Compounds and methods for treating cancer

Abstract

This disclosure provides compounds of Formula (I), Formula (I-I), and Formula (I-II), 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] Attorney Docket No. 49366-0056WO4

[0002] COMPOUNDS AND METHODS FOR TREATING CANCER CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] The present application claims priority to U. S. Provisional Application Serial Nos.

[0004] 63 / 739,008, filed on December 26, 2024; and 63 / 830,333, filed on June 25, 2025, each of which is incorporated by reference in their entirety herein.

[0005] FIELD

[0006] This disclosure provides compounds of Formula (I), Formula (I-I), and Formula (I-II), and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka). These compounds are useful for treating a disease in which increased PI3Ka activation contributes to the pathology, symptoms, and / or progression of the disease (e.g., cancer) in a subject.

[0007] SEQUENCE LISTING

[0008] This application contains a Sequence Listing that has been submitted electronically as an XML file named 49366-0056WO4_SL_ST26.xml. The XML file, created on December 23, 2025, is 2,947 bytes in size. The material in the XML file is hereby incorporated by reference in its entirety.

[0009] BACKGROUND

[0010] Phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka), encoded by the PIK3CA gene is a part of the PI3K / AKT / TOR signaling network and is altered in several human cancers.

[0011] 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. Ther. 2015, 146, 53-60.) However, development of PI3K inhibitors has been problematic for several reasons, in particular, inability to specifically inhibit signaling by mutant PI3Ka while sparing wild-type PI3Ka, and the related dose-limiting toxicities that prevent sustained PI3K pathway suppression. See, Hanker et al., Cancer Discovery, April 2019;9: 482-491. ForAttorney Docket No. 49366-0056WO4

[0012] example, alpelisib is a PI3K inhibitor that is equipotent against wild-type and mutant forms of PI3Ka, which results in dose-limiting toxicities and hyperglycemia.

[0013] Thus, selectively targeting PI3Ka represents an approach for the treatment of proliferative disorders such as cancer.

[0014] SUMMARY

[0015] Some embodiments provide a compound of Formula (I):

[0016]

[0017] or a pharmaceutically acceptable salt thereof, wherein:

[0018] Z is CH orN;

[0019] R1is hydrogen, halogen, cyano, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;

[0020] R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A, 5-14 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-C6 alkoxyalkyl optionally substituted with -C(=O)NRARC, or C1-C6 alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl;

[0021] each R2Ais independently selected from:

[0022] (i) halogen;

[0023] (ii) cyano;

[0024] (iii) hydroxyl;

[0025] (iv) -NRARB;

[0026] (v) -C(=O)NRARB;Attorney Docket No. 49366-0056WO4

[0027] NRARB

[0028] (

[0029]

[0030] vi) O

[0031] (vii) -NHC(=O)Rc;

[0032] (viii) -C(=O)ORD;

[0033] (ix) -SO2RD;

[0034] (x) -NHSO2RD;

[0035] (xi) -SO2NRDRE;

[0036] (xii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB;

[0037] (xiii) C1-C6 haloalkyl;

[0038] (xiv) C1-C6 hydroxyalkyl;

[0039] (xv) -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl);

[0040] (xvi) -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF);

[0041] (xvii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl; cyano; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl or cyano; C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)Rc; -NRARB; -OR7; -SR8; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, or C1-C6 alkyl;

[0042] (xviii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl;

[0043] (xix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;Attorney Docket No. 49366-0056WO4

[0044] (xx) C1-C6 alkoxy optionally substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or-C(=O)C3-C6 cycloalkyl;

[0045] (xxi) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;

[0046] (xxii) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; and (xxiii) 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with hydroxyl;

[0047] each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C2-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-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-C6 alkyl;

[0048] each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6 alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl;

[0049] each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen, and C1-C6 alkyl optionally substituted with oxo or -NRARB;

[0050] each RFis independently selected from cyano, hydroxyl, halogen, C3-C6 cycloalkyl, and C1-C6 alkyl;

[0051] each R3Aand R3Bis independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0052] R4is hydrogen, halogen, C1-C6 alkyl, or acrylamido;

[0053] R5is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;

[0054] R5Aand R5Bare independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;Attorney Docket No. 49366-0056WO4

[0055] R6is hydrogen, halogen, or C1-C6 alkyl;

[0056] each R7is independently selected from C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5- 6 membered heteroaryl are each optionally and independently substituted with 1-3 independently selected R7A;

[0057] each R7Ais independently selected from hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl optionally substituted with hydroxyl;

[0058] R8is C1-C6 alkyl or C1-C6 haloalkyl;

[0059] X is a bond, C

[0060]

[0061] H2, CH(CH3), C(CH3)2, or

[0062] W is NR3Bor O;

[0063] Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5-10 membered heteroaryl are each optionally and independently substituted with 1-3

[0064] * - L1- b- A -4 - (RY1)Z

[0065] independently selected RYor

[0066]

[0067] , wherein * represents the connection of L1to the remainder of the compound of Formula (I);

[0068] each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, -(CH2)n-C(=O)RF, -(CH2)n-NHC(=O)RF, -(CH2)n-NHC(=O)ORF, -CO2RG, -P(=O)RARB, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ, -(CH2)n-S(=O)(=NRH)NRHRI, -

[0069]

[0070] (CH2)nC(=N-OH)RJ, -(CH2)n–SO2RJ, -(CH2)n-C(=O)NRHRI, -(CH2)n-C(=O)NRHORI, and C1-C6 haloalkyl optionally substituted with hydroxyl;

[0071] each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);

[0072] each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);

[0073] each RHand RIis independently selected from: hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, -(CH2)n-SO2(C1-C6 alkyl),Attorney Docket No. 49366-0056WO4

[0074] and C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, –SO2(C1-C6 alkyl), or C1-C6 alkoxy;

[0075] 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-C6 alkyl, and -C(=O)C1-C6 alkyl;

[0076] RJis C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, or C1-C6 alkoxy;

[0077] Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;

[0078] L1is a bond, C1-C6 alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or C1-C6 alkylene optionally substituted with oxo;

[0079] each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2RG, -SO2NRHRI, -NHSO2RJ, -S(=O)(=NRH)RJ, -SO2(C1-C6 alkyl), -C(=O)NRHRI, 4-6 membered heteroaryl, C1-C6 alkoxy optionally substituted with RY2, C1-C6 haloalkyl, C1-C6 alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl;

[0080] RY2is hydroxyl, -NRHRI, -C(=O)NRHRI, or -SO2NRHRI

[0081] n is 0, 1, or 2;

[0082] m is 0, 1, 2, or 3; and

[0083] z is 0, 1, 2, or 3;

[0084] wherein:

[0085] R2is 11-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A; or

[0086] at least one R2Ais

[0087] (a) -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl);

[0088] (b) 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen, C1-C6 haloalkyl optionally substituted with hydroxyl or cyano, -OR7, -SR8; -SO2RD, -NRAC(=O)Rc, -P(=O)RARB, C1-C6 alkyl substituted with cyano, and 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl;Attorney Docket No. 49366-0056WO4

[0089] (c) 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl and C1-C6 haloalkoxy;

[0090] (d) C1-C6 alkoxy substituted with hydroxyl or 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[0091] (e) -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3- C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF); or (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; or at least one of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or Cl- C6 haloalkyl; or

[0092] at least one of RDand REis C3-C6 cycloalkyl or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen; or

[0093] at least one RFis cyano, hydroxyl, halogen, C3-C6 cycloalkyl, or C1-C6 alkyl; or

[0094] R5is C1-C6 haloalkyl; or

[0095] R8is C1-C6 alkyl or C1-C6 haloalkyl; or

[0096] at least one R

[0097]

[0098] Yis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, -(CH2)n-C(=N-OH)RJ, or C3-C6 cycloalkyl; or

[0099] at least one of RHand RIis C1-C6 alkyl substituted with -P(=O)RARB; or

[0100] RJis C1-C6 haloalkyl.

[0101] 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.

[0102] 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.

[0103] 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 PI3Ka 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.

[0104] Provided herein is a method of treating a PI3Ka-associated disease in a subject,Attorney Docket No. 49366-0056WO4

[0105] comprising administering to a subject identified or diagnosed as having a PT3Ka-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.

[0106] This disclosure also provides a method of treating a PI3Ka-associated disease in a subject, comprising: determining that the cancer in the subject is a PI3Ka-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.

[0107] Further provided herein is a method of treating a PI3Ka-associated cancer in a subject, comprising administering to a subject identified or diagnosed as having a PI3Ka-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.

[0108] This disclosure also provides a method of treating a PI3Ka-associated cancer in a subject, comprising: determining that the cancer in the subject is a PI3Ka-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.

[0109] 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 PIK3CA gene, a PI3Kot protein, or expression or activity or level of any of the same.

[0110] This disclosure also provides a method for inhibiting PI3Ka 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

[0111] Other embodiments include those described in the Detailed Description and / or in the claims.

[0112] Additional Definitions

[0113] 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 scientificAttorney Docket No. 49366-0056WO4

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] The term "inhibit" or "inhibition of means to reduce by a measurable amount, or to prevent entirely (e.g., 100% inhibition).

[0120] 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 PI3Ka 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.Attorney Docket No. 49366-0056WO4

[0121] 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.

[0122] 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.

[0123] 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.

[0124] The term “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

[0125] 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.

[0126] The term “hydroxyl” refers to an -OH radical.

[0127] The term “cyano” refers to a -CN radical.

[0128] 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, C1-10indicates 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.

[0129] 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.

[0130] The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with an independently selected halogen (e.g., -CHF2or -CF3).

[0131] The term “alkoxy” refers to an -O-alkyl radical (e.g., -OCH3).Attorney Docket No. 49366-0056WO4

[0132] The term “haloalkoxy” refers to an -O-haloalkyl radical (e.g., -OCHF2or -OCF3).

[0133] The term “alkoxyalkyl” refers to an -alkyl-O-alkyl radical (e.g., -CH2CH2OCH3).

[0134] The term “thioalkyl” refers to an -S-alkyl radical (e.g., -SCH3) or an -alkyl-S-alkyl radical (e.g., -CH2CH2SCH3).

[0135] The term “hydroxyalkyl” refers to an alkyl, in which one or more hydrogen atoms is / are replaced with hydroxyl.

[0136] 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.

[0137] 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, bicyclofl. 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). Nonlimiting 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.

[0138] The term “cycloalkoxy” refers to an -O-cycloalkyl radical (e.g., -O(cyclobutyl)).

[0139] 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.Attorney Docket No. 49366-0056WO4

[0140] 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]pyrimidinyl, pyrrolo[2,3-Z>]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-Z>]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-Z>]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[< ][l,3]dioxole, 2,3 -dihydrobenzofuran, tetrahydroquinoline, 2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline, 7H-spiro[furo[3,4-b]pyridine-5,4'-piperidinyl], spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one, 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

[0141] 0 NO^ N I \ substituents), such as one or more of pyridone (

[0142]

[0143] e.g., -J—, I,, or

[0144]

[0145] 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).

[0146] 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-Attorney Docket No. 49366-0056WO4

[0147] 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, isothiazolidinyl 1,1 -di oxide, 1,2-thiazetidinyl 1,1 -dioxide, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused / bridged heteorocyclyl includes: 2-azabicy clo[ 1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2-azabicyclo[l.l.l]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3-azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7-azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2-azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2-oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5-oxabicyclo[2.1.1]hexane, 3- oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7-oxabicyclo[2.2.1]heptane, 6- oxabicyclo[3.1.1 ]heptane, 7-oxabicyclo[4.2.0]octane, 2-oxabicyclo[2.2.2]octane, 3- oxabicyclo[3.2.1]octane, 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[2.5]octane, 1-azaspiro[3.5]nonane, 2-azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6-azaspiro[2.6]nonane, 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.

[0148] An “aralkyl” refers to an aryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein. Non-limiting examples of an aralkyl group are benzyl, ethylphenyl, methylnaphthyl, and the like.

[0149] A “heteroaralkyl” refers to a heteroaryl group, as defined herein, connected to the remainder of the molecule via a divalent C1-C6 alkyl group, as described herein. Non-limiting examples of an aralkyl group are methylpyridyl, ethylpyrimidinyl, methylimidazolyl, and the like.Attorney Docket No. 49366-0056WO4

[0150] A “heterocyclyl oxy” refers to an -O-heterocyclyl radical, wherein the heterocyclyl group is as defined herein.

[0151] A “heteroaryloxy” refers to an -O-heteroaryl radical, wherein the heteroaryl group is as defined herein.

[0152] A “cycloalkoxy” refers to an -O-cycloalkyl radical, wherein the cycloalkyl group is as defined herein.

[0153] As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like.

[0154] 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.

[0155] 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

[0156] atoms (e.g., [x.x. O] ring systems, in which 0 represents a zero atom bridge (e.g.,

[0157]

[0158] (ii) a single ring atom (spiro-fused ring systems)

[0159]

[0160] (e.g.,,, or or (iii) a contiguous array of ring atoms (bridged ring systems having all bridge lengths > 0)

[0161] (

[0162]

[0163] e.g.,,, or

[0164] 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 withoutAttorney Docket No. 49366-0056WO4

[0165] limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C. For example, the compounds of the present embodiments can be deuterated, wherein one or more hydrogen atoms are replaced with a deuterium atom. For example, a methyl group (-CH3) can be replaced with a deuterated methyl group (-CD3).

[0166] 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:

[0167]

[0168] « encompasses the tautomeric form containing the moiety:

[0169]

[0170] H. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms.

[0171] 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.

[0172] 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.

[0173] DETAILED DESCRIPTION

[0174] This disclosure provides compounds of Formula (I), Formula (I-I), and Formula (I-II), and pharmaceutically acceptable salts thereof, that inhibit phosphatidylinositol 4,5-bisphosphate 3-kinase (PI3K) isoform alpha (PI3Ka). These compounds are useful for treating a disease inAttorney Docket No. 49366-0056WO4

[0175] which increased PI3Ka activation contributes to the pathology, symptoms, and / or progression of the disease (e.g., cancer) in a subject.

[0176] Formulae (I), Formulae (I-I), and Formulae (I-II) Compounds

[0177] Some embodiments provide a compound of Formula (I):

[0178]

[0179] or a pharmaceutically acceptable salt thereof, wherein:

[0180] Z is CH orN;

[0181] R1is hydrogen, halogen, cyano, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;

[0182] R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A, 5-14 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-C6 alkoxyalkyl optionally substituted with -C(=O)NRARc, or C1-C6 alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl;

[0183] each R2Ais independently selected from:

[0184] (i) halogen;

[0185] (ii) cyano;

[0186] (iii) hydroxyl;

[0187] (iv) -NRARB;

[0188] (v) -C(=O)NRARB;

[0189] (vi) O

[0190]

[0191] Attorney Docket No. 49366-0056WO4

[0192] (vii) -NHC(=O)Rc;

[0193] (viii) -C(=O)ORD;

[0194] (ix) -SO2RD;

[0195] (x) -NHSO2RD;

[0196] (xi) -SO2NRDRE;

[0197] (xii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB;

[0198] (xiii) C1-C6 haloalkyl;

[0199] (xiv) C1-C6 hydroxy alkyl;

[0200] (xv) -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl);

[0201] (xvi) -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF);

[0202] (xvii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl; cyano; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl or cyano; C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)Rc; -NRARB; -OR7; -SR8; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, or C1-C6 alkyl;

[0203] (xviii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl;

[0204] (xix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;

[0205] (xx) C1-C6 alkoxy optionally substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or-C(=O)C3-C6 cycloalkyl;Attorney Docket No. 49366-0056WO4

[0206] (xxi) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;

[0207] (xxii) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; and (xxiii) 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with hydroxyl;

[0208] each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C2-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-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-C6 alkyl;

[0209] each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6 alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl;

[0210] each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen, and C1-C6 alkyl optionally substituted with oxo or -NRARB;

[0211] each RFis independently selected from cyano, hydroxyl, halogen, C3-C6 cycloalkyl, and C1-C6 alkyl;

[0212] each R3Aand R3Bis independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0213] R4is hydrogen, halogen, C1-C6 alkyl, or acrylamido;

[0214] R5is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;

[0215] R5Aand R5Bare independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;

[0216] R6is hydrogen, halogen, or C1-C6 alkyl;

[0217] each R7is independently selected from C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-Attorney Docket No. 49366-0056WO4

[0218] 6 membered heteroaryl are each optionally and independently substituted with 1-3 independently selected R7A;

[0219] each R7Ais independently selected from hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl optionally substituted with hydroxyl;

[0220] R8is C1-C6 alkyl or C1-C6 haloalkyl;

[0221] X is a bond, C

[0222]

[0223] H2, CH(CH3), C(CH3)2, or

[0224] W is NR3Bor O;

[0225] Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5-10 membered heteroaryl are each optionally and independently substituted with 1-3

[0226] (RY1)z

[0227] independently selected RYor

[0228]

[0229] , wherein * represents the connection of L1to the remainder of the compound of Formula (I);

[0230] each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C6 cycloalkyl, -(CH2)n-C(=O)RF, -(CH2)n-NHC(=O)RF, -(CH2)n-NHC(=O)ORF, -CO2RG, -P(=O)RARB, -(CH2)n-SO2NRHRT, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ, -(CH2)n-S(=O)(=NRH)NRHRI, -(CH2)n-C(=N-OH)RJ, -(CH2)n-SO2RJ, -(CH2)n-C(=O)NRHRI, -(CH2)„-C

[0231]

[0232] (=O)NRHORI, and C1-C6 haloalkyl optionally substituted with hydroxyl;

[0233] each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);

[0234] each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);

[0235] each RHand RIis independently selected from: hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, -(CH2)n-SO2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy;Attorney Docket No. 49366-0056WO4

[0236] 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-C6 alkyl, and -C(=O)C1-C6 alkyl;

[0237] RJis C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, or C1-C6 alkoxy;

[0238] Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;

[0239] L1is a bond, C1-C6 alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)„-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or C1-C6 alkylene optionally substituted with oxo;

[0240] each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2RG, -SO2NRHRI, -NHSO2RJ, -S(=O)(=NRH)RJ, -SO2(C1-C6 alkyl), -C(=O)NRHRI, 4-6 membered heteroaryl, C1-C6 alkoxy optionally substituted with RY2, C1-C6 haloalkyl, C1-C6 alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl;

[0241] RY2is hydroxyl, -NRHRI, -C(=O)NRHRI, or -SO2NRHRI

[0242] n is 0, 1, or 2;

[0243] m is 0, 1, 2, or 3; and

[0244] z is 0, 1, 2, or 3;

[0245] wherein:

[0246] R2is 11-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A; or

[0247] at least one R2Ais

[0248] (a) -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl);

[0249] (b) 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen, C1-C6 haloalkyl optionally substituted with hydroxyl or cyano, -OR7, -SR8; -SO2RD, -NRAC(=O)Rc, -P(=O)RARB, C1-C6 alkyl substituted with cyano, and 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl;

[0250] (c) 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl and C1-C6 haloalkoxy;Attorney Docket No. 49366-0056WO4

[0251] (d) C1-C6 alkoxy substituted with hydroxyl or 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[0252] (e) -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3- C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF); or (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; or at least one of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or Cl- C6 haloalkyl; or

[0253] at least one of RDand REis C3-C6 cycloalkyl or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen; or

[0254] at least one RFis cyano, hydroxyl, halogen, C3-C6 cycloalkyl, or C1-C6 alkyl; or R5is C1-C6 haloalkyl; or

[0255] R8is C1-C6 alkyl or C1-C6 haloalkyl; or

[0256] at least one RYis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, -(CH2)n-C(=N-OH)RJ, or C3-C6 cycloalkyl; or

[0257] at least one of RHand RIis C1-C6 alkyl substituted with -P(=O)RARB; or

[0258] RJis C1-C6 haloalkyl.

[0259] Some embodiments provide a compound of Formula (I-I):

[0260] R6

[0261] R,5®. bF ^, R1

[0262] R‘

[0263] X R3A

[0264] , W

[0265]

[0266] (I-I)

[0267] or a pharmaceutically acceptable salt thereof, wherein:

[0268] R1is hydrogen, halogen, cyano, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;

[0269] 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 cycloalkylAttorney Docket No. 49366-0056WO4

[0270] 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-C6 alkoxyalkyl optionally substituted with -C(=O)NRARC, or C1-C6 alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl;

[0271] each R2Ais independently selected from:

[0272] (i) halogen;

[0273] (ii) cyano;

[0274] (iii) hydroxyl;

[0275] (iv) -NRARB;

[0276] (v) -C(=O)NRARB;

[0277] (

[0278]

[0279] vi) o;

[0280] (vii) -NHC(=O)Rc;

[0281] (viii) -C(=O)ORD;

[0282] (ix) -SO

[0283]

[0284] 2RD;

[0285] (x) -NHSO2RD;

[0286] (xi) -SO2NRDRE;

[0287] (xii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB;

[0288] (xiii) C1-C6 haloalkyl;

[0289] (xiv) C1-C6 hydroxyalkyl;

[0290] (xv) -C(=O)-(C1-C6 alkyl);

[0291] (xvi) -C(=O)-(4-6 membered heterocyclyl);

[0292] (xvii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -C(=O)NRARB, -NRARB, -OR7, 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl;

[0293] (xviii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB,Attorney Docket No. 49366-0056WO4

[0294] -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl;

[0295] (xiv) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;

[0296] (xv) C1-C6 alkoxy optionally substituted with -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl;

[0297] (xxi) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; and (xxii) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;

[0298] each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C2-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-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-C6 alkyl;

[0299] each RCis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6 alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl;

[0300] each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and C1-C6 alkyl optionally substituted with oxo or -NRARB;

[0301] each R3Aand R3Bis independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0302] R4is hydrogen, halogen, C1-C6 alkyl, or acrylamido;

[0303] R5is hydrogen, halogen, C1-C6 alkyl, cyano, -NR3AR5B, -NR’AC(=O)R5B, or -C(=O)NR5AR5B;Attorney Docket No. 49366-0056WO4

[0304] R5Aand R5Bare independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;

[0305] R6is hydrogen, halogen, or C1-C6 alkyl;

[0306] each R7is independently selected from C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl are each optionally and independently substituted with 1-3 independently selected R7A

[0307] each R7Ais independently selected from hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl optionally substituted with hydroxyl;

[0308] X is a bond, C

[0309]

[0310] H2, CH(CH3), C(CH3)2, or

[0311] W is NR3Bor O;

[0312] Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5-10 membered heteroaryl are each optionally and independently substituted with 1-3

[0313] * - L1- H A -4 - (RY1)Z

[0314] independently selected RYor

[0315]

[0316] x- ', wherein * represents the connection of L1to the remainder of the compound of Formula (I-I);

[0317] each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -(CH2)n-C(=O)RF, -(CH2)n-NHC(=O)RF, -(CH2)n-NHC(=O)ORF, -CO2RG, -P(=O)RARB, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ, -(CH2)n-SO2RJ, -(CH2)n-C(=O)NRHRI, -(CH2)n-C(=O)NRHORI, and C1-C6 haloalkyl optionally substituted with hydroxyl;

[0318] each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);

[0319] each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);

[0320] each RHand RIis independently selected from: hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, -(CH2)n-SO2(C1-C6 alkyl),Attorney Docket No. 49366-0056WO4

[0321] and C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, –SO2(C1-C6 alkyl), or C1-C6 alkoxy;

[0322] 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-C6 alkyl, and -C(=O)C1-C6 alkyl;

[0323] RJis C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, or C1-C6 alkoxy;

[0324] Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;

[0325] L1is a bond, C1-C6 alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or C1-C6 alkylene optionally substituted with oxo;

[0326] each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2RG, -SO2NRHRI, -NHSO2RJ, -S(=O)(=NRH)RJ, -SO2(C1-C6 alkyl), -C(=O)NRHRI, 4-6 membered heteroaryl, C1-C6 alkoxy optionally substituted with RY2, C1-C6 haloalkyl, C1-C6 alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl;

[0327] RY2is hydroxyl, -NRHRI, -C(=O)NRHRI, or -SO2NRHRI

[0328] n is 0, 1, or 2; and

[0329] z is 0, 1, 2, or 3;

[0330] wherein:

[0331] at least one R2Ais

[0332] (a) -C(=O)-(C1-C6 alkyl);

[0333] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[0334] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[0335] (e) -C(=O)-(4-6 membered heterocyclyl); or

[0336] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; orAttorney Docket No. 49366-0056WO4

[0337] at least one of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or Cl-C6 haloalkyl; or

[0338] at least one RYis -P(=O)RARB; or

[0339] at least one of RHand R1is C1-C6 alkyl substituted with -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy; or

[0340] RJis C1-C6 haloalkyl.

