PI3Kalpha INHIBITORS AND USES THEREOF

Abstract

The present disclosure relates to compounds that inhibit PI3Ka. The disclosure further relates to the use of the compounds for the preparation of a medicament for the treatment of diseases and / or conditions through inhibiting PI3Ka. The disclosure further relates to the use of the compounds for the treatment of a disease or condition associated with mutant PI3Ka. The disclosure further relates to the use of the compounds for the treatment of cancers. (Formula (I))

Description

Attorney Docket No.: 1542-WO-PCT PI3Kalpha INHIBITORS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No.63 / 573,830, filed April 3, 2024, which is incorporated herein in its entireties for all purposes. FIELD

[0002] The present disclosure relates to compounds that inhibit PI3Kα. The disclosure further relates to the use of the compounds for the treatment and / or prophylaxis of diseases and / or conditions responsive to PI3Kα inhibition. BACKGROUND

[0003] PI3Kα (Phosphoinositide 3-kinase alpha) is a class IA lipid kinase that catalyzes the phosphorylation of PIP2 to PIP3, initiating downstream AKT / mTOR signaling cascade. PI3Kα is composed of catalytic subunit p110α encoded by PIK3CA and regulatory subunit p85α encoded by PIK3R1.

[0004] Mutations in p110α lead to hyperactivation of the signaling pathway and promote tumor outgrowth. PI3Kα mutations are prevalent in solid tumors, with a high incidence in HR+ / HER2- breast cancer. The three most common hotspot mutations of PIK3CA are H1047R, E545K, and E452K.

[0005] A PI3Kα isoform-selective inhibitor, alpelisib, has been clinically approved for patients with PI3Kα-mutated, HR+ / HER2-breast cancer. The clinical benefit of PI3Kα isoform-selective inhibitors is likely reduced by dose-limiting toxicities.

[0006] A mutant-selective PI3Kα inhibitor that avoids toxicities associated with WT PI3Kα inhibition might achieve sustained target coverage so as to substantially improve efficacy and durability relative to WT PI3Kα inhibitors.

[0007] Therefore, there is a need for the development of mutant-selective PI3Kα inhibitors with desirable potency, selectivity, or reduced adverse effects.Attorney Docket No.: 1542-WO-PCT SUMMARY

[0008] The present disclosure provides compounds useful as PI3Kα inhibitors. The disclosure further relates to the use of the compounds for the treatment of diseases and / or conditions through inhibiting PI3Kα by said compounds. The disclosure further relates to the use of the compounds for the treatment of diseases and / or conditions through inhibiting mutant PI3Kα in tumors by said compounds.

[0009] In one embodiment, provided herein is a compound of Formula (I),or a pharmaceutically acceptable salt thereof, wherein R1is C6-12 aryl, heteroaryl, C3-12 cycloalkyl, heterocyclyl, C1-6 alkyl, or C1-6 haloalkyl; the aryl, heteroaryl, cycloalkyl, heterocyclyl, haloalkyl, or alkyl of R1is optionally substituted with one to three Z1, which may be the same or different; R2is H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkyl; R3is H, CN, C1-6alkyl, C3-6cycloalkyl, C3-6halocycloalkyl, or C1-6haloalkyl; or R2and R3together with the carbon to which they are attached form C3-6cycloalkyl; Y is N, CH, or CR9; each R4is independently halo, CN, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C3-6 halocycloalkyl, C1-6alkyl, or C1-6haloalkyl; R9is halo, C1-6 alkyl, or C1-6 haloalkyl; each Q, X, X1, or X2is independently N, NH, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N or NH; W is O, NR8, S, SO2, C(=O), or CR6R7; R6is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; R7is H, halo, or C1-6alkyl; or R6and R7together with the carbon to which they are attached form C3-6cycloalkyl; each R5is independently halo, oxo, CN, OR12a, -C(O)-N(R12a)(R12b), -N(R12a)C(O)(R12b), -S(O)2R12a, -S(O)2N(R12a)(R12b), C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C6-12aryl, heteroaryl, C3-12cycloalkyl, heterocyclyl, or -N(R12a)( R12b); theAttorney Docket No.: 1542-WO-PCT alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl of R5is optionally substituted with one to three Z5, which may be the same or different; or two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form C5-10cycloalkyl, phenyl, 5 or 10 membered heterocyclyl, or 5 or 6 membered heteroaryl; the cycloalkyl, heterocyclyl, phenyl, or the heteroaryl formed from two R5and two adjacent carbons to which they are attached is optionally substituted with one to three Z6, which may be the same or different; R8is C1-6alkyl, C1-6haloalkyl, C6-12aryl, heteroaryl, C3-12cycloalkyl, or heterocyclyl; the alkyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z8, which may be the same or different; each Z1, Z5, Z6, or Z8is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-12 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O-R12a, -C(O)- N(R12a)(R12b), -C(O)N(R12b)S(O)2(R12a), -N(R12a)( R12b), -N(R12a)C(O)-R12b, -N(R12a)C(O)O-R12b, -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -NR12aS(O)2N(R12b)(R12c), - NR12aS(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)( R12b), -S-R12a, -S(O)R12a, - S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)N(R12a)N(R12b)(R12c), -SF5, or - S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z5, Z6, or Z8is each optionally substituted with one to three Z1a, which may be the same or different; each Z1ais independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-12 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -CN, -O-R12a, -C(O)R12a, -C(O)O- R12a, -C(O)N(R12a)( R12b), -N(R12a)( R12b), -N(R12a)2(R12b)+, -N(R12a)-C(O)R12b, - N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -N(R12a)S(O)2- N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with one to four Z1b, which may be the same or different; each Z1bis independently C1-9alkyl, C1-8haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-12cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, - SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), - O(heterocyclyl), -O(C6-10 aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6alkynyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), -NH(C6-10aryl), -Attorney Docket No.: 1542-WO-PCT NH(heteroaryl), -N(C1-9alkyl)2, -N(C1-8haloalkyl)2, -N(C2-6alkenyl)2, -N(C2-6alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl)2, -N(heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9 alkyl)(C2-6 alkenyl), -N(C1-9 alkyl)(C2-6 alkynyl), -N(C1-9 alkyl)(C3-15 cycloalkyl), -N(C1-9alkyl)(heterocyclyl), -N(C1-9alkyl)(C6-10aryl), -N(C1-9alkyl)(heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(heterocyclyl), -C(O)(C6-10 aryl), -C(O)(heteroaryl), - C(O)O(C1-9alkyl), -C(O)O(C1-8haloalkyl), -C(O)O(C2-6alkenyl), -C(O)O(C2-6alkynyl), -C(O)O(C3-15cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C6-10aryl), - C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6alkynyl), -C(O)NH(C3-15cycloalkyl), -C(O)NH(heterocyclyl), - C(O)NH(C6-10aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9alkyl)2, -C(O)N(C1-8haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, - C(O)N(heterocyclyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C1-8haloalkyl), -NHC(O)(C2-6alkenyl), -NHC(O)(C2-6alkynyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(heteroaryl), - NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15cycloalkyl), -NHC(O)O(heterocyclyl),-NHC(O)O(C6-10aryl), - NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2- 6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10aryl), -NHC(O)NH(heteroaryl), - NHS(O)(C1-9alkyl), -N(C1-9alkyl)(S(O)(C1-9alkyl), -S(C1-9alkyl), -S(C1-8haloalkyl), -S(C2-6alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(heterocyclyl), -S(C6-10 aryl), -S(heteroaryl), - S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(C1-8 haloalkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15cycloalkyl), -S(O)(heterocyclyl), -S(O)(C6-10aryl), -S(O)(heteroaryl), - S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9 alkyl), - S(O)2NH(C1-9alkyl), or -S(O)2N(C1-9alkyl)2; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1bis optionally substituted with one to three C1-9alkyl, C1-8haloalkyl, halogen, -OH, -NH2, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), - O(heteroaryl), -NH(C1-9alkyl), -NH(C1-8haloalkyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), - NH(aryl), -NH(heteroaryl), -N(C1-9alkyl)2, -N(C3-15cycloalkyl)2, -NHC(O)(C1-8haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), - NHC(O)(heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), -Attorney Docket No.: 1542-WO-PCT NHC(O)O(heteroaryl), -NHC(O)NH(C1-9alkyl), S(O)2(C1-9alkyl), -S(O)2(C1-8haloalkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), - S(O)(NH)(C1-9 alkyl), -S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; each R12a, R12b, and R12cis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-15cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each R12a, R12b, and R12cis each optionally substituted with one to four Z1b, which may be the same or different; n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is 5 to 12 membered heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 12 membered heterocyclyl having one to four heteroatoms each independently N, O or S.

[0010] In some embodiments, provided herein are pharmaceutical compositions comprising a compound provided herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0011] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0012] In some embodiments, the present disclosure provides methods of inhibiting PI3Kα in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. DETAILED DESCRIPTION

[0013] The present disclosure relates to inhibitors of PI3Kα. The disclosure also relates to compositions and methods relating to PI3Kα inhibitors and the use of such compounds for treatment of diseases and conditions. The disclosure also relates to compositions and methodsAttorney Docket No.: 1542-WO-PCT of treating cancer or viral infections that include a PI3Kα inhibitorin combination with one or more additional therapeutic agents. Definitions and General Parameters

[0014] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms “a”, “and”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0016] As used in the present specification, the following terms and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0017] A dashthat is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. A solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom. For example, Rain the below structure can be attached to any of the five carbon ring atoms or Racan replace the hydrogen attached to the nitrogen ring atom:.Attorney Docket No.: 1542-WO-PCT

[0018] The prefix “Cu-v” indicates that the following group has from u to v carbon atoms. For example, “C1-6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term “x-y membered” rings, wherein x and y are numerical ranges, such as “3 to12-membered heterocyclyl”, refers to a ring containing x-y atoms (e.g., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0019] Also, certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, or alkylyl group, an “arylene” group or an “arylenyl” group, or arylyl group, respectively.

[0020] “A compound disclosed herein” or “a compound of the present disclosure” or “a compound provided herein” or “a compound described herein” refers to the compounds of Formula (I), (Ia), (Ia-1), (Ia-2), (Ia-3), (Ib), (Ib-1), (Ib-2), (Ib-3), (Ib-4), (Ib-5), (Ib-6), (Ib-7), (Ib-8), (Ib-9), (Ib-10), (Ib-11), (Ib-12), or (Ib-13). Also included are the specific compounds of Examples 1 to 52 provided herein.

[0021] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0022] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-20 alkyl), 1 to 8 carbon atoms (i.e., C1-8 alkyl), 1 to 6 carbon atoms (i.e., C1-6 alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), or 1 to 3 carbon atoms (i.e., C1-3alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, 2-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, 3- hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., - (CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tert-butylAttorney Docket No.: 1542-WO-PCT (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., - CH(CH3)2).

[0023] “Alkenyl” refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20alkenyl), 2 to 8 carbon atoms (i.e., C2-8alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0024] “Alkynyl” refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6alkynyl), or 2 to 4 carbon atoms (i.e., C2-4alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0025] “Acyl” refers to a group -C(=O)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0026] “Alkoxy” refers to an alkyl group having an oxygen atom that connects the alkyl group to the point of attachment: alkyl-O-. As for alkyl group, alkoxy groups will have any suitable number of carbon atoms, such as C1-6. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. The alkoxy groups can be further substituted with a variety of substituents described within. Alkoxy groups can be substituted or unsubstituted.

[0027] “Alkoxyalkyl” refers an alkoxy group linked to an alkyl group which is linked to the remainder of the compound. Alkoxyalkyl have any suitable number of carbon, such as from 2 to 6 (C2-6alkoxyalkyl), 2 to 5 (C2-5alkoxyalkyl), 2 to 4 (C2-4alkoxyalkyl), or 2 to 3 (C2-3alkoxyalkyl). The number of carbons refers to the total number of carbons in the alkoxy and the alkyl group. For example, in some embodiments, C6 alkoxyalkyl refers to ethoxy (C2 alkoxy) linked to a butyl (C4alkyl), and in other embodiments, n-propoxy (C3alkoxy) linked to isopropyl (C3alkyl). Alkoxy and alkyl are as defined above where the alkyl is divalent, and can include, but is not limited to, methoxymethyl (CH3OCH2-), methoxyethyl (CH3OCH2CH2-) and others.Attorney Docket No.: 1542-WO-PCT

[0028] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0029] “Aryl” as used herein refers to a single all carbon aromatic ring or a multicyclic all carbon ring system wherein at least one of the rings is aromatic. For example, in some embodiments, an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryl includes a phenyl radical. Aryl also includes multicyclicring systems (e.g., ring systems comprising 2, 3 or 4 rings) having 9 to 20 carbon atoms, e.g., 9 to 16 carbon atoms, in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., carbocycle). Such multicyclicring systems are optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on any carbocycle portion of the multicyclic ring system. The rings of the multicyclic ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is also to be understood that when reference is made to a certain atom-range membered aryl (e.g., 6-10 membered aryl), the atom range is for the total ring atoms of the aryl. For example, a 6-membered aryl would include phenyl and a 10- membered aryl would include naphthyl and 1,2,3,4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracenyl, and the like.

[0030] “Cyano” or “carbonitrile” refers to the group -CN.

[0031] “Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0032] “Fused” refers to a ring which is bound to an adjacent ring. In some embodiments the fused ring system is a heterocyclyl. In some embodiments the fused ring system is a oxabicyclohexanyl. In some embodiments, the fused ring systemAttorney Docket No.: 1542-WO-PCT

[0033] “Bridged” refers to a ring fusion wherein non-adjacent atoms on a ring are joined by a divalent substituent, such as alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems. In some embodiments the bridged ring is a bicyclopentyl (e.g., bicyclo[1.1.1]pentyl), bicycloheptyl (e.g., bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl), or bicyclooctyl (e.g.,

[0034] “Spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4- benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents. In some embodiments the spiro substituent is a spiropentanyl (spiro[a.b]pentanyl), spirohexanyl, spiroheptanyl, spirooctyl (e.g., spiro[2.5]octyl), spirononanyl (e.g., spiro[3.5]nonanyl), spirodecanyl (e.g., spiro[4.5]decanyl), or spiroundecanyl (e.g., spiro[5.5]undecanyl). In some embodiments the spiro substituent

[0035] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

[0036] “Haloalkyl” as used herein refers to an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a halo substituent, which may be the same or different. For example, C1-4 haloalkyl is a C1-4 alkyl wherein one or more of the hydrogen atoms of the C1-4alkyl have been replaced by a halo substituent. Examples of haloalkyl groups include but are not limited to fluoromethyl, fluorochloromethyl, difluoromethyl, difluorochloromethyl, trifluoromethyl, 1,1,1-trifluoroethyl and pentafluoroethyl.Attorney Docket No.: 1542-WO-PCT

[0037] “Haloalkoxy” refers to an alkoxy group where some or all of the hydrogen atoms are substituted with halogen atoms. As for an alkyl group, haloalkoxy groups can have any suitable number of carbon atoms, such as C1-6. The alkoxy groups can be substituted with 1, 2, 3, or more halogens. When all the hydrogens are replaced with a halogen, for example by fluorine, the compounds are per-substituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, etc.

[0038] The term “heteroaryl” as used herein refers to a single aromatic ring or a multicyclic ring. The term includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic. Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl. The term also includes multicyclic ring systems (e.g., ring systems comprising 2 or 3 rings) wherein a heteroaryl group, as defined above, can be fused with one or more heteroaryls (e.g., naphthyridinyl), carbocycles (e.g., 5,6,7,8-tetrahydroquinolyl) or aryls (e.g., indazolyl) to form a multicyclic ring. Such multicyclic rings may be optionally substituted with one or more (e.g., 1, 2 or 3) oxo groups on the carbocycle portions of the multicyclic ring. It is to be understood that the point of attachment of a heteroaryl multicyclic ring, as defined above, can be at any position of the ring including a heteroaryl, aryl or a carbocycle portion of the ring. Exemplary heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8- tetrahydroisoquinolinyl benzofuranyl, benzimidazolyl and thianaphthenyl.

