-(l-ethoxyvinyl)-7-methyl-3-(tetrahydro- 2H-pyran-4-yl)quinoline:

[1051] A mixture of 5-bromo-2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4- yl)quinoline (500 mg, 1.40 mmol), tributyl(l -ethoxy vinyl)stannane (1.52 g, 4.21 mmol) and Pd(dppf)Ch (102 mg, 140 μmol) in dioxane (5 mL) was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, the crude product 3-benzyloxy-2- (difluoromethyl)-5-(l -ethoxy vinyl)-7-methyl-quinoline (487 mg, crude) was used into the next step without further purification. MS: m / z 370.1 (M+Na+).

[1052] Step 4 - Synthesis of l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4- yl)quinolin-5-yl)ethan-l-one:

[1053] To a solution of 2-(difluoromethyl)-5-(l-ethoxyvinyl)-7-methyl-3-(tetrahydro-2H-pyran- 4-yl)quinoline (487 mg, crude) in dioxane (10 mL) was added HC1 (2 mL, IM in water) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 10% KF solution (20 mL). The mixture was filtered and the filtrate was extracted with EtOAc (50 mL x 2). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (94 mg, 21%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.26 (t, J = 53.4 Hz, 1H), 4.08 - 3.91 (m, 2H), 3.60 - 3.45 (m, 2H), 3.41 - 3.35 (m, 1H), 2.76 (s, 3H), 2.59 (s, 3H), 1.80 - 1.70 (m, 4H). MS: m / z 320.2 (M+H+).

[1054] Step 5 - Synthesis of R ,E)-N -(l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-29- pyran-4-yl)quinolin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide:

[1055] To a solution of l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5- yl)ethan-l-one (94 mg, 294 μmol) in THF (2 mL) was added (R)-2-methylpropane-2-sulfmamide (214 mg, 1.77 mmol) and Ti(z-PrO)4 (836 mg, 2.94 mmol) at room temperature. The mixture was stirred at 75 °C for 16 h. The reaction mixture was diluted with water (10 mL) and filtered, the filtrate was extracted with DCM (10 mL x 3), and then the organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4 and filtered and concentrated in vacuo to give the title compound (80 mg, crude) as a yellow solid that required no further purification. MS: m / z 423.2 (M+H1).

[1056] Step 6 - Synthesis of R )-N-(l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran- 4-yl)quinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide:

[1057] To a solution of (R,E)-N -(l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4- yl)quinolin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (80 mg, 189 μmol) in THF (3 mL) was added NaBH4 (21.49 mg, 568 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min under N2 atmosphere. Then the reaction was quenched with aq. sat. NH4CI (5 mL) and extracted with DCM (20 mL x 3). The organics were washed with aq. sat. NaCl (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (70 mg, 87%, two isomers) as a white solid that required no further purification.1H NMR (400 MHz, DMSO-d6) δ 8.73 - 8.65 (m, 1H), 7.77 (s, 1H), 7.68 - 7.55 (m, 1H), 7.45 - 7.00 (m, 1H), 5.87 - 5.56 (m, 1H), 5.34 - 5.20 (m, 1H), 4.07 - 3.95 (m, 2H), 3.56 - 3.43 (m, 2H), 3.41 -3.35 (m, 1H), 2.53 (s, 3H), 2.06 - 1.92 (m, 2H), 1.74 - 1.66 (m, 2H), 1.65 - 1.53 (m, 3H), 1.12 - 0.99 (m, 9H). MS: m / z 425.1 (M+H+).

[1058] Step 7 - Synthesis of l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4- yl)quinolin-5-yl)ethan-l-amine:

[1059] A solution of (R)-N -((R)- l-(2-(difluoromethyl)-7-methy 1-3 -(tetrahydro-2H-pyran-4- yl)quinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (70 mg, 164 μmol) in MeOH (1 mL) was added 12M HC1 (18 mg, 494 μmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted to pH 8 with sat. NaHCO3solution, then diluted with water (20 mL) and extracted with DCM (30 mL x 3). The organics were dried over Na2SO 4, filtered and concentrated in vacuo to give the title compound (50 mg, crude) as a yellow solid that required no further purification. MS: m / z 321.0 (M+H+).