[0341] Some embodiments provide a compound of Formula (I-II):

[0342] >5 N R

[0343] R‘

[0344] X'

[0345] i

[0346]

[0347] (I-II)

[0348] or a pharmaceutically acceptable salt thereof, wherein:

[0349] R1is hydrogen, halogen, cyano, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;

[0350] R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A, 5-14 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-C6 alkoxyalkyl optionally substituted with -C(=O)NRARC, or C1-C6 alkoxy optionally substituted with -C(=O)NRARC, C4-C10 cycloalkyl, 4-10 membered heterocyclyl, 5-10 membered heteroaryl, or phenyl;

[0351] each R2Ais independently selected from:

[0352] (i) halogen;

[0353] (ii) cyano;

[0354] (iii) hydroxyl;

[0355] (iv) -NRARB;Attorney Docket No. 49366-0056WO4

[0356] (v) -C(=O)NRARB;

[0357] / ^NRARB

[0358] (

[0359]

[0360] vi) °;

[0361] (vii) -NHC(=O)Rc;

[0362] (viii) -C(=O)ORD;

[0363] (ix) -SO2RD;

[0364] (x) -NHSO2RD;

[0365] (xi) -SO2NRDRE;

[0366] (xii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB;

[0367] (xiii) C1-C6 haloalkyl;

[0368] (xiv) C1-C6 hydroxyalkyl;

[0369] (xv) -C(=O)-(C1-C6 alkyl);

[0370] (xvi) -C(=O)-(4-6 membered heterocyclyl);

[0371] (xvii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl; cyano; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl; C3-C6 cycloalkyl optionally substituted with -NRARBor halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)-(C1-C6 alkyl); -NRARB; -OR7; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl;

[0372] (xviii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl;

[0373] (xix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;

[0374] (xx) C1-C6 alkoxy optionally substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or-C(=O)C3-C6 cycloalkyl;Attorney Docket No. 49366-0056WO4

[0375] (xxi) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;

[0376] (xxii) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; and (xxiii) 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with hydroxyl;

[0377] each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C2-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-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-C6 alkyl;

[0378] each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6 alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl;

[0379] each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and C1-C6 alkyl optionally substituted with oxo or -NRARB;

[0380] each R3Aand R3Bis independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, or R3Aand R3B, together with the carbon and nitrogen atoms, respectively, to which they are attached together form a 4-8 membered heterocyclyl group;

[0381] R4is hydrogen, halogen, C1-C6 alkyl, or acrylamido;

[0382] R5is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;

[0383] R5Aand R5Bare independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;

[0384] R6is hydrogen, halogen, or C1-C6 alkyl;

[0385] each R7is independently selected from C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl are each optionally and independently substituted with 1-3 independently selected R7A.Attorney Docket No. 49366-0056WO4

[0386] each R7Ais independently selected from hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl optionally substituted with hydroxyl;

[0387] X is a bond, C

[0388]

[0389] H2, CH(CH3), C(CH3)2, or

[0390] W is NR3Bor O;

[0391] Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5-10 membered heteroaryl are each optionally and independently substituted with 1-3

[0392] * - L1- h- A -4 - (RY1)Z

[0393] independently selected RYor

[0394]

[0395] -, wherein * represents the connection of L1to the remainder of the compound of Formula (I-II);

[0396] each RYis independently selected from: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, -(CH2)n-C(=O)RF, -(CH2)n-NHC(=O)RF, -(CH2)n-NHC(=O)ORF, -CO2RG, -P(=O)RARB, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ, -(CH2)n-S(=O)(=NRH)NRHRI, -(CH2)n-C(=N-OH)RJ, -(CH2)n-SO2RJ, -(CH2)n-C(=O)NRHRI, -(CH2)n-C(=O)NRHORI, and C1-C6 haloalkyl optionally substituted with hydroxyl;

[0397] each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);

[0398] each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);

[0399] each RHand R1is independently selected from: hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, -(CH2)n-SO2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy;

[0400] 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-C6 alkyl, and -C(=O)C1-C6 alkyl;Attorney Docket No. 49366-0056WO4

[0401] RJis C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, or C1-C6 alkoxy;Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;

[0402] L1is a bond, C1-C6 alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or C1-C6 alkylene optionally substituted with oxo;

[0403] each RY1is independently selected from: cyano, hydroxyl, halogen, -C(=O)RF, -NHC(=O)RF, -CO2RG, -SO2NRHRI, -NHSO2RJ, -S(=O)(=NRH)RJ, -SO2(C1-C6 alkyl), -C(=O)NRHRI, 4-6 membered heteroaryl, C1-C6 alkoxy optionally substituted with RY2, C1-C6 haloalkyl, C1-C6 alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl;

[0404] RY2is hydroxyl, -NRHRI, -C(=O)NRHRI, or -SO2NRHRI

[0405] n is 0, 1, or 2; and

[0406] z is 0, 1, 2, or 3;

[0407] wherein:

[0408] R2is 11-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A; or

[0409] at least one R2Ais

[0410] (a) -C(=O)-(C1-C6 alkyl);

[0411] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, -OR7, -SO2RD, -NRAC(=O)-(C1-C6 alkyl) or -P(=O)RARB;

[0412] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with hydroxyl or 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[0413] (e) -C(=O)-(4-6 membered heterocyclyl); or

[0414] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; or at least one of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or Cl- C6 haloalkyl; or

[0415] R5is C1-C6 haloalkyl; orAttorney Docket No. 49366-0056WO4

[0416] at least one RYis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, or -(CH2)n-C(=N-OH)RJ; or

[0417] at least one of RHand R1is C1-C6 alkyl substituted with -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy; or

[0418] RJis C1-C6 haloalkyl.

[0419] In some embodiments, Z is CH.

[0420] In some embodiments, Z is N.

[0421] In some embodiments, R1is hydrogen.

[0422] In some embodiments, R1is halogen. In some embodiments, R1is I, Br, Cl, or F. In some embodiments, R1is Cl or F. In some embodiments, R1is F. In some embodiments, R1is Cl.

[0423] In some embodiments, R1is cyano.

[0424] In some embodiments, R1is C3-C6 cycloalkyl. In some embodiments, R1is cyclopropyl or cyclobutyl.

[0425] In some embodiments, R1is 4-10 membered heterocyclyl.

[0426] In some embodiments, R1is 5-8 membered heterocyclyl.

[0427] In some embodiments, the heterocyclyl of R’ is 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[2.1.1]hexanyl. In some embodiments, the heterocyclyl of R1is 2-oxabicyclo[3.1.1]heptanyl.

[0428] In some embodiments, R1is C1-C6 alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl. In some embodiments, R1is C1-C6 alkyl substituted with with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl. In some embodiments, R1is Cl-C3 alkyl substituted with with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl In some embodiments, R1is C1-C6 alkyl substituted with C3-C6 cycloalkyl. In some embodiments, R1is C1-C6 alkyl substituted with 4-10 membered heterocyclyl. In some embodiments, R1is C1-C6 alkyl. In some embodiments, R1is methyl, ethyl, or isopropyl. In some embodiments, R1is methyl.Attorney Docket No. 49366-0056WO4

[0429] In some embodiments, R1is C1-C6 thioalkyl. 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-thiom ethyl. In some embodiments, R1is thiomethyl.

[0430] In some embodiments, R1is C1-C6 haloalkyl. In some embodiments, R1is C1-C3 haloalkyl. In some embodiments, R1is C1-C3 fluoroalkyl. In some embodiments, R1is CF3. In some embodiments, R1is CHF2.

[0431] In some embodiments, R1is C1-C6 alkoxy. In some embodiments, R1is C1-C3 alkoxy. In some embodiments, R1is -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R1is

[0432] -OCH3.

[0433] In some embodiments, R1is C1-C6 alkoxyalkyl. In some embodiments, R1is C1-C3 alkoxyalkyl. In some embodiments, R1is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R1is -CH2OCH3.

[0434] 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.

[0435] 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 R2A. In some embodiments, R2is phenyl optionally substituted with 3 independently selected R2A. In some embodiments, R2is phenyl.

[0436] 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 optionallyAttorney Docket No. 49366-0056WO4

[0437] substituted with 3 independently selected R2A. Tn some embodiments, R2is 2,3-dihydro-lH-indenyl.

[0438] In some embodiments, R2is 5-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 5-14 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 5-14 membered heteroaryl substituted with 1 R2A. In some embodiments, R2is 5-14 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2is 5-14 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2is 5-14 membered heteroaryl.

[0439] In some embodiments, R2is 11-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A. In some embodiments, R2is 11-14 membered heteroaryl substituted with 1 or 2 independently selected R2A. In some embodiments, R2is 11-14 membered heteroaryl substituted with 1 R2A. In some embodiments, R2is 11-14 membered heteroaryl substituted with 2 independently selected R2A. In some embodiments, R2is 11-14 membered heteroaryl optionally substituted with 3 independently selected R2A. In some embodiments, R2is 11-14 membered heteroaryl. In some embodiments, R2is 7H-spiro[furo[3,4-b]pyridine-5,4'-piperidinyl] or spiro[piperidine-4,3'-pyrrolo[2,3-b]pyridin]-2'(1'H)-one.

[0440] 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.

[0441] 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 R2A. In some embodiments, R2is 6 membered heteroaryl.Attorney Docket No. 49366-0056WO4

[0442] 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.

[0443] 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-cyclopenta[b]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-b]pyridinyl. In some embodiments, the heteroaryl of R2is 3,4-dihydro-2H-pyrano[2,3-Attorney Docket No. 49366-0056WO4

[0444] 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-d]pyrimidinyl, In some embodiments, the heteroaryl of R2is 5,6,7,8-tetrahydroquinazolinyl.

[0445] 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.

[0446] 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 heteroaryl oxy.

[0447] 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 R2A. In some embodiments, R2is 4-10 membered heterocyclyl optionally substituted with 3 independently selected R2A. In some embodiments, R2is 4-10 membered heterocyclyl.

[0448] In some embodiments, R2is 4-10 membered bicyclic ether optionally substituted with 1 or 2 independently selected R2A. In some 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 memberedAttorney Docket No. 49366-0056WO4

[0449] 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.

[0450] 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.

[0451] 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 5-8Attorney Docket No. 49366-0056WO4

[0452] membered heterocyclyloxy optionally substituted with 3 independently selected R2AIn some embodiments, R2is 5-8 membered heterocyclyloxy.

[0453] 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.

[0454] 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 R2A. In 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.

[0455] In some embodiments, the cycloalkyl of R2is cyclopentyl, [l.l.l]bicyclopentyl, 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- IH-indenyl. In some embodiments, the cycloalkyl of R2is bicyclo[2.1.1]hexanyl. In some embodiments, the cycloalkyl ofR2is bicyclo[3.1.0]hexanyl.

[0456] In some embodiments, R2is C1-C6 alkoxy optionally substituted with -C(=O)NRARc, C4-C10 cycloalkyl, or phenyl. In some embodiments, R2is C1-C6 alkoxy substituted with -C(=O)NRARC, C4-C10 cycloalkyl, or phenyl. In some embodiments, R2is C1-C6 alkoxy substituted with -C(=O)NRARc. In some embodiments, R2is C1-C6 alkoxy substituted with C4-C10 cycloalkyl. In some embodiments, R2is C1-C6 alkoxy substituted with C4-C6 cycloalkyl. In some embodiments, R2is C1-C6 alkoxy substituted with phenyl. In some embodiments, R2is C1-C6 alkoxy. In some embodiments, R2is C1-C3 alkoxy. In some embodiments, R2is -OCH3 or-OCH2CH3.

[0457] In some embodiments, R2is C1-C6 alkoxyalkyl optionally substituted with -C(=O)NRARCIn some embodiments, R2is C1-C6 alkoxyalkyl substituted with - C(=O)NRARC. In some embodiments, R2is C3-C6 alkoxyalkyl substituted with -C(=O)NRARc.Attorney Docket No. 49366-0056WO4

[0458] In some embodiments, R2is C1-C6 alkoxyalkyl. In some embodiments, R2is -CH2OCH3, -CH2OCH2CH3, or -CH2CH2OCH3. In some embodiments, R2is -CH2OCH3.

[0459]

[0460] Attorney Docket No. 49366-0056WO4

[0461]

[0462] Attorney Docket No. 49366-0056WO4

[0463]

[0464] 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.Attorney Docket No. 49366-0056WO4

[0465] 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.

[0466] 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.

[0467] 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.

[0468] 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.

[0469] ^

[0470]

[0471] Y ^NRARB

[0472] In some embodiments, 1, 2, 3, or 4 of R2Aare independently °. In some

[0473] ^

[0474]

[0475] |^NRARB

[0476] embodiments, 1 or 2 of R2Aare independently °. In some embodiments, 1 R2Ais A / NRARB

[0477] o

[0478] 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.

[0479] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -SO2RDIn some embodiments, 1 or 2 of R2Aare independently -SO2RD. In some embodiments, 1 R2Ais -SO2RD.

[0480] 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 R2Ais -NHSO2RD.

[0481] 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

[0482] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -NHC(=O)C1-C6 alkyl optionally substituted with NRARB. In some embodiments, 1, 2, or 3 of R2Aare independentlyAttorney Docket No. 49366-0056WO4

[0483] -NHC(=O)C1-C6 alkyl substituted with NRARB. In some embodiments, 1, 2, or 3 of R2Aare independently -NHC(=O)C1-C6 alkyl. In some embodiments, 1 or 2 of R2Aare independently -NHC(=O)C1-C6 alkyl optionally substituted with NRARB. In some embodiments, 1 or 2 of R2Aare independently -NHC(=O)C1-C6 alkyl substituted with NRARB. In some embodiments, 1 or 2 of R2Aare independently -NHC(=O)C1-C6 alkyl. In some embodiments, 1 R2Ais -NHC(=O)C1-C6 alkyl optionally substituted with NRARB.

[0484] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 haloalkyl. 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-C6 haloalkyl.

[0485] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 hydroxyalkyl. In some embodiments, 1 or 2 of R2Aare independently C1-C3 hydroxyalkyl. In some embodiments, 1 R2Ais C1-C3 hydroxyalkyl.

[0486] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -C(=O)-(C1-C6 alkyl or Cl-C6 haloalkyl). In some embodiments, 1 or 2 of R2Aare independently -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl). In some embodiments, 1 R2Ais -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl).

[0487] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -C(=O)-(C1-C6 alkyl). In some embodiments, 1 or 2 of R2Aare independently -C(=O)-(C1-C6 alkyl). In some embodiments, 1 R2Ais -C(=O)-(C1-C6 alkyl). In some embodiments, 1 R2Ais -C(=O)-(C1-C3 alkyl). In some embodiments, 1 R2Ais -C(=O)-CH3.

[0488] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -C(=O)-(C1-C6 haloalkyl). In some embodiments, 1 or 2 of R2Aare independently -C(=O)-(C1-C6 haloalkyl). In some embodiments, 1 R2Ais -C(=O)-(C1-C3 haloalkyl). In some embodiments, 1 R2Ais -C(=O)-(C1-C3 fluoroalkyl).

[0489] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF). In some embodiments, 1 or 2 of R2Aare independently -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF). In some embodiments, 1 R2Ais -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF). In some embodiments, 1 R2Ais -C(=O)-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6Attorney Docket No. 49366-0056WO4

[0490] cycloalkyl, each optionally substituted with 1-3 independently selected RF). Tn some embodiments, 1 R2Ais -C(=O)-(CH2) 111“ (4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF), wherein m is 1, 2, or 3.

[0491] In some embodiments, 1 R2Ais -C(=O)-(4-6 membered heterocyclyl optionally substituted with 1-3 independently selected RF). In some embodiments, 1 R2Ais -C(=O)-(5-6 membered heteroaryl optionally substituted with 1-3 independently selected RF). In some embodiments, 1 R2Ais -C(=O)-(C3-C6 cycloalkyl optionally substituted with 1-3 independently selected RF).

[0492] In some embodiments, 1 R2Ais -C(=O)-(CH2)m-(4-6 membered heterocyclyl optionally substituted with 1-3 independently selected RF), wherein m is 1, 2, or 3. In some embodiments, 1 R2Ais -C(=O)-(CH2)m-(5-6 membered heteroaryl optionally substituted with 1-3 independently selected RF), wherein m is 1, 2, or 3. In some embodiments, 1 R2Ais -C(=O)-(CH2)m-(C3-C6 cycloalkyl optionally substituted with 1-3 independently selected RF), wherein m is 1, 2, or 3.

[0493] In some embodiments, 1, 2, or 3 of RFare cyano. In some embodiments, 1 RFis cyano. In some embodiments, 1, 2, or 3 of RFare hydroxyl. In some embodiments, 1 RFis hydroxyl.

[0494] In some embodiments, 1, 2, or 3 of RFare hydroxyl. In some embodiments, 1 RFis hydroxyl.

[0495] In some embodiments, 1, 2, or 3 of RFare halogen. In some embodiments, 1 RFis halogen. In some embodiments, 1, 2, or 3 of RFare fluoro or chloro. In some embodiments, 1, 2, or 3 of RFare fluoro.

[0496] In some embodiments, 1, 2, or 3 of RFare C3-C6 cycloalkyl. In some embodiments, 1 RFis C3-C6 cycloalkyl. In some embodiments, 1 RFis cyclopropyl.

[0497] In some embodiments, 1, 2, or 3 of RFare C1-C6 alkyl. In some embodiments, 1 RFis C1-C6 alkyl. In some embodiments, 1 RFis C1-C3 alkyl.

[0498] In some embodiments, m is 0.

[0499] In some embodiments, m is 1.

[0500] In some embodiments, m is 2.

[0501] In some embodiments, m is 3.Attorney Docket No. 49366-0056WO4

[0502] In some embodiments, 1, 2, 3, or 4 of R2Aare independently -C(=O)-(4-6 membered heterocyclyl). In some embodiments, 1 or 2 of R2Aare independently -C(=O)-(4-6 membered heterocyclyl). In some embodiments, 1 R2Ais -C(=O)-(4-6 membered heterocyclyl).

[0503] 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; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl; C3-C6 cycloalkyl optionally substituted with -NRARBor halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)-(C1-C6 alkyl); -NRARB; -OR7; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl. 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-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl; C3-C6 cycloalkyl optionally substituted with -NRARBor halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)-(C1-C6 alkyl); -NRARB; -OR7; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl. In some embodiments, 1 R2Ais 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl; cyano; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl; C3-C6 cycloalkyl optionally substituted with -NRARBor halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)-(C1-C6 alkyl); -NRARB; -OR7; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl. In some embodiments, 1 R2Ais 5-10 membered heteroaryl substituted with 1-2 substituents independently selected from hydroxyl; cyano; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl; C3-C6 cycloalkyl optionally substituted with -NRARBor halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)-(C1-C6 alkyl); -NRARB; -OR7; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl. In some embodiments, 1 R2Ais 5-10 membered heteroaryl substituted with 1 substituent independently selected from hydroxyl; cyano; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl; C3-C6 cycloalkyl optionally substituted with -NRARBor halogen; Cl-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -Attorney Docket No. 49366-0056WO4

[0504] NRAC(=O)-(C1-C6 alkyl); -NRARB; -OR7; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl.

[0505] In some embodiments, 1 R2Ais 5-10 membered heteroaryl optionally substituted with 1 substituent independently selected from C1-C6 alkoxy; C1-C6 haloalkoxy; C3-C6 cycloalkyl optionally substituted with -NRARBor halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; -NRAC(=O)-(C1-C6 alkyl); -OR7; -P(=O)RARB; and -SO2RD.

[0506] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected hydroxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -C(=O)NRARB, -NRARB, -OR7, 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl. 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-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -C(=O)NRARB, -NRARB, -OR7, 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl. 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, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -C(=O)NRARB, -NRARB, -OR7, 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl.

[0507] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, and -OR7. In some embodiments, 1 or 2 of R2Aare independently 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, and -OR7. In some embodiments, 1 R2Ais 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, and -OR7. In some embodiments, 1 R2Ais 5-10 membered heteroaryl substituted with 1 substituent independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, and -OR7.Attorney Docket No. 49366-0056WO4

[0508] In some embodiments, 1 of R2Ais 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -C(=O)NRARB, -NRARB, -OR7, 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, 1 of R2Ais 5-6 membered heteroaryl substituted with 1-3 substituents independently selected from hydroxyl, cyano, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, halogen, -C(=O)NRARB, -NRARB, -OR7, 4-10 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl, and C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, 1 of R2Ais 5-6 membered heteroaryl.

[0509] 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; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl or cyano; C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)Rc; -NRARB; -OR7; -SR8; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, or C1-C6 alkyl. In some embodiments, 1 R2Ais 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl; cyano; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl or cyano; C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)Rc; -NRARB; -OR7; -SR8; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, or C1-C6 alkyl.

[0510] 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-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy 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-C6 haloalkyl,Attorney Docket No. 49366-0056WO4

[0511] C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl.

[0512] 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-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl, and C1-C6 alkyl. In some embodiments, 1 of R2Ais 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl, and C1-C6 alkyl.

[0513] 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-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, and C1-C6 alkyl substituted with C1-C6 alkoxy or hydroxyl. In some embodiments, 1 of R2Ais 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl),

[0514] -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl substituted with -NRARB, and C1-C6 alkyl substituted with C1-C6 alkoxy or hydroxyl.

[0515] 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-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkyl, -C(=O)NRARB, -NRARB, or -NHC(=O)C1-C6 alkyl. In some embodiments, 1 of R2Ais 4-10 membered heterocyclyl substituted with 1 substituent independently selected from hydroxyl, cyano, C1-C6 haloalkyl, C1-C6 haloalkoxy,-C(=O)Cl-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkyl, -C(=O)NRARB, -NRARB, or -NHC(=O)C1-C6 alkyl.

[0516] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyl substituted with C1-C6 haloalkoxy. In some embodiments, 1 or 2 of R2Aare independently 4-10Attorney Docket No. 49366-0056WO4

[0517] membered heterocyclyl substituted with C1-C6 haloalkoxy. In some embodiments, 1 of R2Ais 4-10 membered heterocyclyl substituted with C1-C6 haloalkoxy.

[0518] 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.

[0519] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkyl 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-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R2Aare independently C1-C6 alkyl 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-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl. In some embodiments, 1 R2Ais C1-C6 alkyl 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-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl.

[0520] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkyl 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-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl.

[0521] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkyl 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-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or –C(=O)C3-C6 cycloalkyl.

[0522] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkyl substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C3-C10 cycloalkyl, and 4-10 membered heterocyclyl.

[0523] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkyl. 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-C6 alkyl. In someAttorney Docket No. 49366-0056WO4

[0524] embodiments, 1 or 2 of R2Aare independently C1-C3 alkyl. Tn some embodiments, 1 or 2 of R2Aare methyl.

[0525] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkoxy optionally substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or -C(=O)C3-C6 cycloalkyl. In some embodiments, 1 or 2 of R2Aare independently C1-C6 alkoxy optionally substituted with hydroxyl, -NRARB, or 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or-C(=O)C3-C6 cycloalkyl. In some embodiments, 1 R2Ais C1-C6 alkoxy optionally substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or-C(=O)C3-C6 cycloalkyl.

[0526] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkoxy substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or-C(=O)C3-C6 cycloalkyl.

[0527] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkoxy substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or-C(=O)C3-C6 cycloalkyl.

[0528] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen. In some embodiments, 1 or 2 of R2Aare independently C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen. In some embodiments, 1 R2Ais C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen.

[0529] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkoxy substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl.

[0530] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C1-C6 alkoxy.

[0531] 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-C6 alkyl. 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-C6 alkyl. In some embodiments, 1 R2AisAttorney Docket No. 49366-0056WO4

[0532] C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[0533] 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-C6 alkyl.

[0534] 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.

[0535] 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.

[0536] 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.

[0537] In some embodiments, 1, 2, 3, or 4 of R2Aare independently C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, 1 or 2 of R2Aare independently C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, 1 R2Ais C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, 1 R2Ais C3-C6 cycloalkoxy substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, 1 R2Ais C3-C6 cycloalkoxy substituted with hydroxyl. In some embodiments, 1 R2Ais C3-C6 cycloalkoxy.

[0538] In some embodiments, 1, 2, 3, or 4 of R2Aare independently 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with hydroxyl.

[0539] 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.Attorney Docket No. 49366-0056WO4

[0540] 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.

[0541] In some embodiments, R2is phenyl substituted with 1-2 independently selected R2A. In some embodiments, R2is pyridinyl substituted with 1-2 independently selected R2A.

[0542] 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 1,2-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 1,3 -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.

[0543] In some embodiments, X is a bond.

[0544] In some embodiments, X is CH2.

[0545] In some embodiments, X is CH(CH3).

[0546] In some embodiments, X is C(CH3)2.

[0547] In some embodiments,

[0548]

[0549] X is *

[0550] In some embodiments, W is O.

[0551] In some embodiments, R3Ais hydrogen.

[0552] In some embodiments, R3Ais C1-C6 alkyl. In some embodiments, R3Ais methyl or ethyl. In some embodiments, R3Ais methyl.Attorney Docket No. 49366-0056WO4

[0553] In some embodiments, R3Ais C1-C6 alkoxy. In some embodiments, R3Ais C1-C3 alkoxy. In some embodiments, R3Ais -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R3Ais -OCH3.

[0554] In some embodiments, R3Ais C1-C6 haloalkyl. In some embodiments, R3Ais C1-C3 haloalkyl. In some embodiments, R3Ais C1-C3 fluoroalkyl. In some embodiments, R3Ais CF3. In some embodiments, R3Ais CHF2.

[0555] In some embodiments, W is NR3B.

[0556] 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-C6 alkyl. In some embodiments, each of R3Aand R3Bis methyl.

[0557] 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-C6 alkyl and the other of R3Aand R3Bis C1-C6 alkoxy. In some embodiments, R3Ais C1-C6 alkoxy. In some embodiments, R3Ais C1-C3 alkoxy. In some embodiments, R3Ais -OCH3, -OCH2CH3, or -OCH2CH2CH3. In some embodiments, R3Ais -OCH3.

[0558] In some embodiments, one of R3Aand R3Bis hydrogen and the other of R3Aand R3Bis C1-C6 haloalkyl. In some embodiments, one of R3Aand R3Bis C1-C6 alkyl and the other of R3Aand R3Bis C1-C6 haloalkyl. In some embodiments, R3Ais C1-C6 haloalkyl. In some embodiments, R3Ais C1-C3 haloalkyl. In some embodiments, R3Ais C1-C3 fluoroalkyl. In some embodiments, R3Ais CF3. In some embodiments, R3Ais CHF2.

[0559] 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.

[0560] 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.

[0561] In some embodiments, Y is phenyl optionally substituted with R naphthyl substituted with RY, or 5-10 membered heteroaryl substituted with RY.Attorney Docket No. 49366-0056WO4

[0562] 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.

[0563] 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 RYIn some embodiments, Y is naphthyl optionally substituted with 3 independently selected R. In some embodiments, Y is naphthyl.

[0564] 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 RYIn 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.

[0565] 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).

[0566] 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 RYIn some embodiments, Y is 9 membered heteroaryl substituted with 2 independently selected RYIn some embodiments, Y is 9 membered heteroaryl optionally substituted with 3 independently selected RY. In some embodiments, Y is 9 membered heteroaryl.Attorney Docket No. 49366-0056WO4

[0567] 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.

[0568] In some embodiments, 1, 2, or 3 of RYis hydroxyl. In some embodiments, 1 or 2 of RYis hydroxyl.

[0569] In some embodiments, 1, 2, or 3 of RYis cyano. In some embodiments, 1 or 2 of RYis cyano.

[0570] In some embodiments, 1, 2, or 3 of RYis independently C1-C6 alkyl. In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl. In some embodiments, 1 or 2 of RYis independently C1-C3 alkyl.

[0571] In some embodiments, 1, 2, or 3 of RYis independently unsubstituted C1-C6 haloalkyl. In some embodiments, 1 or 2 of RYis independently unsubstituted C1-C3 haloalkyl. In some embodiments, 1 or 2 of RYis trifluorom ethyl.

[0572] In some embodiments, 1, 2, or 3 of RYis independently C1-C6 haloalkyl substituted with hydroxyl. In some embodiments, 1 or 2 of RYis independently C1-C3 haloalkyl substituted with hydroxyl.

[0573] In some embodiments, 1, 2, or 3 of RYis independently C1-C6 alkoxy. In some embodiments, 1 or 2 of RYis independently C1-C3 alkoxy. In some embodiments, 1 or 2 of RYis methoxy.

[0574] In some embodiments, 1, 2, or 3 of RYis independently C1-C6 haloalkoxy. In some embodiments, 1 or 2 of RYis independently C1-C3 haloalkoxy. In some embodiments, 1 or 2 of RYis trifluorom ethoxy.

[0575] In some embodiments, 1, 2, or 3 of RYis independently C1-C6 hydroxyalkyl. 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.

[0576] 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(=O)RF, where n is 1.

[0577] In some embodiments, 1, 2, or 3 of RYis independently -C(=O)RF. In some embodiments, 1 or 2 of RYis independently -C(=O)RF. In some embodiments, 1 of RYis -C(=O)RF. In some embodiments, Y is substituted with 1 RY, and RYis -C(=O)RF.Attorney Docket No. 49366-0056WO4

[0578] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-NHC(=O)RF, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-NHC(=O)RF, where n is 1.