[0039] “Heterocyclyl” or “heterocyclic ring” or “heterocycle” as used herein refers to a single saturated or partially unsaturated ring or a multicyclic ring. The term includes single saturated or partially unsaturated ring (e.g., 3, 4, 5, 6 or 7-membered ring) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring. The ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms. Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl. The term also includes multicyclic ring systems (e.g., ring systems comprising 2 or 3 rings) wherein a heterocycle group (as defined above) can be connected to two adjacent atoms (fused heterocycle) with one or more heterocycles (e.g., decahydronapthyridinyl ), heteroaryls (e.g., 1,2,3,4- tetrahydronaphthyridinyl), carbocycles (e.g., decahydroquinolyl) or aryls. It is to be understoodAttorney Docket No.: 1542-WO-PCT that the point of attachment of a heterocycle multicyclic ring, as defined above, can be at any position of the ring including a heterocyle, heteroaryl, aryl or a carbocycle portion of the ring. Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3- benzodioxolyl and 1,4-benzodioxanyl. Exemplary fused bicyclic heterocycles include, but are not limited to

[0040] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0041] “Oxo” refers to the group (=O) or (O).

[0042] “Sulfonyl” refers to the group -S(O)2Rc, where Rcis alkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0043] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an -NH2group unless otherwise indicated. Similarly, unless otherwise expressed, hydrogen atom(s) are implied and deemed present where necessary in view of the knowledge of one of skill in the art to complete valency or provide stability.

[0044] The terms “optional” or “optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.Attorney Docket No.: 1542-WO-PCT

[0045] The term “substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid, alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. For example, the term “substituted aryl” includes, but is not limited to, “alkylaryl.” Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

[0046] In some embodiments, the term “substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, CN, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments, “substituted cycloalkyl” refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, CN, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl; “substituted heterocyclyl” refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, CN, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl; “substituted aryl” refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano; “substituted heteroaryl” refers to an heteroaryl group having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano and “substituted sulfonyl” refers to a group -S(O)2R, in which R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or moreAttorney Docket No.: 1542-WO-PCT substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0047] In some embodiments, a substituted cycloalkyl, a substituted heterocyclyl, a substituted aryl, and / or a substituted heteroaryl includes a cycloalkyl, a heterocyclyl, an aryl, and / or a heteroaryl that has a substituent on the ring atom to which the cycloalkyl, heterocyclyl, aryl, and / or heteroaryl is attached to the rest of the compound. For example, in the below moiety, the cyclopropyl is substituted with a methyl group:.

[0048] The disclosures illustratively described herein may suitably be practiced in the absence of any element or elements, limitation or limitations, not specifically disclosed herein. Thus, for example, the terms “comprising,” “including,” “containing,” etc., shall be read expansively and without limitation. Additionally, the terms and expressions employed herein have been used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed.

[0049] The compounds of the present disclosure can be in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. The compounds of the present disclosure can be in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present disclosure contain one or more acidic or basic groups, the disclosure also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the present disclosure which contain acidic groups can be present on these groups and can be used according to the disclosure, for example, as alkali metal salts, alkaline earth metal salts or ammonium salts. More precise examples of such saltsAttorney Docket No.: 1542-WO-PCT include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine, amino acids, or other bases known to persons skilled in the art. The compounds of the present disclosure which contain one or more basic groups, i.e., groups which can be protonated, can be present and can be used according to the disclosure in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to persons skilled in the art.

[0050] If the compounds of the present disclosure simultaneously contain acidic and basic groups in the molecule, the disclosure also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example, by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.

[0051] The present disclosure also includes all salts of the compounds of the present disclosure which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. Acids and bases useful for reaction with an underlying compound to form pharmaceutically acceptable salts (acid addition or base addition salts respectively) are known to one of skill in the art. Similarly, methods of preparing pharmaceutically acceptable salts from an underlying compound (upon disclosure) are known to one of skill in the art and are disclosed in for example, Berge, at al. Journal of Pharmaceutical Science, Jan.1977 vol.66, No.1, and other sources.

[0052] Furthermore, compounds disclosed herein may be subject to tautomerism. Where tautomerism, e.g., keto-enol tautomerism, of compounds or their prodrugs may occur, the individual forms, like, e.g., the keto and enol form, are each within the scope of the disclosure as well as their mixtures in any ratio. The same applies for stereoisomers, like, e.g., enantiomers, cis / trans isomers, diastereomers, conformers, and the like.Attorney Docket No.: 1542-WO-PCT

[0053] The term “protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See e.g., Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency of desired chemical reactions, e.g., making and breaking chemical bonds in an ordered and planned fashion. The term “deprotecting” refers to removing the protecting group.

[0054] It will be appreciated by the skilled person that when lists of alternative substituents include members which, because of their valency requirements or other reasons, cannot be used to substitute a particular group, the list is intended to be read with the knowledge of the skilled person to include only those members of the list which are suitable for substituting the particular group.

[0055] Further the compounds of the present disclosure may be present in the form of solvates, such as those which include as solvate water, or pharmaceutically acceptable solvates, such as alcohols, in particular ethanol. A “solvate” is formed by the interaction of a solvent and a compound.

[0056] In certain embodiments, provided are optical isomers, racemates, or other mixtures thereof (e.g., scalemic mixtures) of the compounds described herein or a pharmaceutically acceptable salt or a mixture thereof. If desired, isomers can be separated by methods well known in the art, e.g., by liquid chromatography. In those situations, the single enantiomer or diastereomer, i.e., optically active form, can be obtained by asymmetric synthesis or by resolution. Resolution can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using for example, a chiral high-pressure liquid chromatography (HPLC) column.

[0057] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. Unless otherwise indicated, the description is intended to include individual stereoisomers as well as mixtures. The methodsAttorney Docket No.: 1542-WO-PCT for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see, e.g., Chapter 4 of Advanced Organic Chemistry, 4th ed., J. March, John Wiley and Sons, New York, 1992).

[0058] Compounds disclosed herein and their pharmaceutically acceptable salts may, in some embodiments, include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. Some embodiments include all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein, “scalemic mixture” is a mixture of stereoisomers at a ratio other than 1:1.

[0059] Compositions provided herein that include a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof may include racemic mixtures, or mixtures containing an enantiomeric excess of one enantiomer or single diastereomers or diastereomeric mixtures. All such isomeric forms of these compounds are expressly included herein the same as if each and every isomeric form were specifically and individually listed.

[0060] Any formula or structure given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen,Attorney Docket No.: 1542-WO-PCT oxygen, phosphoros, fluorine and chlorine, such as, but not limited to2H (deuterium, D),3H (tritium),11C,13C,14C,15N,18F,31P,32P,35S,36Cl and125I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H,13C and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0061] The disclosure also includes “deuterated analogs” of compounds disclosed herein, in which from 1 to n hydrogens attached to a carbon atom is / are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds may exhibit increased resistance to metabolism and thus be useful for increasing the half-life of any compound of Formula (I) when administered to a mammal, e.g., a human. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci.5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0062] Deuterium labelled or substituted therapeutic compounds of the disclosure may have beneficial DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F labeled compound may be useful for PET or SPECT studies.

[0063] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium.Attorney Docket No.: 1542-WO-PCT

[0064] Furthermore, the present disclosure provides pharmaceutical compositions comprising a compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.

[0065] “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present disclosure can encompass any composition made by admixing at least one compound of the present disclosure and a pharmaceutically acceptable carrier.

[0066] As used herein, “pharmaceutically acceptable carrier” includes excipients or agents such as solvents, diluents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like that are not deleterious to the disclosed compound or use thereof. The use of such carriers and agents to prepare compositions of pharmaceutically active substances is well known in the art (see, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0067] “IC50” or “EC50” refers to the inhibitory concentration required to achieve 50% of the maximum desired effect.

[0068] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival. In some embodiments, the term “treatment” or “treating” means administering a compound orAttorney Docket No.: 1542-WO-PCT pharmaceutically acceptable salt of Formula (I) for the purpose of: (i) delaying the onset of a disease, that is, causing the clinical symptoms of the disease not to develop or delaying the development thereof; (ii) inhibiting the disease, that is, arresting the development of clinical symptoms; and / or (iii) relieving the disease, that is, causing the regression of clinical symptoms or the severity thereof.

[0069] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0070] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0071] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to PI3Kα inhibitors. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one or ordinary skill in the art. List of Abbreviations and AcronymsAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCT δ parts per million referenced to residual solvent peakCompounds

[0072] In one embodiment, the present disclosure provides a compound of Formula (I),or a pharmaceutically acceptable salt thereof, wherein R1is C6-12aryl, heteroaryl, C3-12cycloalkyl, heterocyclyl, C1-6alkyl, or C1-6haloalkyl; the aryl, heteroaryl, cycloalkyl, heterocyclyl, haloalkyl, or alkyl of R1is optionally substituted with one to three Z1, which may be the same or different; R2is H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkyl; R3is H, CN, C1-6alkyl, C3-6cycloalkyl, C3-6halocycloalkyl, or C1-6haloalkyl; or R2and R3together with the carbon to which they are attached form C3-6 cycloalkyl; Y is N, CH, or CR9; each R4is independently halo, CN, C3-6cycloalkyl, C1-3alkoxy, C1-3haloalkoxy, C3-6halocycloalkyl, C1-6 alkyl, or C1-6 haloalkyl; R9is halo, C1-6 alkyl, or C1-6 haloalkyl; each Q, X, X1, or X2is independently N, NH, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N or NH; W is O, NR8, S, SO2, C(=O), or CR6R7; R6is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; R7is H, halo, or C1-6alkyl; or R6and R7together with the carbon to which they are attached form C3-6 cycloalkyl; each R5is independently halo, oxo, CN, OR12a, -C(O)-N(R12a)(R12b), -N(R12a)C(O)(R12b), -S(O)2R12a, -S(O)2N(R12a)(R12b), C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6haloalkyl, C1-6alkoxy, C1-6 haloalkoxy, C6-12 aryl, heteroaryl, C3-12 cycloalkyl, heterocyclyl, or -N(R12a)( R12b); the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl of R5is optionally substituted with one to three Z5, which may be the same or different;Attorney Docket No.: 1542-WO-PCT or two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form C5-10 cycloalkyl, phenyl, 5 or 10 membered heterocyclyl, or 5 or 6 membered heteroaryl; the cycloalkyl, heterocyclyl, phenyl, or the heteroaryl formed from two R5and two adjacent carbons to which they are attached is optionally substituted with one to three Z6, which may be the same or different; R8is C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, heteroaryl, C3-12 cycloalkyl, or heterocyclyl; the alkyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z8, which may be the same or different; each Z1, Z5, Z6, or Z8is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-12cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O-R12a, -C(O)- N(R12a)(R12b), -C(O)N(R12b)S(O)2(R12a), -N(R12a)( R12b), -N(R12a)C(O)-R12b, -N(R12a)C(O)O-R12b, -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -NR12aS(O)2N(R12b)(R12c), - NR12aS(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)( R12b), -S-R12a, -S(O)R12a, - S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)N(R12a)N(R12b)(R12c), -SF5, or - S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z5, Z6, or Z8is each optionally substituted with one to three Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-12cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -NO2, -CN, -O-R12a, -C(O)R12a, -C(O)O- R12a, -C(O)N(R12a)( R12b), -N(R12a)( R12b), -N(R12a)2(R12b)+, -N(R12a)-C(O)R12b, - N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -N(R12a)S(O)2- N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with one to four Z1b, which may be the same or different; each Z1bis independently C1-9alkyl, C1-8haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-12 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, - SH, -O(C1-9alkyl), -O(C1-8haloalkyl), -O(C2-6alkenyl), -O(C2-6alkynyl), -O(C3-15cycloalkyl), - O(heterocyclyl), -O(C6-10aryl), -O(heteroaryl), -NH(C1-9alkyl), -NH(C1-8haloalkyl), -NH(C2-6alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), - NH(heteroaryl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10aryl)2, -N(heteroaryl)2, -N(C1-9alkyl)(C1-8Attorney Docket No.: 1542-WO-PCT haloalkyl), -N(C1-9alkyl)(C2-6alkenyl), -N(C1-9alkyl)(C2-6alkynyl), -N(C1-9alkyl)(C3-15cycloalkyl), -N(C1-9 alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15cycloalkyl), -C(O)(heterocyclyl), -C(O)(C6-10aryl), -C(O)(heteroaryl), - C(O)O(C1-9 alkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C6-10 aryl), - C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C1-9alkyl), -C(O)NH(C1-8haloalkyl), -C(O)NH(C2-6alkenyl), -C(O)NH(C2-6alkynyl), -C(O)NH(C3-15cycloalkyl), -C(O)NH(heterocyclyl), - C(O)NH(C6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6alkenyl)2, -C(O)N(C2-6alkynyl)2, -C(O)N(C3-15cycloalkyl)2, - C(O)N(heterocyclyl)2, -C(O)N(C6-10aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C1-9alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3- 15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(heteroaryl), - NHC(O)O(C1-9alkyl), -NHC(O)O(C1-8haloalkyl), -NHC(O)O(C2-6alkenyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl),-NHC(O)O(C6-10 aryl), - NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6alkenyl), -NHC(O)NH(C2-6alkynyl), -NHC(O)NH(C3-15cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(heteroaryl), - NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(C1-9 alkyl), -S(C1-8 haloalkyl), -S(C2-6 alkenyl), -S(C2-6alkynyl), -S(C3-15cycloalkyl), -S(heterocyclyl), -S(C6-10aryl), -S(heteroaryl), - S(O)N(C1-9alkyl)2, -S(O)(C1-9alkyl), -S(O)(C1-8haloalkyl), -S(O)(C2-6alkenyl), -S(O)(C2-6alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(heterocyclyl), -S(O)(C6-10 aryl), -S(O)(heteroaryl), - S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1bis optionally substituted with one to three C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, -O(C1-9alkyl), -O(C1-8haloalkyl), -O(C3-15cycloalkyl), -O(heterocyclyl), -O(aryl), - O(heteroaryl), -NH(C1-9alkyl), -NH(C1-8haloalkyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), - NH(aryl), -NH(heteroaryl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C1-8 haloalkyl), -NHC(O)(C3-15cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), - NHC(O)(heteroaryl), -NHC(O)O(C1-9alkyl), -NHC(O)O(C1-8haloalkyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), - NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C3-15cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -Attorney Docket No.: 1542-WO-PCT S(O)(NH)(C1-9alkyl), -S(O)2NH(C1-9alkyl), or -S(O)2N(C1-9alkyl)2; each R12a, R12b, and R12cis independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each R12a, R12b, and R12cis each optionally substituted with one to four Z1b, which may be the same or different; n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is 5 to 12 membered heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 12 membered heterocyclyl having one to four heteroatoms each independently N, O or S.

[0073] In some embodiments, the compound of Formula (I) is a compound of Formula (II),or a pharmaceutically acceptable salt thereof, wherein R1is C6-12aryl, C3-6cycloalkyl, 4 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl; the aryl, cycloalkyl, heterocyclyl, or heteroaryl of R1is optionally substituted with one to three Z1, which may be the same or different; each Z1is independently -COOH, halo, oxo, 5 to 10 membered heteroaryl, -C(O)N(R12b)S(O)2(R12a), or -S(O)2R12a; R2is H, C1-6alkyl, or C1-6haloalkyl; R3is H, C1-6 alkyl, or C1-6 haloalkyl; Y is N or CH; each R4is independently halo; each Q, X, X1, or X2is independently N, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N; W is O, S, or NR8; each R5is independently halo, CN, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkynyl, C6-12 aryl, 5 to 10 membered heteroaryl, C3-12 cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, C1-6alkoxy, alkynyl, aryl, heteroaryl, cycloalkyl, orAttorney Docket No.: 1542-WO-PCT heterocyclyl is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently OH, halo, phenyl, C1-6 alkyl, or C1-6 haloalkyl; or two R5are attached to two adjacent carbons, and the two R5together with the two adjacent carbons to which they are attached form phenyl, 5 to 10 membered heterocyclyl or 5 to 6 membered heteroaryl; R8is C1-6 alkyl optionally substituted with one to two Z8, which may be the same or different; each Z8is independently cyclopropyl or phenyl; R12ais C1-6alkyl; R12bis H, C1-6 alkyl; and n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is heterocyclyl having one to four heteroatoms each independently N, O or S.