[1060] Step 8 - Synthesis of tert-butyl R )-2-((l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro- 2H-pyran-4-yl)quinolin-5-yl)ethyl)amino)benzoate & tert-butyl (S)-2-((l-(2- (difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5- yl)ethyl)amino)benzoate:

[1061] A mixture of l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5- yl)ethan-l -amine (50 mg, crude), tert-butyl 2-iodobenzoate (71 mg, 234 μmol), Pd2(dba)3(14 mg, 15 μmol), XantPhos (18 mg, 31μmol) and CS2CO3 (152 mg, 468 μmol) in dioxane (1 mL) was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was filtered and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 20% EtOAc in petroleum ether) to give tert-butyl-2-((l-(2- (difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran-4-yl)quinolin-5-yl)ethyl) amino)benzoate (60 mg, 77%, two isomers 3:2) as a white solid. The mixture was purified by using chiral SFC (DAICEL CHIRALPAK OD (250mm*30mm, lOum); Supercritical CO2 / EtOH + 0.1% NH3.H2O = 25 / 75; 80 mL / min) to afford tert-butyl (S)-2-((l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro- 2H-pyran-4-yl)quinolin-5-yl)ethyl)amino) benzoate (23 mg, first peak) and tert-butyl (R)-2-((l- (2-(difluoromethyl)-7-methyl-3-(tetrahydro-2Zf-pyran-4-yl)quinolin-5-yl)ethyl)amino)benzoate (30 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m / z 497.3 (M+H+).

[1062] Step 9 - Synthesis of R )-2-((l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H-pyran- 4-yl)quinolin-5-yl)ethyl)amino)benzoic acid:

[1063] To a mixture of tert-butyl (R)-2-((l-(2-(difluoromethyl)-7-methyl-3-(tetrahydro-2H- pyran-4-yl)quinolin-5-yl)ethyl)amino)benzoate (30 mg, 60 μmol) in DCM (2 mL) was added TFA (1.54 g, 13.46 mmol). The reaction mixture was stirred at room temperature for 16 h. Then the reaction mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 63% - 93% / 0.225% formic acid in water) to give the title compound (14 mg, 52%) as a white solid.1HNMR (400 MHz, DMSO--d6) δ 12.79 (s, 1H), 8.75 (s, 1H), 8.52 (s, 1H), 7.85 - 7.78 (m, 1H), 7.77 - 7.73 (m, 1H), 7.52 - 7.47 (m, 1H), 7.40 - 7.09 (m, 2H), 6.57 - 6.43 (m, 2H), 5.71 - 5.51 (m, 1H), 4.12 - 3.88 (m, 2H), 3.57 - 3.45 (m, 2H), 3.42 - 3.36 (m, 1H), 2.45 (s, 3H), 2.06 - 1.88 (m, 2H), 1.77 - 1.65 (m, 2H), 1.60 (d, J= 6.4 Hz, 3H). MS: m / z 441.2 (M+H+).

[1064] Example 23: 2-(((R)-l-(2-(difluoromethyl)-7-methyl-3-((«S)-tetrahydro-2H-pyran-3- yl)quinolin-5-yl)ethyl)amino)benzoic acid (Compound 39)

[1065] Step 1 - Synthesis of 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbaldehyde:

[1066] A mixture of 3-(benzyloxy)-5-bromo-2,7-dimethylquinoline (14 g, 40.91 mmol) and SeOz (5.49 g, 49.50 mmol) in dioxane (100 mL) was stirred at 80 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was dissolved in H2O (30 mL) and stirred at room temperature for another 30 min. The reaction was filtered and the filter cake was concentrated in vacuo to give the title compound (17 g, crude) as a yellow solid that required no further purification. NMR (400 MHz, DMSOd6) δ 10.50 - 10.19 (m, 1H), 8.01 - 7.82 (m, 3H), 7.64 - 7.54 (m, 2H), 7.48 - 7.40 (m, 2H), 7.39 - 7.32 (m, 1H), 5.47 - 5.35 (m, 2H), 2.47 (s, 3H). MS: m / z 355.9 (M+H+).