[0579] 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.

[0580] In some embodiments, 1, 2, or 3 of RYis independently -CO2RGIn some embodiments, 1 or 2 of RYis independently –CO2RGIn some embodiments, 1 of RYis –CO2RG. In some embodiments, Y is substituted with 1 RY, and RYis –CO2RGIn some embodiments, Y is substituted with 1 R and RYis –CO2H.

[0581] In some embodiments, 1, 2, or 3 of RYis independently -P(=O)RARB. In some embodiments, 1 or 2 of RYis independently -P(=O)RARB. In some embodiments, 1 of RYis -P(=O)RARB. In some embodiments, Y is substituted with 1 RY, and R is -P(=O)RARB. In some embodiments, Y is substituted with 1 RY, and RYis -P(=O)RARB.

[0582] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-SO2NRHRI, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-SO2NRHRI, where n is 1.

[0583] In some embodiments, 1, 2, or 3 of RYis independently -SO2NRHRI. In some embodiments, 1 or 2 of R' is independently -SO2NRHRI. In some embodiments, 1 of RYis -SO2NRHRI. In some embodiments, Y is substituted with 1 RY, and RYis -SO2NRHRI.

[0584] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-NHSO2RJ, where n is 1 or 2. In some embodiments, 1 of R is independently -(CH2)n-NHSO2RJ, where n is 1.

[0585] In some embodiments, 1, 2, or 3 of RYis independently -NHSChR1. In some embodiments, 1 or 2 of RYis independently -NHSChR1. In some embodiments, 1 of RYis -NHSChR. In some embodiments, Y is substituted with 1 R and RYis -NHSO2RJ.

[0586] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-S(=O)(=NRH)RT, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-S(=O)(=NRH)RJ, where n is 1.

[0587] 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 R1is -S(=O)(=NRH)RJ. In some embodiments, Y is substituted with 1 RY, and RYis - S(=O)(=NRH)RJ.Attorney Docket No. 49366-0056WO4

[0588] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-SO2RJ, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-SO2RJ, where n is 1.

[0589] 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 –SO2RJ. In some embodiments, 1, 2, or 3 of RYis independently -SO2(C1-C6 alkyl). 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.

[0590] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-S(=O)(=NRH)NRHRI, where n is 1 or 2. In some embodiments, 1 of R is independently -(CH2)n-S(=O)(=NRH)RJ, where n is 1.

[0591] In some embodiments, 1, 2, or 3 of RYis independently -S(=O)(=NRH)NRHRI. In some embodiments, 1 or 2 of RYis independently -S(=O)(=NRH)NRHRI. In some embodiments, 1 of RYis -S(=O)(=NRH)NRHRI. In some embodiments, Y is substituted with 1 RY, and RYis -S(=O)(=NRH)NRHRI. In some embodiments, Y is substituted with 1 RY, and RYis -

[0592]

[0593] S(=O)(=NRH)NRHRI. In some embodiments, Y is substituted with 1 RY, and RYis –S(=O)(=NH)NH2.

[0594] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-C(=N-OH)RJ, where n is 1 or 2. In some embodiments, 1 of RYis independently -(CH2)n-C(=N-OH)RJ, where n is 1.

[0595] In some embodiments, 1, 2, or 3 of RYis independently -C(=N-OH)RJ. In some embodiments, 1 or 2 of RYis independently -C(=N-OH)RJ. In some embodiments, 1 of RYis –C(=N-OH)RJ. In some embodiments, Y is substituted with 1 RY, and RYis -C(=N-OH)RJ. In some embodiments, Y is substituted with 1 RY, and RYis -C(=N-OH)CH3.

[0596] 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.

[0597] In some embodiments, 1, 2, or 3 of R is 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.

[0598] 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.

[0599] In some embodiments, 1, 2, or 3 of RYis independently -(CH2)n-C(=O)NRHORI. In some embodiments, 1 or 2 of RYis independently -(CH2)n-C(=O)NRHORI. In some embodiments, 1 ofAttorney Docket No. 49366-0056WO4

[0600] RYis -(CH2)n-C(=O)NRHORI. In some embodiments, Y is substituted with 1 RY, and RYis -(CH2)n-C(=O)NRHORI.

[0601] 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.

[0602] In some embodiments, 1 or 2 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.

[0603] In some embodiments, 1 RYis halogen, -CO2H, -SO2NH2, -SO2CH3, -C(=O)NH2, -C(=O)NHRH, -(CH2)n-C(=O)NHORI, or –(CH2)n–S(=O)(=NH)RJ.

[0604] In some embodiments, 1, 2, or 3 of RYis independently C3-C6 cycloalkyl. In some embodiments, 1 or 2 of RYis independently C3-C6 cycloalkyl. In some embodiments, 1 of RYis C3-C6 cycloalkyl. In some embodiments, 1 of RYis cyclopropyl.

[0605] 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

[0606] - L1- (- A - (RY1)z

[0607] with ', wherein * represents the connection of L1to the remainder of the compound of Formula (I).

[0608] In some embodiments, Y is phenyl and the phenyl is substituted with

[0609] * - L1- H A H - (RY1)Z

[0610]

[0611] - ', wherein * represents the connection of L1to the remainder of the compound of Formula (I).

[0612] In some embodiments, Y is naphthyl and the naphthyl is substituted with

[0613] * - L1- (- A -) - (RY1)Z

[0614] , wherein * represents the connection of L1to the remainder of the compound of Formula (I).Attorney Docket No. 49366-0056WO4

[0615] In some embodiments, Y is 5-10 membered heteroaryl and the 5-10 membered heteroaryl

[0616] * - L1- b- A -4 - (RY1)Z

[0617] is substituted with

[0618]

[0619] x- ', wherein * represents the connection of L1to the remainder of the compound of Formula (I).

[0620] In some embodiments, Ring A is phenyl.

[0621] 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.

[0622] 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.

[0623] 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.

[0624] In some embodiments, L1is a bond.

[0625] In some embodiments, L1is C1-C6 alkoxylene.

[0626] In some embodiments, L1is -(CH2)n-NHC(=O)-.

[0627] In some embodiments, L1is -C(=O)NH-(CH2)n-.

[0628] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0629] In some embodiments, L1is -CO2-.

[0630] In some embodiments, L1is -SO2-.

[0631] In some embodiments, L1is -NHSO2-.

[0632] In some embodiments, L1is -SO2NH-.

[0633] In some embodiments, L1is -S(=O)(=NRG)-.

[0634] In some embodiments, L1is –SO2(C1-C6 alkylene)-.

[0635] In some embodiments, L1is -C(=O)C(=O)NH-.

[0636] In some embodiments, L1is C1-C6 alkylene optionally substituted with oxo. In some embodiments, L1is unsubstituted C1-C6 alkylene. In some embodiments, L1is C1-C6 alkylene substituted with oxo.

[0637] In some embodiments, z is 0. In some embodiments, z is 1. In some embodiments, z is 2. In some embodiments, z is 3.Attorney Docket No. 49366-0056WO4

[0638] 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.

[0639] In some embodiments, 1, 2, or 3 of RY1is hydroxyl. In some embodiments, 1 or 2 of RY1is hydroxyl.

[0640] In some embodiments, 1, 2, or 3 of RY1is cyano. In some embodiments, 1 or 2 of RY1is cyano.

[0641] In some embodiments, 1, 2, or 3 of RY1is independently C1-C6 alkyl. In some embodiments, 1 or 2 of RY1is independently C1-C6 alkyl. In some embodiments, 1 or 2 of RY1is independently C1-C3 alkyl.

[0642] In some embodiments, 1, 2, or 3 of RY1is independently C1-C6 alkyl substituted with RY2. In some embodiments, 1 or 2 of RY1is independently C1-C6 alkyl substituted with RY2. In some embodiments, 1 or 2 of RY1is independently C1-C3 alkyl substituted with RY2.

[0643] In some embodiments, 1, 2, or 3 of RY1is independently unsubstituted C1-C6 haloalkyl. In some embodiments, 1 or 2 of RY1is independently unsubstituted C1-C3 haloalkyl. In some embodiments, 1 or 2 of RY1is trifluoromethyl.

[0644] In some embodiments, 1, 2, or 3 of RY1is independently C1-C6 alkoxy 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.

[0645] In some embodiments, RY2is hydroxyl.

[0646] In some embodiments, RY2is -NRHRI.

[0647] In some embodiments, RY2is -C(=O)NRHRI.

[0648] In some embodiments, R2is -SO2NRHRI.

[0649] In some embodiments, 1, 2, or 3 of RY1is independently C1-C6 alkoxy. In some embodiments, 1 or 2 of RY1is independently C1-C3 alkoxy. In some embodiments, 1 or 2 of RY1is methoxy.

[0650] In some embodiments, 1, 2, or 3 of RY1is independently -C(=O)RF. In some embodiments, 1 or 2 of RY1is independently -C(=O)RF. In some embodiments, 1 of RY1is -C(=O)RF. In some embodiments, Ring A is substituted with 1 R and RY1is -C(=O)RF.Attorney Docket No. 49366-0056WO4

[0651] 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.

[0652] In some embodiments, 1, 2, or 3 of RY1is independently –CO2RG. In some embodiments, 1 or 2 of RY1is independently –CO2RGIn some embodiments, 1 of RY1is –CO2RGIn some embodiments, Y is substituted with 1 RY1, and RY1is –CO2RG. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -CO2H.

[0653] In some embodiments, 1, 2, or 3 of RY1is independently -SO2NRHRI. In some embodiments, 1 or 2 of RY1is independently -SO2NRHRI. In some embodiments, 1 of RY1is -SO2NRHRI. In some embodiments, Ring A is substituted with 1 R and RY1is -SO2NRHRI.

[0654] In some embodiments, 1, 2, or 3 of RY1is independently -NHSO2RJ. In some embodiments, 1 or 2 of RY1is independently -NHSO2RJ. In some embodiments, 1 of RY1is -NHSO2RJ. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -NHSO2R'.

[0655] 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 RY1is –S(=O)(=NRH)RJ. In some embodiments, Ring A is substituted with 1 RY1, and RY1is -S(=O)(=NRH)RJ.

[0656] In some embodiments, 1, 2, or 3 of RY1is independently –SO2(C1-C6 alkyl). 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.

[0657] 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.

[0658] 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.

[0659] 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.Attorney Docket No. 49366-0056WO4

[0660] In some embodiments, 1, 2, or 3 of RY1is independently 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl. In some embodiments, 1, 2, or 3 of RY1is independently 4-6 membered heterocyclyl substituted with hydroxyl or C1-C6 alkyl. In some embodiments, 1, 2, or 3 of RY1is independently 4-6 membered heterocyclyl.

[0661] 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.

[0662] 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.

[0663] In some embodiments, 1 RY1is hydroxyl, cyano, -SO2NH2, -C(=O)RF, -C(=O)NH2, Cl-C3 alkoxy optionally substituted with hydroxyl, and C1-C3 alkyl optionally substituted with hydroxyl.

[0664] In some embodiments, 1, 2, or 3 of RYis independently heteroaralkyl. In some embodiments, 1 of RYis independently heteroaralkyl.

[0665] 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 R is 4-6 membered heterocyclyl substituted with

[0666] R where RY1is hydroxyl. In some embodiments,

[0667]

[0668] RYis. In some embodiments,

[0669]

[0670] In some embodiments, Y is selected from the group consisting of:

[0671]

[0672]

[0673] Attorney Docket No. 49366-0056WO4

[0674]

[0675] Attorney Docket No. 49366-0056WO4

[0676]

[0677] Attorney Docket No. 49366-0056WO4

[0678] In some embodiments, Y is selected from the group consisting of:

[0679]

[0680]

[0681] In some embodiments, Y is selected from the group consisting of:

[0682]

[0683]

[0684] In some embodiments, 1, 2, or 3 of RYis independently C1-C6 alkyl optionally substituted with -CO2RAor 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RYis independently C1-C6 alkyl substituted with -CO2RAor 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1, 2, or 3 of RYis independently C1-C6 alkyl substituted with –CO2RAor 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1, 2, or 3 of RYis independently C1-C6 alkyl substituted with -C02RAor 5-6 membered heteroaryl. In some embodiments, Y is substituted with 1 RY, and R1Attorney Docket No. 49366-0056WO4

[0685] is C1-C6 alkyl substituted with –CO2RA. In some embodiments, Y is substituted with 1 RY, and RYis C1-C6 alkyl substituted with –CO2H.

[0686] In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl optionally substituted with –CO2RAor 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl substituted with –CO2RAor 5-6 membered heteroaryl optionally substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl substituted with –CO2RAor 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl substituted with –CO2RAor 5-6 membered heteroaryl.

[0687] In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl substituted with - CO2RA. In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl substituted 5-6 membered heteroaryl optionally substituted with R. In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl substituted with 5-6 membered heteroaryl substituted with RY1. In some embodiments, 1 or 2 of RYis independently C1-C6 alkyl substituted with 5-6 membered heteroaryl.

[0688] In some embodiments, 1, 2, or 3 of RYis independently C1-C6 alkyl. 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-C6 alkyl). In some embodiments, RY1is –SO2CH3.

[0689] In some embodiments, RY1is C1-C6 alkyl optionally substituted with oxo. In some embodiments, RY1is C1-C6 alkyl substituted with oxo. In some embodiments, RY1is acetyl, 1-oxoethyl, or 1-oxopropyl. In some embodiments, RY1is C1-C6 alkyl. In some embodiments, RY1is methyl. In some embodiments, R4is hydrogen.

[0690] In some embodiments, R4is halogen. In some embodiments, R4is fluoro or chloro. In some embodiments, R4is fluoro. In some embodiments, R4is chloro.

[0691] In some embodiments, R4is C1-C6 alkyl. In some embodiments, R4is methyl or ethyl. In some embodiments, R4is methyl.

[0692] In some embodiments, R4is acrylamido.

[0693] In some embodiments, R5is hydrogen.

[0694] In some embodiments, R5is C1-C6 alkyl. In some embodiments, R5is methyl or ethyl. In some embodiments, R5is methyl.Attorney Docket No. 49366-0056WO4

[0695] In some embodiments, R5is C1-C6 haloalkyl. In some embodiments, R5is C1-C3 haloalkyl. In some embodiments, R5is CF3 or CHF2.

[0696] In some embodiments, R5is halogen. In some embodiments, R5is fluoro or chloro. In some embodiments, R5is fluoro. In some embodiments, R5is chloro.

[0697] In some embodiments, R5is cyano.

[0698] In some embodiments, R5is -NR5AR5B.

[0699] In some embodiments, R5is -NR5AC(=O)R5B.

[0700] In some embodiments, R5is -C(=O)NR5AR5B.

[0701] In some embodiments, one of R5Aand R5Bis hydrogen and the other of R5Aand R5Bis C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, one of R5Aand R5Bis C1-C6 alkyl and the other of R5Aand R5Bis C1-C6 alkyl, C2-C6 alkenyl, or C1-C6 hydroxyalkyl. In some embodiments, each of R5Aand R5Bis hydrogen. In some embodiments, each of R5Aand R5Bis an independently selected C1-C6 alkyl. In some embodiments, each of R5Aand R5Bis methyl. In some embodiments, the C1-C6 hydroxyalkyl of R5Aand R5Bis hydroxymethyl, 1 -hydroxy ethyl, 2-hydroxyethyl, dihydroxypropyl or dihydroxybutyl.

[0702] In some embodiments, R5is acrylamido.

[0703] In some embodiments, R6is hydrogen.

[0704] In some embodiments, R6is halogen. In some embodiments, R6is fluoro. In some embodiments, R6is chloro.

[0705] In some embodiments, each R7is independently selected from C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl are each optionally and independently substituted with 1-3 independently selected R7A. In some embodiments, R7is independently selected from C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl are each optionally and independently substituted with 1-3 independently selected R7A.

[0706] In some embodiments, R7is C3-C6 cycloalkyl optionally substituted with 1-3 independently selected R7A. In some embodiments, R7is C3-C6 cycloalkyl substituted with 1-3 independently selected R7A. In some embodiments, R7is C3-C6 cycloalkyl substituted with 1 R7A.Attorney Docket No. 49366-0056WO4

[0707] In some embodiments, R7is 4-6 membered heterocyclyl optionally substituted with 1-3 independently selected R7A. In some embodiments, R7is 4-6 membered heterocyclyl substituted with 1-3 independently selected R7A. In some embodiments, R7is 4-6 membered heterocyclyl substituted with 1 R7A.

[0708] In some embodiments, R7is 5-6 membered heteroaryl optionally substituted with 1-3 independently selected R7A. In some embodiments, R7is 5-6 membered heteroaryl substituted with 1-3 independently selected R7A. In some embodiments, R7is 45-6 membered heteroaryl substituted with 1 R7A. In some embodiments, each R7Ais independently selected from hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R7Ais hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, or C1-C6 alkyl optionally substituted with hydroxyl.

[0709] In some embodiments, R7Ais hydroxyl.

[0710] In some embodiments, R7Ais cyano.

[0711] In some embodiments, R7Ais halogen.

[0712] In some embodiments, R7Ais C1-C6 alkoxy.

[0713] In some embodiments, R7Ais C1-C6 haloalkyl.

[0714] In some embodiments, R7Ais C1-C6 haloalkoxy.

[0715] In some embodiments, R7Ais C1-C6 alkyl optionally substituted with hydroxyl. In some embodiments, R7Ais C1-C6 alkyl substituted with hydroxyl. In some embodiments, R7Ais C1-C6 alkyl.

[0716] In some embodiments, R6is C1-C6 alkyl. In some embodiments, R6is methyl.

[0717] In some embodiments, R8is C1-C6 alkyl. In some embodiments, R8is C1-C3 alkyl. In some embodiments, R8is methyl.

[0718] In some embodiments, R8is C1-C6 haloalkyl. In some embodiments, R8is C1-C3 haloalkyl. In some embodiments, R8is -CF3 or -CHF2.

[0719] In some embodiments, each of RAand RBare independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C2-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.Attorney Docket No. 49366-0056WO4

[0720] In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C2-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy.

[0721] In some embodiments, one or both of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C1-C6 haloalkyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C1-C6 haloalkyl.. In some embodiments, one of RAand RBis C1-C6 alkyl and the other of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C1-C6 haloalkyl.

[0722] In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis hydroxyl. In some embodiments, one of R and RBis hydrogen and the other of RAand RBis C1-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-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with hydroxyl. In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl substituted with C1-C6 alkoxy.

[0723] In some embodiments, one of RAand RBis hydrogen and the other of RAand RBis C1-C6 alkyl. In some embodiments, each of RAand RBare hydrogen. In some embodiments, each of RAand RBare an independently selected C1-C6 alkyl optionally substituted with hydroxyl or C1-C6 alkoxy. In some embodiments, each of RAand RBare an independently selected C1-C6 alkyl. In some embodiments, each of RAand RBare methyl.

[0724] 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-C6 alkyl, hydroxyl, and -C(=O)C1-C6 alkyl.

[0725] 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-C6 alkyl, hydroxyl, and -C(=O)C1-C6 alkyl.

[0726] In some embodiments, RAand RBtogether with the nitrogen atom to which they are attached form a 4-10 membered heterocyclyl substituted with halogen, C1-C6 alkyl, hydroxyl, orAttorney Docket No. 49366-0056WO4

[0727] -C(=O)C1-C6 alkyl. 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.

[0728] 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.

[0729] In some embodiments, each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6 alkyl substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARBor with 4-10 membered heterocyclyl substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl substituted with -NRARBor with 4-10 membered heterocyclyl. In some embodiments, each Rcis independently C3-C6 cycloalkyl, -C(=O)NHRY1, or a C1-C6 alkyl.

[0730] 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-C6 alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl. In some embodiments, each Rcis independently C1-C6 alkyl substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl.

[0731] In some embodiments, each RDis independently selected from hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and C1-C6 alkyl optionally substituted with oxo or -NRARB.

[0732] In some embodiments, each RDis independently selected from hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen, and C1-C6 alkyl optionally substituted with oxo or -NRARB.

[0733] In some embodiments, RDis hydrogen.

[0734] In some embodiments, RDis hydroxyl.

[0735] In some embodiments, RDis phenyl.

[0736] In some embodiments, RDis C1-C6 alkoxy.Attorney Docket No. 49366-0056WO4

[0737] In some embodiments, RDis C1-C6 alkyl optionally substituted with oxo or -NRARBIn some embodiments, RDis unsubstituted C1-C6 alkyl. In some embodiments, RDis C1-C6 alkyl substituted with oxo or -NRARB. In some embodiments, RDis C1-C6 alkyl substituted with -NRARB.

[0738] In some embodiments, RDis C3-C6 cycloalkyl. In some embodiments, RDis cyclopropyl. In some embodiments, RDis 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen. In some embodiments, RDis 5-6 membered heteroaryl substituted with C1-C6 alkyl or halogen. In some embodiments, RDis 5-6 membered heteroaryl.

[0739] In some embodiments, each REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, and C1-C6 alkyl optionally substituted with oxo or -NRARB.

[0740] In some embodiments, REis hydrogen.

[0741] In some embodiments, REis hydroxyl.

[0742] In some embodiments, REis phenyl.

[0743] In some embodiments, REis C1-C6 alkoxy.

[0744] In some embodiments, REis C1-C6 alkyl optionally substituted with oxo or -NRARB. In some embodiments, REis unsubstituted C1-C6 alkyl. In some embodiments, REis C1-C6 alkyl substituted with oxo or -NRARB. In some embodiments, REis C1-C6 alkyl substituted with -NRARB.

[0745] In some embodiments, one of RDand REis hydrogen and the other of RDand REis hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy. In some embodiments, one of RDand REis hydrogen and the other of RDand REis hydroxyl. In some embodiments, one of RDand REis hydrogen and the other of RDand REis C1-C6 alkyl. In some embodiments, one of RDand REis hydrogen and the other of RDand REis C1-C6 alkoxy. 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-C6 alkyl. In some embodiments, each of RDand REis methyl.

[0746] In some embodiments, each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or –SO2(C1-C6 alkyl).

[0747] In some embodiments, RFis C3-C6 cycloalkyl.

[0748] In some embodiments, RFis 5-6 membered heteroaryl.Attorney Docket No. 49366-0056WO4

[0749] In some embodiments, RFis 4-6 membered heterocyclyl.

[0750] In some embodiments, RFis C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl). In some embodiments, RFis unsubstituted C1-C6 alkyl. In some embodiments, RFis C1-C6 alkyl substituted with hydroxyl or -SO2(C1-C6 alkyl). In some embodiments, RFis C1-C6 alkyl substituted with hydroxyl. In some embodiments, RFis C1-C6 alkyl substituted with -SO2(C1-C6 alkyl).

[0751] In some embodiments, each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -–SO2(C1-C6 alkyl).

[0752] In some embodiments, RGis hydrogen.

[0753] In some embodiments, RGis C3-C6 cycloalkyl.

[0754] In some embodiments, RGis 5-6 membered heteroaryl.

[0755] In some embodiments, RGis 4-6 membered heterocyclyl.

[0756] In some embodiments, RGis C1-C6 alkyl optionally substituted with hydroxyl or -–SO2(C1-C6 alkyl). In some embodiments, RGis unsubstituted C1-C6 alkyl. In some embodiments, RGis C1-C6 alkyl substituted with hydroxyl or -–SO2(C1-C6 alkyl). In some embodiments, RGis C1-C6 alkyl substituted with hydroxyl. In some embodiments, RGis C1-C6 alkyl substituted with -SO2(C1-C6 alkyl).

[0757] In some embodiments, each RHand R1is independently selected from: hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, -(CH2)n-SO2(Cl-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy.

[0758] In some embodiments, RHis hydrogen.

[0759] In some embodiments, RHis C1-C6 alkoxy.

[0760] In some embodiments, RHis C3-C6 cycloalkyl.

[0761] In some embodiments, RHis C2-C6 alkenyl.

[0762] In some embodiments, RHis -(CH2)n-C(=O)NH2.

[0763] In some embodiments, RHis -(CH2)n-SO2NH2.

[0764] In some embodiments, R

[0765]

[0766] His -(CH2)n-SO2(Cl-C6 alkyl).

[0767] In some embodiments, RHis C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy. In some embodiments, RHis unsubstitutedAttorney Docket No. 49366-0056WO4

[0768] C1-C6 alkyl. Tn some embodiments, RHis C1-C6 alkyl substituted with hydroxyl, -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy. In some embodiments, RHis C1-C6 alkyl substituted with hydroxyl. In some embodiments, RHis C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, RHis C1-C6 alkyl substituted with hydroxyl. In some embodiments, RHis C1-C6 alkyl substituted with -P(=O)RARB. In some embodiments, RHis C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, RHis C1-C6 alkyl substituted with C1-C6 alkoxy.

[0769] In some embodiments, R1is hydrogen.

[0770] In some embodiments, R1is C1-C6 alkoxy.

[0771] In some embodiments, R1is C3-C6 cycloalkyl.

[0772] In some embodiments, R1is C2-C6 alkenyl.

[0773] In some embodiments, R1is -(CH2)n-C(=O)NH2.

[0774] In some embodiments, R1is -(CH2)n-SO2NH2.

[0775] In some embodiments, R1is -(CH2)n-SC>2(Cl-C6 alkyl).

[0776] In some embodiments, R1is C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, -–SO2(C1-C6 alkyl), or C1-C6 alkoxy. In some embodiments, R1is unsubstituted C1-C6 alkyl. In some embodiments, R1is C1-C6 alkyl substituted with hydroxyl, -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy. In some embodiments, R1is C1-C6 alkyl substituted with hydroxyl. In some embodiments, R1is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R1is C1-C6 alkyl substituted with hydroxyl. In some embodiments, R1is C1-C6 alkyl substituted with -P(=O)RARB. In some embodiments, R1is C1-C6 alkyl substituted with -SO2(C1-C6 alkyl). In some embodiments, R1is C1-C6 alkyl substituted with C1-C6 alkoxy.

[0777] In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is phenyl or C1-C6 alkyl optionally substituted with oxo or -NRARB. In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is phenyl or C1-C6 alkyl substituted with oxo or -NRARD. In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is phenyl or C1-C6 alkyl. In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is phenyl. In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is C1-C6 alkyl optionally substituted with oxo or -NRARB. In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is C1-C6 alkyl substituted with oxo or -NRARB. In some embodiments, each of RHand R1is hydrogen. In some embodiments, each of RHand R1is an independently selected C1-C6 alkyl. In some embodiments, each of RHand R1is methyl.Attorney Docket No. 49366-0056WO4

[0778] In some embodiments, each of RHand R1is hydrogen.

[0779] In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is C1-C6 alkoxy, C3-C6 cycloalkyl, or C2-C6 alkenyl.

[0780] In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy.

[0781] In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, -(CH2)n-P(=O)RARB, or -(CH2)n-SO2(C1-C6 alkyl). In some embodiments, one of RHand R1is hydrogen and the other of RHand R1is -(CH2)n-P(=O)RARB.