[0074] In some embodiments, the compound of Formula (I) or (II) is a compound of Formula (IIa),or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the compound of Formula (I), (II), or (IIa) is a compound of Formula (IIb),or a pharmaceutically acceptable salt thereof.Attorney Docket No.: 1542-WO-PCT

[0076] In some embodiments, the compound of Formula (I), (II), or (IIa) is a compound of Formula (IIc),or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the compound of Formula (I), (II), or (IIa) is a compound of Formula (IId),or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the compound of Formula (I), (II), (IIa), or (IId) is a compound of Formula (IIe),or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compound of Formula (I), (II), (IIa), (IId), or (IIe) is a compound of Formula (IIf),Attorney Docket No.: 1542-WO-PCTor a pharmaceutically acceptable salt thereof.

[0080] In some embodiments, the compound of Formula (I), (II), (IIa), (IId), (IIe), or (IIf) is a compound of Formula (IIf-1),or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the compound of Formula (I), (II), or (IIa) is a compound wherein R1is C6-12 aryl, C3-6 cycloalkyl, 4 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl; the aryl, cycloalkyl, heterocyclyl, or heteroaryl of R1is optionally substituted with one to three Z1, which may be the same or different; R2is H, C1-6 alkyl, or C1-6 haloalkyl; R3is H, CN, C1-6alkyl, or C1-6haloalkyl; Y is N, CH, or CR9; each R4is independently halo, CN, C1-6 alkyl, or C1-6 haloalkyl; R9is halo, C1-6 alkyl, or C1-6 haloalkyl; each Q, X, X1, or X2is independently N, NH, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N or NH; W is O, S, NR8; each R5is independently halo, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6alkynyl, C6-12aryl, 5 to 10 membered heteroaryl, C3-12cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, C1-6 alkoxy, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z5, which may be the same or different;Attorney Docket No.: 1542-WO-PCT each Z5is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6alkoxyalkyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -CN, -O-R12a, - C(O)-R12a, -C(O)O-R12a, -C(O)-N(R12a)(R12b), -C(O)N(R12b)S(O)2(R12a), - N(R12a)( R12b), -N(R12a)C(O)-R12b, -N(R12a)C(O)O-R12b, -N(R12a)S(O)2(R12b), -OC(O)- N(R12a)( R12b), -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z5is each optionally substituted with one to three Z1a, which may be the same or different; or two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form C5-10 cycloalkyl, phenyl, 5 to 10 membered heterocyclyl, or 5 or 6 membered heteroaryl; R8is C1-6alkyl, C1-6haloalkyl, C3-12cycloalkyl, or heterocyclyl; the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one to two Z8, which may be the same or different; each Z1is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, halogen, C3-15cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -CN, -O- R12a, -C(O)-N(R12a)(R12b), -C(O)N(R12b)S(O)2(R12a), -N(R12a)( R12b), -N(R12a)C(O)-R12b, - N(R12a)S(O)2(R12b), -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; each Z8is independently C3-15cycloalkyl, heterocyclyl, C6-10aryl, or heteroaryl; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, -CN, -O- R12a, -C(O)R12a, -C(O)O-R12a, or -S(O)2R12a; each R12a, R12b, and R12cis independently H, C1-6alkyl, C3-15cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; and n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is 5 to 12 membered heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 12 membered heterocyclyl having one to four heteroatoms each independently N, O or S.

[0082] In some embodiments, the compound of Formula (I), (II), or (IIa) is a compound wherein R1is C6-12aryl, or 5 to 10 membered heteroaryl; the aryl or heteroaryl of R1is optionally substituted with one to three Z1, which may be the same or different; each Z1is independently - COOH, halo, 5 to 10 membered heteroaryl, or -S(O)2R12a; R2is H, C1-6 alkyl, or C1-6 haloalkyl;Attorney Docket No.: 1542-WO-PCT R3is H, C1-6alkyl, or C1-6haloalkyl; Y is N or CH; each R4is independently halo; each Q, X, X1, or X2is independently N, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N; W is O, or NR8; each R5is independently halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C6-12aryl, 5 to 10 membered heteroaryl, C3-6cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently C1-6alkyl; or two R5are attached to two adjacent carbons, and the two R5together with the two carbons to which they are attached form phenyl or 5 to 10 membered heterocyclyl; R8is C1-6 alkyl optionally substituted with one to two Z8, which may be the same or different; each Z8is independently cyclopropyl or phenyl; R12ais C1-6 alkyl; and n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to four heteroatoms each independently N, O or S.

[0083] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X is N. In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X is CH.

[0084] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X1is CH. In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X1is CH.

[0085] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is a compound wherein X2is N. In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is a compound wherein X2is CH.

[0086] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein W is O. In some embodiments, the compound of FormulaAttorney Docket No.: 1542-WO-PCT (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein W is NR8. In some embodiments, R8is C1-3 alkyl optionally substituted with C3-6 cycloalkyl or phenyl.

[0087] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein Y is N. In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein Y is CH.

[0088] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein each R4is independently C1-3alkyl or halo. In some embodiments, R4is -CH3. In some embodiments, R4is halo. In some embodiments, R4is F.

[0089] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein n is 1.

[0090] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein R2is H.

[0091] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), or (IIf) is a compound wherein R3is C1-3alkyl. In some embodiments, R3is -CH3.

[0092] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein R1is phenyl, thiazoyl, or pyridyl; the phenyl, thiazoyl, or pyridyl of R1is optionally substituted with one to three Z1, which may be the same or different; each Z1is independently -COOH, halo, 5 to 6 membered heteroaryl, or -S(O)2R12a. In some embodiments, Z1is -C(O)N(R12b)S(O)2(R12a). In some embodiments, R12bis H, and R12ais C1-3 alkyl.

[0093] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein R1is phenyl, thiazoyl, or pyridyl; the phenyl, thiazoyl, or pyridyl of R1is substituted -COOH; the phenyl or pyridyl of R1is optionally additionally substituted with one or two Z1, which may be the same or different; each Z1is independently halo or -S(O)2R12a; and R12ais C1-3 alkyl.

[0094] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein R1is phenyl; the phenyl of R1is substituted -COOH; the phenyl of R1is optionally additionally substituted with one or two Z1, which may be the same or different; each Z1is independently halo or -S(O)2R12a; and R12ais C1-3 alkyl.Attorney Docket No.: 1542-WO-PCT

[0095] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe),

[0096] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R5is independently halo, C1-6 alkyl, C1-6 haloalkyl, C6-12aryl, 5 to 10 membered heteroaryl, C3-6cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z5, which may be the same or different.

[0097] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R5is independently phenyl or 5 to 10 memberedAttorney Docket No.: 1542-WO-PCT heteroaryl; wherein the phenyl or heteroaryl of R5is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently C1-6 alkyl, or C1-6 haloalkyl.

[0098] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R5is independently phenyl, pyridyl, morpholinyl, pyrimidinyl, pyrazinyl, pyrazolyl; wherein the phenyl, pyridyl, morpholinyl, pyrimidinyl, pyrazinyl, pyrazolyl of R5is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently C1-6alkyl, or C1-6haloalkyl.

[0099] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe),embodiments, R5is phenyl. In some embodiments, R5is pyridyl. In some embodiments, R5is

[0100] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R5is independently halo, C1-6 haloalkyl, or cyclopropyl; the cyclopropyl is optionally substituted with one to three Z5, which may be the same or different.

[0101] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound whereinAttorney Docket No.: 1542-WO-PCT

[0102] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each R5is independently C3-6 cycloalkyl; the cycloalkyl is optionally substituted with one to three Z5, which may be the same or different.

[0103] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe),

[0104] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein R5is -N(R12a)C(O)(R12b); R12ais C1-6 alkyl; R12bis phenyl or cyclopropyl, the phenyl or cyclopropyl of R12bis optionally substituted with one to three Z1b, and each Z1bis independently halo or phenyl. In some embodiments,Attorney Docket No.: 1542-WO-PCT

[0105] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1) is a compound wherein each Z5is independently C1-6 alkyl, or C1-6 haloalkyl.

[0106] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form 5 or 10 membered heterocyclyl; wherein the heterocyclyl formed from two R5and two adjacent carbons to which they are attached is monocyclic heterocyclyl. In some embodiments, the heterocyclyl formed from two R5and two adjacent carbons to which they are attached is bicyclic heterocyclyl. In some embodiments, the heterocyclyl formed from two R5and two adjacent carbons to which they are attached is spiro bicyclic heterocyclyl. In some embodiments, the heterocyclyl formed from two R5and two adjacent carbons to which they are attached is bridged or fused bicyclic heterocyclyl. In some embodiments, the heterocyclyl formed from two R5and two adjacent carbons to which they are attached is optionally substituted with one to two Z6, which may be the same or different.

[0107] In some embodiments, the present disclosure provides a compound having the structure of Example 1-121, or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the present disclosure provides a racemic mixture comprising the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a racemic mixture comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a scalemic mixture comprising the compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1), or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a scalemic mixture comprising the compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0109] One of skill in the art is aware that each and every embodiment of a group (e.g., R1) disclosed herein may be combined with any other embodiment of each of the remaining groups (e.g., R2, R3, Z1, Z5, etc.) to generate a complete compound of Formula (I), (II), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), or (IIf-1), or any Formula described herein or a pharmaceutically acceptable salt, stereoisomer, mixture of stereoisomers, or tautomer thereof, each of which is deemed within the ambit of the present disclosure.Attorney Docket No.: 1542-WO-PCT Pharmaceutical Compositions and Modes of Administration

[0110] Furthermore, the present disclosure provides pharmaceutical compositions comprising at least one compound of the present disclosure, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.

[0111] In some embodiments, the pharmaceutical composition of the present disclosure may additionally comprise one or more other compounds as active ingredients like a prodrug compound or other enzyme inhibitors.

[0112] The compositions are suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

[0113] In practical use, the compounds of the present disclosure can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.

[0114] Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or non-aqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amountAttorney Docket No.: 1542-WO-PCT of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasally as, for example, liquid drops or spray.

[0115] The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

[0116] Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

[0117] In some embodiments, the compounds of the present disclosure may also be used as salts with various countercations to yield an orally available formulation.

[0118] The compounds of the present disclosure may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.

[0119] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0120] Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present disclosure. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules,Attorney Docket No.: 1542-WO-PCT creams, ointments, aerosols, and the like. In some embodiments, compounds of the present disclosure are administered orally. Method of Treatment

[0121] Disclosed herein are methods of treatment of a disease in which inhibition of PI3Kα is beneficial, the method comprising administering a compound disclosed herein.

[0122] Provided herein are inhibitors of PI3Kα useful for treating one or more disorders associated with activity of PI3Kα or mutants thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a PI3Kα containing at least one of the following mutations: H1047R, E542K, and E545K.

[0123] In some embodiments, the disorder is a proliferative disease. In some embodiments, the proliferative disease is cancer. In some embodiments, the cancer is a tumor. In some embodiments, the cancer is a solid tumor. In some embodiments, the proliferative disease is a tumor and / or cancerous cell growth.

[0124] In some embodiments, the proliferative disease has mutant PI3Kα. In some embodiments, the cancer has mutant PI3Kα. In some embodiments, the proliferative disease is breast cancer having mutant PI3Kα. In some embodiments, the proliferative disease is ovarian cancer having mutant PI3Kα.

[0125] In some embodiments, the proliferative disease has PI3Kα containing at least one of the following mutations: H1047R, E542K, E545K, H1047L, and H1047Y. In some embodiments, the cancer has PI3Kα containing at least one of the following mutations: H1047R, E542K, E545K, H1047L, and H1047Y. In some embodiments, the proliferative disease is cancer having PI3Kα mutation of H1047R. In some embodiments, the proliferative disease is breast cancer having PI3Kα containing at least one of the following mutations: H1047R, E542K, E545K, H1047L, and H1047Y. In some embodiments, the proliferative disease is breast cancer having PI3Kα mutation of H1047R. In some embodiments, the proliferative disease is ovarian cancer having PI3Kα containing at least one of the following mutations: H1047R, E542K, E545K, H1047L, and H1047Y. In some embodiments, the proliferative disease is ovarian cancer having PI3Kα mutation of H1047R.

[0126] In some embodiments, the cancer is selected from actinic keratosis, an adenoma, adrenal gland cancer, basal cell carcinoma, brain cancer, breast cancer (including sporadic breastAttorney Docket No.: 1542-WO-PCT cancer, Cowden disease, and ER+ / HER2- breast cancer), bronchus cancer, carcinoma of the brain, a carcinoma, colon carcinoma, colon cancer, colorectal adenoma endometrial cancer, esophagus cancer, essential thrombocythemia, gastric cancer, gastrointestinal cancer, glioblastoma, glioma, hepatocellular cancer, intrahepatic bile duct cancer, kidney cancer, larynx cancer, leukemia (acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia), liver cancer, lung cancer, a lymphoma, mammary carcinoma, melanoma, multiple myeloma myelofibrosis with myeloid metaplasia, neck and head cancer, neoplasia of epithelial character, neoplasia, non-Hodgkin lymphoma, oral cavity and pharynx cancer, ovarian cancer (including clear cell ovarian cancer), pancreatic cancer, prostate cancer, rectum cancer, renal pelvis cancer, a sarcoma, small intestine cancer, squamous cell carcinoma, stomach cancer, thyroid cancer, urinary bladder cancer, uterine cervix cancer, uterine corpus, vagina cancer, villous colon adenoma, and Waldenstrom macroglobulinemia.

[0127] In some embodiments, the proliferative disease displays overexpression or amplification of PI3Kα, somatic mutation of PIK3CA, germline mutations or somatic mutation of PTEN, or mutations and translocation of p85e that serve to up-regulate the p85- p110 complex. In some embodiments, the proliferative disease displays overexpression or amplification of PI3Kα. In some embodiments, the proliferative disease displays somatic mutation of PIK3CA. In some embodiments, the proliferative disease displays germline mutations or somatic mutation of PTEN. In some embodiments, the proliferative disease displays mutations and translocation of p85e that serve to up-regulate the p85-p110 complex.

[0128] In some embodiments, the PI3Kα-mediated disorder is selected from the group consisting of acute arterial ischemia, alopecia areata, alveolitis, ARDS, asthma, atherosclerosis, atopic dermatitis, autoimmune haematogical disorders (e.g., haemolytic anaemia, aplastic anaemia, pure red cell anaemia and idiopathic thrombocytopenia), autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), bronchopulmonary aspergillosis, bullous pemphigoid, cardiovascular diseases, chronic active hepatitis, chronic hypersensitivity pneumonitis, conditions characterized by elevated intraocular pressure or secretion of ocular aqueous humor, such as glaucoma; contact dermatitis, COPD, coronary artery disease, deep venous thrombosis, dermatitis herpetiformis, dermatomyositis, endocrine opthalmopathy, eosinophilic granuloma, eosinophilic pneumonia, eosinophil-related disorders affecting the airways occasioned by drug-reaction, epidermolysis bullosa acquisita, erythema multiforme, essential thrombocythemia, glomerulonephritis, Graves’ disease, hypersensitivity angiitis, hypertension, idiopathic sprue, interstitial lung fibrosis, Loffler's syndrome, lupusAttorney Docket No.: 1542-WO-PCT erythematosus, multiple sclerosis, myasthenia gravis, myelofibrosis with myeloid metaplasia, myocardial infarction, parasitic (in particular metazoan) infestation (including tropical eosinophilia), pemphisus, peripheral thrombotic occlusions, polyarteritis nodosa (including Churg-Strauss syndrome), polychondritis, polycythemia vera, primary biliary cirrhosis, PROS (PI3K-related overgrowth syndrome), psoriasis, psoriatic arthritis, pulmonary embolism, reperfusion injuries, retinopathy, such as diabetic retinopathy or hyperbaric oxygen-induced retinopathy, sarcoidosis, scleroderma, Steven-Johnson syndrome, stroke, systemic lupus erythematosus, thromboembolism, thrombolytic diseases, unstable angina, urticaria, uveitis (anterior and posterior), venous malformation, vitiligo, and Wegener granulomatosis. Dosage

[0129] The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.