[1067] Step 2 - Synthesis of 3-(benzyloxy)-5-bromo-2-(difluoromethyl)-7-methylquinoline:

[1068] To a solution of 3-benzyloxy-5-bromo-7-methyl-quinoline-2-carbaldehyde (10 g, 28.07 mmol) in DCM (100 mL) was added DAST (13.58 g, 84.22 mmol) at 0 °C. After the addition, the reaction mixture was stirred at 0 °C for 1 h. The mixture was quenched with saturated NaHCO3(80 mL), extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether) to give the title compound (4.16 g, 39%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1H), 7.92 - 7.87 (m, 2H), 7.59 - 7.53 (m, 2H), 7.46 - 7.40 (m, 2H), 7.38 - 7.34 (m, 1H), 7.33 - 7.11 (m, 1H), 5.45 (s, 2H), 2.49 - 2.43 (m, 3H). MS: m / z 378.0 (M+H+). Step 3 - Synthesis of l-(3-(benzyloxy)-2-(difluoromethyl)-7-methylquinolin-5- yl)ethan-l-one:

[1069] A mixture of 3-benzyloxy-5-bromo-2-(difluoromethyl)-7-methyl-quinoline (1 g, 2.64 mmol), tributyl(l-ethoxyvinyl)stannane (1.91 g, 5.29 mmol) and Pd(dppf)C12 (193 mg, 264 μmol) in dioxane (10 mL) was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, HC1 (2 mL, IM in water) was added to reaction mixture. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched with 10% KF solution (30 mL). The mixture was filtered and the filtrate was extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (671 mg, 74%) as a white solid. NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.25 (s, 1H), 8.07 (s, 1H), 7.60 - 7.53 (m, 2H), 7.47 - 7.40 (m, 2H), 7.40 - 7.07 (m, 2H), 5.34 (s, 2H), 2.75 (s, 3H), 2.57 (s, 3H). MS: m / z 342.1 (M+H1).

[1070] Step 4 - Synthesis of l-(3-(benzyloxy)-2-(difluoromethyl)-7-methylquinolin-5- yl)ethan-l-amine:

[1071] A mixture of l-(3-(benzyloxy)-2-(difluoromethyl)-7-methylquinolin-5-yl)ethan-l-one (3.5 g, 10.25 mmol), NH4OAc (7.90 g, 102.53 mmol) and HOAc (615 mg, 10.25 mmol) in MeOH (50 mL) was stirred at room temperature for 30 min. Then NaBH3CN (1.93 g, 30.76 mmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL). The mixture was washed with saturated NaHCO3solution (20 mL x 3), brine (20 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated to give the title compound (3.51 g, crude) as a brown solid that required no further purification. MS: m / z 343.2 (M+H“).

[1072] Step 5 - Synthesis of tert-butyl (l-(3-(benzyloxy)-2-(difluoromethyl)-7- methylquinolin-5-yl)ethyl)car hamate:

[1073] A mixture of l-(3-(benzyloxy)-2-(difluoromethyl)-7-methylquinolin-5-yl)ethan-l-amine (3.51 g, 10.25 mmol), TEA (5.19 g, 51.26 mmol) and BOC2O (3.36 g, 15.38 mmol) in DCM (30 mL) was stirred at room temperature for 1 h. The mixture was diluted with H2O (20 mL), extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (1.2 g, 26%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 8 8.16 (s, 1H), 7.73 (s, 1H), 7.61 (d, J= 8.0 Hz, 1H), 7.59 - 7.53 (m, 2H), 7.50 - 7.47 (m, 1H), 7.46 - 7.47 (m, 2H), 7.39 - 7.33 (m, 1H), 7.32 - 7.08 (m, 1H), 5.48 - 5.31 (m, 3H), 2.49 (s, 3H), 1.43 - 1.37 (m, 12H). MS: m / z 443.2 (M+H+).