[0782] 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-C6 alkyl, and -C(=O)C1-C6 alkyl. 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-C6 alkyl, 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 1 substituent independently selected from halogen, C1-C6 alkyl, 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 independently selected from halogen, C1-C6 alkyl, and -C(=O)C1-C6 alkyl.

[0783] In some embodiments, RJis C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 alkoxy.

[0784] In some embodiments, RJis C1-C6 alkyl. In some embodiments, RJis C1-C3 alkyl.

[0785] In some embodiments, RJis C3-C6 cycloalkyl.

[0786] In some embodiments, RJis C1-C6 alkoxy.

[0787] In some embodiments, RJis C1-C6 haloalkyl.

[0788] In some embodiments, R2is 11-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A.

[0789] In some embodiments, at least one R2Ais

[0790] (a) -C(=O)-(C1-C6 alkyl);Attorney Docket No. 49366-0056WO4

[0791] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, -OR7, -SO2RD, -NRAC(=O)-(C1-C6 alkyl) or -P(=O)RARI

[0792] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogl

[0793] (e) -C(=O)-(4-6 membered heterocyclyl); or

[0794] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, at least one R2Ais

[0795] (a) -C(=O)-(C1-C6 alkyl);

[0796] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[0797] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[0798] (e) -C(=O)-(4-6 membered heterocyclyl); or

[0799] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, at least one of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C1-C6 haloalkyl.

[0800] In some embodiments, at least one RYis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, or -(CH2)n-C(=N-OH)RJ. In some embodiments, one RYis -P(=O)RARB. In some embodiments, one RYis -S(=O)(=NRH)NRHRI. In some embodiments, one RYis -(CH2)n-C(=N-OH)RJ.

[0801] In some embodiments, at least one of RHand R1is C1-C6 alkyl substituted with -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy.

[0802] In some embodiments, RJis C1-C6 haloalkyl.

[0803] In some embodiments, one R2Ais

[0804] (a) -C(=O)-(C1-C6 alkyl);

[0805] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;Attorney Docket No. 49366-0056WO4

[0806] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen

[0807] (e) -C(=O)-(4-6 membered heterocyclyl); or

[0808] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, one of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C1-C6 haloalkyl.

[0809] In some embodiments, one RYis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, or -(CH2)n-C(=N-OH)RJ.

[0810] In some embodiments, one of RHand R1is C1-C6 alkyl substituted with -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy.

[0811] In some embodiments, R2is 11-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A.

[0812] In some embodiments, at least one R2Ais

[0813] (a) -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl);

[0814] (b) 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen, C1-C6 haloalkyl optionally substituted with hydroxyl or cyano, -OR7, -SR8; -SO2RD, -NRAC(=O)Rc, -P(=O)RARB, C1-C6 alkyl substituted with cyano, and 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl;

[0815] (c) 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl and C1-C6 haloalkoxy;

[0816] (d) C1-C6 alkoxy substituted with hydroxyl or 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[0817] (e) -C(=O)-(CH2) m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3- C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF); or (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; orAttorney Docket No. 49366-0056WO4

[0818] at least one of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or Cl-C6 haloalkyl.

[0819] In some embodiments, at least one of RDand REis C3-C6 cycloalkyl or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen.

[0820] In some embodiments, at least one RFis cyano, hydroxyl, halogen, C3-C6 cycloalkyl, or C1-C6 alkyl.

[0821] In some embodiments, R5is C1-C6 haloalkyl.

[0822] In some embodiments, R8is C1-C6 alkyl or C1-C6 haloalkyl.

[0823] In some embodiments, at least one RYis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, -(CH2)n-C(=N-OH)RJ, or C3-C6 cycloalkyl.

[0824] In some embodiments, at least one of RHand R1is C1-C6 alkyl substituted with -P(=O)RARB.

[0825] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (LAI):

[0826] R6

[0827] R^ X ^N R1

[0828] R4I'XyIXZIX^R2

[0829] NR^R3A

[0830]

[0831] Y (LAI)

[0832] or a pharmaceutically acceptable salt thereof.

[0833] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (LB1):

[0834] R6

[0835] RUVNx / -R1

[0836] T T I

[0837] R4^Y^Z^R2

[0838] OZ / XR3A

[0839]

[0840] Y (LB1)

[0841] or a pharmaceutically acceptable salt thereof.

[0842] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A2):Attorney Docket No. 49366-0056WO4

[0843] Z R2

[0844] HN^ R

[0845] I

[0846]

[0847] Y (I-A2)

[0848] or a pharmaceutically acceptable salt thereof.

[0849] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- A3):

[0850] R6

[0851] i5 N R1

[0852]

[0853] (I-A3)

[0854] or a pharmaceutically acceptable salt thereof.

[0855] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B2):

[0856] N

[0857] O

[0858] I

[0859]

[0860] Y (I-B2)

[0861] or a pharmaceutically acceptable salt thereof.

[0862] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A5):

[0863] R6

[0864] R,5^ J-^N_R1

[0865]

[0866] or a pharmaceutically acceptable salt thereof.Attorney Docket No. 49366-0056WO4

[0867] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B3):

[0868]

[0869] Y (I-B3)

[0870] or a pharmaceutically acceptable salt thereof.

[0871] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A5):

[0872] R6

[0873]

[0874] Y (I-A5)

[0875] or a pharmaceutically acceptable salt thereof.

[0876] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B4):

[0877]

[0878] (I-B4)

[0879] or a pharmaceutically acceptable salt thereof.

[0880] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A6):Attorney Docket No. 49366-0056WO4

[0881]

[0882] or a pharmaceutically acceptable salt thereof.

[0883] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A6a):

[0884]

[0885] or a pharmaceutically acceptable salt thereof.

[0886] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B5):

[0887]

[0888] or a pharmaceutically acceptable salt thereof.

[0889] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B5a):Attorney Docket No. 49366-0056WO4

[0890] (RY)l-3

[0891]

[0892] (I-B5a)

[0893] or a pharmaceutically acceptable salt thereof.

[0894] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A7):

[0895]

[0896] or a pharmaceutically acceptable salt thereof.

[0897] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A7a):

[0898]

[0899] (I-A7a)

[0900] or a pharmaceutically acceptable salt thereof.

[0901] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A8):

[0902]

[0903] Attorney Docket No. 49366-0056WO4

[0904] or a pharmaceutically acceptable salt thereof.

[0905] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B6):

[0906]

[0907] or a pharmaceutically acceptable salt thereof.

[0908] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A9):

[0909]

[0910] or a pharmaceutically acceptable salt thereof.

[0911] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B7):

[0912]

[0913] or a pharmaceutically acceptable salt thereof.

[0914] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A10):Attorney Docket No. 49366-0056WO4

[0915]

[0916] or a pharmaceutically acceptable salt thereof.

[0917] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A11):

[0918]

[0919] or a pharmaceutically acceptable salt thereof.

[0920] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B8):

[0921]

[0922] (I-B8)

[0923] or a pharmaceutically acceptable salt thereof.

[0924] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A12):

[0925] RBRAN

[0926]

[0927] (I-A12)

[0928] or a pharmaceutically acceptable salt thereof.Attorney Docket No. 49366-0056WO4

[0929] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A13):

[0930] CN

[0931] R2

[0932] RBRAN

[0933]

[0934] (I-A13)

[0935] or a pharmaceutically acceptable salt thereof.

[0936] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A14):

[0937]

[0938] (I-A14)

[0939] or a pharmaceutically acceptable salt thereof.

[0940] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A15):

[0941]

[0942] (I-A15)

[0943] or a pharmaceutically acceptable salt thereof.

[0944] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A16):Attorney Docket No. 49366-0056WO4

[0945] CN

[0946]

[0947] (I-A16)

[0948] or a pharmaceutically acceptable salt thereof.

[0949] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A16a):

[0950] HN S

[0951] N

[0952]

[0953] (I-A16a)

[0954] or a pharmaceutically acceptable salt thereof.

[0955] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A17):

[0956] CI\Z^ / Nx / CN

[0957] T T T

[0958] V'^^R2

[0959] 5s'

[0960]

[0961] (I-A17)

[0962] or a pharmaceutically acceptable salt thereof.

[0963] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A17a):Attorney Docket No. 49366-0056WO4

[0964]

[0965] or a pharmaceutically acceptable salt thereof.

[0966] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A18):

[0967]

[0968] or a pharmaceutically acceptable salt thereof.

[0969] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A19):

[0970]

[0971] or a pharmaceutically acceptable salt thereof.

[0972] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A20):

[0973]

[0974] Attorney Docket No. 49366-0056WO4

[0975] or a pharmaceutically acceptable salt thereof, wherein Ring B is C6 aryl or C5-C6 heteroaryl optionally substituted with 1-2 independently selected RY.

[0976] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A21):

[0977] HN

[0978] B

[0979]

[0980] (I-A21)

[0981] or a pharmaceutically acceptable salt thereof, wherein Ring B is C6 aryl or C5-C6 heteroaryl optionally substituted with 1-2 independently selected RY.

[0982] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A22):

[0983] CN T I T

[0984] V'^^R2

[0985]

[0986] (I-A22)

[0987] or a pharmaceutically acceptable salt thereof.

[0988] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A22a):

[0989] S

[0990] N

[0991]

[0992] (I-A22a)

[0993] or a pharmaceutically acceptable salt thereof.

[0994] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A23):Attorney Docket No. 49366-0056WO4

[0995]

[0996] or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[0997] (a) -C(=O)-(C1-C6 alkyl);

[0998] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[0999] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1000] (e) -C(=O)-(4-6 membered heterocyclyl); or

[1001] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl. In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A24):

[1002]

[1003] or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1004] (a) -C(=O)-(C1-C6 alkyl);

[1005] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[1006] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1007] (e) -C(=O)-(4-6 membered heterocyclyl); orAttorney Docket No. 49366-0056WO4

[1008] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRAR, -C(=N)OR, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1009] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A25):

[1010] N HN

[1011] :s

[1012]

[1013] (I-A25) or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1014] (a) -C(=O)-(C1-C6 alkyl);

[1015] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[1016] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1017] (e) -C(=O)-(4-6 membered heterocyclyl); or

[1018] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1019] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A26):

[1020] HN S

[1021] N

[1022]

[1023] (I-A26) or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1024] (a) -C(=O)-(C1-C6 alkyl);

[1025] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;Attorney Docket No. 49366-0056WO4

[1026] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1027] (e) -C(=O)-(4-6 membered heterocyclyl); or

[1028] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4- 10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1029] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A27):

[1030]

[1031] (I-A27) or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1032] (a) -C(=O)-(C1-C6 alkyl);

[1033] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[1034] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1035] (e) -C(=O)-(4-6 membered heterocyclyl); or

[1036] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1037] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B9):

[1038]

[1039] Attorney Docket No. 49366-0056WO4

[1040] or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1041] (a) -C(=O)-(C1-C6 alkyl);

[1042] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[1043] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1044] (e) -C(=O)-(4-6 membered heterocyclyl); or

[1045] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1046] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A22):

[1047] 0?

[1048] RBL ’

[1049]

[1050] (I-A28)

[1051] or a pharmaceutically acceptable salt thereof.

[1052] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A22a):

[1053]

[1054] (I-A29)

[1055] or a pharmaceutically acceptable salt thereof.

[1056] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A30):Attorney Docket No. 49366-0056WO4

[1057]

[1058] (I-A30) or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1059] (a) -C(=O)-(C1-C6 alkyl);

[1060] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[1061] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1062] (e) -C(=O)-(4-6 membered heterocyclyl); or

[1063] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1064] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A31):

[1065] R2A

[1066]

[1067] (I-A31) or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1068] (a) -C(=O)-(C1-C6 alkyl);

[1069] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[1070] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1071] (e) -C(=O)-(4-6 membered heterocyclyl); orAttorney Docket No. 49366-0056WO4

[1072] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1073] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A32):

[1074]

[1075] or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1076] (a) -C(=O)-(C1-C6 alkyl);

[1077] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;

[1078] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1079] (e) -C(=O)-(4-6 membered heterocyclyl); or

[1080] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1081] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A33):

[1082]

[1083] (I-A33) or a pharmaceutically acceptable salt thereof, wherein at least one R2Ais

[1084] (a) -C(=O)-(C1-C6 alkyl);

[1085] (b) 5-10 membered heteroaryl substituted with at least one C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C1-C6 haloalkyl, or -OR7;Attorney Docket No. 49366-0056WO4

[1086] (c) 4-10 membered heterocyclyl substituted with at least one C1-C6 haloalkoxy; (d) C1-C6 alkoxy substituted with 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;

[1087] (e) -C(=O)-(4-6 membered heterocyclyl); or

[1088] (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4- 10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

[1089] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A34):

[1090]

[1091] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl and wherein R1is cyano or C1-C3 haloalkyl.

[1092] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- A35):

[1093] (halogen)

[1094]

[1095] (I- A35)

[1096] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl and wherein R1is cyano or C1-C3 haloalkyl.

[1097] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- A36):Attorney Docket No. 49366-0056WO4

[1098]

[1099] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl and wherein R1is cyano or C1-C3 haloalkyl.

[1100] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- A37):

[1101]

[1102] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl and wherein R1is cyano or C1-C3 haloalkyl.

[1103] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- A38):

[1104] R2A

[1105]

[1106] (I- A38)

[1107] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl and wherein R1is cyano or C1-C3 haloalkyl.

[1108] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I- A39):Attorney Docket No. 49366-0056WO4

[1109] R2A

[1110]

[1111] (I- A39)

[1112] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl and wherein R1is cyano or C1-C3 haloalkyl.

[1113] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A40):

[1114]

[1115] (I-A40) or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl and wherein R1is cyano or C1-C3 haloalkyl.

[1116] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A41):

[1117]

[1118] (I-A41) or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl and wherein R1is cyano or C1-C3 haloalkyl.

[1119] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A42):Attorney Docket No. 49366-0056WO4

[1120] R1

[1121] R2

[1122] RY

[1123]

[1124] (I-A42)

[1125] or a pharmaceutically acceptable salt thereof.

[1126] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A43):

[1127] R1

[1128] R2

[1129]

[1130] (I-A43)

[1131] or a pharmaceutically acceptable salt thereof.

[1132] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A44):

[1133]

[1134] (I-A44)

[1135] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl, and RQis hydrogen, methyl, hydroxyl, or cyano, and wherein R1is cyano or C1-C3 haloalkyl.

[1136] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A45):Attorney Docket No. 49366-0056WO4

[1137]

[1138] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl, and RQis hydrogen, methyl, hydroxyl, or cyano, and wherein R1is cyano or C1-C3 haloalkyl.

[1139] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A46):

[1140]

[1141] (I-A46)

[1142] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl, and RQis hydrogen, methyl, hydroxyl, or cyano, and wherein R1is cyano or C1-C3 haloalkyl.

[1143] In some embodiments, the compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A47):

[1144]

[1145] (I-A47)

[1146] or a pharmaceutically acceptable salt thereof, wherein R2Ais 5-6 membered heteroaryl substituted with C1-C6 haloalkyl, and RQis hydrogen, methyl, hydroxyl, or cyano, and wherein R1is cyano or C1-C3 haloalkyl.Attorney Docket No. 49366-0056WO4

[1147] Non-Limiting Exemplary Compounds

[1148] In some embodiments, the compound is selected from the group consisting of the compounds 1-362, or a pharmaceutically acceptable salt thereof, or any combination of the foregoing.

[1149] In some embodiments, the compound is selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof.

[1150] Table ACompound Number | Structure12

[1151]

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[1175]

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[1177]

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[1181]

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[1189]

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[1199]

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[1378] In some embodiments, the compounds of Formula (I), Formula (I-I), and Formula (I-II) encompass various stereochemical forms. In some embodiments, the compounds of Formula (I), Formula (I-I), and Formula (I-II) 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. In some embodiments, the compounds of Formula (I), Formula (I-I), and Formula (I-II) have one or more chiral centers wherein the compound may independently be of R-configuration or S- configuration or a mixture thereof. In some embodiments, the compounds of Formula (I), Formula (I-I), and Formula (I-II) may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In some embodiments, the compounds of Formula (I), Formula (I-I), and Formula (I-II)Attorney Docket No. 49366-0056WO4

[1379] can be stereoisomers of the compounds depicted in Table A (Compounds 1-362), for example, when a compound in Table A is depicted as being the R isomer, that compound also encompasses the S isomer, and mixtures of the S isomer and R isomer thereof, including diastereomers thereof, or a stereoisomeric mixture, if applicable.

[1380] Pharmaceutical Compositions

[1381] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[1382] 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.

[1383] Methods of Treatment

[1384] A “PI3Ka inhibitor” as used herein (e.g., compounds of Formula (I), Formula (I-I), and Formula (I-II), and pharmaceutically acceptable salts thereof) includes any compound exhibiting PI3Ka inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a PI3Ka inhibitor can be selective for PI3Ka over one or more other kinases. In some embodiments, a PI3Kot inhibitor can be selective for a PI3Koc having one or more mutations.

[1385] The ability of test compounds to act as inhibitors of PI3Ka may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as PI3Ka 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.

[1386] Potency of a PI3Ka inhibitor as provided herein can be determined by EC50value. A compound with a lower EC50value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC50value.Attorney Docket No. 49366-0056WO4

[1387] Potency of a PI3Ka 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 PI3Ka-dependent phosphorylation level, in vitro or in vivo.

[1388] The selectivity between wild type PI3Ka and PI3Ka 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 PI3Ka activity, and / or proliferation assays where cell proliferation is dependent on mutant PI3Ka kinase activity.

[1389] In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of PI3Ka. For example, the compounds provided herein can bind to the helical phosphatidylinositol kinase homology domain catalytic domain of PI3Ka. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a PI3Ka kinase including one or more mutations, for example, the mutations in Table 1.

[1390] In some embodiments, the compounds of Formula (I), Formula (I-I), or Formula (I-II),or a pharmaceutically acceptable salt thereof, can selectively target PI3Ka. For example, a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, can selectively target PI3Ka over another kinase or non-kinase target.

[1391] In some embodiments, a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of PI3Ka 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 PI3Ka. In some embodiments, a compound of Formula (I), Formula (I-I), or Formula (I-II), 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 PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, can exhibit up to 1,000-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, can exhibit up to 10,000-fold greater inhibition ofAttorney Docket No. 49366-0056WO4

[1392] PI3Ka having a combination of mutations described herein relative to inhibition of wild type PI3Ka.

[1393] In some embodiments, a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of PI3Kot containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1,000-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka. In some embodiments, a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10,000-fold greater inhibition of PI3Ka containing one or more mutations as described herein relative to inhibition of wild type PI3Ka.

[1394] Compounds of Formula (I), Formula (I-I), or Formula (I-II), or pharmaceutically acceptable salts thereof, are useful for treating diseases which can be treated with a PI3Ka inhibitor, such as PI3Ka-associated diseases, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced or metastatic solid tumors).

[1395] In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same (a PI3Ka-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 PI3Ka 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 PIK3CA gene, a PI3Ka 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 PI3Ka protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such usingAttorney Docket No. 49366-0056WO4

[1396] a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a PI3Ka -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 PI3Ka 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).

[1397] In certain embodiments, compounds of Formula (I), Formula (I-I), or Formula (I-II), or 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.

[1398] The term “PI3Ka-associated disease” as used herein refers to diseases associated with or having a dysregulation of a PIK3CA gene, a PI3Ka 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 PI3Ka protein, or the expression or activity or level of any of the same described herein). Non-limiting examples of a PI3Ka-associated disease include, for example, proliferative disorders such as cancer (e.g., PI3Ka-associated cancer).

[1399] The term “PI3Ka-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same. Non-limiting examples of PI3Ku-associated cancer are described herein.

[1400] The phrase “dysregulation of a PIK3CA gene, a PI3Ka 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 PI3Ka that includes a deletion of at least one amino acid as compared to a wild type PI3Ka, a mutation in a PIK3CA gene that results in the expression of PI3Ka with one or more point mutations as compared to a wild type PI3Ka, a mutation in a PIK3CA gene that results in the expression of PI3Ka with at least one inserted amino acid as compared to a wild type PI3Ka, a gene duplication that results in an increased level of PI3Ka in a cell, or a mutation in a regulatory sequence (e.g., a promoter and / or enhancer) that results in an increased level of PI3Ka in a cell), an alternative spliced version of PI3Ka mRNA that results in PI3Ka having a deletion of at least one amino acid in the PI3Ka as compared to the wild type PI3Ka), or increased expression (e.g., increased levels) of a wild type PI3Ka in a mammalian cell due to aberrant cell signaling and / or dysregulated autocrine / paracrine signaling (e.g., asAttorney Docket No. 49366-0056WO4

[1401] compared to a control non-cancerous cell). As another example, a dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity, or level of any of the same, can be a mutation in a PIK3CA gene that encodes a PI3Ka that is constitutively active or has increased activity as compared to a protein encoded by a PIK3CA gene that does not include the mutation. Nonlimiting examples of PI3Ka point mutations / substitutions / insertions / deletions are described in Table 1.

[1402] The term “wild type” describes a nucleic acid (e.g., a PIK3CA gene or a PI3Ka mRNA) or protein (e.g., a PI3Kot) sequence that is typically found in a subject that does not have a disease related to the reference nucleic acid or protein.

[1403] The term “wild type PI3Ka” or “wild-type PI3Ka” describes a normal PI3Ka nucleic acid (e.g., a PIK3CA or PI3Ka mRNA) or protein that is found in a subject that does not have a PI3Ka-associated disease, e.g., a PI3Ka -associated cancer (and optionally also does not have an increased risk of developing a PI3Ka -associated disease and / or is not suspected of having a PI3Ka-associated disease), or is found in a cell or tissue from a subject that does not have a PI3Ka-associated disease, e.g., a PI3Ka -associated cancer (and optionally also does not have an increased risk of developing a PI3Ka -associated disease and / or is not suspected of having a PI3Ka-associated disease).

[1404] Provided herein is a method of treating cancer (e.g., a PI3Ka-associated cancer) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating PI3Ka-associated cancer in a subject in need thereof, comprising a) detecting a dysregulation of PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof. Some embodiments provide a method of treating cancer in a subject previously determined to have a PI3Ka-associated cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), Formula (I-I), or Formula (I-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 PI3Ka-associated cancer, the method comprising administering to the subject aAttorney Docket No. 49366-0056WO4

[1405] therapeutically effective amount of a compound of Formula (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[1406] In some embodiments, the dysregulation of a PIK3CA gene, a PI3Ka protein, or the expression or activity or level of any of the same includes one or more a PI3Ka protein substitutions / point mutations / insertions. Non-limiting examples of PI3Ka protein substitutions / insertions / deletions are described in Table 1.

[1407] In some embodiments, the PI3Ka 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 PI3Ka protein substitution / insertion / deletion is H1047X, where X is any amino acid other than H. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E542X, where X is any amino acid other than E. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E545X, where X is any amino acid other than E. In some embodiments, the PI3Ka protein substitution / insertion / deletion is H1047R. In some embodiments, the PI3Ka protein substitution / insertion / deletion is E545K.

[1408] In some embodiments, the dysregulation of a PIK3CA gene, a PI3Ka protein, or expression or activity or level of any of the same, includes a splice variation in a PI3Ka mRNA which results in an expressed protein that is an alternatively spliced variant of PI3Ka having at least one residue deleted (as compared to the wild type PI3Ka protein) resulting in a constitutive activity of a PI3Ka protein domain.

[1409] In some embodiments, the dysregulation of a PIK3CA gene, a PI3Ka 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 PI3Ka protein that has one or more amino acid substitutions or insertions or deletions in a PIK3CA gene that results in the production of a PI3Ka protein that has one or more amino acids inserted or removed, as compared to the wild type PI3Ka protein. In some cases, the resulting mutant PI3Ka protein has increased activity, as compared to a wild type PI3Ka protein or a PI3Ka protein not including the same mutation. In some embodiments, the compounds described herein selectively inhibit the resulting mutant PI3Ka protein relative to a wild type PI3Ka protein or a PI3Ka protein not including the same mutation.Attorney Docket No. 49366-0056WO4

[1410] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Ka-associated cancer) is selected from a hematological cancer and a solid tumor.

[1411] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Ka-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 neuroendocrine 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.

[1412] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Ka-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 neuroendocrine 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.

[1413] In some embodiments of any of the methods or uses described herein, the cancer (e.g., PI3Ka-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.

[1414] In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is breast cancer. In some embodiments of any of the methods or usesAttorney Docket No. 49366-0056WO4

[1415] described herein, the PI3Ka-associated cancer is colorectal cancer. In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is endometrial cancer. In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is lung cancer.

[1416] In some embodiments of any of the methods or uses described herein, the PI3Ka-associated cancer is selected from the cancers described in Table 1.

[1417] Table 1. PI3Ka Protein Amino Acid Substitutions / Insertions / DeletionsA

[1418] Amino Acid Non-Limiting Non-Limiting Exemplary PI3Ka Associated Cancer(s) Position Exemplary

[1419] Mutations

[1420] 1043 M1043I, Breast Invasive Lobular Carcinoma M1043L, Tubular Stomach Adenocarcinoma M1043T, Uterine Endometrioid Carcinoma M1043V Mucinous Adenocarcinoma of the Colon and Rectum Papillary Thyroid Cancer Esophageal Squamous Cell Carcinoma Colon Adenocarcinoma

[1421] Breast Invasive Ductal Carcinoma Bladder Urothelial Carcinoma Pancreatic Adenocarcinoma Oligodendroglioma

[1422] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma

[1423] Glioblastoma Multiforme

[1424] Head and Neck Squamous Cell Carcinoma 1044 N1044I, N1044K, Uterine Endometrioid Carcinoma N1044Y Breast Invasive Ductal Carcinoma

[1425] 1045 D1045A, Uterine Endometrioid Carcinoma D1045V Lung Squamous Cell Carcinoma

[1426] 1047 H1047L, Esophageal Squamous Cell Carcinoma H1047Q, Uterine Endometrioid Carcinoma H1047R, H1047Y Hepatocellular Carcinoma Cutaneous Melanoma

[1427] Mucinous Adenocarcinoma of the Colon and Rectum Bladder Urothelial Carcinoma Cervical Squamous Cell Carcinoma

[1428]

[1429] Intrahepatic CholangiocarcinomaAttorney Docket No. 49366-0056WO4

[1430] Uterine Mixed Endometrial Carcinoma Breast Invasive Ductal Carcinoma Renal Clear Cell Carcinoma

[1431] Uterine Serous Carcinoma / Uterine Papillary Serous Carcinoma

[1432] Head and Neck Squamous Cell Carcinoma Lung Squamous Cell Carcinoma Breast Invasive Lobular Carcinoma Breast Invasive Carcinoma (NOS)

[1433] Astrocytoma

[1434] Colon Adenocarcinoma Leiomyosarcoma

[1435] Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor Oligodendroglioma

[1436] Serous Ovarian Cancer Mucinous Stomach Adenocarcinoma Rectal Adenocarcinoma

[1437] Intestinal Type Stomach Adenocarcinoma Diffuse Type Stomach Adenocarcinoma Prostate Adenocarcinoma

[1438] Lung Adenocarcinoma

[1439] Stomach Adenocarcinoma

[1440] Tubular Stomach Adenocarcinoma Adrenocortical Carcinoma Undifferentiated Pleomorphic Sarcoma / Malignant Fibrous Histiocytoma / High-Grade Spindle Cell Sarcoma Glioblastoma Multiforme Oligoastrocytoma

[1441] 1048 H1048R Colon Adenocarcinoma

[1442] Renal Clear Cell Carcinoma

[1443] 1049 G1049R Intestinal Type Stomach Adenocarcinoma Bladder Urothelial Carcinoma

[1444] Renal Clear Cell Carcinoma

[1445] Breast Invasive Ductal Carcinoma Breast Invasive Lobular Carcinoma Uterine Endometrioid Carcinoma

[1446] Colon Adenocarcinoma

[1447] 1052 T1052K Hepatocellular Carcinoma

[1448]

[1449] Colon AdenocarcinomaAttorney Docket No. 49366-0056WO4

[1450] 1055 M1055I Uterine Mixed Endometrial Carcinoma

[1451] 1058 I1058M Uterine Carcinosarcoma / Uterine Malignant Mixed Mullerian Tumor

[1452] 1065 H1065L Breast Invasive Lobular Carcinoma

[1453] 1066 A1066V Uterine Mixed Endometrial Carcinoma

[1454] 1068 N1068Y, Pleural Mesothelioma, Epithelioid Type N1068fs*5 Dedifferentiated Liposarcoma

[1455] (Frame Shift Head and Neck Squamous Cell Carcinoma

[1456]

[1457] Insertion)

[1458] 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, pl1 (2013).