[0130] When treating a PI3Kα-mediated disorder or condition for which compounds of the present disclosure are indicated, generally satisfactory results are obtained when the compounds of the present disclosure are administered at a daily dosage of from about 0.1 milligram to about 300 milligram per kilogram of animal body weight. In some embodiments, the compounds of the present disclosure are given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1 milligram to about 1000 milligrams, or from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 0.1 milligrams to about 200 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response. In some embodiments, the total daily dosage is from about 1 milligram to about 900 milligrams, about 1 milligram to about 800 milligrams, about 1 milligram to about 700 milligrams, about 1 milligram to about 600 milligrams, about 1 milligram to about 400 milligrams, about 1 milligram to about 300 milligrams, about 1 milligram to about 200 milligrams, about 1 milligram to about 100 milligrams, about 1 milligram to about 50 milligrams, about 1 milligram to about 20 milligram, or about 1 milligram to about 10 milligrams.Attorney Docket No.: 1542-WO-PCT

[0131] The compounds of the present application or the compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

[0132] In some embodiments, the methods provided herein comprise administering to the subject an initial daily dose of about 1 to 800 mg of a compound described herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, or once per week. Combination

[0133] Disclosed herein are methods of treating cancer using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0134] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.

[0135] In some embodiments, the additional therapeutic agent is an anticancer agent.

[0136] In some embodiments, the additional therapeutic agents is an ALK inhibitor (e.g., crizotinib, NVP- TAE684, ceritinib, alectinib, brigatinib, entrecinib, or lorlatinib), an androgen receptor inhibitor (e.g., enzalutamide, apalutamide, abiraterone acetate, orteronel, galeterone, seviteronel, bicalutamide, or flutamide), an antineoplastic agent (e.g., oxaliplatin, carboplatin, orAttorney Docket No.: 1542-WO-PCT cisplatin), an aromatase inhibitor (e.g., exemestane, letrozole, anastrozole, fulvestrant, or tamoxifen), a BCL-2 inhibitor (e.g., venetoclax), a BCR-ABL inhibitor (e.g., imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, or PF03814735), a BRAF inhibitor (e.g., vemurafenib or dabrafenib), a CD20 antibody (e.g., rituximab, tositumomab, or ofatumumab), a CDK4 / 6 inhibitor (e.g., alvocidib, palbociclib, ribociclib, trilaciclib, or abemaciclib), a CTLA-4 inhibitor (e.g., tremelimumab or ipilimumab), a DNA synthesis inhibitor (e.g., capecitabine, gemcitabine, nelarabine, or hydroxycarbamide), an epidermal growth factor receptor (EGFR) inhibitor (e.g., gefitnib, osimertinib, cetuximab, or panitumumab), an ERK inhibitor (e.g., ulixertinib, MK 8353, or LY 3214996), a KRAS inhibitor (e.g., AMG-510, MRTX849, or ARS-3248), an FGFR inhibitor (e.g., infigratinib, dovitinib, erdafitinib, TAS-120, pemigatinib, BLU-554, or AZD4547), an FLT3 inhibitor (e.g., sunitinib, midostaurin, tanutinib, sorafenib, lestaurtinib, quizartinib, or crenolanib), a Heat Shock Protein (HSP) inhibitor (e.g., tanespimycin), a Hedgehog antagonist (e.g., vismodegib), an HER2 receptor inhibitor (e.g., trastuzumab, pertuzumab, neratinib, lapatinib, or lapatinib), a Histone deacetylase inhibitor (HDI) (e.g., vorinostat), an immunomodulator (e.g., afutuzumab, lenalidomide, thalidomide, or pomalidomide), a CD40 inhibitor (e.g., dacetuzumab), a MEK inhibitor (e.g., trametinib, cobimetinib, binimetinib, or selumetinib), a MET inhibitor (e.g., crizotinib or cabozantinib), an mTOR inhibitor (e.g., temsirolimus, ridaforolimus, everolimus, or sirolimus), a PD1 inhibitor (e.g., nivolumab, or pembrolizumab), a PDL1 inhibitor (e.g., MSB0010718C; YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105), a PI3K inhibitor (e.g., pictilisib, dactolisib, alpelisib, buparlisib, taselisib, idelalisib, duvelisib, or umbralisib), a PIK3CA inhibitor, a pro-apoptotic receptor agonist (PARA) (e.g., dulanermin), a proteasome inhibitor (e.g., bortezomib), a SHP2 inhibitor, or a tyrosine kinase inhibitor (e.g., erlotinib, linifanib, sunitinib, or pazopanib). EXAMPLES

[0137] The following examples are included to demonstrate specific embodiments of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques to function well in the practice of the disclosure, and thus can be considered to constitute specific modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that these examples are exemplary and not exhaustive. Many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.Attorney Docket No.: 1542-WO-PCT

[0138] Compounds disclosed herein can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present disclosure claimed herein can be readily prepared. The examples further illustrate details for the preparation of the compounds of the present disclosure. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. For synthesizing compounds which are embodiments described in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. In some cases, the identity of the final product can render apparent the identity of the necessary starting materials by a process of inspection, given the examples herein. Compounds can be isolated in the form of their pharmaceutically acceptable salts, such as those described above. Compounds described herein are typically stable and isolatable at room temperature and pressure.

[0139] An illustration of the preparation of compounds disclosed herein is shown below. Unless otherwise indicated, variables have the same meaning as described above. The examples presented below are intended to illustrate particular embodiments of the disclosure. Suitable starting materials, building blocks and reagents employed in the synthesis as described below are commercially available from AbovChem, Acros Organics, Astatech, Combi Blocks, Oakwood Chemical, or Sigma-Aldrich, for example, or can be routinely prepared by procedures described in the literature, for example in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 5thEdition; John Wiley & Sons or T. Eicher, S. Hauptmann "The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application", 2ndedition, Wiley-VCH 2003; Fieser et al. “Fiesers´ Reagents for organic Synthesis” John Wiley & Sons 2000.Attorney Docket No.: 1542-WO-PCT General Reaction Scheme 1:

[0140] Compounds of the formula 1.3 may be produced by reacting intermediate 1.1 (where U = BPin, B(OH)2, BF3K, SnBu3) with compounds of formula 1.2 (where T = Br, I, Cl, OTf; V = F, Cl, Br; Z = Cl, Br) in the presence of a suitable metal catalyst (e.g. PdCl2dppf), and base (e.g. Na2CO3, K2CO3, Cs2CO3) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature. A compound of formula 1.3 (where V = F, Cl) can be subsequently cyclized with an appropriate base (e.g. DIPEA, Cs2CO3, K2CO3) to produce an intermediate of formula 1.4. Alternatively, compounds of formula 1.3 (where V = Cl, Br) can be converted to an intermediate of formula 1.4 in the presence of an appropriate metal catalyst (e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, RockPhos G3), and base (e.g. Na2CO3, K2CO3, Cs2CO3) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature. Compounds of formula 1.4 can then be reacted with a suitable coupling partner of formula 1.5 where R5= aryl, heteroaryl, alkenyl and T = BPin, B(OH)2, BF3K, SnBu3, ZnCl, or ZnBr under metal-catalyzed cross-coupling conditions (e.g. Suzuki, Stille, Negishi coupling conditions) to produce compounds of formula 1.6. Alternatively, compounds of the formula 1.6 may be produced by reacting intermediate 1.4 (where Z = Br, Cl) with a compound of formula 1.5 (where T = Br, I, Cl, OTf) in the presence of a suitable palladium or nickel catalyst with a suitable reducing reagent (e.g. Zn, Mn, TMS silane). Compounds of formula 1.7 can be synthesized by reacting compounds of formula 1.6 with tert-butylsulfinamide and Lewis acid (e.g. TiCl4, Ti(iPrO)4) at elevated temperature, followed by reduction with a suitable reducing reagent (e.g. NaBH4, LiBH4, DIBAL) in a presence or absence of a Lewis acid (e.g. CeCl3-6H2O). A compound of formula 1.7 can be subsequently deprotected under suitable conditions (e.g. trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula 1.8 that contains a primary amine. Compounds ofAttorney Docket No.: 1542-WO-PCT formula 1.8 can then be reacted with a suitable coupling partner of formula 1.9 where R1= aryl or heteroaryl and T = Br, Cl, I, OTf, or B(OH)2 under metal-catalyzed cross-coupling conditions (e.g. Buchwald coupling conditions, Chan-Lam coupling conditions) using a suitable metal catalyst (e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, Cu(OAc)2), and base (e.g. Na2CO3, K2CO3, Cs2CO3, DBU) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature to produce compounds of formula I.a. General Reaction Scheme 2:

[0141] Compounds of the formula 2.2 may be produced by reacting intermediate 2.1 (where U = BPin, B(OH)2, BF3K, SnBu3) with compounds of formula 1.2 (where T = Br, I, Cl, OTf; V = F, Cl, Br; Z = Cl, Br) in the presence of a suitable metal catalyst (e.g. PdCl2dppf), and base (e.g. Na2CO3, K2CO3, Cs2CO3) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature. The methoxy group of formula 2.2 can be subsequently deprotected with an appropriate Lewis acid (e.g. BBr3, AlCl3, MgCl2, TMSI) to reveal a compound of formula 2.3 that contains a phenol. A compound of formula 2.3 (where V = F, Cl) can be subsequently cyclized with an appropriate base (e.g. DIPEA, Cs2CO3, K2CO3) to produce an intermediate of formula 2.4. Alternatively, compounds of formula 2.3 (where V = Cl, Br) can be converted to an intermediate of formula 2.4 in the presence of an appropriate metal catalyst (e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, RockPhos G3), and base (e.g. Na2CO3, K2CO3, Cs2CO3) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature. Compounds of formula 2.4 can then be reacted with a suitable coupling partner of formula 1.5 where R5= aryl, heteroaryl, alkenyl and T = BPin, B(OH)2, BF3K, SnBu3, ZnCl, or ZnBr under metal-catalyzed cross-coupling conditions (e.g. Suzuki, Stille, Negishi coupling conditions) to produce compounds of formula 2.5. Alternatively, compounds of the formula 2.5 may be produced byAttorney Docket No.: 1542-WO-PCT reacting intermediate 2.4 (where Z = Br, Cl) with a compound of formula 1.5 (where T = Br, I, Cl, OTf) in the presence of a suitable palladium or nickel catalyst with a suitable reducing reagent (e.g. Zn, Mn, TMS silane). Compounds of formula 2.6 can then be synthesized by reacting compounds of formula 2.5 with a suitable alkylating reagent (e.g. R3MgCl, R3MgBr, R3Li). The alcohol group of formula 2.6 can be oxidized using an appropriate oxidant (e.g. Dess–Martin periodinane, PCC, Swern conditions) to produce compounds of formula 2.7. General Reaction Scheme 3:

[0142] Compounds of formula 3.1 can be synthesized by reacting compounds of formula 1.4 with tert-butylsulfinamide and Lewis acid (e.g. TiCl4, Ti(iPrO)4) at elevated temperature, followed by reduction with a suitable reducing reagent (e.g. NaBH4, LiBH4, DIBAL) in a presence or absence of a Lewis acid (e.g. CeCl3-6H2O). A compound of formula 3.1 can be subsequently deprotected under suitable conditions (e.g. trifluoroacetic acid or hydrochloric acid) to reveal a compound of formula 3.2. The primary amine of formula 3.2 can be subsequently protected with a suitable carbonate group (e.g. Boc, Cbz) using appropriate conditions (e.g. di-tert-butylcarbonate, CbzCl) and base (e.g. Et3N, DIPEA) to produce compounds of formula 3.3 (Pg: amine protecting group). Compounds of formula 3.3 can then be reacted with a suitable coupling partner of formula 1.5 where R5= aryl, heteroaryl, alkenyl and T = BPin, B(OH)2, BF3K, SnBu3, ZnCl, or ZnBr under metal-catalyzed cross-coupling conditions (e.g. Suzuki, Stille, Negishi coupling conditions) to produce compounds of formula 3.4. Alternatively, compounds of the formula 3.4 may be produced by reacting intermediate 3.3 (where Z = Br, Cl) with a compound of formula 1.5 (where T = Br, I, Cl, OTf) in the presence of a suitable palladium or nickel catalyst with a suitable reducing reagent (e.g. Zn, Mn, TMS silane). A compound of formula 3.4 can be subsequently deprotected under suitable conditionsAttorney Docket No.: 1542-WO-PCT (e.g. trifluoroacetic acid or hydrochloric acid for Boc, palladium catalyst with H2for Cbz) to reveal a compound of formula 3.5 that contains a primary amine. Compounds of formula 3.5 can then be reacted with a suitable electrophilic partner of formula 3.6 where R1= aryl or heteroaryl and T = F or Cl using a suitable base (e.g. DIPEA, DBU, K2CO3, Cs2CO3) in an inert solvent (e.g. DMF, DMA, NMP, DMSO) at elevated temperature to produce compounds of formula I.a. General Reaction Scheme 4:

[0143] Compounds of formula 3.3 (where Z = Cl or F) can be reacted with a suitable primary or secondary amine of formula 4.1 using a suitable base (e.g. DIPEA, DBU, K2CO3, Cs2CO3) in an inert solvent (e.g. DMF, DMA, NMP, DMSO) at elevated temperature to produce compounds of formula 4.2. Alternatively, compounds of formula 4.2 can be produced by reacting intermediate 3.3 (where Z = Cl, Br) with a suitable primary or secondary amine of formula 4.1 in the presence of an appropriate metal catalyst (e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, RockPhos G3), and base (e.g. Na2CO3, K2CO3, Cs2CO3) in an inert solvent (e.g.1,4- dioxane, DMF, toluene) at elevated temperature. A compound of formula 4.2 can be subsequently deprotected under suitable conditions (e.g. trifluoroacetic acid or hydrochloric acid for Boc, palladium catalyst with H2 for Cbz) to reveal a compound of formula 4.3 that contains a primary amine. Compounds of formula 4.3 can then be reacted with a suitable coupling partner of formula 1.9 where R1= aryl or heteroaryl and T = Br, Cl, I, OTf, or B(OH)2 under metal- catalyzed cross-coupling conditions (e.g. Buchwald coupling conditions, Chan-Lam coupling conditions) using a suitable metal catalyst (e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, Cu(OAc)2), and base (e.g. Na2CO3, K2CO3, Cs2CO3, DBU) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature to produce compounds of formula I.b.Attorney Docket No.: 1542-WO-PCT General Reaction Scheme 5:

[0144] Compounds of formula 3.3 (where Z = Cl or Br) can be reacted with a suitable alcohol or phenol of formula 5.1 under metal-catalyzed cross-coupling conditions (e.g. Buchwald coupling conditions) using a suitable metal catalyst (e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, RockPhos Pd G3), and base (e.g. Na2CO3, K2CO3, Cs2CO3) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature to produce compounds of formula 5.2. Alternatively, compounds of formula 5.2 can be produced by reacting intermediate 3.3 (where Z = Cl, F) with a suitable alcohol or phenol of formula 5.1 in the presence of an appropriate base (e.g. K2CO3, Cs2CO3, NaH, KHMDS) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature. A compound of formula 5.2 can be subsequently deprotected under suitable conditions (e.g. trifluoroacetic acid or hydrochloric acid for Boc, palladium catalyst with H2for Cbz) to reveal a compound of formula 5.3 that contains a primary amine. Compounds of formula 5.3 can then be reacted with a suitable coupling partner of formula 1.9 where R1= aryl or heteroaryl and T = Br, Cl, I, OTf, or B(OH)2 under metal-catalyzed cross- coupling conditions (e.g. Buchwald coupling conditions, Chan-Lam coupling conditions) using a suitable metal catalyst (e.g. XantPhos Pd G3, XPhos Pd G3, RuPhos Pd G3, Cu(OAc)2), and base (e.g. Na2CO3, K2CO3, Cs2CO3, DBU) in an inert solvent (e.g.1,4-dioxane, DMF, toluene) at elevated temperature to produce compounds of formula I.c.Attorney Docket No.: 1542-WO-PCT General Reaction Scheme 6:

[0145] A compound of formula 2.6 can be converted to an intermediate of formula 6.1 (where T = Br, Cl, or OMs) using a suitable reagent (e.g. PBr3 for Br, cyanuric chloride for Cl, mesyl chloride for OMs) in the presence or absence of an appropriate base (e.g. DIPEA, pyridine). Compounds of formula 6.1 can be reacted with a suitable primary amine of formula 6.2 (where R1= aryl, heteroaryl, or alkyl) in the presence or absence of a suitable base (e.g. DIPEA) in an inert solvent (e.g. DMF, DMSO, 2-methylbutan-2-ol) at ambient or elevated temperature to produce compounds of formula I.a. Procedure I-A1 for the Preparation of INT-A1-6

[0146] Step 1: 3-(4-chloro-3-fluoro-2-pyridyl)-2-methoxy-5-methyl-benzaldehyde (INT- A1-1) A screw-cap vial was charged with 2-bromo-4-chloro-3-fluoro-pyridine (2.16 mmol), (3- formyl-2-methoxy-5-methyl-phenyl)boronic acid (2.37 mmol), and (1,1'- bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.216 mmol) followed by 1,2- dimethoxyethane (12 mL) and aqueous sodium carbonate (2.0 M, 3.2 mL). It was degassed with nitrogen, sealed, and heated to 80 °C for 4 h. It was diluted with ethyl acetate and washed sequentially with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica (5% to 50% ethyl acetate in hexanes) to yield the product. LCMS (m / z) 280.0.Attorney Docket No.: 1542-WO-PCT

[0147] Step 2: 3-(4-chloro-3-fluoro-2-pyridyl)-2-hydroxy-5-methyl-benzaldehyde (INT- A1-2) To a solution of INT-A1-1 (1.82 mmol) in dichloromethane (5.7 mL) was added aluminum chloride (729 mg), and the reaction was allowed to stir for 16 h. It was diluted with water and treated with saturated sodium bicarbonate until a pH of 7 was reached. It was extracted three times with ethyl acetate, and the combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to yield the product which was used without further purification. LCMS (m / z) 266.0.