[1074] Step 6 - Synthesis of tert-butyl (l-(2-(difluoromethyl)-3-hydroxy-7-methylquinolin-5- yl)ethyl)carbamate:

[1075] To a solution of tert-butyl (l-(3-(benzyloxy)-2-(difluoromethyl)-7-methylquinolin-5- yl)ethyl)carbamate (500 mg, 1.13 mmol) in MeOH (20 mL) was added wet Pd on carbon (500 mg, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 1 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filtrate was concentrated to afford the title compound (410 mg, 92%) as white solid that required no further purification.1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 7.82 (s, 1H), 7.66 (s, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.32 - 6.97 (m, 1H), 5.25 - 5.10 (m, 1H), 2.45 (s, 3H), 1.43 - 1.36 (m, 12H). MS: m / z 353.2 (M+H+).

[1076] Step 7 - Synthesis of 5-(l-((tert-butoxycarbonyl)amino)ethyl)-2-(difluoromethyl)-7- methylquinolin-3-yl trifluoromethanesulfonate:

[1077] To a solution of tert-butyl (l-(2-(difluoromethyl)-3-hydroxy-7-methylquinolin-5- yl)ethyl)carbamate (410 mg, 1.16 mmol) in DCM (5 mL) was added pyridine (276.11 mg, 3.49 mmol) and Tf2O (492 mg, 1.75 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with DCM (30 mL) and washed with 0.5M HC1 (10 mL), and then the organic layer was washed with NaHCO3(10 mL x 2), dried over anhydrous Na2SO4and filtered and concentrated in vacuo to give the title compound (260 mg, 46%) as a white solid that required no further purification.1HNMR(400 MHz, DMSO-d6) δ 8.81 (s, 1H), 7.92 (s, 1H), 7.69 (s, 1H), 7.60 (d, J= 7.6 Hz, 1H), 7.42 - 7.13 (m, 1H), 5.43 - 5.25 (m, 1H), 2.57 (s, 3H), 1.47 (d, J= 6.4 Hz, 3H), 1.36 (s, 9H). MS: m / z 485.2 (M+H+).

[1078] Step 8 - Synthesis of tert-butyl (l-(2-(difluoromethyl)-3-(5,6-dihydro-2H-pyran-3-yl)- 7-methylquinolin-5-yl)ethyl)carbamate:

[1079] A mixture ooff 5-(l-((tert-butoxycarbonyl)amino)ethyl)-2-(difluoromethyl)-7- methylquinolin-3-yl trifluoromethanesulfonate (590 mg, 1.22 mmol), 2-(5,6-dihydro-2H-pyran-3- yl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (255 mg, 1.22 mmol), Pd(PPh3)4(140.74 mg, 121 μmol) and K2CO3 (504.97 mg, 3.65 mmol) in dioxane (5 mL) and H2O (0.5 mL). The mixture was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 10% EtOAc in petroleum ether)...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:Z is N or CH;R1is hydrogen, halogen, cyano, C3-C6 cycloalkyl, C1-C6thioalkyl, C1-C6haloalkyl, C1- C6 alkoxy, C1-C6alkoxyalkyl, 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; or C1-C6alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyl optionally substituted with 1-4 independently selected R2A, C4-C10 cycloalkyl optionally substituted with 1-4 independently selected R2A, 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A, 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A, C1-C6alkoxyalkyl optionally substituted with - C(=O)NRARC, or C1-C6alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl; each R2Ais independently selected from:(i) halogen;(ii) cyano;(iii) hydroxyl;(iv) -NRARB;(v) -C(=O)NRARB;(vii) -NHC(=O)Rc;(viii) -C(=O)ORD;(ix) -SO2RD;(x) -NHSO2RD;(xi) -SO2NRDRE;(xii) -NHC(=O)C1-C6alkyl optionally substituted with NRARB;(xiii) C1-C6haloalkyl;(xiv) C1-C6hydroxyalkyl;(xv) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, -C(=O)NRARB, -NRARB, C1-C6alkyl optionally substituted with hydroxyl; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;(xvi) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6haloalkyl, -C(=O)C1-C6alkyl, - SO2(C1-C6alkyl), -SO2NRDRE, C1-C6alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6alkyl optionally substituted with -NRARB, and C1-C6alkyl optionally substituted with C1-C6alkoxy or hydroxyl;(xvii) C1-C6alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;(xviii) C1-C6alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl;(xix) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=NH)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl; and(xx) 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6alkyl optionally substituted with hydroxyl; each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, and C 1-C6 alkyl optionally substituted with hydroxyl or C 1-C6 alkoxy, or RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 memberedheterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1- C6 alkyl, and -C(=O)C1-C6alkyl; each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl or with C1-C6hydroxylalkyl; each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6alkoxy, and C1-C6alkyl optionally substituted with oxo or -NRARB; each R3Aand R3Bis independently selected from hydrogen, C1-C6alkyl, C1-C6alkoxy, and C1-C6haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;R4is hydrogen, halogen, C1-C6alkyl, or acrylamido;R5is hydrogen, halogen, C1-C6alkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;R5Aand R5Bare independently selected from hydrogen, C1-C6alkyl, C2-C6 alkenyl, and C1-C6hydroxyalkyl;R6is hydrogen, halogen, or C1-C6alkyl;X is a bond, CH2, CH(CH3), C(CH3)2, orW is NR3Bor O;Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5- 10 membered heteroaryl are optionally and independently substituted with 1-3 independently selected RYor wherein * represents the connection of L1to theremainder of the compound of Formula (I); each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, C1-C6hydroxyalkyl, -(CH2)n-C(=O)RF-(CH2)n-NHC(=O)RF-(CH2)n-NHC(=O)ORF, -C(=O)C(=O)NHRF, -CO2R0, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ. -(CH2)n-SO2RJ, -( CH2)(-C(=O)NRHR1, -(CH2)n-C(=O)NRHORI, and C1-C6haloalkyl optionally substituted with hydroxyl;each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl optionally substituted with C1-C6alkyl; and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RG is independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6alkyl optionally substituted with hydroxyl or -SO2(C1-C6alkyl); each RHand R1is independently selected from: hydrogen, C1-C6alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n- SO2NH2, -(CH2)n-SO2(C1-C6alkyl), C1- C6 alkyl optionally substituted with 1-2 subistutients independelty selected from hydroxyl, -SO2(C1-C6alkyl), C1-C6alkoxy, 5-6 membered heteroaryl, C3-C6 cycloalkyl, and - C(=O)NRK1RK2; or RHand R1together with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from halogen, C1-C6alkyl, and -C(=O)C1-C6alkyl;RJis C1-C6alkyl, C3-C6 cycloalkyl, or C1-C6alkoxy; each RK1and RK2is independently hydrogen or C1-C6alkyl;Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;L1is a bond, C1-C6alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6alkylene)-, -C(=O)C(=O)NH-, or C1-C6alkylene optionally substituted with oxo; each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2R0, -SO2NRHRI, -NHSO2R2-S(=O)(=NRH)RJ, -SO2(C1-C6alkyl), -C(=O)NRHR1, 4-6 membered heteroaryl, C1-C6alkoxy optionally substituted with RY2, C1-C6haloalkyl, C1-C6alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl;RY2is hydroxyl, -NRHRI, -C(=O)NRHRI, or -SO2NRHRI; n is 0, 1, or 2; and z is O, 1, 2, or 3.