[1459] f Velho S, Oliveira C, Ferreira A, Ferreira AC, Suriano G, Schwartz S Jr, Duval A, Carneiro F, Machado JC, Hamelin R, Seruca R. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur J Cancer. 2005 Jul;41(11):1649-54. doi: 10.1016 / j.ejca.2005.04.022. PMID: 15994075.

[1460] Exemplary Sequence of Human Phosphatidylinositol 4, 5 -bisphosphate 3-kinase isoform alpha (UniProtKB entry P42336) (SEQ ID NO: 1)

[1461] MPPRPSSGEL WGIHLMPPRI LVECLLPNGM IVTLECLREA TLITIKHELF KEARKYPLHQ LLQDESSYIF VSVTQEAERE EFFDETRRLC DLRLFQPFLK VIEPVGNREE KILNREIGFA IGMPVCEFDM VKDPEVQDFR RNILNVCKEA VDLRDLNSPH SRAMYVYPPN VESSPELPKH IYNKLDKGQI IVVIWVIVSP NNDKQKYTLK INHDCVPEQV IAEAIRKKTR SMLLSSEQLK LCVLEYQGKY ILKVCGCDEY FLEKYPLSQY KYIRSCIMLG RMPNLMLMAK ESLYSQLPMD CFTMPSYSRR ISTATPYMNG ETSTKSLWVI NSALRIKILC ATYVNVNIRD IDKIYVRTGI YHGGEPLCDN VNTQRVPCSN PRWNEWLNYD IYIPDLPRAA RLCLSICSVK GRKGAKEEHC PLAWGNINLF DYTDTLVSGK MALNLWPVPH GLEDLLNPIG VTGSNPNKET PCLELEFDWF SSVVKFPDMS VIEEHANWSV SREAGFSYSH AGLSNRLARD NELRENDKEQ LKAISTRDPL SEITEQEKDF LWSHRHYCVT IPEILPKLLL SVKWNSRDEV AQMYCLVKDW PPIKPEQAME LLDCNYPDPM VRGFAVRCLE KYLTDDKLSQ YLIQLVQVLK YEQYLDNLLV RFLLKKALTN QRIGHFFFWH LKSEMHNKTV SQRFGLLLES YCRACGMYLKAttorney Docket No. 49366-0056WO4

[1462] HLNRQVEAME KLINLTDILK QEKKDETQKV QMKFLVEQMR RPDFMDALQG FLSPLNPAHQ LGNLRLEECR IMSSAKRPLW LNWENPDIMS ELLFQNNEII FKNGDDLRQD MLTLQIIRIM ENIWQNQGLD LRMLPYGCLS IGDCVGLIEV VRNSHTIMQI QCKGGLKGAL QFNSHTLHQW LKDKNKGEIY DAAIDLFTRS CAGYCVATFI LGIGDRHNSN IMVKDDGQLF HIDFGHFLDH KKKKFGYKRE RVPFVLTQDF LIVISKGAQE CTKTREFERF QEMCYK AYLA IRQHANLFIN LFSMMLGSGM PELQSFDDIA YIRKTLALDK TEQEALEYFM KQMNDAHHGG WTTKMDWIFH TIKQHALN

[1463] Also provided is a method for inhibiting PI3Ka activity in a cell, comprising contacting the cell with a compound of Formula (I), Formula (I-I), or Formula (I-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 (I), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant PI3Ka 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 PI3Ka-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 PI3Ka 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 PI3Ka protein, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the PI3Ka protein.

[1464] 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), Formula (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein.

[1465] 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), Formula (I-I), or Formula (I-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 (I), FormulaAttorney Docket No. 49366-0056WO4

[1466] (I-I), or Formula (I-II), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death.

[1467] In some embodiments, the PI3Ka is human PI3Ka. In some embodiments, the PI3Ka has one or more point mutations in the PIK3CA gene. In some embodiments, the point mutations include a substitution at amino acid position 1047 of a human PI3Ka protein. In some embodiments, the substitution is H1047R.

[1468] When employed as pharmaceuticals, the compounds of Formula (I), Formula (I-I), or Formula (I-II), including pharmaceutically acceptable salts thereof, can be administered in the form of pharmaceutical compositions as described herein.

[1469] EXAMPLES

[1470] Example A: Compound Preparation

[1471] The general methods for the preparation of the compounds of Formula (I), Formula (I-I), or Formula (I-II) 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. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B, March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, T. W., Wuts, P. G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art.Attorney Docket No. 49366-0056WO4

[1472] 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 Bruker AVANCE III HD (300 or 400) MHz spectrometer or Bruker 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-20 ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector.

[1473] Standard abbreviations and acronyms as defined in Journal of Organic Chemistry’s Author’s Guideline, and in Hans Reich’s Collection. Organic Acronyms are used herein. Other abbreviations and acronyms used herein are as follows:

[1474] Ac acetate

[1475] AcOH acetic acid

[1476] AcOK Potassium acetate

[1477] aq. aqueous

[1478] Boc tert-butyloxycarbonyl

[1479] B₂pin₂ (pinacolato)diboron

[1480] B₂(Neop)₂ Bis(neopentyl glycolato)diboron

[1481] C Celsius

[1482] CBS Corey-Bakshi-Shibata catalyst

[1483] Dba dibenzylideneacetone

[1484] DCM dichloromethane

[1485] DCE di chloroethane

[1486] DIPEA N,N-diisopropylethylamine

[1487] DMA dimethylacetamide

[1488] DMAP 4-dimethylaminopyridine

[1489] DMF dimethylformamide

[1490] DMSO dimethyl sulfoxide

[1491] ESI Electrospray ionization

[1492] EtOAc ethyl acetate

[1493] Et ethyl

[1494] Et2O diethyl ether

[1495] equiv equivalents

[1496] FA Formic acid

[1497] h hours

[1498] HBpin 4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[1499] HFIP 1,1,1,3,3,3-Hexafluoro-2-propanol

[1500] HPLC high performance liquid chromatography

[1501] g grams

[1502]

[1503] L literAttorney Docket No. 49366-0056WO4

[1504] LCMS liquid chromatography – mass spectrometry

[1505] liq. liquid

[1506] M molar

[1507] Me methyl

[1508] Mel methyl iodide

[1509] MeOH methanol

[1510] MeCN acetonitrile

[1511] MTBE Methyl t-butyl ether

[1512] min minute

[1513] mg milligrams

[1514] mL milliliter

[1515] mm millimeters

[1516] mmol millimoles

[1517] mol moles

[1518] MS mass spectrometry

[1519] MsOH methanesulfonic acid

[1520] MsCl methanesulfonyl chloride

[1521] NBS N-bromosuccinimide

[1522] nm nanometers

[1523] Pd / C palladium supported on carbon

[1524] Pd-PEPPSI-IHeptCl 3-chloropyridine;4,5-dichloro-l,3-bis[2,6-di(heptan-4-yl)phenyl]- 2H-imidazol-2-ide;dichloropalladium

[1525] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[1526] Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4tetrakis(triphenylphosphine)palladium(0)

[1527] Pd(PPh3)Cl2bis(triphenylphosphine)palladium(ll) dichloride

[1528] PPh3triphenylphosphine

[1529] PyBOP Benzotriazole-l-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate)

[1530] RT room temperature

[1531] RP Reverse phase

[1532] sat. saturated

[1533] THF tetrahydrofuran

[1534] UV Ultraviolet light

[1535] µL microliter

[1536] µW microwave reactor

[1537] µm micrometers

[1538] v / v volume / volume

[1539]

[1540] wt weight

[1541] The compounds in Table A not included below can be prepared using procedures analogous to those disclosed below with appropriate modifications.

[1542] IntermediatesAttorney Docket No. 49366-0056WO4

[1543] Intermediate: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile

[1544]

[1545] Step 1: Synthesis of 5-bromo-3-chloro-7-methylquinolin-2(lH)-one.

[1546] 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). MS: 273.1 m / z (M+H+).1H NMR (400 MHz, DMSO) 5 12.49 (s, 1H), 8.17 (s, 1H), 7.42 (s, 1H), 7.14 (s, 1H), 2.38 (s, 3H).

[1547] Step 2: Synthesis of 5-acetyl-3-chloro-7-methylquinolin-2(1H)-one.

[1548] To a suspension of 5-bromo-3-chloro-7-methyl-2-quinolinol (2 g, 7.34 mmol) in 1,4-dioxane (120 mL, 1.41 mol), 1, T-Bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (537 mg, 0.1 eq., 734 pmol) and tributyl(l -ethoxy ethenyl) 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). MS: 264.1 m / z (M+H+).

[1549] 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 xAttorney Docket No. 49366-0056WO4

[1550] 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). MS: 236.1 m / z (M+H+). ¹H 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).

[1551] Step 3: 5-acetyl-3-chloro-7-methylquinolin-2-yl trifluoromethanesulfonate.

[1552] 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(trifluoromethanesulfonyl)methane (641 pL, 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 NaHCO3 mixture. The mixture was poured into a separatory funnel, and the organic layer was separated. The aqueous layer was extracted with DCM (10 mL) 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 mg). MS: 367.1 m / z (M+H+). 'H NMR (400 MHz, CDC13) 5 9.52 (s, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 2.77 (s, 3H), 2.63 (s, 3H).

[1553] Step 4: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile.

[1554] 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 pmol) 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). MS: 245.1 m / zAttorney Docket No. 49366-0056WO4

[1555] (M+H+). ¹H NMR (400 MHz, DMSO) δ 9.29 (s, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 2.77 (s, 3H), 2.63 (s, 3H).

[1556] Intermediate 2: Synthesis of l-(3-chloro-2-(difluoromethyl)-7-methylquinolin-5-yl)ethan-l-one

[1557] F N A

[1558] Cl

[1559]

[1560] Step 1: Synthesis of 3-(benzyloxy)-5-bromo-2,7-dimethylquinoline:

[1561]

[1562] To a solution of 2-amino-6-bromo-4-methylbenzaldehyde (10 g, 46.72 mmol) in EtOH (100 mL) and H2O (10 mL) was added 1 -(benzyloxy)propan-2-one (9.20 g, 56.06 mmol) and NaOH (3.74 g, 93.43 mmol). The mixture was stirred at 80 °C for 1 h. After cooling to room temperature, the reaction was filtered and the filter cake was concentrated in vacuo to give the title compound (13 g) as a yellow solid that required no further purification. '¹H NMR (400 MHz, DMSO-d6) δ 7.1 (s, 2H), 7.66 (s, 1H), 7.59 - 7.4 (m, 2H), 7.48 - 7.41 (m, 2H), 7.40 - 7.31 (m, 1H), 5.34 (s, 2H), 2.54 - 2.52 (m, 3H), 2.46 (s, 3H). MS: m / z 341.9 (M+H+).

[1563] Step 2 - Synthesis of 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbaldehyde:

[1564]

[1565] A mixture of 3-(benzyloxy)-5-bromo-2,7-dimethylquinoline (14 g, 40.91 mmol) and SeO2 (5.49 g, 49.50 mmol) in dioxane (100 mL) was stirred at 80 °C for 2 h. After cooling to room temperature, The mixture was diluted with H2O (200 mL), extracted with DCM (300 mL x 3). The combined organic layers were washed with brine (80 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 100% DCM in hexanes) to give the title compound (17 g-crude, contain SeCh) as a red solid. ¹H NMR (400 MHz, DMSO-d6)–δ 10.50 - 10.19 (m, -H),Attorney Docket No. 49366-0056WO4

[1566] 8.01 - 7.82 (m, -H), 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+).

[1567] Step 3 - Synthesis of 3-(benzyloxy)-5-bromo-2-(difluoromethyl)-7-methylquinoline:

[1568] N

[1569]

[1570] 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 NaHCCh (80 mL), extracted with DCM (200 mL x 3). 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 hexanes) to give the title compound (4.16 g) as a yellow solid.rH NMR (400 MHz, DMSO-d6) δ 7.95 (s, -H), 7.92 - 7.87 (m, -H), 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+).

[1571] Step 4 - Synthesis of l-(3-(benzyloxy)-2-(difluoromethyl)-7-methylquinolin-5-yl)ethan-l-one:

[1572] N

[1573]

[1574] A mixture of 3-benzyloxy-5-bromo-2-(difluoromethyl)-7-methyl-quinoline (5 g, 13.54 mmol), tributyl(l -ethoxy vinyl)stannane (9.78 g, 27.07 mmol) and Pd(dppf)Ch (990 mg, 1.35 mmol) in dioxane (50 mL) was stirred at 90 °C for 16 h under N2 atmosphere. After cooling to room temperature, HC1 (10 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 (50 mL). The mixture was filtered and the filtrate was extracted with DCM (100 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 chromatographyAttorney Docket No. 49366-0056WO4

[1575] (solvent gradient: 0 - 5% MeOH in DCM) to give the title compound (4.6 g) as a white solid. ¹H-NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.15 (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+H+).

[1576] Step 5 - Synthesis of l-(2-(difluoromethyl)-3-hydroxy-7-methylquinolin-5-yl)ethan-1-one:

[1577]

[1578] Hydrogenation debenzylation: To a solution of l-(3-(benzyloxy)-2-(difluoromethyl)-7-methylquinolin-5-yl)ethan-l-one (11 g, 10.74 mmol) in EtOH (100 mL) and THF (150 mL) was added wet Pd on carbon (11 g, 10% Pd, 50% wet with water). The reaction was stirred at room temperature for 8 h under H2 atmosphere (15 psi). The reaction was filtered through diatomaceous earth and the filter was triturated with EtOAc (100 mL) at room temperature for 30 min. After filtration, the solid was collected and dried under reduced pressure to afford the title compound (3.8 g) as a yellow solid. The filtrate was concentrated to recycle starting material (5.1 g) as a yellow solid. MS: m / z 252.1 (M+H+).

[1579] TFA debenzylation: To a solution of l-(3-(benzyloxy)-2-(difluoromethyl)-7-methylquinolin-5-yl)ethan-l-one (5.1 g, 14.94 mmol) in TFA (50 mL) was stirred at 80 °C for 16 h. After cooling to room temperature. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with EtOAc (60 mL) at room temperature for 30 min. After filtration, the solid was collected and dried under reduced pressure to afford the title compound (3.4 g) as a yellow solid. MS: m / z 252.1 (M+H+).

[1580] Step 6 - Synthesis of 5-acetyl-2-(difluoromethyl)-7-methylquinolin-3-yl trifluoromethanesulfonate:

[1581]

[1582] Attorney Docket No. 49366-0056WO4

[1583] To a mixture of l-(2-(difluoromethyl)-3-hydroxy-7-methylquinolin-5-yl)ethan-l-one (3.8 g, 15.13 mmol) and pyridine (5 mL, 60.50 mmol) in DCM (40 mL) was added Tf2O (5 mL, 30.25 mmol) at 0 °C, the resulting mixture was stirred at 0 °C for 1 h. The reaction was diluted with H2O (30 mL), extracted with DCM (50 mL x 3), the combined organic layers were washed with 10% citric acid aqueous solution (20 mL x 2) and sat. aq. NaHCO3(20 mL x 2). Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (5.7 g) as a brown solid, which was used in the next step without further purification. 'H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 7.31 (t, J = 52.8 Hz, 1H), 2.79 (s, 3H), 2.65 (s, 3H). MS: m / z 384.1 (M+H+).

[1584] Step 7 - Synthesis of l-(2- 231 uinolineomethyl)-7-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-5-yl)ethan-l-one:

[1585] N

[1586] r

[1587] B i'

[1588] O

[1589] O

[1590]

[1591] To a solution of 5-acetyl-2-(difluoromethyl)-7-methylquinolin-3-yl trifluoromethanesulfonate (5.6 g, 14.82 mmol) in dry dioxane (9 mL) was added B2Pin2(11.29 g, 44.46 mmol), KOAc (4.36 g, 44.46 mmol) and Pd(dppf)C12 (1 g, 1.48 mmol). The mixture was evacuated and purged with N2 3 times, then the mixture was stirred at 100 °C for 1 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 -10% MeOH in DCM) to give the title compound (5.3 g) as a yellow solid.!H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 8.24 (s, 1H), 8.11 (s, 1H), 7.35 (t, J= 54.8 Hz, 1H), 2.76 (s, 3H), 2.61 (s, 3H), 1.36 (s, 12H). MS: m / z 362.1 (M+H+).

[1592] Step 8 - Synthesis of l-(3-chloro-2-(difluoromethyl)-7-methylquinolin-5-yl)ethan-lone:

[1593] F

[1594] l\L J- Cl

[1595]

[1596] Attorney Docket No. 49366-0056WO4

[1597] A mixture of l-(2-(difluoromethyl)-7-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinolin-5-yl)ethan-l-one (5.4 g, 15.14 mmol), NCS (2.22 g, 16.66 mmol), CuCl (3.15 g, 31.8 mmol) in MeCN (1 L). The mixture was stirred at 100 °C for 72 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% DCM in hexanes) to give the title compound (3.7 g) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.21 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.30 (t, J= 53.2 Hz, 1H), 2.76 (s, 3H), 2.60 (s, 3H). MS: m / z 270.1 (M+H+).

[1598] Intermediate A: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile

[1599]

[1600] Step 1: Preparation of 2,6-dibromo-4-methylbenzaldehyde:

[1601] To a stirred mixture of l,3-dibromo-5-methylbenzene (150 g, 600.161 mmol, 1 equiv) in THF (1 L) was added LDA(2.0M in THF / heptane) (360.10 mb, 720.200 mmol, 1.20 equiv) dropwise at -78°C under nitrogen atmosphere. To the above mixture was added DMF (52.64 g, 720.193 mmol, 1.2 equiv) dropwise over 10 min at -78°C. The resulting mixture was stirred at -78°C for additional Ih. The reaction was monitored by proton NMR. Desired product could be detected by H-NMR. The reaction was quenched with aq. HC1 (1 mol / L) at 0°C. The resulting mixture was extracted with EtOAc (3 x 800mL). The combined organic layers were washed with brine (2 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. ' H NMR (400 MHz, DMSO-r / d) 5 10.12 (s, IH), 7.68 (s, 2H), 2.36 (s, 3H).

[1602] Step 2: Preparation of 2-(2,6-dibromo-4-methylphenyl)-l,3-dioxolane:

[1603] A mixture of 2,6-dibromo-4-methylbenzaldehyde (150 g, 539.679 mmol, 1 equiv), ethylene glycol (40.20 g, 647.615 mmol, 1.2 equiv) and p-Toluenesulfonic acid (46.47 g, 269.839 mmol, 0.5 equiv) in toluene (200 mL) was stirred at 120°C overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CH2CI2 (3 xAttorney Docket No. 49366-0056WO4

[1604] 500mL). The combined organic layers were washed with brine (1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (150:1-100:1) to afford 2-(2,6-dibromo-4-methylphenyl)-l,3-dioxolane (100 g) as a yellow solid. LC-MS: (ES+H, m / z):

[1605] [M+H]+= 323.0 / 321.0 / 325.0. 'HNMR (400 MHz, CDC13) 57.39 (d, J=0.8 Hz, 2H), 6.36 (s, 1H), 4.36-4.30 (m, 2H), 4.09-4.04 (m, 2H), 2.29 (d,.7=0.7 Hz, 3H).

[1606] Step 3: Preparation of A-[3-bromo-2-(l,3-dioxolan-2-yl)-5-methylphenyl]-l,l-diphenylmethanimine:

[1607] To a stirred mixture of benzenemethanimine, a-phenyl- (28.14 g, 155.281 mmol, 1.00 equiv) and 2-(2,6-dibromo-4-methylphenyl)-l,3-di oxolane (50 g, 155.281 mmol, 1.00 equiv) in toluene (200 mL) were added BINAP (9.67 g, 15.528 mmol, 0.1 equiv), Cs2CO3(101.19 g, 310.562 mmol, 2 equiv) and Pd(OAc)2 (1.74 g, 7.764 mmol, 0.05 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered. The filter cake was washed with CH2CI2 (3 x 500 mL). The filtrate was concentrated under reduced pressure. The residue was-purified by silica gel column chromatography, eluted with PE / EA (30:1 - 20:1) to afford A-[3-bromo-2-(l,3-dioxolan-2-yl)-5-methylphenyl]-l,l-diphenylmethanimine (50 g) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=422.1 / 424.1.

[1608] Step 4: Preparation of 2-amino-6-bromo-4-methylbenzaldehyde:

[1609] A mixture of A-[3-bromo-2-(l,3-dioxolan-2-yl)-5-methylphenyl]-l,l-diphenylmethanimine (100 g, 142.072 mmol, 1 equiv, 60%) and HC1 (IM) (355.18 mL, 355.180 mmol, 2.5 equiv) in THF (300 mL) was stirred at 80°C for 2 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture neutralized to pH 9 with 4M NaOH. The resulting mixture was extracted with CH2CI2 (3 x 500mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1-15:1) to afford 2-amino-6-bromo-4-methylbenzaldehyde (20 g) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+=214.0 / 216.0. 'H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.60 (s, 2H), 6.69 (d, J= 1.6 Hz, 1H), 6.58 (s, 1H), 2.19 (s, 3H).Attorney Docket No. 49366-0056WO4

[1610] Step 5: Preparation of 5-bromo-3-chloro-7-methyl-177-quinolin-2-one:

[1611] Into a 1 L 3 -necked round-bottom flask were added 2-amino-6-bromo-4-methylbenzaldehyde (30 g, 140.146 mmol, 1 equiv), THF (300mL) and LiHMDS (280.29 mL, 280.292 mmol, 2 equiv) at -78°C. The resulting mixture was stirred at -78°C for 1 h under nitrogen atmosphere. To the above mixture was added ethyl chloroacetate (44.80 mL, 420.438 mmol, 3 equiv) dropwise over 3 min at -78°C. The resulting mixture was stirred at -78°C for additional 2 h. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with water at room temperature. The resulting mixture was extracted with CH2CI2 (3 x 500 mL). The combined organic layers were washed with water (500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (250 mL). The precipitated solids were collected by filtration and washed with PE (50 mL). This resulted in 5-bromo-3-chloro-7-methyl-12 / -quinolin-2-one (20 g) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 272.1 / 274.1.!H NMR (400 MHz, DMSO) 8 8.14 (d, J= 0.7 Hz, 1H), 7.38 (d, J= 1.5 Hz, 1H), 7.14 (dt, J= 1.6, 0.9 Hz, 1H), 2.37 (s, 3H).

[1612] Step 6: Preparation of 5-acetyl-3-chloro-7-methyl-l / / -quinolin-2-one:

[1613] A solution of 5-bromo-3-chloro-7-methyl-l / / -quinolin-2-one (28 g, 102.741 mmol, 1 equiv), tributyl(l-ethoxyethenyl)stannane (44.53 g, 123.289 mmol, 1.2 equiv) in Dioxane (200 mL) was treated with Pd(dppf)C12 (7517.66 mg, 10.274 mmol, 0.1 equiv) at 90°C for 3 h under nitrogen atmosphere, followed by the addition of HC1(4M) (200 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with MeCN (200 mL). The residue was purified by trituration with MeCN (100 mL). This resulted in 5-acetyl-3-chloro-7-methyl-l / / -quinolin-2-one (18 g) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=236.2. 'H NMR (400 MHz, DMSO) 5 12.43 (s, 1H), 8.70 (s, 1H), 7.71 (d, J= 1.6 Hz, 1H), 7.33 (d, J= 1.5 Hz, 1H), 2.66 (s, 3H), 2.45 (s, 3H).

[1614] Step 7: Preparation of 5-acetyl-3-chloro-7-methylquinolin-2-yl tri fluoromethanesulfonate:

[1615] To a stirred mixture of 5-acetyl-3-chloro-7-methyl-177-quinolin-2-one (4.5 g, 19.094 mmol, 1 equiv) and triflic anhydride (10.77 g, 38.188 mmol, 2 equiv) in DCM (50 mL) wasAttorney Docket No. 49366-0056WO4

[1616] added pyridine (4.53 g, 57.282 mmol, 3 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was extracted with CH2CI2 (2 x 500mL). The combined organic layers were washed with water (4 x 300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with PE (150 mL). The precipitated solids were collected by filtration and washed with PE (2 x 20 mL). This resulted in 5-acetyl-3-chloro-7-methylquinolin-2-yl trifluoromethanesulfonate (6 g) as a white solid. LC-MS: (ES+H, m / z): [M+H]+=368.1.

[1617] Step 8: Preparation of 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile:

[1618] A mixture of 5-acetyl-3-chloro-7-methylquinolin-2-yl trifluoromethanesulfonate (22 g, 59.828 mmol, 1 equiv), Pd(PPh3)4 (3.46 g, 2.991 mmol, 0.05 equiv) and Zn(CN)2 (14.05 g, 119.656 mmol, 2 equiv) in DMF (200 mL) was stirred at 90°C for overnight under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The precipitated solids were collected by filtration and washed with MeOH (10 x 300 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2 x 1000 mL). The combined organic layers were washed with brine (3 x 500 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / CH2CI2 (1:5-1:4) to afford 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile (8 g) as a white solid. LC-MS: (ES+H, m / z):

[1619] [M+H]+=245.1H NMR (400 MHz, Chloroform-^ δ 9.48 (s, 1H), 8.09 (s, 2H), 2.78 (s, 3H), 2.65 (s, 3H).