[0148] Step 3: 4-chloro-8-methyl-benzofuro[3,2-b]pyridine-6-carbaldehyde (INT-A1-3) To a solution of INT-A1-2 (1.62 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (3.2 mmol), and the reaction was stirred and heated to 70 °C for 1 h. It was cooled to ambient temperature and precipitated by the addition of water. The solids were collected to yield the product. LCMS (m / z) 246.0.

[0149] Step 4: 8-methyl-4-phenyl-benzofuro[3,2-b]pyridine-6-carbaldehyde (INT-A1-4) A screw-cap vial was charged with INT-A1-3 (0.18 mmol), phenylboronic acid (0.20 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.018 mmol) followed by 1,2-dimethoxyethane (1 mL) and aqueous sodium carbonate (2.0 M, 0.28 mL). It was degassed with nitrogen, sealed, and heated to 80 °C for 4 h. It was cooled to ambient temperature, diluted with ethyl acetate, and dried over anhydrous sodium sulfate. It was filtered and concentrated. It was purified by flash chromatography on silica (5% to 50% ethyl acetate in hexanes) to yield the product. LCMS (m / z) 288.1.

[0150] Step 5: 1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethan-1-ol (INT-A1-5). To a solution of INT-A1-4 (5.89 mmol) in dichloromethane (16.0 mL) and 2- methyltetrahydrofuran (24 mL) at 0 °C was added a solution of methyl magnesium bromide in tetrahydrofuran (3 M, 2.55 mL) dropwise over 5 min. The mixture was stirred for 20 min before addition of saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was washed 3 times with dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound. LCMS (m / z) 304.1.

[0151] Step 6: 1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethan-1-one (INT-A1- 6). To a solution of INT-A1-5 (5.89 mmol) in dichloromethane (50.0 mL) was added Dess- Martin Periodinane (7.67 mmol). The mixture was stirred for 2 h before addition of saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was washed 3 times withAttorney Docket No.: 1542-WO-PCT dichloromethane (50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 302.1.

[0152] The following Examples were made using the general route described in Procedure I- A1 and are shown below in Table A1. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-A1 and are noted in the last column of Table A1 – “Changes to Procedure I-A1: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-A1 were replaced with the different reagents / starting materials noted below. Table A1:Procedure I-A2 for the Preparation of INT-A2-1

[0153] Step 1: 4-chloro-5-fluoro-6-phenylpyrimidine (INT-A2-1). To a mixture of 4,6- dichloro-5-fluoro-pyrimidine (2.4 mmol), phenylboronic acid (0.2.4 mmol), [1,1′-Attorney Docket No.: 1542-WO-PCT bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.24 mmol) in 1,4-dioxane (10.0 mL) was added aqueous sodium carbonate (2.0 M, 5.0 mL) at room temperature. The mixture was purged with argon and vigorously stirred at 90 °C. After 5 h, the resulting mixture was cooled to room temperature, and water (30 mL) and ethyl acetate (30 mL) were added sequentially. The organic layer was washed with brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 50% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 209.0.

[0154] The following Examples were made using the general route described in Procedure I- A2 and are shown below in Table A2. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-A2 and are noted in the last column of Table A2 – “Changes to Procedure I-A2: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-A2 were replaced with the different reagents / starting materials noted below. Table A2:Procedure I-A3 for the Preparation of INT-A3-3Attorney Docket No.: 1542-WO-PCT

[0155] Step 1: 1-(2-hydroxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl)ethan-1-one (INT-A3-1). 1-(3-bromo-2-hydroxy-5-methylphenyl)ethan-1-one (8.73 mmol), bis(pinacolato)diboron (10.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.865 mmol) in 1,4-dioxane (50 mL) was treated with potassium propionate (26.2 mmol) at room temperature. The mixture was purged with argon and heated at 100 °C for 2 h. The mixture was carried to the next step without further purification. LCMS (m / z) 277.0.

[0156] Step 2: 1-(3-(4-chloro-3-fluoropyridin-2-yl)-2-hydroxy-5-methylphenyl)ethan-1- one (INT-A3-2).2-bromo-4-chloro-3-fluoro-pyridine (8.69 mmol) and sodium carbonate (2.0 M, 17.6 mmol) were added to the mixture sequentially. The mixture was heated at 100 °C for 1 h. The mixture was diluted with ethyl acetate and washed with water, and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 279.8.

[0157] Step 3: 1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethan-1-one (INT-A3-3). 1-(3-(4-chloro-3-fluoropyridin-2-yl)-2-hydroxy-5-methylphenyl)ethan-1-one (2.97 mmol) dissolved in N,N-dimethylformamide (9 mL) was treated with potassium carbonate (8.90 mmol). The mixture was heated at 70 °C for 1 h. The mixture was diluted with dichloromethane and washed with water, and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 259.9.

[0158] The following Examples were made using the general route described in Procedure I- A3 and are shown below in Table A3. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-A3 and are noted in the last column of Table A3 – “Changes to Procedure I-A3: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-A3 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table A3:Attorney Docket No.: 1542-WO-PCTProcedure I-A4 for the Preparation of INT-A4-1

[0159] Step 1: 1-(8-methyl-4-phenylbenzofuro[3,2-c]pyridin-6-yl)ethan-1-one (INT-A4- 1). To a mixture of INT-A3-4 (0.40 mmol), phenylboronic acid (0.80 mmol), and XPhos Pd G3 (0.060 mmol) in 1,4-dioxane (2.0 mL) was added aqueous sodium carbonate (2.0 M, 1.0 mL) at room temperature. The mixture was purged with argon and vigorously stirred at 100 °C. After 1 h, the resulting mixture was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added sequentially. The organic layer was washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% to 90% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 302.0.

[0160] The following Examples were made using the general route described in Procedure I- A4 and are shown below in Table A4. To prepare the below Examples, differentAttorney Docket No.: 1542-WO-PCT reagents / starting materials were used than some of those described in Procedure I-A4 and are noted in the last column of Table A4 – “Changes to Procedure I-A4: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-A4 were replaced with the different reagents / starting materials noted below. Table A4:Attorney Docket No.: 1542-WO-PCT Procedure I-A5 for the Preparation of INT-A5-4

[0161] Step 1: 2-fluoro-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzaldehyde (INT-A5-1) A screw-cap vial was charged with 3-bromo-2-fluoro-5-methyl- benzaldehyde (9.22 mmol), bis(pinacolato)diboron (11.1 mmol) potassium acetate (27.6 mmol) and (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.92 mmol). To this, 1,4- dioxane (10 mL) was added, and it was degassed with nitrogen. It was sealed and heated to 100 °C for 16 h. It was cooled to ambient temperature, filtered over Celite, and concentrated. It was purified by flash chromatography on silica (5% to 50% ethyl acetate in hexanes) to yield the product.1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 7.79 (dd, J = 5.4, 2.5 Hz, 1H), 7.75 (dd, J = 6.5, 2.5 Hz, 1H), 2.36 (s, 3H), 1.38 (s, 12H).

[0162] Step 2: 3-(4-chloro-3-fluoro-2-pyridyl)-2-fluoro-5-methyl-benzaldehyde (INT-A5- 2) A screw-cap vial was charged with 2-bromo-4-chloro-3-fluoro-pyridine (3.33 mmol), INT- A5-1 (3.66 mmol), and (1,1'-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.33 mmol) followed by 1,2-dimethoxyethane (18.5 mL) and aqueous sodium carbonate (2.0 M, 5.0 mL). It was degassed with nitrogen, sealed, and heated to 80 °C for 4 h. It was diluted with ethyl acetate and washed sequentially with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica (5% to 50% ethyl acetate in hexanes) to yield the product.1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.45 (d, J = 5.1 Hz, 1H), 7.80 (dd, J = 6.1, 2.4 Hz, 1H), 7.67 (dd, J = 6.6, 2.4 Hz, 1H), 7.47 (t, J = 5.2 Hz, 1H), 2.44 (s, 3H).

[0163] Step 3: 2-fluoro-3-(3-fluoro-4-phenyl-2-pyridyl)-5-methyl-benzaldehyde (INT-A5- 3) A screw-cap vial was charged with INT-A5-2 (1.49 mmol), phenylboronic acid (1.64 mmol), and XPhos Pd G3 (0.075 mmol) followed by 1,2-dimethoxyethane (7.0 mL) and aqueous sodium carbonate (2.0 M, 2.24 mL). It was degassed with nitrogen, sealed, and heated to 80 °CAttorney Docket No.: 1542-WO-PCT for 16 h. It was diluted with ethyl acetate and washed sequentially with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica (5% to 50% ethyl acetate in hexanes) to yield the product. LCMS (m / z) 310.1.

[0164] Step 4: 8-methyl-4-phenyl-benzothiopheno[3,2-b]pyridine-6-carbaldehyde (INT- A5-4) To a solution of INT-A5-3 (1.62 mmol) in N,N-dimethylformamide (16 mL) was added (4-methoxyphenyl)methanethiol (3.39 mmol) and potassium carbonate (559 mg), and it was heated to 100 °C for 16 h. It was cooled to ambient temperature, diluted with ethyl acetate, and washed with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica (5% to 50% ethyl acetate in hexanes) to yield the product. LCMS (m / z) 304.1. Procedure I-A6 for the Preparation of INT-A6-7

[0165] Step 1: 3-hydroxy-N-methoxy-N,6-dimethylpicolinamide (INT-A6-1) A vial was charged with 3-hydroxy-6-methylpicolinic acid (19.6 mmol), N,O-dimethylhydroxylamine hydrochloride (29.4 mmol), HATU (29.4 mmol), N,N-diisopropylethylamine (58.8 mmol), and N,N-dimethylformamide (50 mL). The mixture was allowed to stir overnight at ambientAttorney Docket No.: 1542-WO-PCT temperature. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (3 x 100 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound.

[0166] Step 2: 1-(3-hydroxy-6-methylpyridin-2-yl)ethan-1-one (INT-A6-2) A vial was charged with INT-A6-1 (3.1 mmol) and 2-methyltetrahydrofuran (30 mL). The mixture was cooled to 0 °C, and methylmagnesium iodide (9.3 mmol, 3M in diethyl ether) was added dropwise. The mixture was stirred for 1 h, saturated aqueous ammonium chloride (5 mL) was added and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound. LCMS (m / z): 151.9.

[0167] Step 3: 1-(4-bromo-3-hydroxy-6-methylpyridin-2-yl)ethan-1-one (INT-A6-3) A vial was charged with INT-A6-2 (1.1 mmol) and N,N-dimethylformamide (5 mL), followed by N-bromosuccinimide (1.3 mmol). The mixture was allowed to stir for 18 h at ambient temperature. The mixture was concentrated and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound. LCMS (m / z): 230.0.

[0168] Step 4: 3-fluoro-4-phenylpyridine (INT-A6-4) A vial was charged with 4-bromo-3- fluoropyridine (1.7 mmol), phenylboronic acid (2.2 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.17 mmol), cesium carbonate (5.1 mmol), 1,4-dioxane (5 mL), and water (1mL). The mixture was stirred at 100 °C for 18 h. The mixture was filtered, concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound.

[0169] Step 5: 3-fluoro-4-phenyl-2-(tributylstannyl)pyridine (INT-A6-5) A vial was charged with INT-A6-4 (1.6 mmol) and tetrahydrofuran (5 mL). The mixture was cooled to -78 °C, and lithium diisopropylamide (2.4 mmol, 1M in THF / hexanes) was added dropwise. The mixture was allowed to stir for 30 min. Tributyltin chloride (2.0 mmol) was then added dropwise. The mixture was allowed to warm to ambient temperature over 1 h. Saturated aqueous ammonium chloride (5 mL) was added and the mixture was extracted with ethyl acetate (3 x 5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The crude material was used without further purification. LCMS (m / z): 464.2.Attorney Docket No.: 1542-WO-PCT

[0170] Step 6: 1-(3-fluoro-3'-hydroxy-6'-methyl-4-phenyl-[2,4'-bipyridin]-2'-yl)ethan-1- one (INT-A6-6) A vial was charged with INT-A6-3 (0.26 mmol), INT-A6-5 (0.30 mmol), copper(I) iodide (0.05 mmol), cesium fluoride (0.52 mmol), tricyclohexylphosphine (0.052 mmol), Pd(OAc)2(0.026 mmol), and 1,4-dioxane (1 mL). The mixture was heated to 100 °C for 18 h, concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound.

[0171] Step 7: 1-(8-methyl-4-phenylfuro[3,2-b:5,4-c']dipyridin-6-yl)ethan-1-one (INT- A6-7) A vial was charged with INT-A6-6 (0.23 mmol), cesium carbonate (0.91 mmol), and N,N-dimethylformamide (1 mL). The mixture was heated to 90 °C for 1 h. The mixture was concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound. LCMS (m / z): 302.9. Procedure I-A7 for the Preparation of INT-A7-3

[0172] Step 1: (Z)-2-benzylidene-7-bromo-5-methylbenzofuran-3(2H)-one (INT-A7-1) A flask was charged with 7-bromo-5-methylbenzofuran-3(2H)-one (4.4 mmol), benzaldehyde (5.3 mmol), basic alumina (22 mmol), and dichloromethane (40 mL). The mixture was stirred for 18 h, filtered, and concentrated. The residue was recrystallized from DCM / hexane (~10 mL 1:10) to afford the title product.1H NMR (400 MHz, Chloroform-d) δ 8.01 – 7.93 (m, 2H), 7.72 – 7.59 (m, 1H), 7.59 – 7.40 (m, 4H), 6.94 (s, 1H), 2.41 (s, 3H).

[0173] Step 2: N-(2-((Z)-benzylidene)-7-bromo-5-methylbenzofuran-3(2H)-ylidene)-4- methylbenzenesulfonamide (INT-A7-2) A vial was charged with INT-A7-1 (1.9 mmol), 4- methylbenzenesulfonamide (2.9 mmol), triethylamine (3.8 mmol), and toluene (20 mL). Titanium tetrachloride (1.9 mmol) was then added, and the mixture was heated to 100 °C for 18 h. The mixture was cooled to ambient temperature, and water (1 mL) was added. The mixture was filtered, concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound.1HAttorney Docket No.: 1542-WO-PCT NMR (400 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.01 – 7.96 (m, 2H), 7.96 – 7.90 (m, 2H), 7.73 – 7.61 (m, 1H), 7.52 – 7.33 (m, 5H), 7.14 (s, 1H), 2.48 (s, 3H), 2.46 (s, 3H).