2. The compound of Claim 1, wherein Z is CH.

3. The compound of Claim 1, wherein Z is N.

4. The compound of any one of Claims 1-3, wherein R1is hydrogen.

5. The compound of any one of Claims 1 -3, wherein R1is halogen.

6. The compound of any one of Claims 1-3, wherein R1cyano.

7. The compound of any one of Claims 1-3, wherein R1is C3-C6 cycloalkyl.

8. The compound of any one of Claims 1-3, wherein R1is C1-C6alkyl optionally substituted with C3-C6 cycloalkyl, or 4-10 membered heterocyclyl.

9. The compound of any one of Claims 1-3 or 8, wherein R1is C1-C6alkyl10. The compound of any one of Claims 1-3, 8, or 9, wherein R1is methyl.

11. The compound of any one of Claims 1-3, wherein R1is 4-10 membered heterocyclyl optionally substituted with C1-C6alkyl.

12. The compound of any one of Claims 1-3, wherein R1is C1-C6thioalkyl.

13. The compound of any one of Claims 1-3, wherein R1is C1-C6haloalkyl.

14. The compound of any one of Claims 1-3, wherein R1is C1-C6alkoxy.

15. The compound of any one of Claims 1-3, wherein R1is C1-C6alkoxyalkyl.

16. The compound of any one of Claims 1-15, wherein R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A.

17. The compound of any one of Claims 1-15, wherein R2is phenyl optionally substituted with 1-4 independently selected R2A.

18. The compound of any one of Claims 1-15, wherein R2is 5-10 membered heteroaryl optionally substituted with 1-4 independently selected R2A.

19. The compound of any one of Claims 1-15, wherein R2is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A.

20. The compound of any one of Claims 1-15, wherein R2is 4-10 membered heterocyclyl substituted with 1-3 independently selected R2A.

21. The compound of any one of Claims 1-15, wherein R2is 4-10 membered heterocyclyl.

22. The compound of any one of Claims 1-15, wherein R2is C4-C10 cycloalkyl optionally substituted with 1-3 independently selected R2A.

23. The compound of any one of Claims 1-15, wherein R2is 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A.

24. The compound of any one of Claims 1-15, wherein R2is 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A.

25. The compound of any one of Claims 1-15, wherein R2is C1-C6alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl.

26. The compound of any one of Claims 1-15, wherein R2is C1-C6alkoxyalkyl optionally substituted with -C(=O)NRARc.

27. The compound of any one of Claims 1-26, wherein each R2Ais independently selected from:(i) halogen;(ii) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, or -C(=N)ORD;(iii) methyl;(iv) C1-C2 haloalkyl;(v) 4-6 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from halogen, hydroxyl, -C(=O)NRARB, -C(=O)C1-C6alkyl, -NRARB, and C1-C6alkyl optionally substituted with hydroxyl; and(vi) 5-6 membered heteroaryl optionally substituted with halogen, cyano, C1-C6alkyl optionally substituted with hydroxyl, hydroxyl, -C(=O)NRARB, -NRARB, or 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6alkyl.