[1620] Intermediate A: Preparing of INT A, Method 2: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile

[1621] Step 1: Preparation of 3-(benzyloxy)-5-bromo-7-methylquinoline:

[1622] To a stirred solution of 2-amino-6-bromo-4-methylbenzaldehyde (55 g, 256.93 mmol, 1 equiv) in 1-butanol (400 mL) were added 2-(benzyloxy)acetaldehyde (50.16 g, 334.01 mmol, 1.3 equiv) and NaOH (20.55 g, 513.86 mmol, 2.00 equiv) in H2O (40 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 2h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could beAttorney Docket No. 49366-0056WO4

[1623] detected by LCMS The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under vacuum to afford 3-(benzyloxy)-5-bromo-7-methylquinoline (61 g, crude) as a brown solid. The residue was purified by trituration with ethanol (200 mL). The precipitated solids were collected by filtration and washed with Et2O (100 mL) dried in vacuo to afford 3-(benzyloxy)-5-bromo-7-methylquinoline (58 g) as alight yellow solid. LC-MS: (ES+H, m / z) [M+H]-= 327.9 / 329.9.

[1624] Step 2: Preparation of 3-(benzyloxy)-5-bromo-7-methylquinolin-l-ium-l-olate

[1625] To a stirred solution of 3-(benzyloxy)-5-bromo-7-methylquinoline (58 g, 176.71 mmol, 1 equiv) in DCM (600 mL) was added m-CPBA (71.75 g, 353.43 mmol, 2.00 equiv, 85%) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of Na2SOa solution at 0°C until the starch KI paper did not change color. The mixture was basifted to pH 8 with 2M NaOH aqueous solution and extracted with CH2CI2 (3 x 200 mL). The combined organic layers were washed with brine (2 x 300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(benzyloxy)-5-bromo-7-methyl quinolin- 1-ium-l-olate (53 g, crude) as a yellow solid. The residue was purified by trituration with tert-butyl methyl ether (150 mL). The precipitated solids were collected by filtration and washed with tert-butyl methyl ether (2 x 50 mL). This resulted in 3-(benzyloxy)-5-bromo-7-methylquinolin- 1-ium-l-olate (50 g) as a light yellow solid. LC-MS: (ES+H, m / z) [M+H]~ = 343.8 / 345.8. 'H NMR (400 MHz, CDCI3) δ 8.46 - 8.40 (m, 2H), 7.73 (d, J= 1.6 Hz, 1H), 7.50 - 7.39 (m, 6H), 5.22 (s, 2H), 2.52 (s, 3H).

[1626] Step 3: Preparation of 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbonitrile

[1627] To a stirred solution of 3-(benzyloxy)-5-bromo-7-methylquinolin-l-ium-l-olate (50 g, 145.26 mmol, 1 equiv) in DCM (200 mL) were added diethyl phosphonate (37.42 mL, 290.52 mmol, 2 equiv), CCI4 (28.03 mL, 290.52 mmol, 2 equiv) and EtaN (40.38 mL, 290.52 mmol, 2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 20 min under nitrogen atmosphere. To the above mixture was added TMSCN (17.29 g, 174.31 mmol, 1.2 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (300 mL) at roomAttorney Docket No. 49366-0056WO4

[1628] temperature. The resulting mixture was extracted with CH2CI2 (2 x 300mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbonitrile (50 g, crude). The crude was purified by trituration with MeOH (100 mL). The precipitated solids were collected by filtration and washed with Et2O (2x50 mL). After filtration, the solid was collected and dried in vacuo to afford 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbonitrile (40 g) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+ = 353.1 / 355.1. 'H-NMR. (400 MHz, DMSO-d6) - 8.01 (s, 1H), 7.98 -d, J = 1.6 Hz, 1H), -.86 (d, J= 1.7 Hz, 1H), 7.61 - 7.53 (m, 2H), 7.51 - 7.43 (m, 2H), 7.42 - 7.37 (m, 1H), 5.48 (s, 2H), 2.50 (s, 3H).

[1629] Step 4: Preparation of 5-acetyl-3-hydroxy-7-methylquinoline-2-carbonitrile

[1630] To a stirred solution of 3-(benzyloxy)-5-bromo-7-methylquinoline-2-carbonitrile (20 g, 113.24 mmol, 1 equiv) and Pd(dppf)C12 (2.07 g, 56.622 mmol, 0.05 equiv) in Dioxane (100 mL) were added tributyl(l -ethoxy ethenyl)stannane (30.67 g, 169.86 mmol, 1.5 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 3h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. To the above mixture was added HC1 (100 mL, 4M) dropwise at room temperature. The resulting mixture was stirred at room temperature for additional Ih. The resulting mixture was diluted with water (100 mL), and filtered. The resulting cake was triturated with methanol (80 mL) at room temperature for 10 min. After filtration, the solid was collected and dried in vacuo to afford a yellow solid (15 g). To the product in DCM (250 mL) was added MsOH (50 mL) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 40 °C in vacuo overnight under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The mixture was basified to pH 8 with saturated NaHCCh (aq.) at 0°C. The precipitated solids were collected by filtration and washed with water (2 x 150 mL). The filtered cake was acidified / dis solved to pH 5 with HC1 (6M) at 25°C. The precipitated solids were collected by filtration and washed with water (2 x 200 mL). The residue was purified by trituration with MeOH (40 mL). After filtration the filtered cake was triturated with Et2O (50 mL) at room temperature for 10 min. After filtration, the solid was collected and dried in vacuo to afford 5-acetyl-3-hydroxy-7-Attorney Docket No. 49366-0056WO4

[1631] methylquinoline-2-carbonitrile (8.65 g) as a grey solid. LC-MS: (ES+H, m / z): [M+H]+= 227.1.

[1632] NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.78 (s, 1H), 8.26 (d, J= 1.7 Hz, 1H), 7.97 (s, 1H), 2.73 (s, 3H), 2.54 (s, 3H).

[1633] Step 5: Preparation of 5-acetyl-2-cyano-7-methylquinolin-3-yl trifluoromethanesulfonate To a stirred solution of 5-acetyl-3-hydroxy-7-methylquinoline-2-carbonitrile (8 g, 35.361 mmol, 1 equiv) and (trifluoromethane)sulfonyl trifluoromethanesulfonate (15.96 g, 56.578 mmol, 1.6 equiv) in DCM (100 mL) were added pyridine (5.59 g, 70.722 mmol, 2 equiv) in portions at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with DCM (3 x 250 mL). The combined organic layers were washed with brine (2 x 150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1-1:1) to afford 5-acetyl-2-cyano-7-methylquinolin-3-yl trifluoromethanesulfonate (10 g) as ayellow solid. LC-MS: (ES+H, m / z): [M+H]+= 359.1.

[1634] Step 6: Preparation of 5-acetyl-7-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-2-carbonitrile

[1635] To a stirred solution of 5-acetyl-2-cyano-7-methylquinolin-3-yl trifluoromethanesulfonate (5 g, 13.955 mmol, 1 equiv) and Pin2B2 (1.06 g, 41.865 mmol, 3 equiv) in Dioxane (25 mL) were added AcOK (4.1 g, 41.865 mmol, 3 equiv) and Pd(dppf)Ch CH2CI2 (1.14 g, 1.396 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for additional 1 h. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was fdtered, the filter cake was washed with DCM (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / DCM (1:3-1:4) to afford 5-acetyl-7-methyl-3-(4, 4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-2-carbonitrile (2.5 g) as a white solid. LC-MS: (ES+H, m / z): [M+H]+ = 255.2.

[1636] Step 7: Preparation of 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile

[1637] A mixture of 5-acetyl-7-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-2-carbonitrile (500 mg, 1.487 mmol, 1 equiv), CuCl (0.44 g, 4.462 mmol, 3 equiv) and NCSAttorney Docket No. 49366-0056WO4

[1638] (0.596 g, 4.462 mmol, 3 equiv) in NMP (20 mL) was stirred at 90°C for 2h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The residue was dissolved in water (200mL). The precipitated solids were collected by filtration and washed with water (2 x 30 mL). The residue was purified by silica gel column chromatography, eluted with PE / CH2CI2 (1:4 - 1:5) to afford 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile (200 mg) as a white solid. LC-MS: (ES+H, m / z): [M+H] =245.2.XH NMR (400 MHz, Chloroform - ) δ 9.48 (s, 1H), 8.09 (s, 2H), 2.78 (s, 3H), 2.65 (s, 3H).

[1639] Intermediate C: 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile

[1640] Cl

[1641]

[1642] Step 1: Preparation of l-[3-chloro-2-(hydroxymethyl)-7-methylquinolin-5-yl]ethanone: A solution of 5-acetyl-3-chloro-7-methylquinolin-2-yl trifluoromethanesulfonate (15 g, 40.792 mmol, 1 equiv), (tributyl stannyl)methanol (17.03 g, 53.030 mmol, 1.3 equiv), AS2O3 (807.03 mg, 4.079 mmol, 0.1 equiv) and Pd(dppf)C12. CH2C12 (1.67 g, 2.040 mmol, 0.05 equiv) in toluene (200 mL) was stirred at 80°C for 5h under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product was detected by LCMS. The reaction was quenched by the addition of sat. KF (aq.) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with brine (1 x 1000 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1). The resulting mixture was concentrated under reduced pressure. The resulting solid was dried under vacuum to afford l-[3-chloro-2-(hydroxymethyl)-7-methylquinolin-5-yl]ethanone (5 g) as a white solid. L

[1643]

[1644] C-MS: (ES+H, m / z): [M+H]+= 250.2 / 252.2 NMR (400 MHz, DMSO-d6) δ 9.06 (d, J= 0.9 Hz, 1H), 8.22 (d, J= 1.7 Hz, 1H), 8.07 - 8.04 (m, 1H), 5.36 (t, J= 5.8 Hz, 1H), 4.80 (d, J= 5.8 Hz, 2H), 2.75 (s, 3H), 2.60 (d, J= 1.0 Hz, 3H).

[1645] Step 2: Preparation of 5-acetyl-3-chloro-7-methylquinoline-2-carbaldehyde:

[1646] A solution of l-[3-chloro-2-(hydroxymethyl)-7-methylquinolin-5-yl]ethanone (2.4 g, 9.612 mmol, 1 equiv) and selenium dioxide (1.07 g, 9.612 mmol, 1 equiv) in THF (10 mL) wasAttorney Docket No. 49366-0056WO4

[1647] stirred at 50°C for Ih under nitrogen atmosphere. The reaction was monitored by TLC. New point could be found by TLC (PE / EA = 2:1, Rf = 0.3). The resulting mixture was filtered, the filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was washed with water (2 x 100 mL). The resulting solid was dried under vacuum to afford 5-acetyl-3-chloro-7-methylquinoline-2-carbaldehyde (2.1 g) as a brown solid. 'H NMR (400 MHz, DMSO-d6) δ 10.18 (s, IH), 9.19 (s, IH), 8.38 (d, J= 1.7 Hz, IH), 8.20 (s, IH), 2.77 (s, 3H), 2.63 (s, 3H).

[1648] Step 3: Preparation of l-[3-chloro-2-(difluoromethyl)-7-methylquinolin-5-yl]ethanone: A solution of 5-acetyl-3-chloro-7-methylquinoline-2-carbaldehyde (2.1 g, 8.479 mmol, 1 equiv) and diethylaminosulfur trifluoride (1.64 g, 10.175 mmol, 1.20 equiv) in DCM (15 mL) was stirred at -5°C for 40 min under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched by the addition of sat. NaHCCh (aq.) (100 mL) at 0°C. The resulting mixture was extracted with CH2CI2 (3 x 100 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 1- [3-chloro-2-(difluoromethyl)-7-methylquinolin-5-yl]ethanone (2 g) as a white solid. LC-MS: (ES+H, m / z): [M+H]+= 270.0 / 272.0. 'H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J= 0.9 Hz, IH), 8.35 (d, J= 1.7 Hz, IH), 8.18 - 8.13 (m, IH), 7.31 (t, J= 53.1 Hz, IH), 2.77 (s, 3H), 2.62 (d, J= 1.0 Hz, 3H).

[1649] Exemplary Compounds of Formula (I), Formula (I-I), and Formula (I-II):

[1650] Example 1: 3-((l-(2-cyano-3-(6-(l-(difluoromethyl)-l / 7-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)pyrazine-2-sulfonamide (Compound 71)

[1651] N

[1652] F

[1653] N —

[1654] N F

[1655]

[1656] Step 1 - Synthesis of 3-((1-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide:Attorney Docket No. 49366-0056WO4

[1657] A solution of 3-amino-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide (700 mg, 1.69 mmol) in DMA (10 mL) was evacuated and backfilled with N2 for 3 times. After cooling to 0 °C, NaH (74 mg, 1.86 mmol, 60% purity) was added, followed by stirring for 0.5 h under N2 atmosphere. Then, a solution of 5-(l-bromoethyl)-3-(6-chloropyridin-3-yl)-7-methylquinoline-2-carbonitrile (718 mg, 1.86 mmol) in DMA (5 mL) was added, the mixture was slowly raised to room temperature, and stirred for another 1 h. The reaction mixture was quenched with sat. aq. NH4Cl (10 mL) and H2O (50 mL) at 0 °C, then extracted with EtOAc (50 mL x 2). The combined organic layers were washed with H2O (50 mL x 2) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 30% - 50% EtOAc in hexanes) to give the title compound (1 g) as a yellow solid. MS: m / z 720.3 (M+H+).

[1658] Step 2 - Synthesis of 3-((l-(2-cyano-3-(6-(l-(difluoromethyl)-LH-pyrazoI-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)- / V, / V-bis(4-methoxybenzyl)pyrazine-2-sulfonamide:

[1659] To a solution of 3-((l-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide (700 mg, 0.97 mmol) in dioxane (6 mL) and H2O (0.3 mL) was added 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (356 mg, 1.42 mmol), Pd(dppf)C12(71 mg, 97 pmol) and K2CO3 (403 mg, 2.92 mmol). The mixture was evacuated and backfilled with N2 for 3 times, and then it was stired at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in hexanes) to give the title compound (640 mg) as a yellow solid. MS: m / z 802.1 (M+H+).

[1660] Step 3 - Synthesis of 3-((l-(2-cyano-3-(6-(l-(difluoromethyl)-LH-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)pyrazine-2-sulfonamide:

[1661] A solution of 3-((l-(2-cyano-3-(6-(l-(difluoromethyl)-l / -pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(4-methoxybenzyl)pyrazine-2-sulfonamide (640 mg, 0.79 mmol) in TFA (5 mL) was stirred at room temperature for 24 h. The reaction mixture was poured into H2O (50 mL). The resulting suspension was filtered, and the filter cake was dried in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 20 - 50% EtOAc in hexanes) to give the title compound (280 mg) as a white solid. MS: m / z 562.1 (M+H+).Attorney Docket No. 49366-0056WO4

[1662] Example 2: (7?)-2-((l-(2-cyano-3-(6-(4-cyclopropyl-lH-imidazol-l-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide (Compound 12)

[1663]

[1664] Step 1 - Synthesis of 2-((l-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(3,5-dimethoxybenzyl)benzenesulfonamide:

[1665] To a solution of 5-(l-bromoethyl)-3-(6-chloropyridin-3-yl)-7-methylquinoline-2-carbonitrile (7.0 g, 18.10 mmol) in MeCN (70 mL) was added DIEA (6.3 mL, 36.21 mmol), 2-amino-N,N-bis(3,4-dimethylbenzyl)benzenesulfonamide (9.0 g, 19.05 mmol) and KI (1.5 g, 9.05 mmol). The mixture was evacuated and backfilled with N2 for 3 times, and then it was stired at 100 °C for 3 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was diluted with H2O (150 mL), extracted with DCM (100mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was stirred in MeOH / DCM (110 mL, v / v = 10:1) (200 mL) at room temperature for 1 h. The suspension was filtered and the filter cake was dried in vacuo to give the title compound (8.6 g) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.10 (s, 1H), 8.86 (d, J= 2.4 Hz, 1H), 8.37 -8.33 (m, 1H), 7.90 (s, 1H), 7.80 (d, J= 8.4 Hz, 1H), 7.63 (s, 1H), 7.60 - 7.56 (m, 1H), 7.25 - 7.21 (m, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.72 - 6.62 (m, 2H), 6.55 (d, J = 8.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 2H), 6.36 - 6.32 (m, 2H), 5.69 - 5.56 (m, 1H), 4.38 - 4.25 (m, 4H), 3.70 (s, 6H), 3.56 (s, 6H), 2.41 (s, 3H), 1.55 (d, J= 6.4 Hz, 3H). MS: m / z 778.3 (M+H+).

[1666] Step 2 - Synthesis of ( )-2-((l-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide and (R)-2-((1-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide:

[1667] 2-((l-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-N, N-bis(2,4-dimethoxybenzyl)benzenesulfonamide (2 g, 2.57 mol) was separated by using chiral SFC (DAICEL CHIRALCEL OD (250mm*50mm,10um); Supercritical CO2 / z-PrOH+ 0.1%Attorney Docket No. 49366-0056WO4

[1668] NH3•H2O = 45 / 55; 200 mL / min) to afford (S)-2-((l-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-7V, / V-bis(2,4-dimethoxybenzyl)benzenesulfonamide (0.92 g, second peak) and (R)-2-((1-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide (0.94 g, second peak) both as yellow solid. Absolute configuration was arbitrarily assigned to each enantiomer. MS: m / z 778.3 (M+H+).

[1669] Step 3 - Synthesis of (R)-2-((1-(2-cyano-3-(6-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(3,4-dimethylbenzyl)benzenesulfonamide:

[1670] To a solution of (R)-2-((1-(3-(6-chloropyridin-3-yl)-2-cyano-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(2,4-dimethoxybenzyl)benzenesulfonamide (100 mg, 128 μmol) in dioxane (2 mL) was added 4-cyclopropyl-1H-imidazole (42 mg, 385 μmol), K3PO4 (82 mg, 385 μmol) and Gphos Pd G6 (12 mg, 13 μmol). The mixture was evacuated and backfilled with N2 for 3 times, and then it was stired at 110 °C for 16 h under N2 atmosphere. The reaction mixture was diluted with H2O (10 mb), extracted with EtOAc (15 mb x 2). The combined organic layers were washed with brine (10 mb x 3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (109 mg) as colorless oil. MS: m / z 850.4 (M+H+).

[1671] Step 4 - Synthesis of (R)-2-((1-(2-cyano-3-(6-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide:

[1672] To a solution of (R)-2-((1-(2-cyano-3-(6-(4-cyclopropyl-1H-imidazol-1-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)-N,N-bis(3,4-dimethylbenzyl)benzenesulfonamide (109 mg, 150 μmol) in DCM (2 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 1 h. The mixture was filtrated and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 25% - 55% / 0.225% formic acid in water) to give the title compound (30.85 mg) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1H), 8.92 (d, J= 2.4 Hz, 1H), 8.52 (d, J= 1.2 Hz, 1H), 8.50 - 8.46 (m, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.89 (s, 1H), 7.84 - 7.78 (m, 2H), 7.66 - 7.63 (m, 1H), 7.62 (s, 2H), 7.16 - 7.10 (m, 1H), 6.66 - 6.60 (m, 1H), 6.47 - 6.40 (m, 2H), 5.72 - 5.62 (m, 1H), 2.50 (s, 3H), 2.01 -1.82 (m, 1H), 1.62 (d, J= 6.4 Hz, 3H), 0.89 - 0.81 (m, 2H), 0.79 - 0.70 (m, 2H). MS: m / z 550.1 (M+H+).Attorney Docket No. 49366-0056WO4

[1673] Example 3: ( / ?)-5-chloro-2-(l -(2-cyano-3-(6-(l -(difluoromethyl)-l H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (Compound 72) and (. S)-5-chloro-2-(l-(2-cyano-3-(6-(l-(difluoromethyl)-l / / -pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (Compound 66)

[1674]

[1675] Step 1 – Synthesis of 5-acetyl-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile:

[1676] To a mixture of 5-acetyl-3-(6-chloropyridin-3-yl)-7-methylquinoline-2-carbonitrile (500 mg, 1.55 mmol), l-(difluoromethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-177-pyrazole (568 mg, 2.33 mmol) and K2CO3 (644 mg, 4.66 mmol) in dioxane (5 mL) and water (0.5 mL) was added Pd(dppf)C12 (113 mg, 155 pmol) at room temperature. The reaction mixture was evacuated and backfilled 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 mixture was quenched with water (10 mL), and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent gradient: 0 - 50% EtOAc in petroleum ether) to give the title compound (310 mg) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J= 0.8 Hz, 1H), 8.97 (s, 1H), 8.92 - 8.88 (m, 1H), 8.49 (s, 1H), 8.40 (d, J= 1.2 Hz, 1H), 8.26 - 8.24 (m, 1H), 8.21 (s, 1H), 8.08 - 7.75 (m, 2H), 2.79 (s, 3H), 2.49 (s, 3H). MS: m / z: 404.0 (M+H+).

[1677] Step 2 – Synthesis of 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-5-(1-hydroxyethyl)-7-methylquinoline-2-carbonitrile:

[1678] To a mixture of acetyl-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile (310 mg, 768 μmol) in DCM (15 mL) was added NaBH4 (58 mg, 1.54 mmol) and MeOH (2 mL) at 0 °C. The resulting reaction was stirred at 0 °C for 1 h underAttorney Docket No. 49366-0056WO4

[1679] N2. After that, the reaction was quenched with sat. aq. NH4CI (10 mL) at 0 °C, extracted with DCM (10 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (311 mg) as yellow oil. MS: m / z 406.1 (M+H+).

[1680] Step 3 – Synthesis of 5-(1-bromoethyl)-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile:

[1681] To a mixture of 3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-5-(1-hydroxyethyl)-7-methylquinoline-2-carbonitrile (311 mg, 764 μmol) and PPh3 (401 mg, 1.53 mmol) in DCM (5 mL) was evacuated and backfilled with N2 for 3 times, CBr4 (507 mg, 1.53 mmol) was added at 0°C slowly and then the mixture was stirred at 0 °C for 1 h under N2 atmosphere.

[1682] The reaction mixture was quenched with sat. aq. NaHCO3 (10 mL) at 0 °C, and extracted with DCM (15 mL x 3). The combined organic layers were washed with brine (20 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (solvent gradient: 0 - 25% EtOAc in petroleum ether) to give the title compound (248 mg) as an off-white solid. ’H NMR (400 MHz, DMSO-cA) 89.04 -9.00 (m, 1H), 8.99 (s, 2H), 8.50 (s, 1H), 8.35 - 8.29 (m, 1H), 8.08 (d, J= 8.8 Hz, 1H), 8.07 - 7.76 (m, 3H), 6.57 - 6.32 (m, 1H), 2.62 (s, 3H), 2.24 - 1.99 (m, 3H). MS: m / z 468.0 (M+H+).

[1683] Step 4 - Synthesis of 5-chloro-2-(1-(2-cyano-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide:

[1684] To a solution of 5-(1-bromoethyl)-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile (248 mg, 529 μmol) in DMF (5 mL) was added K2CO3 (220 mg, 1.59 mmol) and 5-chloro-2-hydroxy-benzenesulfonamide (165 mg, 794 pmol). The mixture was stirred at room temperature for 16 h. After that, the reaction was quenched with water (10 mL), extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile 45% - 75% / 0.225% formic acid in water) to give the title compound (190 mg) as a yellow solid. MS: m / z 595.1 (M+H+).

[1685] Step 5 - Synthesis of (l?)-5-chloro-2-(l-(2-cyano-3-(6-(l-(difluoromethyl)-l / / -pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide & (5)-5-Attorney Docket No. 49366-0056WO4

[1686] chloro-2-(l-(2-cyano-3-(6-(l-(difluoromethyl)-l / / -pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide:

[1687] 5-chloro-2-(1-(2-cyano-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (190 mg) was separated by chiral SFC (Phenomenex-Cellulose-2 (250mm*30mm,10um); Supercritical CO2 / MeOH: MeCN = 1: 1 (0.1% NH3H2O) = 40 / 60; 80 mL / min) to afford (R)-5-chloro-2-(1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (76 mg, first peak) and (S)-5-chloro-2-(1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (49 mg, second peak) both as yellow solid. Absolute configuration was arbitrarily assigned to each enantiomer. First Peak (Compound 72): 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 9.02 (d, J= 2.0 Hz, 1H), 8.99 (s, 1H), 8.50 (s, 1H), 8.36 -8.33 (m, 1H), 8.08 (d, J= 8.4 Hz, 1H), 8.07 - 7.78 (m, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.49 - 7.41 (m, 3H), 7.11 (d, J= 9.2 Hz, 1H), 6.63 - 6.58 (m, 1H), 2.52 (s, 3H), 1.77 (d, J= 6.0 Hz, 3H). MS: m / z 595.1 (M+H+). Second peak (Compound 66): 1H NMR (400 MHz, DMSO-d6) δ 9.12 (s, 1H), 9.02 (d, J= 2.0 Hz, 1H), 8.99 (s, 1H), 8.50 (s, 1H), 8.36 - 8.33 (m, 1H), 8.08 (d, J= 8.0 Hz, 1H), 8.06 - 7.77 (m, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.72 (d, J= 2.8 Hz, 1H), 7.43 (s, 1H), 7.48 - 7.45 (m, 2H), 7.11 (d, J = 8.8 Hz, 1H), 6.65 - 6.57 (m, 1H), 2.52 (s, 3H), 1.77 (d, J= 6.0Hz, 3H). MS: m / z 595.1 (M+H+).

[1688] Example 4: (R)-2-((1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide (Compound 11) and (5)-2-((l-(2-cyano-3-(6-(l-(difluoromethyl)-l / / -pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide (Compound 67)

[1689]

[1690] Step 1 - Synthesis of 2-((1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide:Attorney Docket No. 49366-0056WO4

[1691] A mixture of 5-(1-bromoethyl)-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile (330 mg, 704 μmol) and 2-aminobenzenesulfonamide (243 mg, 1.41 mmol) in dioxane (3 mL) was stirred at 100 °C for 16 h. After cooling to room temperature, the reaction mixture was quenched with water (10 mL), extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile 50% - 80% / 0.225% formic acid in water) to give the title compound (100 mg) as an off-white solid. MS: m / z 560.1 (M+H+).