[0174] Step 3: 6-bromo-2-cyclopropyl-8-methyl-4-phenylbenzofuro[3,2-b]pyridine (INT- A7-3) A vial under argon was charged with Cu(MeCN)4BF4(0.071 mmol), XantPhos (0.071 mmol), and 1,4-dioxane (2 mL). The mixture stirred at ambient temperature for 1 h. INT-A7-2 (0.36 mmol), triethylamine (0.36 mmol), and ethynylcyclopropane (1.1 mmol) were then added, and the mixture was heated to 60 °C for 24 h. The mixture was cooled to ambient temperature and potassium hydroxide (1.4 mmol) was added. The mixture was heated to 80 °C for 2 h. The mixture was cooled to ambient temperature, concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound. LCMS (m / z): 378.0. Procedure I-A8 for the Preparation of INT-A8-1

[0175] Step 1: 9-bromo-7-methyl-11-phenylbenzofuro[3,2-b]quinoline (INT-A8-1) A vial was charged with INT-A7-2 (0.21 mmol), potassium fluoride (1.5 mmol), 18-crown-6 (1.5 mmol), and acetonitrile (2 mL), followed by 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (0.75 mmol). The mixture was heated to 50 °C for 5 h, cooled to ambient temperature, concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title product. LCMS (m / z): 388.0 Procedure I-A9 for the Preparation of INT-A9-1Attorney Docket No.: 1542-WO-PCT

[0176] Step 1: 1-(2-cyclopropyl-8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethan-1- one (INT-A9-1) A vial was charged with INT-A7-3 (0.093 mmol), tributyl(1- ethoxyvinyl)stannane (0.19 mmol), copper(I) iodide (0.019 mmol), cesium fluoride (0.19 mmol), tricyclohexylphosphine (0.028 mmol), Pd(OAc)2(0.014 mmol), and 1,4-dioxane (1 mL). The mixture was heated to 100 °C for 16 h, cooled to ambient temperature, and concentrated. To the residue was added methanol (1 mL) and HCl (1N in water, 1 mL), and the mixture stirred for 1 h. Water (5 mL) was added, and the mixture extracted with ethyl acetate (3 x 5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title product. LCMS (m / z): 342.0.

[0177] The following Examples were made using the general route described in Procedure I- A9 and are shown below in Table 5. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-A9 and are noted in the last column of Table 5 – “Changes to Procedure I-A9: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-A9 were replaced with the different reagents / starting materials noted below. Table 5:Attorney Docket No.: 1542-WO-PCT Procedure I-A10 for the Preparation of INT-A10-3

[0178] Step 1: (R,E)-N-(1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethylidene)-2- methylpropane-2-sulfinamide (INT-A10-1). To a mixture INT-A3-3 (1.2 mmol) and (R)-2- methylpropane-2-sulfinamide (2.3 mmol) in tetrahydrofuran (6 mL), was added Ti(i-PrO)4 (3.5 mmol). The mixture was vigorously stirred at 75 °C. After 48 h, the mixture was cooled to room temperature and quenched with brine (10 mL). The mixture was left to stir for 30 min, then the filter cake was washed with ethyl acetate (30 mL). The aqueous layer was washed with ethyl acetate (10 mL). The organic layers were combined and washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% to 30% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 363.0.

[0179] Step 2: (R)-N-((R)-1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethyl)-2- methylpropane-2-sulfinamide (INT-A10-2). To a solution of INT-A10-1 (1.3 mmol) in dichloromethane (2 mL) and methanol (2 mL), was added CeCl3 • 7H2O (0.6 mmol). The mixture was cooled to 0 °C and sodium borohydride (1.9 mmol) was slowly added. The solution was left to stir at 0 °C. After 30 min, the mixture was quenched with saturated aqueous ammonium chloride (10 mL) and warmed to room temperature. The aqueous layer was washed with ethyl acetate (10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10% to 50% ethyl acetate in hexanes to afford the title compound. LCMS (m / z) 365.0.

[0180] Step 3: (R)-1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethan-1-amine (INT-A10-3) A flask was charged with INT-A10-2 (1.0 mmol) and dissolved in HCl (4.0 M in 1,4-dioxane, 4.9 mL). The solution was left to stir at room temperature. After 2 h, the mixture was concentrated under reduced pressure and carried forward without further purification. LCMS (m / z) 261.0.Attorney Docket No.: 1542-WO-PCT

[0181] The following Examples were made using the general route described in Procedure I- A10 and are shown below in Table A10. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-A10 and are noted in the last column of Table A10 – “Changes to Procedure I-A10: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-A10 were replaced with the different reagents / starting materials noted below. Table A10:Attorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTProcedure I-A11 for the Preparation of INT-A11-1

[0182] Step 1: tert-butyl (R)-(1-(4-chloro-8-methylbenzofuro[3,2-b]pyridin-6- yl)ethyl)carbamate (INT-A11-1). To a mixture of INT-A10-3 (1.0 mmol) in DCM (4.0 mL) was added triethylamine (0.8 mL) followed by di-tert-butyl dicarbonate (1.5 mmol) at room temperature. The mixture was stirred vigorously at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (10% to 60% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 361.0.

[0183] The following Examples were made using the general route described in Procedure I- A11 and are shown below in Table A11. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-A11 and are noted in the last column of Table A11 – “Changes to Procedure I-A11: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-A11 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table A11:Procedure I-A12 for the Preparation of INT-A12-5

[0184] Step 1: 1-(2-amino-3-bromo-5-methylphenyl)ethenone (INT-A12-1) To a stirred solution of 2,6-dibromo-4-methylaniline (754.9 mmol) and tributyl(1-ethoxyethenyl)stannane (754.9 mmol) in 1,4-dioxane (2.5 L) was added Pd(PPh3)2Cl2 (37.7 mmol) in one portion at room temperature under nitrogen atmosphere. The mixture was heated to 90 °C and stirred at 90 °C for 2 h. After cooling to 50 °C, aqueous hydrochloric acid (2 N, 200 mL) was added and the mixture was stirred for 30 min. The mixture was cooled to room temperature and stirred with saturated potassium fluoride solution (200 mL) for 10 min. The resulting mixture was extracted with ethyl acetate (3 x 500 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated underAttorney Docket No.: 1542-WO-PCT reduced pressure to afford the title product which was used without further purification. LCMS (m / z) 228.0.

[0185] Step 2: (R)-N-(1-(2-amino-3-bromo-5-methylphenyl)ethylidene)-2-methylpropane- 2-sulfinamide (INT-A12-2) To a solution of INT-A12-1 (381.4) and (R)-2-methylpropane-2- sulfinamide (762.9 mmol) in tetrahydrofuran (600 mL) was added titanium(IV) isopropoxide (812.4 mmol) dropwise at room temperature under nitrogen atmosphere. The reaction solution was heated to 80 °C and stirred at 80 °C for 16 h. Following this time, the mixture was cooled to room temperature and diluted with brine (500 mL). The mixture was filtered over Celite and washed with ethyl acetate (500 mL). The filtrate was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluting with 8:1 petroleum ether / ethyl acetate) to afford the title compound. LCMS (m / z) 331.0.

[0186] Step 3:(1R)-1-(2-amino-3-bromo-5-methylphenyl)ethyl)-2-methylpropane- 2-sulfinamide (INT-A12-3) A solution of INT-A12-2 (274.7 mmol) in tetrahydrofuran (300 mL) was slowly added to a solution of diisobutylaluminum hydride (824.0 mmol) in tetrahydrofuran (300 mL) at -78 °C under nitrogen atmosphere. The mixture was stirred for 3 h at -78 °C under nitrogen atmosphere. Then the mixture was quenched with brine (300 mL) and extracted with ethyl acetate (3 x 300 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title product which was used without further purification. LCMS (m / z) 333.1.

[0187] Step 4: (R)-2-(1-aminoethyl)-6-bromo-4-methylaniline dihydrochloride (INT-A12- 4) A mixture of INT-A12-3 (30.0 mmol) in a solution of HCl (gas) in 1,4-dioxane (100 mL) was stirred for 1 h at room temperature. The resulting mixture was concentrated under reduced pressure to give the title product which was used without further purification. LCMS (m / z) 229.0.

[0188] Step 5: tert-butyl (R)-(1-(2-amino-3-bromo-5-methylphenyl)ethyl)carbamate (INT-A12-5) To a mixture of INT-A12-4 (109.1 mmol) and di-tert-butyl dicarbonate (109.1 mmol) in dichloromethane (150 mL) was added N,N-diisopropylethylamine (327.3 mmol) dropwise at 25 ℃ under nitrogen atmosphere. The reaction mixture was stirred at 25 ℃ for 5 h. Following this time, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluting with 10:1 petroleum ether / ethyl acetate) to afford the title compound.1H NMR (400 MHz, DMSO-d6) δ 7.36 (d, J = 8.2 Hz,Attorney Docket No.: 1542-WO-PCT 1H), 7.11 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 2.1 Hz, 1H), 4.90 (s, 2H), 4.79 – 4.65 (m, 1H), 2.15 (s, 3H), 1.38 (s, 9H), 1.27 (d, J = 6.9 Hz, 3H). LCMS (m / z) 329.1. Procedure I-A13 for the Preparation of INT-A13-4

[0189] Step 1: tert-butyl (R)-(1-(2-(benzylamino)-3-bromo-5- methylphenyl)ethyl)carbamate (INT-A13-1). A solution of INT-A12-5 (0.46 mmol), benzyl bromide (0.59 mmol), and potassium carbonate (1.4 mmol) in tetrahydrofuran (0.4 mL) was stirred for 18 h. The reaction was filtered through Celite. The filtrate was concentrated, and the residue was purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 419.0.

[0190] Step 2: tert-butyl (R)-(1-(2-(benzylamino)-3-(4-fluoropyridin-3-yl)-5- methylphenyl)ethyl)carbamate (INT-A13-2). A solution of INT-A13-1 (0.46 mmol), 4-fluoro- 3-(tributylstannyl)pyridine (0.60 mmol), palladium(II) chloride (0.092 mmol), copper(I) iodide (0.18 mmol), cesium fluoride (0.92 mmol), and tricyclohexyl phosphine (0.18 mmol) in N,N- dimethylformamide (3mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction was capped and stirred at 100 °C for 6 h. The reaction was cooled and filtered through Celite. The filtrate was absorbed onto silica gel and purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes, then 0% to 50% MeOH in EtOAc) to afford the title compound. LCMS (m / z) 434.2.

[0191] Step 3: (R)-2-(1-aminoethyl)-N-benzyl-6-(4-fluoropyridin-3-yl)-4-methylaniline (INT-A13-3). A solution of INT-A13-2 (0.21 mmol) in dichloromethane (0.5 mL) was added HCl (4.0 M in 1,4-dioxane, 0.53 mL). The reaction was stirred for 1 h and then concentrated to afford the title compound.19F NMR (DMSO-d6) δ 105.4 (m, 1F). LCMS (m / z) 316.2.Attorney Docket No.: 1542-WO-PCT

[0192] Step 4: (R)-1-(5-benzyl-8-methyl-5H-pyrido[4,3-b]indol-6-yl)ethan-1-amine (INT- A13-4). A solution of INT-A13-3 (0.085 mmol) and cesium carbonate (0.43 mmol) in N,N- dimethylformamide (0.5 mL) was stirred at 70 °C for 18 h and then, concentrated to afford the title compound. LCMS (m / z) 316.2. Procedure I-A14 for the Preparation of INT-A14-3

[0193] Step 1: tert-butyl (R)-(1-(3-bromo-2-((cyclopropylmethyl)amino)-5- methylphenyl)ethyl)carbamate (INT-A14-1). To a mixture of INT-A12-5 (0.91 mmol) and cyclopropanecarbaldehyde (1.0 mmol) in methanol (3.0 mL) was added acetic acid (0.16 mL) at room temperature. The mixture was stirred vigorously for 15 min before addition of sodium cyanoborohydride (2.7 mmol) in one portion. After stirring at room temperature for 20 h, saturated aqueous sodium carbonate (20 mL) and ethyl acetate (20 mL) were added sequentially. The organic layer was washed with brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 60% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 383.0.

[0194] Step 2: tert-butyl (R)-(1-(9-(cyclopropylmethyl)-6-methyl-9H-pyrido[2,3-b]indol- 8-yl)ethyl)carbamate (INT-A14-2). To a mixture of INT-A14-1 (0.18 mmol), (2-fluoro-3- pyridyl)boronic acid (0.36 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.018 mmol) in 1,4-dioxane (5.0 mL) was added aqueous sodium carbonate (2.0 M, 0.55 mL) at room temperature. The mixture was purged with argon and vigorously stirred at 90 °C. After 5 h, the resulting mixture was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added sequentially. The organic layer was washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 50% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 380.2.

[0195] Step 3: (R)-1-(9-(cyclopropylmethyl)-6-methyl-9H-pyrido[2,3-b]indol-8-yl)ethan- 1-amine (INT-A14-3). To a solution of INT-A14-2 (0.11 mmol) in 1,4-dioxane (2.0 mL) was added HCl (4.0 M in 1,4-dioxane, 2.0 mL) at room temperature. After stirring at roomAttorney Docket No.: 1542-WO-PCT temperature 20 h, the resulting mixture was concentrated under reduced pressure to afford the title compound without further purification. LCMS (m / z) 280.0.

[0196] The following Examples were made using the general route described in Procedure I- A14 and are shown below in Table A14. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-A14 and are noted in the last column of Table A14 – “Changes to Procedure I-A14: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-A14 were replaced with the different reagents / starting materials noted below. Table A14:Procedure I-A15 for the Preparation of INT-A15-3

[0197] Step 1: tert-butyl (R)-(1-(3-(3-bromopyridin-2-yl)-2-((cyclopropylmethyl)amino)- 5-methylphenyl)ethyl) carbamate (INT-A15-1). A mixture of INT-A14-4 (0.26 mmol), bis(pinacolato)diboron (0.52 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.034 mmol) and potassium propionate (0.78 mmol) in 1,4-dioxane (3.0 mL) was purged with argon and vigorously stirred at 100 °C. After 1 h, the resulting mixture was cooled to room temperature, and 3-bromo-2-iodo-pyridine (0.39 mmol) and aqueous sodium carbonate (2.0 M, 0.65 mL) were added sequentially. The mixture was purged with argon and vigorously stirred at 90 °C. After 3 h, the resulting mixtureAttorney Docket No.: 1542-WO-PCT was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added sequentially. The organic layer was washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 50% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 460.2.

[0198] Step 2: tert-butyl (R)-(1-(5-(cyclopropylmethyl)-8-methyl-5H-pyrido[3,2-b]indol- 6-yl)ethyl)carbamate (INT-A15-2). A mixture of INT-A15-1 (0.043 mmol), cesium carbonate (0.22 mmol), and XantPhos Pd G3 (0.0087 mmol) in 1,4-dioxane (1.0 mL) was purged with argon and vigorously stirred at 100 °C. After 2 h, the resulting mixture was cooled to room temperature, and water (5 mL) and ethyl acetate (5 mL) were added sequentially. The organic layer was washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 80% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 380.2.

[0199] Step 3: (R)-1-(5-(cyclopropylmethyl)-8-methyl-5H-pyrido[3,2-b]indol-6-yl)ethan- 1-amine (INT-A15-3). To a solution of INT-A15-2 (0.042 mmol) in 1,4-dioxane (1.0 mL) was added HCl (4.0 M in 1,4-dioxane, 0.20 mL) at room temperature. After stirring at room temperature 20 h, the resulting mixture was concentrated under reduced pressure to afford the title compound without further purification. LCMS (m / z) 280.0. Procedure I-A16 for the Preparation of INT-A16-3

[0200] Step 1: 8-methyl-4-(pyridin-3-yl)benzofuro[3,2-b]pyridine-6-carbaldehyde (INT- A16-1) A vial was charged with INT-A1-3 (6.5 mmol), 3-(tributylstannyl)pyridine (8.5 mmol),Attorney Docket No.: 1542-WO-PCT copper(I) iodide (1.3 mmol), cesium fluoride (19.6 mmol), XPhos Pd G4 (0.65 mmol), and 1,4- dioxane (15 mL). The mixture was heated to 100 °C for 3 h. The mixture was cooled to room temperature, filtered over Celite, and concentrated. The residue was subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound. LCMS (m / z): 288.9.