28. The compound of any one of Claims 1-27, wherein X is a bond.

29. The compound of any one of Claims 1-27, wherein X is CH2.

30. The compound of any one of Claims 1-27, wherein X is CH(CH3).

31. The compound of any one of Claims 1-27, wherein X is C(CH3)2.

32. The compound of any one of Claims 1-27, wherein X is33. The compound of any one of Claims 1-32, wherein W is O.

34. The compound of any one of Claims 1-33, wherein R3Ais hydrogen.

35. The compound of any one of Claims 1-33, wherein R3Ais C1-C6alkyl.

36. The compound of any one of Claims 1-33, wherein R3Ais C1-C6alkoxy.

37. The compound of any one of Claims 1-33, wherein R3Ais C1-C6haloalkyl.

38. The compound of any one of Claims 1-32, wherein W is NR3B.

39. The compound of any one of Claims 1-32 or 38, wherein R3Bis hydrogen.

40. The compound of any one of Claims 1-32 or 38, wherein R3Bis methyl.

41. The compound of any one of Claims 1-40, wherein Y is unsubstituted 5-10 membered heteroaryl.

42. The compound of any one of Claims 1-40, wherein Y is phenyl optionally substituted with 1-3 independently selected RY.

43. The compound of any one of Claims 1-40, wherein Y is naphthyl optionally substituted with 1-3 independently selected RY.

44. The compound of any one of Claims 1-40, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY.

45. The compound of any one of Claims 1-40 or 42-44, wherein each RYis independently selected from: halogen, -CO2H, -SO2NH2, -SO2CH3, -C(=O)NH2, -C(=O)NHRH, -(CH2)n-C(=O)NHORIand -(CH2)n-S(=O)(=NH)RJ.

46. The compound of any one of Claims 1-40, wherein Y is phenyl substituted with wherein * represents the connection of L1to the remainder of thecompound of Formula (I).

47. The compound of any one of Claims 1-40, wherein Y is naphthyl substituted with wherein * represents the connection of L1to the remainder of thecompound of Formula (I).

48. The compound of any one of Claims 1-40, wherein Y is 5-10 membered heteroaryl substituted with, wherein * represents the connection of L1to the remainder of the compound of Formula (I).

49. The compound of any one of Claims 1-40 or 46-48, wherein each RY1is independently selected from: hydroxyl, cyano, -SO2NH2, -C(=O)RF, -C(=O)NH2, C1-C3 alkoxy optionally substituted with hydroxyl, and C1-C3 alkyl optionally substituted with hydroxyl.

50. The compound of any one of Claims 1-49, wherein R4is hydrogen.

51. The compound of any one of Claims 1-49, wherein R4is halogen.

52. The compound of any one of Claims 1-49, wherein R4is C1-C6alkyl.

53. The compound of any one of Claims 1-49, wherein R4is acrylamido.

54. The compound of any one of Claims 1-53, wherein R3is hydrogen.

55. The compound of any one of Claims 1-53, wherein R3is halogen.

56. The compound of any one of Claims 1-53, wherein R5is C1-C6alkyl.

57. The compound of any one of Claims 1-53, wherein R3is cyano.

58. The compound of any one of Claims 1-53, wherein R5is -NR5AR5B.

59. The compound of any one of Claims 1-53, wherein R5is-C(=O)NR3AR3B.

60. The compound of any one of Claims 1-53, wherein R5is -NR5AC(=O)R5B.

61. The compound of any one of Claims 1-60, wherein R6is hydrogen.

62. The compound of any one of Claims 1-60, wherein R6is halogen.

63. The compound of any one of Claims 1-60, wherein R6is C1-C6alkyl.

64. The compound of any one of Claims 1-50, wherein R4is hydrogen, R3is methyl, and R6is hydrogen.

65. The compound of any one of Claims 1-50, wherein R4is hydrogen, R3is chloro, and R6is hydrogen.

66. The compound of Claim 64 or 65, wherein R1is methyl or cyano.

67. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof.

68. A pharmaceutical composition comprising a compound of any one of Claims 1-67, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

69. A method for treating cancer in a subj ect in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 68.

70. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a PIK3CA gene, a PI3Kα protein, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-67, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 68.

71. A method of treating a PI3Kα-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Kα-associated cancer a therapeutically effective amount of a compound of any one of Claims 1-67 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 68.

72. A method for inhibiting mutant PI3Kα activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Claims 1-67, or a pharmaceutically acceptable salt thereof.

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