[1692] Step 2 - Synthesis of (l?)-2-((l-(2-cyano-3-(6-(l-(difluoromethyl)-l / / -pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide & (A)-2-((l-(2-cyano-3-(6-( l-(difluoromethyl)- LH-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide:

[1693] 2-((1-(2-Cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide (100 mg) was separated by chiral SFC (Phenomenex-Cellulose-2 (250mm*30mm,10um); Supercritical CO2 / MeOH: MeCN = 1: 1 (0.1% NH3H2O) = 40 / 60; 80 mL / min) to afford (R)-2-((1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide (42 mg, first peak) and (S)-2-((1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)benzenesulfonamide (41 mg, second peak) both as a white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First Peak (Compound 11): ‘HNMR (400 MHz, DMSO-6) 5 9.13 (s, 1H), 9.02 - 9.01 (m, 1H), 8.98 (s, 1H), 8.50 (s, 1H), 8.36 - 8.33 (m, 1H), 8.07 (d, J= 8.0 Hz, 1H), 8.06 - 7.77 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.66 - 7.63 (m, 1H), 7.61 (s, 2H), 7.17 - 7.11 (m, 1H), 6.66 - 6.61 (m, 1H), 6.47 - 6.42 (m, 2H), 5.69 - 5.66 (m, 1H), 2.49 (s, 3H), 1.62 (d, J= 6.4 Hz, 3H). MS: m / z 560.2 (M+H+). Second peak (Compound 67): 1H NMR (400 MHz, DMSO-d6) δ 9.13 (s, 1H), 9.02 (d, J= 2.0 Hz, 1H), 8.98 (s, 1H), 8.50 (s, 1H), 8.36 - 8.33 (m, 1H), 8.07 (d, J= 8.0 Hz, 1H), 8.06 - 7.77 (s, 1H), 7.89 (s, 1H), 7.79 (s, 1H), 7.66 - 7.63 (m, 1H), 7.61 (s, 2H), 7.17 - 7.11 (m, 1H), 6.65 - 6.62 (m, 1H), 6.47 - 6.42 (m, 2H), 5.69 - 5.66 (m, 1H), 2.49 (s, 3H), 1.62 (d, J = 6.4 Hz, 3H). MS: m / z 560.2 (M+H+).

[1694] Example 5: (R)-5-chloro-2-(1-(2-cyano-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (Compound 73) and (A)-Attorney Docket No. 49366-0056WO4

[1695] 5-chloro-2-(1-(2-cyano-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (Compound 68)

[1696]

[1697] Step 1 – Synthesis of 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridine:

[1698] To a solution of 2-chloro-5-iodo-pyridine (2 g, 8.35 mmol) in dioxane (20 mL) and H2O (2 mL) was added 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.45 g, 10.02 mmol), K2CO3 (2.31 g, 16.71 mmol) and Pd(dppf)Cl2 (306 mg, 418 μmol). The mixture was evacuated and backfilled with N2 3 times, and then it was stired at 100 °C for 3 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was quenched with H2O (20 mL), extracted with EtOAc (20 mL x 3). 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 (1.9 g) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (s, 1H), 8.81 (d, J= 2.4 Hz, 1H), 8.40 (s, 1H), 8.21 - 8.17 (m, 1H), 7.87 (t, J= 59.6 Hz 1H), 7.58 (d, J= 8.4 Hz, 1H). MS: m / z 229.9 (M+H+).

[1699] Step 2 – Synthesis of 5-acetyl-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinoline-2-carbonitrile:

[1700] To a solution of 5-acetyl-7-methyl-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)quinoline-2-carbonitrile (660 mg, 1.96 mmol) in dioxane (10 mL) and H2O (0.5 mL) was added 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridine (542 mg, 2.36 mmol), Pd2(dba)3 (180 mg, 197 μmol), XPhos (187.65 mg, 393.63 μmol, 0.2 eq) and CsF (896.88 mg, 5.90 mmol, 3 eq). The mixture was evacuated and purged with N2 3 times, then the mixture was stirred at 110 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with H2O (10 mL), extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 2), dried over anhydrous Na2SO4, filtered and concentratedAttorney Docket No. 49366-0056WO4

[1701] under reduced pressure to give the crude product, which was purified by silica gel chromatography (solvent gradient: 0 - 30% EtOAc in petroleum ether) to give the title compound (260 mg) as yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.23 (d, J= 1.6 Hz, 1H), 9.10 - 8.93 (m, 2H), 8.52 (s, 1H), 8.48 - 8.44 (m, 1H), 8.40 (d, J= 1.6 Hz, 1H), 8.21 (s, 1H), 8.07 (d, J= 7.6 Hz, 1H), 2.79 (s, 3H), 2.66 (s, 3H). MS: m / z 404.1 (M+H+).

[1702] Step 3 – Synthesis of 3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-5-(1-hydroxyethyl)-7-methylquinoline-2-carbonitrile:

[1703] To a solution of 5-acetyl-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinoline-2-carbonitrile (260 mg, 645 μmol) in DCM (4 mL) was added NaBH4 (29 mg, 773 pmol) at 0 °C under N2 atmosphere, MeOH (0.5 mL) was added until the reaction was completely clear. The resulting reaction was kept stirring at 0 °C for 2 h. The reaction was quenched with sat. aq. NH4CI (10 mL) at 0 °C and extracted with DCM (20 mL x 3). 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: 30 - 50% EtOAc in petroleum ether) to give the title compound (151 mg) as a yellow solid. MS: m / z 406.1 (M+H+).

[1704] Step 4 – Synthesis of 5-(1-bromoethyl)-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinoline-2-carbonitrile:

[1705] To a solution of 3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-5-(1-hydroxyethyl)-7-methylquinoline-2-carbonitrile (151 mg, 372 μmol) in DCM (2 mL) was added CBr4 (371mg, 1.12 mmol) and PPh3 (293 mg, 1.12 mmol). The mixture was stirred at 0 °C for 1 h. The reaction mixture was used for the next step directly without further purification. MS: m / z 468.0 (M+H+).

[1706] Step 5 – Synthesis of 5-chloro-2-(1-(2-cyano-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide:

[1707] To a solution of 5-(1-bromoethyl)-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinoline-2-carbonitrile (above mentioned reaction solution, in DCM) was added DMF (2 mL), followed by 5-chloro-2-hydroxybenzenesulfonamide (154 mg, 743 μmol) and K2CO3 (154 mg, 1.11 mmol). The mixture was stirred at room temperature for 16 h under N2 atmosphere. The reaction was diluted with H2O (10 mL), extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (30 mL x 3), dried over anhydrous Na2SO4,Attorney Docket No. 49366-0056WO4

[1708] filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 55% - 58% / 0.225% formic acid in water) to give the title compound (100 mg) as a white solid. MS: m / z 595.1 (M+H+).

[1709] Step 6 - Synthesis of (7?)-5-chloro-2-(l-(2-cyano-3-(5-(l-(difluoromethyl)-l / T-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide & (S)-5-chloro-2-(l-(2-cyano-3-(5-(l-(difluoromethyl)-l / / -pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide:

[1710] 5-chloro-2-(l-(2-cyano-3-(5-(l -(difluoromethyl)- l / 7-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (100 mg, 168 pmol) was separated by using chiral SFC (DAICEL CHIRALPAK IC (250mm*30mm,10um); Supercritical CO2 / MeOH +0.1% NH3‘H2O = 45 / 55; 140 mL / min) to afford (R)-5-chloro-2-(1-(2-cyano-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (33.8 mg, first peak) and (S)-5-chloro-2-(1-(2-cyano-3-(5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-2-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (33.7 mg, second peak) both as white solid. Absolute configuration was arbitrarily assigned to each enantiomer. First peak (Compound 73): 1H NMR (400 MHz, DMSO-d6) δ 9.25 - 9.21 (m, 2H), 9.03 (s, 1H), 8.55 (s, 1H), 8.42 - 8.40 (m, 1H), 8.24 (d, J= 8.0 Hz, 1H), 8.09 - 7.77 (m, 3H), 7.72 (d, J= 2.8 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.43 (s, 2H), 7.09 (d, J= 9.2 Hz, 1H), 6.67 - 6.62 (m, 1H), 2.51 (s, 3H), 1.79 (d, J= 6.4 Hz, 3H). MS: m / z 595.1 (M+H+). Second peak (Compound 68): 1H NMR (400 MHz, DMSO-d6) δ 9.25 - 9.21 (m, 2H), 9.03 (s, 1H), 8.55 (s, 1H), 8.42 - 8.40 (m, 1H), 8.24 (d, J = 8.0 Hz, 1H), 8.09 - 7.77 (m, 3H), 7.72 (d, J = 2.8 Hz, 1H), 7.48 - 7.44 (m, 1H), 7.43 (s, 2H), 7.09 (d, J= 9.2 Hz, 1H), 6.67 -6.62 (m, 1H), 2.51 (s, 3H), 1.79 (d, J= 6.4 Hz, 3H). MS: m / z 595.1 (M+H+).

[1711] Example 6: (7?)-6-chloro-3-(l-(2-cyano-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)pyridine-2-sulfonamide (Compound 69) and (5)-6-chloro-3-(l-(2-cyano-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)pyridine-2-sulfonamide (Compound 70)Attorney Docket No. 49366-0056WO4

[1712]

[1713] Step 1 - Synthesis of 5-acetyl-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile:

[1714] A mixture of 5-acetyl-3-(6-chloro-3-pyridyl)-7-methyl-quinoline-2-carbonitrile (450 mg, 1.4 mmol), (2-methoxypyrimidin-5-yl)boronic acid (322.92 mg, 2.1 mmol), Pd(dppf)C12 (102 mg, 140 pmol) and K2CO3 (579 mg, 4.2 mmol) in dioxane (9 mL) and water (0.9 mL) was evacuated and backfilled with N2 for 3 times, and then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was quenched by water (25 mL) and filtered, the filter cake was washed by MeOH (25 mL) and concentrated under vacuum to give the title compound (550 mg, crude) as a yellow solid. The crude was used for the next step directly without further purification. 'H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.35 (s, 1H), 9.27 (s, 1H), 9.01 (d, J= 12.8 Hz, 1H), 8.41 (s, 1H), 8.36 - 8.28 (m, 1H), 8.23 (s, 1H), 7.63 - 7.39 (m, 1H), 4.02 (s, 3H), 2.80 (s, 3H), 2.68 (s, 3H). MS: m / z 396.1 (M+H+).

[1715] Step 2 - Synthesis of 5-(l-hydroxyethyl)-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile:

[1716] To a solution of 55-acetyl-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile (610 mg, 1.54 mmol) in DCM (10 mL) was added NaBH4 (210 mg, 5.55 mmol) and MeOH (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere. After that, the reaction mixture was quenched with sat. aq. NH4CI (20 mL) at 0 °C, extracted with DCM (50 mL x 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the title compound (650 mg, crude) as a yellow solid. MS: m / z 398.1 (M+H+).

[1717] Step 3 - Synthesis of 5-(l-bromoethyl)-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile:Attorney Docket No. 49366-0056WO4

[1718] To a solution of 5-(l-hydroxyethyl)-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile (300 mg, 755 pmol) in DCM (10 mL) was added PPh3 (594 mg, 2.26 mmol) and CBr4 (751.00 mg, 2.26 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h under N2 atmosphere. After that, the reaction mixture was quenched with water (10 mL) at 0 °C, extracted with DCM (10 mL x 2). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give the title compound (300 mg, crude) as yellow oil. MS: m / z 460.0 (M+H+).

[1719] Step 4 - Synthesis of 6-chloro-3-(l-(2-cyano-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)pyridine-2-sulfonamide:

[1720] To a solution of 5-(l-bromoethyl)-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile (300 mg, 652 pmol) in DMF (10 mL) was added K2CO3 (450 mg, 3.26 mmol) and 6-chloro-3-hydroxy-pyridine-2-sulfonamide (272 mg, 1.3 mmol). The mixture was stirred at room temperature for 16 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organics were washed with brine (50 mL x 3), dried over Na2SO4, filtered and concentrated. The crude residue was purified by silica gel chromatography (solvent gradient: 0 -60% (25% ethyl alcohol in EtOAc) in hexanes) to give the title compound (125 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 2H), 9.13 (d, J= 1.2 Hz, 1H), 9.10 (s, 1H), 8.46 - 8.42 (m, 1H), 8.32 (d, J= 8.0 Hz, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.76 (d, J= 9.2 Hz, 1H), 7.62 (s, 1H), 7.60 - 7.58 (m, 2H), 6.70 - 6.60 (m, 1H), 4.03 (s, 3H), 2.53 (s, 3H), 1.75 (d,.7= 6.4 Hz, 3H). MS: m / z 588.1 (M+H+).

[1721] Step 5 - Synthesis of (l?)-6-chloro-3-(l-(2-cyano-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)pyridine-2-sulfonamide and (5)-6-chloro-3-(l-(2-cyano-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)pyridine-2-sulfonamide:

[1722] 6-chloro-3-(l-(2-cyano-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methyl quinolin-5-yl)ethoxy)pyridine-2-sulfonamide (100 mg, 170 pmol) was separated by using chiral SFC (DAICEL CHIRALPAK AD (250mm x 30mm, lOum); Supercritical CO2 / EtOH + 0.1% NH3·H2O = 55 / 45; 140 mL / min) to afford (A)-6-chloro-3-(l-(2-cyano-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)pyridine-2-sulfonamide (21.4 mg, first peak) and (5)-6-chloro-3-(l-(2-cyano-3-(6-(2-methoxypyrimidin-5-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethoxy)pyridine-2-sulfonamide (34.7 mg, second peak) both as yellowAttorney Docket No. 49366-0056WO4

[1723] solid. First Peak (Compound 69):1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 2H), 9.12 (s, 1H), 9.09 (s, 1H), 8.47 - 8.41 (m, 1H), 8.31 (d, J= 8.0 Hz, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.65 - 7.56 (m, 3H), 6.72 - 6.60 (m, 1H), 4.02 (s, 3H), 2.53 (s, 3H), 1.75 (d, J= 5.6 Hz, 3H). MS: m / z 588.1 (M+H+). Second Peak (Compound 70):1H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 2H), 9.13 (d, J= 2.4 Hz, 1H), 9.09 (s, 1H), 8.47 - 8.41 (m, 1H), 8.31 (d, J= 8.4 Hz, 1H), 8.00 (s, 1H), 7.95 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.63 - 7.68 (m, 3H), 6.70 - 6.62 (m, 1H), 4.02 (s, 3H), 2.53 (s, 3H), 1.75 (d, J= 6.4 Hz, 3H). MS: m / z 588.1 (M+H+).

[1724] Example 7: (l?)-6-chloro-3-((l-(2-cyano-3-(6-(l-(difluoromethyl)-lH-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)pyridine-2-sulfonamide (Compound 22)

[1725]

[1726] Step 1 - Synthesis of 5-acetyl-3-(6-(l-(difluoromethyl)-l / Z-pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile:

[1727] To a solution of 5-acetyl-3-(6-chloro-3-pyridyl)-7-methyl-quinoline-2-carbonitrile (1.3 g, 4.04 mmol) in dioxane (25 mL) with H2O (5 mL) was added 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.08 g, 4.44 mmol), Pd(dppf)C12 (296 mg, 0.40 mmol) and K2CO3 (1.12 g, 8.08 mmol). The mixture was evacuated and backfilled with N2 for 3 times, then the mixture was stirred at 100 °C for 2 h under N2 atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash silica gel column (0 - 50% EtOAc in hexanes) to afford the title compound (720 mg) as a white solid. 'H NMR (400 MHz, CDCI3) 8 9.23 (s, 1H), 8.97 (s, 1H), 8.93 - 8.89 (m, 1H), 8.49 (s, 1H), 8.43 - 8.38 (m, 1H), 8.28 - 8.23 (m, 1H), 8.20 (s, 1H), 8.08 (s, 1H), 8.05 - 7.75 (m, 1H), 2.79 (s, 3H), 2.66 (s, 3H). MS: m / z 404.2 (M+H+).

[1728] Step 2 - Synthesis of (R,E)-N-(1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide:Attorney Docket No. 49366-0056WO4

[1729] To a solution of 5-acetyl-3-(6-(l-(difluoromethyl)-l / / -pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile (720 mg, 1.78 mmol) in THF (25 mL) was added Ti(Oi-Pr)4 (5.07 g, 17.85 mmol) and (R)-2-methylpropane-2-sulfinamide (1.08 g, 8.92 mmol). The mixture was stirred at 65 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was quenched by addition of H2O (40 mL) at room temperature, and then extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (900 mg, crude) as yellow oil that required no further purification. MS: m / z 507.3 (M+H+).

[1730] Step 3 - Synthesis of (R)-N-((R)-1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide:

[1731] To a solution of (R,E)-N-(1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethylidene)-2-methylpropane-2-sulfinamide (900 mg, 1.78 mmol) in THF (15 mL) was added NaBH4 (80.66 mg, 2.13 mmol). The mixture was stirred at room temperature for 1 h under N2 atmosphere. The reaction was quenched with sat. aq. NH4CI (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by reverse phase chromatography (acetonitrile 33% - 63% / 0.225% formic acid in water) to give the title compound (340 mg) as a white solid. MS: m / z 509.3 (M+H+).

[1732] Step 4 - Synthesis of (R)-5-(1-aminoethyl)-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile:

[1733] To a solution of (R)-N-((R)-1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (340 mg, 669 pmol) in dioxane (2 mL) was added HC1 (10 mL, 2M in dioxane) at room temperature. The mixture was stirred at room temperature for 1 h. The reaction was quenched with sat. aq. NaHCCh (20 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (900 mg, crude) as yellow oil that required no further purification. (210 mg) as yellow oil. MS: m / z 405.2 (M+H+).

[1734] Step 5 - Synthesis of (R)-N-(tert-butyl)-6-chloro-3-((1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)pyridine-2-sulfonamide:Attorney Docket No. 49366-0056WO4

[1735] To a solution of (7?)-5-(l-aminoethyl)-3-(6-(l-(difluoromethyl)-l / 7-pyrazol-4-yl)pyridin-3-yl)-7-methylquinoline-2-carbonitrile (271 mg, 670 pmol) in DMF (5 mL) was added 3-bromo-N-(tert-butyl)-6-chloropyridine-2-sulfonamide (329 mg, 1.01 mmol) (prepared according to the procedure in WO2023212693), Cui (25.52 mg, 134.02 pmol), N1,N2-bis(furan-2-ylmethyl)oxalamide (33 mg, 134 pmol) and Cs2CO3(436.67 mg, 1.34 mmol). The mixture was evacuated and backfilled with N2 for 3 times, then the mixture was stirred at 100 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction was quenched with H2O (15 mL), extracted with EtOAc (20 mL x 3). 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 - 50% EtOAc in hexanes) to give the title compound (210 mg) as a yellow solid. MS: m / z 651.3 (M+H+).

[1736] Step 6 - Synthesis of (R)-6-chloro-3-((1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)pyridine-2-sulfonamide:

[1737] To a solution of (R)-N-(tert-butyl)-6-chloro-3-((1-(2-cyano-3-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-3-yl)-7-methylquinolin-5-yl)ethyl)amino)pyridine-2-sulfonamide (210 mg, 322 pmol) in DCM (5 mL) was added TFA (120 pL, 1.61 mmol). The reaction mixture was stirred at room temperature for 48 h. The mixture was concentrated and the residue was purified by reverse phase chromatography (acetonitrile 44% - 74% / 0.225% formic acid in water) to give the title compound (102 mg) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.08 (s, 1H), 9.05 - 9.02 (m, 1H), 8.99 (s, 1H), 8.51 (s, 1H), 8.41 - 8.31 (m, 1H), 8.13 - 7.76 (m, 5H), 7.67 (m, 1H), 7.32 (d, J = 8.8 Hz, 1H), 7.05 (d, J = 9.2 Hz, 1H), 6.92 (d, J = 9.2 Hz, 1H), 5.77 - 5.67 (m, 1H), 2.52 (s, 3H), 1.64 (d, J= 6.0 Hz, 3H). MS: m / z 595.2 (M+H+).

[1738] Example 8: 2-[(ll?)-l-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-l-yl]-7-methylquinolin-5-yl}ethoxy]benzenesulfonamide (Compound 272) and (5)-2-(l-(2-cyano-3-(4-(2-methoxypyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (Compound 362)Attorney Docket No. 49366-0056WO4

[1739]

[1740] Step 1 - Preparation of tert-butyl 4-(5-acetyl-2-cyano-7-methylquinolin-3-yl)piperazine-l-carboxylate:

[1741] To a stirred solution of 5-acetyl-3-chloro-7-methylquinoline-2-carbonitrile (1.4 g, 5.722 mmol, 1 equiv) and Cs2CO3(4.66 g, 14.305 mmol, 2.5 equiv) in 1,4-dioxane (14 mL) were added tert-butyl piperazine- 1 -carboxylate (2.13 g, 11.444 mmol, 2 equiv) and (SP-4-l)-[l,3-BIs[2,6-bis(l-ethylpropyl)phenyl]-4,5-dichl oro-1, 3-dihy dro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (480.71 mg, 0.572 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1 to 1:1) to afford tert-butyl 4-(5-acetyl-2-cyano-7-methylquinolin-3-yl)piperazine-l -carboxylate (2 g) as a yellow solid. LC-MS: (ES+H, m / z): [M+H]+= 395.1.1H NMR (400 MHz, DMSO-d6) 5 8.76 (s, 1H), 8.29 (d, J= 1.7 Hz, 1H), 8.06 - 8.00 (m, 1H), 3.58 (t, J= 4.7 Hz, 4H), 3.16 (t, J= 4.9 Hz, 4H), 2.75 (s, 3H), 2.57 (s, 3H), 1.45 (s, 9H).

[1742] Step 2 - Preparation of tert-butyl 4-[2-cyano-5-(1-hydroxyethyl)-7-methylquinolin-3-yl]piperazine-1-carboxylate:

[1743] A solution of tert-butyl 4-(5-acetyl-2-cyano-7-methylquinolin-3-yl)piperazine-l-carboxylate (2 g, 5.070 mmol, 1 equiv) and NaBH4 (383.60 mg, 10.140 mmol, 2.00 equiv) in THF (20 mL) was stirred at 0°C for 30min under nitrogen atmosphere. The reaction was quenched by the addition of water (4 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL). The aqueous layer was extracted with CH2CI2 (3x10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford tert-butyl 4-[2-cyano-5-(l-hydroxyethyl)-7-methylquinolin-3-yl]piperazine-l-carboxylateAttorney Docket No. 49366-0056WO4

[1744] (2 g, crude) as a yellow solid. Which is used directly for the following step. LC-MS: (ES+H, m / z): [M+H]+= 397.2.

[1745] Step 3 - Preparation of tert-butyl 4-[2-cyano-5-(l-{2-[(£)- [(dimethylamino)methylidene]aminosulfonyl]phenoxy}ethyl)-7-methylquinolin-3-yl] piperazine-l-carboxylate:

[1746] To a stirred solution of tert-butyl 4-[2-cyano-5-(l-hydroxyethyl)-7-methylquinolin-3-yl]piperazine-l -carboxylate (2 g, 5.044 mmol, 1 equiv) and (£)-N'-(2-hydroxybenzenesulfonyl)-N, N-dimethylmethanimidamide (1727.18 mg, 7.566 mmol, 1.5 equiv) in toluene (20 mL) was added Acetonitrile, 2-(tributylphosphoranylidene)-[CMBP] (3652.43 mg, 15.132 mmol, 3 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for overnight under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1 to 1:10) to afford tert-butyl 4-[2-cyano-5-(l-{2-[(E)-[(dimethylamino)methylidene]aminosulfonyl]phenoxy}ethyl)-7-methylquinolin-3-yl]piperazine-1-carboxylate (2 g, over 2 steps) as a yellow solid. LC-MS: (ES+H, m / z) [M+H]+= 607.1.

[1747] Step 4 - Preparation of (E)- / V'-(2-{l-[2-cyano-7-methyl-3-(piperazin-l-yl)quinolin-5-yl] ethoxy} benzenesulfonyl)-7V, A-diniethylniethaniniidaniide:

[1748] A solution of tert-butyl 4-[2-cyano-5-(l-{2-[(£)- [(dimethylamino)methylidene]aminosulfonyl]phenoxy}ethyl)-7-methylquinolin-3-yl]piperazine-1 -carboxylate (2 g, 3.296 mmol, 1 equiv) and HC1 in 1,4-dioxane (4.0 M) (20 mL) in 1,4-di oxane (20 mL) was stirred at room temperature for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (50 mL). The mixture was basified to pH 8 with NH3·H2O. The aqueous layer was extracted with CH2CI2 (3x20 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (100% PE to 1:1) to afford (E)-A"-(2-{l-[2-cyano-7 -methyl-3 -(piperazin- 1 -yl)quinolin-5 -y 1] ethoxy } benzenesulfony 1)-A, A-dimethylmethanimidamide (1.6 g) as a yellow solid. LC-MS: (ES+H, m z): [M+H]+= 507.3.1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 8.13 (s, 1H), 7.83 (dd, J= 7.8, 1.8 Hz, 1H), 7.74 (s, 1H), 7.64 (d, J= 1.7 Hz, 1H), 7.37 (ddd, J= 8.7, 7.4, 1.8 Hz, 1H), 7.04 - 6.95 (m, 1H), 6.90 (d, JAttorney Docket No. 49366-0056WO4

[1749] = 8.3 Hz, 1H), 6.46 (q, J = 6.2 Hz, 1H), 3.26-3.14 (m, 4H), 3.05 (s, 3H), 3.01-2.93 (m, 4H), 2.91 (s, 3H), 2.41 (d, J= 1.1 Hz, 3H), 1.66 (d, J = 6.2 Hz, 3H).

[1750] Step 5 - Preparation of (E)-N'-[2-(1-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-1-yl]-7-methylquinolin-5-yl}ethoxy)benzenesulfonyl]-N,N-dimethylmethanimidamide:

[1751] To a stirred solution of (E)-N'-(2-{1-[2-cyano-7-methyl-3-(piperazin-1-yl)quinolin-5-yl]ethoxy}benzenesulfonyl)-N,N-dimethylmethanimidamide (200 mg, 0.395 mmol, 1 equiv) and Cs2CO3 (321.56 mg, 0.988 mmol, 2.5 equiv) in 1,4-dioxane (4 mL) were added 5-iodo-2-methoxypyrimidine (139.75 mg, 0.593 mmol, 1.5 equiv), Pd2(dba)3 (72.30 mg, 0.079 mmol, 0.2 equiv) and XPhos (37.64 mg, 0.079 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2h under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1 to 1:10) to afford (E)-A-[2-(l-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-l-yl]-7-methylquinolin-5-yl}ethoxy)benzenesulfonyl]-A, A-dimethylmethanimidamide (160 mg) as a yellow solid. LC-MS: (ES+H, m z). [M+H]+= 615.3.