[0201] Step 2: 1-(8-methyl-4-(pyridin-3-yl)benzofuro[3,2-b]pyridin-6-yl)ethan-1-ol (INT- A16-2) A vial was charged with INT-A16-1 (3.5 mmol) and THF (10 mL). The mixture as cooled to 0 °C, and methylmagnesium iodide (6.9 mmol, 3M in diethyl ether) was added. The mixture was allowed to stir for 1 h, after which saturated aqueous ammonium chloride (10 mL) was added. The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound.1H NMR (400 MHz, Chloroform-d) δ 9.28 (d, J = 2.3 Hz, 1H), 8.80 – 8.74 (m, 1H), 8.74 – 8.62 (m, 1H), 8.31 (dt, J = 8.0, 2.0 Hz, 1H), 8.04 – 7.94 (m, 1H), 7.59 – 7.48 (m, 3H), 5.62 – 5.30 (m, 1H), 2.56 (s, 3H), 1.71 (d, J = 6.5 Hz, 3H).

[0202] Step 3: 6-(1-bromoethyl)-8-methyl-4-(pyridin-3-yl)benzofuro[3,2-b]pyridine (INT- A16-3) A vial was charged with INT-A16-2 (0.74 mmol) and dichloromethane (5 mL). The mixture as cooled to 0 °C, and phosphorus tribromide (1.5 mmol, 1M in DCM) was added. The mixture was stirred 30 min, after which aqueous potassium carbonate (2.0 M, 5 mL) was added. The mixture was extracted with dichloromethane (3x 10 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give the title compound, which was used without further purification. LCMS (m / z): 366.9.

[0203] The following Examples were made using the general route described in Procedure I- B1 and are shown below in Table A16. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B1 and are noted in the last column of Table A16 – “Changes to Procedure I-B1: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B1 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table A16:Procedure I-A17 for the Preparation of INT-A17-9

[0204] Step 1: ethyl 1-(3,5-difluoropyridin-4-yl)cyclopentane-1-carboxylate (INT-A17-1) A flask was charged with ethyl cyclopentanecarboxylate (11.3 mmol) and tetrahydrofuran (50 mL). The mixture was cooled to -78 °C, and lithium diisopropylamide (15.0 mmol, 1 M in THF / hexanes) was added. The mixture was allowed to stir 30 min.3,4,5-trifluoropyridine (7.5 mmol) was added, and the mixture was allowed to warm to ambient temperature over 1 h, after which saturated aqueous ammonium chloride (50 mL) was added. The mixture was extracted with ethyl acetate (3 x 50 mL). The combined organics were dried over sulfate, filtered, andAttorney Docket No.: 1542-WO-PCT concentrated. The residue was subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound.

[0205] Step 2: 4'-fluoro-2'H-spiro[cyclopentane-1,3'-furo[2,3-c]pyridine] (INT-A17-2) A flask was charged with INT-A17-1 (3.7 mmol), tetrahydrofuran (10 mL), and isopropanol (0.5 mL), followed by lithium borohydride (3.67 mmol). The flask was equipped with a reflux condenser, and the mixture was heated to reflux for 18 h. The mixture was allowed to cool to ambient temperature after which water (20 mL) was added. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The residue was subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound. LCMS (m / z): 194.0.

[0206] Step 3: 5'-bromo-4'-fluoro-2'H-spiro[cyclopentane-1,3'-furo[2,3-c]pyridine] (INT- A17-3) A vial was charged with INT-A17-2 (0.84 mmol) and THF (5 mL). The mixture was cooled to -78 °C, and lithium diisopropylamide (1.7.0 mmol, 1 M in THF / hexanes) was added. The mixture was allowed to stir 30 min. Bromine (2.5 mmol) was then added, and the mixture was allowed to warm to ambient temperature over 1 h. The mixture was concentrated and subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound. LCMS (m / z): 271.9.

[0207] Step 4: 3-(4'-fluoro-2'H-spiro[cyclopentane-1,3'-furo[2,3-c]pyridin]-5'-yl)-2- methoxy-5-methylbenzaldehyde (INT-A17-4) A vial was charged with INT-A17-2 (0.26 mmol), (3-formyl-2-methoxy-5-methylphenyl)boronic acid (0.39 mmol), [1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.026 mmol), aqueous potassium carbonate (2.0 M, 0.78 mmol), and 1,4-dioxane (3 mL). The mixture was heated to 100 °C for 18 h. The mixture was cooled to ambient temperature, concentrated, and subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound. LCMS (m / z): 342.0.

[0208] Step 5: 3-(4'-fluoro-2'H-spiro[cyclopentane-1,3'-furo[2,3-c]pyridin]-5'-yl)-2- hydroxy-5-methylbenzaldehyde (INT-A17-5) A vial was charged with INT-A17-4 (0.15 mmol) and dichloromethane (1 mL), followed by boron tribromide (0.32 mmol, 1M in DCM). The mixture stirred at ambient temperature for 2 h. Water (2 mL) was added. The mixture was extracted with dichloromethane (3 x 2 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated to give the title compound, which was used without further purification.Attorney Docket No.: 1542-WO-PCT

[0209] Step 6: 7-methyl-2H-spiro[benzofuro[3,2-b]furo[3,2-d]pyridine-1,1'- cyclopentane]-9-carbaldehyde (INT-A17-6) A vial was charged with INT-A17-5 (0.15 mmol), cesium carbonate (0.90 mmol), and N,N-dimethylformamide (1 mL). The mixture was heated to 80 °C for 18 h. The mixture was concentrated and subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound. LCMS (m / z): 308.0.

[0210] Step 7: (S,E)-2-methyl-N-((7-methyl-2H-spiro[benzofuro[3,2-b]furo[3,2- d]pyridine-1,1'-cyclopentan]-9-yl)methylene)propane-2-sulfinamide (INT-A17-7) A vial was charged with INT-A17-6 (0.088 mol), (S)-2-methylpropane-2-sulfinamide (0.18 mmol), 2- methyltetrahydrofuran (1 mL), followed by titanium(IV) isopropoxide (0.35 mmol). The mixture was heated to 80 °C for 2 h, cooled to ambient temperature, concentrated, and subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound. LCMS (m / z): 411.1.

[0211] Step 8: (S)-2-methyl-N-((R)-1-(7-methyl-2H-spiro[benzofuro[3,2-b]furo[3,2- d]pyridine-1,1'-cyclopentan]-9-yl)ethyl)propane-2-sulfinamide (INT-A17-8) A vial was charged with INT-A17-7 (0.071 mmol) and tetrahydrofuran (1.0 mL). The mixture was cooled to 0 °C, and methylmagnesium iodide (0.14 mmol, 3M in diethyl ether) was added. The mixture was allowed to warm to ambient temperature over 1 h, was concentrated and subjected to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes to 50% methanol in ethyl acetate) to give the title compound. LCMS (m / z): 427.1.

[0212] Step 9: (R)-1-(7-methyl-2H-spiro[benzofuro[3,2-b]furo[3,2-d]pyridine-1,1'- cyclopentan]-9-yl)ethan-1-amine (INT-A17-9) A vial was charged with INT-A17-8 (0.070 mmol), and methanol (0.5 mL). HCl (4.0 M in 1,4-dioxane, 0.5 mL) was added the mixture stirred for 1 h. The mixture was concentrated to afford the title compound, which was used without further purification. LCMS (m / z): 323.1.Attorney Docket No.: 1542-WO-PCT Procedure I-A18 for the Preparation of INT-A18-3

[0213] Step 1: (1S)-1-(4-chloro-8-methyl-benzofuro[3,2-c]pyridazin-6-yl)ethanol (INT- A18-1) To a mixture of INT-A3-7 (268.53 mmol) in dichloromethane (500 mL) was added RuCl[(S,S)-TsDPEN](mesitylene) (7.81 mmol), triethylamine (58.23 g, 575.42 mmol, 2.1 eq) and formic acid (671.32 mmol) at 0 °C. The mixture was stirred at 25 °C for 3 hours. To the reaction mixture was added water (500 mL), and it was extracted with ethyl acetate (500 mL x 3). The organic phase was separated, dried over sodium sulfate and concentrated. The crude residue was purified by flash chromatography on silica gel (0 - 100% ethyl acetate in petroleum ether) to afford the crude residue. This was further purified by SFC to yield the title compound. LCMS (m / z) 263.1.

[0214] Step 2: tert-butyl 2-[[(1R)-1-(4-chloro-8-methyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]-(2,4-dinitrophenyl)sulfonyl-amino]benzoate (INT-A18-2) To a mixture of INT-A18- 1 (1.43 mmol) in tetrahydrofuran (3.75 mL) at 0 °C was added tert-butyl 2-[(2,4- dinitrophenyl)sulfonylamino]benzoate (2.14 mmol), triphenylphosphine (2.14 mmol) and tert- butyl N-tert-butoxycarbonyliminocarbamate (2.14 mmol). The mixture was allowed to warm to ambient temperature and stirred for 72 hours. It was concentrated, and the crude residue was purified by flash chromatography on silica gel (0 - 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 668.1.Attorney Docket No.: 1542-WO-PCT

[0215] Step 3: tert-butyl 2-[[(1R)-1-(4-chloro-8-methyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]amino]benzoate (INT-A18-3) To a mixture of INT-A18-2 (1.05 mmol) in dichloromethane (6.6 mL) was added diisopropylethylamine (2.1 mmol) and 70% aqueous thioglycolic acid (1.36 mmol). The mixture was stirred for 1.5 hours. Saturated aqueous sodium bicarbonate was added, and the mixture was extracted twice with dichloromethane. The combined extracts were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was purified by flash chromatography on silica gel (0 - 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 438.1. Procedure I-A19 for the Preparation of INT-A19-5

[0216] Step 1: 1-(1,3-dioxoisoindolin-2-yl) 3-methyl bicyclo[1.1.1]pentane-1,3- dicarboxylate (INT-A19-1) A reactor was charged with 3- (methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.06 mol), N-hydroxyphthalimide (1.16 mol), N,N-dimethylaminopyridine (0.106 mol), and dichloromethane (1.8 L). To this, N,N'- diisopropylcarbodiimide (1.16 mol) was added dropwise. It was stirred at ambient temperature for 8 hours. The reaction mixture was filtered through a silica gel plug, and the filter cake was washed twice with dichloromethane. The filtrate was concentrated and triturated with methanol. The solids were collected and further washed with methanol to yield the title compound.1H NMR: (CDCl3 400 MHz): δ 7.92 - 7.87 (m, 2H), 7.84 - 7.78 (m, 2H), 3.73 (s, 3H), 2.56 (s, 6H).Attorney Docket No.: 1542-WO-PCT

[0217] Step 2: methyl 3-(3-fluoropyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (INT- A19-2) A reactor was charged with INT-A19-1 (317 mmol), 4-bromo-3-fluoropyidine (381 mmol), [bipyridine]nickel(II) dichloride (31.7 mmol), zinc powder (1.59 mol), and dimethylacetamide (1 L). It was degassed with nitrogen and cooled to 0 °C. Chlorotrimethylsilane (951 mmol) was added dropwise to the reaction mixture. It was stirred at 0 °C for two hours, then was warmed to ambient temperature and stirred for an additional 8 hours. The reaction mixture was diluted with MTBE and added to an aqueous solution of 5% potassium carbonate. It was filtered, and the solids were washed with MTBE twice. The combined filtrate and washings were separated, and the aqueous layer was extracted with MTBE three times. The combined organic phases were washed with brine and concentrated. The residue was purified by flash chromatography on silica gel (0-10% ethyl acetate in hexanes) to yield the title compound. LCMS (m / z) 222.1.

[0218] Step 3: 3-(3-fluoropyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (INT-A19-3) A reactor was charged with INT-A19-2 (173 mmol) and methanol (230 mL). To this, a solution of lithium hydroxide hydrate (347 mmol) in water (77 mL) was charged into the reactor dropwise. It was stirred for 3 hours, then was concentrated to approximately 150 mL. It was diluted with water and washed twice with MTBE. The aqueous was treated with 3N hydrochloric acid until a pH of 4 was reached. The resulting precipitate was collected via filtration, and the solids were washed twice with water and dried in vacuo to yield the title compound.1H NMR: (DMSO-d6 400 MHz): δ 8.48 (d, J = 1.6 Hz, 1H), 8.37 (d, J = 4.8 Hz, 1H), 7.30 (dd, J = 5.2, 6.8 Hz, 1H), 2.35 (s, 6H).

[0219] Step 4: 3-(2-bromo-3-fluoropyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (INT-A19-4) A reactor was charged with 2,2,6,6-tetramethylpiperidine (6.5 mmol) and tetrahydrofuran (5 mL) and cooled to -60 °C. To this, n-butyllithium (2.5M in hexanes, 6.03 mmol), and the reaction was stirred at -60 °C for 30 minutes. Next, INT-A19-3 (2.41 mmol) was charged in portions to the reactor, and it was stirred at -60 °C for 30 minutes. To this, a solution of N-bromosuccinimide (4.83 mmol) in tetrahydrofuran (10 mL) was charged into the reactor dropwise, and the reaction was stirred at -60 °C for 2 hours. The reaction mixture was poured onto a solution of 5% aqueous citric acid then was extracted three times with ethyl acetate. The combined organics were washed with brine and concentrated. The residue was purified by flash chromatography on silica gel (18-25% ethyl acetate in heptane) to yield the title compound. LCMS (m / z) 286.0.Attorney Docket No.: 1542-WO-PCT

[0220] Step 5: methyl 3-(2-bromo-3-fluoropyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (INT-A19-5) A reactor was charged with INT-A19-4 (29.7 mmol), dimethylformamide (2.97 mmol), and dichloromethane (85 mL). To this, oxalyl chloride (44.6 mmol) was charged dropwise into the reactor. It was stirred for 30 minutes. Methanol (148 mmol) was charged into the reactor dropwise, and the reaction was stirred for 30 minutes. It was concentrated, diluted with ethyl acetate, and poured onto saturated aqueous sodium bicarbonate. The organic phase was separated, and the aqueous phase was further extracted twice with ethyl acetate. The combined organics were washed with brine and concentrated. The residue was purified by flash chromatography on silica gel (2-5% ethyl acetate in heptane) to yield the title compound. LCMS (m / z) 300.0. Procedure I-A20 for the Preparation of INT-A20-8

[0221] Step 1: 1-(3-bromo-2-((4-methoxybenzyl)oxy)-5-methylphenyl)ethan-1-one (INT- A20-1) A flask was charged with 1-(3-bromo-2-hydroxy-5-methylphenyl)ethanone (3.06 mol), 1-(chloromethyl)-4-methoxybenzene (3.67 mol), potassium carbonate (6.1 mol), and dimethylformamide (2.5 L). It was stirred and heated to 80 °C for 1 hour. The reaction mixture was extracted three times with ethyl acetate, and the combined organics were washed 8 times withAttorney Docket No.: 1542-WO-PCT brine. It was dried over sodium sulfate, filtered, and concentrated to yield the title compound. LCMS (m / z) 349.

[0222] Step 2: (R)-N-(1-(3-bromo-2-((4-methoxybenzyl)oxy)-5-methylphenyl)ethylidene)-2- methylpropane-2-sulfinamide (INT-A20-2) A 5L flask was charged with INT-A20-1 (3.3 mol), (R)-2-methylpropane-2-sulfinamide (5.3 mol) and tetraethoxytitanium (2.5 L) at ambient temperature. The mixture was heated to 130 °C for 2 hours under nitrogen. It was diluted with brine and extracted three times with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the title compound. LCMS (m / z) 452.

[0223] Step 3: (R)-N-((R)-1-(3-bromo-2-((4-methoxybenzyl)oxy)-5-methylphenyl)ethyl)-2- methylpropane-2-sulfinamide (INT-20-3) Into a flask was charged INT-A20-2 (3.3 mol) and tetrahydrofuran (2.5 L). It was cooled to -78 °C and diisobutylaluminum hydride (1.0 M in THF, 6.6 mol) was added dropwise over 30 minutes. It was stirred at this temperature for 3 hours. It was quenched by the addition of saturated aqueous ammonium chloride at 0 °C. The mixture was extracted three times with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to yield the title compound. LCMS (m / z) 454.