[1752] Step 6 - Preparation of 2-(1-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-1-yl]-7-methylquinolin-5-yl}ethoxy)benzenesulfonamide:

[1753] A solution of (E)-N'-[2-(1-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-1-yl]-7-methylquinolin-5-yl}ethoxy)benzenesulfonyl]-N,N-dimethylmethanimidamide (160 mg, 0.260 mmol, 1 equiv) and N2H4 H2O (1 mL) in EtOH (5 mL) was stirred at 80°C for 30 min under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18; mobile phase, MeCN in Water (0.5% FA), 40% to 70% gradient in 15 min; detector, UV 254 nm to afford 2-(l-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-l-yl]-7-methylquinolin-5-yl}ethoxy)benzenesulfonamide (70 mg) as a yellow solid. LC-MS: (ES+H, m / z) [M+H]+= 560.1.Attorney Docket No. 49366-0056WO4

[1754] Step 7 - Preparation of 2-[(1R)-1-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-1-yl]-7-methylquinolin-5-yl}ethoxy]benzenesulfonamide and (S)-2-(1-(2-cyano-3-(4-(2-methoxypyrimidin-5-yl)piperazin-1-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide:

[1755] The product (70 mg) was purified by Prep-Chiral-HPLC with the following conditions (Column: CHIRALPAK IF 3*25 cm, 5 pm; Mobile Phase A: MTBE(10mMNH3)--HPLC, Mobile Phase B: MeOH— HPLC; Flow rate: 40 mL / min; Gradient (B%): isocratic 10% B; Wave Length: 220 / 254 nm; RTl(min): 6.73; RT2(min): 10.08; Sample Solvent: HFIP MeOH DCM-HPLC; Injection Volume: 1.5 mL; Number Of Runs: 3) to afford 2-[(1R)-1-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-1-yl]-7-methylquinolin-5-yl}ethoxy]benzenesulfonamide (23.6 mg, 33.71%) and (S)-2-(1-(2-cyano-3-(4-(2-methoxypyrimidin-5-yl)piperazin-1-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide(23.0 mg) as a yellow solid.

[1756] 2-[(17?)-l-{2-cyano-3-[4-(2-methoxypyrimidin-5-yl)piperazin-l-yl]-7-methylquinolin-5-yl}ethoxy]benzenesulfonamide (Compound 272):

[1757] LC-MS: (ES+H, m / z) [M+H] = 560.2

[1758] 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 2H), 8.37 (s, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.80-7.73 (m, 2H), 7.43-7.34 (m, 1H), 7.17 (s, 2H), 7.06-6.95 (m, 2H), 6.47 (q, J = 6.3 Hz, 1H), 3.87 (s, 3H), 3.49-3.43 (m, 4H), 3.43-3.38 (m, 4H), 2.44 (s, 3H), 1.78 (d, J = 6.3 Hz, 3H).

[1759] (»S)-2-(l-(2-cyano-3-(4-(2-methoxypyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (Compound 362):

[1760] LC-MS: (ES+H, m / z): [M+H]+= 560.2

[1761] 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 2H), 8.37 (s, 1H), 7.87 (d, J = 1.7 Hz, 1H), 7.80-7.73 (m, 2H), 7.43-7.34 (m, 1H), 7.17 (s, 2H), 7.06-6.95 (m, 2H), 6.47 (q, J = 6.2 Hz, 1H), 3.87 (s, 3H), 3.50-3.43 (m, 4H), 3.43-3.38 (m, 4H), 2.44 (s, 3H), 1.78 (d, J = 6.2 Hz, 3H).

[1762] Step 8 - Preparation of (E)-N'-(2-hydroxybenzenesulfonyl)-N,N-dimethylmethanimidamide:

[1763] A solution of 2-hydroxybenzenesulfonamide (10 g, 57.740 mmol, 1 equiv) in DMF-DMA (50 mL) was stirred at 50 °C for Ih under nitrogen atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with diethyl ether (3 x lOOmL). The precipitated solids were collected by filtration and washed withAttorney Docket No. 49366-0056WO4

[1764] diethyl ether (3 x 50 mL) to afford (E)-N'-(2-hydroxybenzenesulfonyl)-N,N-dimethylmethanimidamide (10 g) as a off-white solid. LC-MS: (ES+H, m / z): [M+H]+= 229.2.

[1765] Example 9: (7?)-2-(l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide (Compound 136)

[1766] F

[1767]

[1768] Step 1 - Synthesis of tert-butyl 4-(2-(difluoromethyl)pyrimidin-5-yl)piperazine-l-carboxylate:

[1769] To a solution of 5-bromo-2-(difluoromethyl)pyrimidine (422 mg, 2.02 mmol) and tertbutyl piperazine- 1 -carboxylate (564 mg, 3.03 mmol) in toluene (8 mL) was added Cs2CO3(1.32 g, 4.04 mmol), Pd2(dba)3 (185 mg, 202 pmol) and BINAP (251 mg, 404 pmol). The mixture was evacuated and backfilled with N2 3 times, and then the mixture was stirred at 100 °C for 12 h under N2 atmosphere. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (0 - 35% EtOAc in hexanes) to give the title compound (620 mg) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 2H), 6.83 (t, J= 54.4 Hz, 1H), 3.51 - 3.44 (m, 4H), 3.40 - 3.33 (m, 4H), 1.42 (s, 9H). MS: m / z 315.1 (M+H+).

[1770] Step 2 - Synthesis of 2-(difluoromethyl)-5-(piperazin-l-yl)pyrimidine:

[1771] A solution of tert-butyl 4-[2-(difluoromethyl)pyrimidin-5-yl]piperazine-l-carboxylate (620 mg, 1.97 mmol) in HCl / dioxane (10 mL, 2M) was stirred at room temperature for 2 h. The reaction mixture was concentrated and diluted with water (10 mL). The solution was washed with EtOAc (20 mL x 3). The aqueous layer was adjusted pH to 7-8 with saturated aqueous NaHCO.y and then concentrated under reduced pressure. The residue was triturated with DCM (50 mL) at room temperature for 30 min. The suspension was filtered and the filtrate was concentrated under reduced pressure to give the title compound (262 mg, crude) as a yellow solid, which was used for next step directly without further purification. MS: m / z 215.2 (M+H+).Attorney Docket No. 49366-0056WO4

[1772] Step 3 - Synthesis of l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethan-l-one:

[1773] A mixture of l-(3-chloro-2-(difluoromethyl)-7-methylquinolin-5-yl)ethanone (220 mg, 799.48 pmol), 2-(difluoromethyl)-5-(piperazin-l-yl)pyrimidine (242 mg, 1.07 mmol), Ruphos Pd G2 (93 mg, 120 pmol) and Cs2CO3(782 mg, 2.40 mmol) in dioxane (4 mL) was degassed and purged with N2 3 times, and then the mixture was stirred at 120 °C for 16 h under N2 atmosphere. After cooling to room temperature, the reaction mixture was filtered. The filter cake was washed with DCM (35 mL x 3). The filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (solvent gradient: 0 - 40% EtOAc in hexanes) to give the title compound (170 mg) as a yellow solid. MS: m / z 448.3 (M+H+).

[1774] Step 4 - Synthesis of l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethan-l-ol:

[1775] To a solution of l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethan-l-one (170 mg, 372 pmol) in DCM (3 mL) and MeOH (0.3 mL) was added NaBH4 (28 mg, 745 μmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. The reaction was quenched with sat. aq. NH4CI (10 mL) at 0 °C and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (170 mg, crude) as a white solid, which was used for the next step directly without further purification. MS: m / z 450.2 (M+H+).

[1776] Step 5 - Synthesis of l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-l-yl)-7-methyIquinolin-5-yl)ethyl methanesulfonate:

[1777] To a solution of l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethan-l-ol (207 mg, 0.46 mmol) in DCM (10 mL) was added Et₃N (140 mg, 1.38 mmol) and MS2O (96 mg, 0.552 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 0.5 h. The mixture was quenched with sat. aq. NaHCO3(10 mL), extracted with DCM (15 mL x 3). The combined organic layers were washed with H2O (30 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the title compound (243 mg, crude) as yellow oil. The crude was used for the next step directly without further purification.Attorney Docket No. 49366-0056WO4

[1778] Step 6 - Synthesis of 2-(l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethoxy)benzenesulfonamide:

[1779] To a solution of l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-l-yl)-7-methylquinolin-5-yl)ethyl methanesulfonate (243 mg, 0.46 mmol) in THF (10 mL) was added K2CO3 (191 mg, 1.38 mmol) and 2-hydroxybenzenesulfonamide (96 mg, 0.55 mmol). The mixture was stirred at 60 °C for 16 h. After cooling to room temperature, the reaction was quenched with water (10 mL), extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (10 mL), dried over anhydrous NazSCL, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (acetonitrile 45% -75% / 0.225% formic acid in water) to give the title compound (120 mg) as a yellow solid. MS: m / z 605.3 (M+H+).

[1780] Step 7 - Synthesis of (?)-2-(l-(2-(difluoromethyl)-3-(4-(2-(difluoromethyl)pyrimidin-5-yl)piperazin-...

Claims

1. Attorney Docket No. 49366-0056WO4WHAT IS CLAIMED IS:

1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein:Z is CH orN;R1is hydrogen, halogen, cyano, C3-C6 cycloalkyl, 4-10 membered heterocyclyl, C1-C6 thioalkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkoxyalkyl, or C1-C6 alkyl optionally substituted with (i) C3-C6 cycloalkyl or (ii) 4-10 membered heterocyclyl;R2is C6-C10 aryl optionally substituted with 1-4 independently selected R2A, 5-14 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-C6 alkoxyalkyl optionally substituted with -C(=O)NRARC, or C1-C6 alkoxy 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;^Y^NRARB(vi) o;(vii) -NHC(=O)Rc;(viii) -C(=O)ORD;Attorney Docket No. 49366-0056WO4(ix) -SO2RD;(x) -NHSO2RD;(xi) -SO2NRDRE;(xii) -NHC(=O)C1-C6 alkyl optionally substituted with NRARB;(xiii) C1-C6 haloalkyl;(xiv) C1-C6 hydroxy alkyl;(xv) -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl);(xvi) -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF);(xvii) 5-10 membered heteroaryl optionally substituted with 1-3 substituents independently selected from hydroxyl; cyano; C1-C6 alkoxy; C1-C6 haloalkoxy; C1-C6 alkyl optionally substituted with hydroxyl or cyano; C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen; C1-C6 haloalkyl optionally substituted with hydroxyl or cyano; halogen; -C(=O)NRARB; -NRAC(=O)Rc; -NRARB; -OR7; -SR8; -P(=O)RARB; -SO2RD; and 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, halogen, or C1-C6 alkyl;(xviii) 4-10 membered heterocyclyl optionally substituted with 1-3 substituents independently selected from hydroxyl, cyano, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, -C(=O)C1-C6 alkyl, -SO2(C1-C6 alkyl), -SO2NRDRE, C1-C6 alkoxy, -C(=O)NRARB, -NRARB, -NHC(=O)C1-C6 alkyl optionally substituted with -NRARB, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy or hydroxyl;(xix) C1-C6 alkyl optionally substituted with 1-3 substituents independently selected from hydroxyl, oxo, -NRARB, -C(=O)NRARB, C1-C6 alkoxy, and 4-10 membered heterocyclyl optionally substituted with hydroxyl, C1-C6 alkyl, aralkyl, heteroaralkyl, -C(=O)NRARB, or -C(=O)C3-C6 cycloalkyl;(xx) C1-C6 alkoxy optionally substituted with hydroxyl, -NRARBor 4-10 membered heterocyclyl optionally substituted with hydroxyl, cyano, halogen, C1-C6 alkyl, aralkyl, heteroaralkyl, or-C(=O)C3-C6 cycloalkyl;(xxi) C3-C6 cycloalkyl optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl;Attorney Docket No. 49366-0056WO4(xxii) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; and (xxiii) 4-10 membered heterocyclyloxy optionally substituted with hydroxyl, cyano, halogen, or C1-C6 alkyl optionally substituted with hydroxyl;each RAand RBis independently selected from hydrogen, hydroxyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 4-6 membered heterocyclyl, 5-6 membered heteroaryl, C2-C6 alkenyl, C1-C6 haloalkyl, and C1-C6 alkyl optionally substituted with hydroxyl or C1-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-C6 alkyl;each Rcis independently selected from C3-C6 cycloalkyl, -C(=O)NHRY1, and a C1-C6 alkyl optionally substituted with -NRARBor with 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl or with C1-C6 hydroxylalkyl;each RDand REis independently selected from hydrogen, hydroxyl, phenyl, C1-C6 alkoxy, C3-C6 cycloalkyl, 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen, and C1-C6 alkyl optionally substituted with oxo or -NRARB;each RFis independently selected from cyano, hydroxyl, halogen, C3-C6 cycloalkyl, and C1-C6 alkyl;each R3Aand R3Bis independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 haloalkyl, 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-C6 alkyl, or acrylamido;R5is hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, cyano, -NR5AR5B, -NR5AC(=O)R5B, or -C(=O)NR5AR5B;R’Aand R5Bare independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C1-C6 hydroxyalkyl;R6is hydrogen, halogen, or C1-C6 alkyl;each R7is independently selected from C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, wherein the C3-C6 cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl are each optionally and independently substituted with 1-3 independently selected R7A;Attorney Docket No. 49366-0056WO4each R7Ais independently selected from hydroxyl, cyano, halogen, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, and C1-C6 alkyl optionally substituted with hydroxyl;R8is C1-C6 alkyl or C1-C6 haloalkyl;X is a bond, CH2, CH(CH3), C(CHs)2, orW is NR3Bor O;Y is phenyl, naphthyl, or 5-10 membered heteroaryl, wherein the phenyl, napthyl, and 5-10 membered heteroaryl are each optionally and independently substituted with 1-3* - L1- k A -j - (RY1)Zindependently selected RYorxS, wherein * represents the connection of L1to the remainder of the compound of Formula (I);each R1is independently selected from: halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 hydroxy alkyl, C3-C6 cycloalkyl, -(CH2)n-C(=O)RF, -(CH2)n-NHC(=O)RF, -(CH2)n-NHC(=O)ORF, -CO2RG, -P(=O)RARB, -(CH2)n-SO2NRHRI, -(CH2)n-NHSO2RJ, -(CH2)n-S(=O)(=NRH)RJ, -(CH2)n-S(=O)(=NRH)NRHRI, -(CH2)n-C(=N-OH)RJ, -(CH2)n-SO2RT, -(CH2)n-C(=O)NRHRI, -(CH2)n-C(=O)NRHORI, and C1-C6 haloalkyl optionally substituted with hydroxyl;each RFis independently selected from: C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);each RGis independently selected from: hydrogen, C3-C6 cycloalkyl, 5-6 membered heteroaryl, 4-6 membered heterocyclyl, and C1-C6 alkyl optionally substituted with hydroxyl or -SO2(C1-C6 alkyl);each RHand R1is independently selected from: hydrogen, C1-C6 alkoxy, C3-C6 cycloalkyl, C2-C6 alkenyl, -(CH2)n-C(=O)NH2, -(CH2)n-SO2NH2, -(CH2)n-SO2(C1-C6 alkyl), and C1-C6 alkyl optionally substituted with hydroxyl, -P(=O)RARB, -SO2(C1-C6 alkyl), or C1-C6 alkoxy;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-C6 alkyl, and -C(=O)C1-C6 alkyl;Attorney Docket No. 49366-0056WO4RJis C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, or C1-C6 alkoxy;Ring A is phenyl, 4-10 membered heteroaryl, 4-10 membered heterocyclyl, or C4-C10 cycloalkyl;L1is a bond, C1-C6 alkoxylene, -(CH2)n-NHC(=O)-, -C(=O)NH-(CH2)n-, -CO2-, -SO2-, -NHSO2-, -SO2NH-, -S(=O)(=NRG)-, -SO2(C1-C6 alkylene)-, -C(=O)C(=O)NH-, or C1-C6 alkylene 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, -SO2(C1-C6 alkyl), -C(=O)NRHRI, 4-6 membered heteroaryl, C1-C6 alkoxy optionally substituted with RY2, C1-C6 haloalkyl, C1-C6 alkyl optionally substituted with RY2, and 4-6 membered heterocyclyl optionally substituted with hydroxyl or C1-C6 alkyl;RY2is hydroxyl, -NRHRI, -C(=O)NRHRI, or -SO2NRHRIn is 0, 1, or 2;m is 0, 1, 2, or 3; andz is 0, 1, 2, or 3;wherein:R2is 11-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A; orat least one R2Ais(a) -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl);(b) 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen, C1-C6 haloalkyl optionally substituted with hydroxyl or cyano, -OR7, -SR8; -SO2RD, -NRAC(=O)Rc, -P(=O)RARB, C1-C6 alkyl substituted with cyano, and 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl;(c) 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl and C1-C6 haloalkoxy;(d) C1-C6 alkoxy substituted with hydroxyl or 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;Attorney Docket No. 49366-0056WO4(e) -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3- C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF); or (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl; or at least one of RAand RBis 4-6 membered heterocyclyl, 5-6 membered heteroaryl, or Cl- C6 haloalkyl; orat least one of RDand REis C3-C6 cycloalkyl or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen; orat least one RFis cyano, hydroxyl, halogen, C3-C6 cycloalkyl, or C1-C6 alkyl; or R5is C1-C6 haloalkyl; orR8is C1-C6 alkyl or C1-C6 haloalkyl; orat least one RYis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, -(CH2)n-C(=N-OH)RJ, or C3-C6 cycloalkyl; orat least one of RHand RIis C1-C6 alkyl substituted with -P(=O)RARB; orRJis C1-C6 haloalkyl.

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-C6 alkyl 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-C6 alkyl10. 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.

12. The compound of any one of Claims 1-3, wherein R1is C1-C6 thioalkyl.

13. The compound of any one of Claims 1-3, wherein R1is C1-C6 haloalkyl.

14. The compound of any one of Claims 1-3, wherein R1is C1-C6 alkoxy.

15. The compound of any one of Claims 1-3, wherein R1is C1-C6 alkoxyalkyl.Attorney Docket No. 49366-0056WO416. 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 5-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A.

19. The compound of any one of Claims 1-15, wherein R2is 11-14 membered heteroaryl optionally substituted with 1-4 independently selected R2A.

20. The compound of any one of Claims 1-15, wherein R2is 4-10 membered heterocyclyl optionally substituted with 1-3 independently selected R2A.

21. The compound of any one of Claims 1-15, wherein R2is 4-10 membered heterocyclyl substituted with 1-3 independently selected R2A.

22. The compound of any one of Claims 1-15, wherein R2is 4-10 membered heterocyclyl.

23. The compound of any one of Claims 1-15, wherein R2is C4-C10 cycloalkyl optionally substituted with 1-3 independently selected R2A.

24. The compound of any one of Claims 1-15, wherein R2is 4-10 membered heterocyclyloxy optionally substituted with 1-4 independently selected R2A.

25. The compound of any one of Claims 1-15, wherein R2is 5-10 heteroaryloxy optionally substituted with 1-4 independently selected R2A.

26. The compound of any one of Claims 1-25, wherein at least one R2Ais(a) -C(=O)-(C1-C6 alkyl or C1-C6 haloalky 1);(b) 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen, C1-C6 haloalkyl optionally substituted with hydroxyl or cyano, -OR7, -SR8; -SO2RD, -NRAC(=O)RC, -P(=O)RARB, C1-C6 alkyl substituted with cyano, and 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl;(c) 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl and C1-C6 haloalkoxy;Attorney Docket No. 49366-0056WO4(d) C1-C6 alkoxy substituted with hydroxyl or 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen;(e) -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3- C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF); or (f) C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

27. The compound of any one of Claims 1-26, wherein at least one R2Ais -C(=O)-(C1-C6 alkyl or C1-C6 haloalkyl).

28. The compound of any one of Claims 1-26, wherein at least one R2Ais 5-10 membered heteroaryl substituted with 1-3 substituents independently selected from C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen, C1-C6 haloalkyl optionally substituted with hydroxyl or cyano, -OR7, -SR8; -SO2RD, -NRAC(=O)RC, -P(=O)RARB, C1-C6 alkyl substituted with cyano, and 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl.

29. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with C1-C6 alkoxy.

30. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with C1-C6 haloalkoxy.

31. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with C3-C6 cycloalkyl optionally substituted with cyano, hydroxyl, -NRARB, or halogen.

32. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with C1-C6 haloalkyl optionally substituted with hydroxyl or cyano.

33. The compound of any one of Claims 1-26 or 32, wherein R2Ais 5-10 membered heteroaryl substituted with C1-C6 haloalkyl.

34. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with -OR7.

35. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with -SR8.Attorney Docket No. 49366-0056WO436. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with -SO2RD.

37. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with -NRAC(=O)RC.

38. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with -P(=O)RARB.

39. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with C1-C6 alkyl substituted with cyano.

40. The compound of any one of Claims 1-26, wherein R2Ais 5-10 membered heteroaryl substituted with 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from halogen and C1-C6 alkyl.

41. The compound of any one of Claims 1-26, wherein at least one R2Ais 4-10 membered heterocyclyl substituted with 1-3 substituents independently selected from hydroxyl and C1-C6 haloalkoxy.

42. The compound of any one of Claims 1-26, wherein at least one R2Ais C1-C6 alkoxy substituted with hydroxyl or 4-10 membered heterocyclyl substituted with hydroxyl, cyano, or halogen.

43. The compound of any one of Claims 1-26, wherein at least one R2Ais -C(=O)-(CH2)m-(4-6 membered heterocyclyl, 5-6 membered heteroaryl, or C3-C6 cycloalkyl, each optionally substituted with 1-3 independently selected RF).

44. The compound of any one of Claims 1-26, wherein at least one R2Ais C3-C6 cycloalkoxy optionally substituted with hydroxyl, -C(=O)NRARB, -C(=N)ORD, or 4-10 membered heterocyclyl optionally substituted with C1-C6 alkyl.

45. The compound of any one of Claims 1-44, wherein X is a bond.

46. The compound of any one of Claims 1-44, wherein X is CH2.

47. The compound of any one of Claims 1-44, wherein X is CH(CH3).

48. The compound of any one of Claims 1-44, wherein X is C(CH3)2.

49. The compound of any one of Claims 1-44, wherein X is50. The compound of any one of Claims 1-49, wherein W is O.

51. The compound of any one of Claims 1-50, wherein R3Ais hydrogen.Attorney Docket No. 49366-0056WO452. The compound of any one of Claims 1-50, wherein R3Ais C1-C6 alkyl.

53. The compound of any one of Claims 1-50, wherein R3Ais C1-C6 alkoxy.

54. The compound of any one of Claims 1-50, wherein R3Ais C1-C6 haloalkyl.

55. The compound of any one of Claims 1-49, wherein W is NR3B.

56. The compound of any one of Claims 1-49 or 55, wherein R3Bis hydrogen.

57. The compound of any one of Claims 1-49 or 55, wherein R3Bis methyl.

58. The compound of any one of Claims 1-57, wherein Y is unsubstituted 5-10 membered heteroaryl.

59. The compound of any one of Claims 1-57, wherein Y is phenyl optionally substituted with 1-3 independently selected RY.

60. The compound of any one of Claims 1-57, wherein Y is naphthyl optionally substituted with 1-3 independently selected R.

61. The compound of any one of Claims 1-57, wherein Y is 5-10 membered heteroaryl optionally substituted with 1-3 independently selected RY.

62. The compound of any one of Claims 1-57, wherein Y is 6 membered heteroaryl optionally substituted with 1-3 independently selected RY.

63. The compound of any one of Claims 1-57, wherein Y is 5 membered heteroaryl optionally substituted with 1-3 independently selected RY.

64. The compound of any one of Claims 1-57 or 59-63, 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.

65. The compound of any one of Claims 1-57 or 59-63, wherein 1, 2, or 3 of RYis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, -(CH2)n-C(=N-OH)RJ, or C3-C6 cycloalkyl.

66. The compound of any one of Claims 1-57 or 59-63, wherein 1 RYis -P(=O)RARB, -(CH2)n-S(=O)(=NRH)NRHRI, or -(CH2)n-C(=N-OH)RJ.

67. The compound of any one of Claims 1-57, wherein Y is phenyl substituted with* - L1- H A H - (RY1)ZS, wherein * represents the connection of L1to the remainder of the compound of Formula (I).Attorney Docket No. 49366-0056WO468. The compound of any one of Claims 1-57, wherein Y is naphthyl substituted with* - L1- H A -d - (RY1)Zx- / , wherein * represents the connection of L1to the remainder of the compound of Formula (I).

69. The compound of any one of Claims 1-57, wherein Y is 5-10 membered* - L1- k A j - (RY1)Zheteroaryl substituted with', wherein * represents the connection of L1to the remainder of the compound of Formula (I).

70. The compound of any one of Claims 1-57 or 67-69, 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.

71. The compound of any one of Claims 1-70, wherein R4is hydrogen.

72. The compound of any one of Claims 1-70, wherein R4is halogen.

73. The compound of any one of Claims 1-70, wherein R4is C1-C6 alkyl.

74. The compound of any one of Claims 1-70, wherein R4is acrylamido.

75. The compound of any one of Claims 1-74, wherein R5is hydrogen.

76. The compound of any one of Claims 1-74, wherein R5is halogen.

77. The compound of any one of Claims 1-74, wherein R5is C1-C6 alkyl.

78. The compound of any one of Claims 1-74, wherein R5is cyano.

79. The compound of any one of Claims 1-74, wherein R5is -NR5AR5B.

80. The compound of any one of Claims 1-74, wherein R5is -C(=O)NR5AR5B.

81. The compound of any one of Claims 1-74, wherein R5is -NR’AC(=O)R5B.

82. The compound of any one of Claims 1-81, wherein R6is hydrogen.

83. The compound of any one of Claims 1-81, wherein R6is halogen.

84. The compound of any one of Claims 1-81, wherein R6is C1-C6 alkyl.

85. The compound of any one of Claims 1-84, wherein R4is hydrogen, R5is methyl, and R6is hydrogen.Attorney Docket No. 49366-0056WO486. The compound of any one of Claims 1-84, wherein R4is hydrogen, R5is chloro, and R6is hydrogen.

87. The compound of Claim 85 or 86, wherein R1is methyl or cyano.

88. The compound of any one of claims 1-66 or 71-87, wherein at least one of RHand RIis C1-C6 alkyl substituted with -P(=O)RARB.

89. The compound of any one of claims 1-66 or 71-88, wherein RJis C1-C6 haloalkyl.

90. The compound of any one of claims 1-74 or 82-89, wherein R5is C1-C6 haloalkyl.

91. The compound of any one of claims 1-90, wherein R8is C1-C6 alkyl or C1-C6 haloalkyl.

92. The compound of any one of claims 1-91, wherein at least one of RDand REis C3-C6 cycloalkyl or 5-6 membered heteroaryl optionally substituted with C1-C6 alkyl or halogen.

93. The compound of any one of claims 1-91, wherein at least one RFis cyano, hydroxyl, halogen, C3-C6 cycloalkyl, or C1-C6 alkyl.

94. A compound selected from the group consisting of the compounds in Table A, or a pharmaceutically acceptable salt thereof.

95. A pharmaceutical composition comprising a compound of any one of Claims 1-94, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

96. 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 Claims 1-94, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 95.

97. 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 PI3Ka 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 1-94, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 95.

98. A method of treating a PI3Ka-associated cancer in a subject, comprisingAttorney Docket No. 49366-0056WO4administering to a subject identified or diagnosed as having a PI3Ka-associated cancer a therapeutically effective amount of a compound of any one of Claims 1-94 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 95.

99. A method for inhibiting mutant PI3Ka activity in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of Claims 1-94, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 95.

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