[0224] Step 4: (R)-2-(1-aminoethyl)-6-bromo-4-methylphenol (INT-A20-4) A flash was charged with INT-A20-3 (3.3 mol), 1,4-dioxane (6 L), and HCl (4.0 M in dioxane, 6 L) at 0 °C. It was allowed to warm to ambient temperature and stir for 12 hours under nitrogen. It was concentrated to yield the title compound. LCMS (m / z) 230.

[0225] Step 5: tert-butyl (R)-(1-(3-bromo-2-hydroxy-5-methylphenyl)ethyl)carbamate (INT-A20-5) A flask was charged with INT-A20-4 (2.2 mol), di-tert-butyl decarbonate (2.6 mol), triethylamine (6.5 mol), and dichloromethane (5 L). It was stirred at ambient temperature for 12 hours under nitrogen. The resulting mixture was concentrated and dissolved in methanol (3 L). To this, potassium carbonate (4.35 mol) was added in portions, and the resulting mixture was heated to 60 °C and stirred for 16 hours. It was cooled to ambient temperature and was extracted three times with ethyl acetate. The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica gel (5:1 petroleum ether / ethyl acetate) to yield the title compound. LCMS (m / z) 330.Attorney Docket No.: 1542-WO-PCT

[0226] Step 6: tert-butyl (R)-(1-(2-hydroxy-5-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenyl)ethyl)carbamate (INT-A20-6) A flask was charged with INT-A20- 5 (636 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.54 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (64 mmol), potassium acetate (1.91 mol) and 1,4-dioxane (2 L). It was stirred at 80 °C under nitrogen for 3 hours. The mixture was extracted three times with ethyl acetate, and the combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica gel (10:1 petroleum ether / ethyl acetate) to yield the title compound. LCMS (m / z) 378.

[0227] Step 7: Methyl (R)-3-(2-(3-(1-((tert-butoxycarbonyl)amino)ethyl)-2-hydroxy-5- methylphenyl)-3-fluoropyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (INT-A20-7) A screw-cap vial was charged with INT-A20-6 (0.40 mmol), INT-A19-5 (0.33 mmol), and (1,1'- bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.08 mmol) followed by 1,4-dioxane (3.0 mL) and aqueous sodium carbonate (1.5 M, 0.55 mL). The mixture was degassed with argon for 5 minutes and then the reaction vial sealed and heated to 90 °C for 1 h. Following this time, the mixture was filtered through celite and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 471.1.

[0228] Step 8: Methyl (R)-3-(6-(1-((tert-butoxycarbonyl)amino)ethyl)-8- methylbenzofuro[3,2-b]pyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylate (INT-A20-8) To a solution of INT-A20-7 (0.17 mmol) in N,N-dimethylformamide (2.0 mL) was added cesium carbonate (0.33 mmol). The mixture was sparged with argon and then heated to 50 °C for 2 h. The mixture was filtered through celite, concentrated in vacuo, and subjected to flash column chromatography on silica gel (10% to 100% ethyl acetate in hexanes) to give the title compound. LCMS (m / z): 451.1. Procedure I-B1 for the Preparation of INT-B1-2Attorney Docket No.: 1542-WO-PCT

[0229] Step 1: tert-butyl (R)-(1-(8-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzofuro[3,2- b]pyridin-6-yl)ethyl)carbamate (INT-B1-1). To a mixture of INT-A11-1 (0.10 mmol), (1- methyl-1H-pyrazol-4-yl)boronic acid (0.3 mmol), and XPhos Pd G3 (0.017 mmol) in 1,4- dioxane (2.0 mL) was added aqueous sodium carbonate (2.0 M, 0.4 mL) at room temperature. The mixture was purged with argon and vigorously stirred at 100 °C. After 1 h, the resulting mixture was cooled to room temperature, and water (10 mL) and ethyl acetate (10 mL) were added sequentially. The organic layer was washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% to 90% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 407.0.

[0230] Step 2: (R)-1-(8-methyl-4-(1-methyl-1H-pyrazol-4-yl)benzofuro[3,2-b]pyridin-6- yl)ethan-1-amine (INT-B1-2). To a solution of INT-B1-1 (0.094 mmol) in dioxane (1 mL) was added hydrochloric acid (4.0 M in 1,4-dioxane, 0.5 mL). The solution was left to stir at room temperature. After 2 h, the mixture was concentrated under reduced pressure and carried forward without further purification. LCMS (m / z) 307.2.

[0231] The following Examples were made using the general route described in Procedure I- B1 and are shown below in Table B1. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B1 and are noted in the last column of Table B1 – “Changes to Procedure I-B1: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B1 were replaced with the different reagents / starting materials noted below. Table B1:Attorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTProcedure I-B2 for the Preparation of INT-B2-2

[0232] Step 1: tert-butyl (R)-(1-(8-methyl-4-(pyridin-2-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)carbamate (INT-B2-1). A solution of INT-A11-1 (0.064 mmol), 2- (tributylstannyl)pyridine (0.096 mmol), XPhos Pd G4 (0.0064 mmol), copper(I) iodide (0.026 mmol), and cesium fluoride (0.13 mmol), in N,N-dimethylformamide (0.4 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction was capped and stirred at 100 °C for 3 h. The reaction was cooled. To the reaction was added an aqueous saturated solution of sodium bicarbonate (10 mL) and the aqueous layer was washed with EtOAc (2x 5 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes, then 0% to 50% MeOH in EtOAc) to afford the title compound. LCMS (m / z) 404.3.

[0233] Step 2: (R)-1-(8-methyl-4-(pyridin-2-yl)benzofuro[3,2-b]pyridin-6-yl)ethan-1- amine (INT-B2-2). A solution of INT-B2-1 (0.050 mmol) in dichloromethane (0.2 mL) was added HCl (4.0 M in 1,4-dioxane, 0.12 mL). The reaction was stirred for 1 h and then concentrated to afford the title compound. LCMS (m / z) 304.1.

[0234] The following Examples were made using the general route described in Procedure I- B2 and are shown below in Table B2. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B2 and areAttorney Docket No.: 1542-WO-PCT noted in the last column of Table B2 – “Changes to Procedure I-B2: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B2 were replaced with the different reagents / starting materials noted below. Table B2:Attorney Docket No.: 1542-WO-PCTProcedure I-B3 for the Preparation of INT-B3-2

[0235] Step 1: tert-butyl (R)-(1-(8-methyl-4-morpholinobenzofuro[3,2-b]pyridin-6- yl)ethyl)carbamate (INT-B3-1). A mixture of INT-A11-1 (0.083 mmol), morpholine (0.42 mmol), and N,N-diisopropylethylamine (0.67 mmol) in dimethyl sulfoxide (1.0 mL) was purged with argon and vigorously stirred at 100 °C. After 20 h, the resulting mixture was cooled to room temperature, and water (5 mL) and ethyl acetate (5 mL) were added sequentially. TheAttorney Docket No.: 1542-WO-PCT organic layer was washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 20% methanol in ethyl acetate) to afford the title compound. LCMS (m / z) 412.2.

[0236] Step 2: (R)-1-(8-methyl-4-morpholinobenzofuro[3,2-b]pyridin-6-yl)ethan-1-amine (INT-B3-2). To a solution of INT-B3-1 (0.061 mmol) in 1,4-dioxane (1.0 mL) was added HCl (4.0 M in 1,4-dioxane, 0.30 mL) at room temperature. After stirring at room temperature 20 h, the resulting mixture was concentrated under reduced pressure to afford the title compound without further purification. LCMS (m / z) 312.2.

[0237] The following Examples were made using the general route described in Procedure I- B3 and are shown below in Table B3. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B3 and are noted in the last column of Table B3 – “Changes to Procedure I-B3: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B3 were replaced with the different reagents / starting materials noted below. Table B3:Attorney Docket No.: 1542-WO-PCTProcedure I-B4 for the Preparation of INT-B4-2

[0238] Step 1: (R)-2-methyl-N-((R)-1-(8-methyl-4-(piperidin-1-yl)benzofuro[3,2- b]pyridin-6-yl)ethyl)propane-2-sulfinamide (INT-B4-1) A vial was charged with INT-A10-4 (0.041 mmol), piperidine (0.082 mmol), N,N-diisopropylethylamine (0.12 mmol), and MeCN (0.5 mL). The mixture was heated to 90 °C for 18 h, concentrated, and subject to flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to give the title compound.

[0239] Step 2: (R)-1-(8-methyl-4-(piperidin-1-yl)benzofuro[3,2-b]pyridin-6-yl)ethan-1- amine (INT-B4-2). A vial was charged with INT-B4-1 (0.040 mmol), methanol (1 mL), and HCl (4.0 M in 1,4-dioxane, 1 mL). The mixture was stirred for 1 h at ambient temperature, and then concentrated to give the title compound, which was used without further purification. LCMS (m / z): 310.2.

[0240] The following Examples were made using the general route described in Procedure I- B4 and are shown below in Table B4. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B4 and are noted in the last column of Table B4 – “Changes to Procedure I-B4: DifferentAttorney Docket No.: 1542-WO-PCT Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B4 were replaced with the different reagents / starting materials noted below. Table B4:Procedure I-B5 for the Preparation of INT-B5-3

[0241] Step 1: tert-butyl N-[(1R)-1-[4-(3,6-dihydro-2H-pyran-4-yl)-8-methyl- benzofuro[3,2-b]pyridin-6-yl]ethyl]carbamate (INT-B5-1) A screw-cap vial was charged with INT-A11-1 (0.14 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (0.21 mmol), and XPhos Pd G3 (0.007 mmol) followed by 1,2-dimethoxyethane (0.65 mL) and aqueous sodium carbonate (2.0 M, 0.21 mL). It was degassed with nitrogen, sealed, and heated to 80 °C for 4 h. It was diluted with ethyl acetate and washed sequentiallyAttorney Docket No.: 1542-WO-PCT with water and saturated sodium chloride. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica (5% to 100% ethyl acetate in hexanes) to yield the product. LCMS (m / z) 409.2.

[0242] Step 2: tert-butyl N-[(1R)-1-(8-methyl-4-tetrahydropyran-4-yl-benzofuro[3,2- b]pyridin-6-yl)ethyl]carbamate (INT-B5-2) To a solution of INT-B5-1 (0.11 mmol) in ethanol (1.0 mL) was added 10% palladium on carbon (0.01 mmol), and the vessel was evacuated and backfilled with hydrogen gas three times. It was stirred vigorously for 16 h. The vessel was evacuated and backfilled with air, and the mixture was filtered over Celite. The filtrated was concentrated to yield the product, which was taken onto the next step without further purification. LCMS (m / z) 411.2.

[0243] Step 3: (1R)-1-(8-methyl-4-tetrahydropyran-4-yl-benzofuro[3,2-b]pyridin-6- yl)ethanamine (INT-B5-3) A screw-cap vial was charged with INT-B5-2 (0.11 mmol) and trifluoroacetic acid (2 mL), and it was stirred for 1 h. It was concentrated to yield the product, which was taken onto the next reaction without further purification. LCMS (m / z) 311.2.

[0244] The following Examples were made using the general route described in Procedure I- B5 and are shown below in Table B5. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B5 and are noted in the last column of Table B5 – “Changes to Procedure I-B5: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B5 were replaced with the different reagents / starting materials noted below. Table B5:Attorney Docket No.: 1542-WO-PCTProcedure I-B6 for the Preparation of INT-B6-2

[0245] Step 1: Tert-butyl (R)-(1-(4-(benzyloxy)-8-methylbenzofuro[3,2-b]pyridin-6- yl)ethyl)carbamate (INT-B6-1). INT-A11-1 (0.027 mmol) in toluene (1.0 mL) was treated with phenylmethanol (0.055 mmol), followed by RockPhos Pd G3 (0.006 mmol), and cesium carbonate (0.0829 mmol). The mixture was purged with argon and heated at 100 °C for 30 min. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 432.9.

[0246] Step 2: (R)-1-(4-(benzyloxy)-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethan-1-amine dihydrochloride (INT-B6-2). INT-B6-1 (0.028 mmol) in methanol (1 mL) was treated with HCl (4.0 M in dioxane, 0.50 mmol). The mixture was stirred at room temperature for 7 h and then concentrated to give the title compound, which was used without further purification. LCMS (m / z) 332.9.Attorney Docket No.: 1542-WO-PCT Procedure I-B7 for the Preparation of INT-B7-2

[0247] Step 1: Tert-butyl N-[(1R)-1-(4-tert-butyl-8-methyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]carbamatee (INT-B7-1). A mixture of tert-butylmagnesium chloride (2.0M in ether, 2.21 mmol) and copper (I) cyanide (1.11 mmol) in THF (0.5 mL) was stirred at -78 °C for 20 minutes. To this, INT-A11-2 (0.138 mmol) was added. The mixture was stirred at -78 °C for 2 hours, then was warmed to room temperature overnight. It was quenched by the dropwise addition of saturated ammonium hydroxide, then was extracted three times with chloroform. The extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 384.1.

[0248] Step 2: (1R)-1-(4-tert-butyl-8-methyl-benzofuro[3,2-c]pyridazin-6-yl)ethanamine (INT-B7-2). INT-B7-1 (0.021 mmol) in dichloromethane (0.6 mL) was treated with HCl (4.0 M in dioxane, 0.23 mmol). The mixture was stirred at room temperature for 1 h and then concentrated to give the title compound, which was used without further purification. LCMS (m / z) 284.1. Procedure I-B8 for the Preparation of INT-B8-3Attorney Docket No.: 1542-WO-PCT

[0249] Step 1: Tert-butyl N-[(1R)-1-[8-methyl-4-(trideuteriomethylamino)benzofuro[3,2- c]pyridazin-6-yl]ethyl]carbamate (INT-B8-1). A mixture of INT-A11-2 (0.21 mmol), methyl- d3-amine hydrochloride (2.1 mmol), and potassium carbonate (2.5 mmol) in dimethyl sulfoxide (0.75 mL) was stirred at 80 °C for 16 hours, then at 100 °C for 6 hours. It was cooled to ambient temperature and precipitated by the addition of water. The solids were collected to yield the title compound without further purification. LCMS (m / z) 360.2.

[0250] Step 2: Tert-butyl N-[(1R)-1-[4-[(3,5-difluorobenzoyl)-(trideuteriomethyl)amino]- 8-methyl-benzofuro[3,2-c]pyridazin-6-yl]ethyl]carbamate (INT-B8-2). To a mixture of INT- B8-1 (0.18 mmol), triethylamine (0.53 mmol), and 4-dimethylaminopyridine (0.018 mmol) in dichloromethane (1.3 mL) was added 3,5-difluorobenzoyl chloride (0.35 mmol), and the mixture was stirred at ambient temperature for 30 minutes. It was concentrated, and the residue was purified by flash chromatography on silica gel (0-100% ethyl acetate / hexanes) to yield the title compound. LCMS (m / z) 500.2.

[0251] Step 3: N-[6-[(1R)-1-aminoethyl]-8-methyl-benzofuro[3,2-c]pyridazin-4-yl]-3,5- difluoro-N-(trideuteriomethyl)benzamide (INT-B8-3). INT-B8-2 (0.18 mmol) in dichloromethane (0.9 mL) was treated with HCl (4.0 M in dioxane, 1.8 mmol). The mixture was stirred at room temperature for 1 h and then concentrated to give the title compound, which was used without further purification. LCMS (m / z) 400.1.

[0252] The following Examples were made using the general route described in Procedure I- B8 and are shown below in Table B8. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B8 and are noted in the last column of Table B8 – “Changes to Procedure I-B8: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B8 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table B8:Attorney Docket No.: 1542-WO-PCT Procedure I-B9 for the Preparation of INT-B9-4

[0253] Step 1: methyl 6-[(1R)-1-(tert-butoxycarbonylamino)ethyl]-8-methyl- benzofuro[3,2-c]pyridazine-4-carboxylate (INT-B9-1) To a mixture of INT-A11-2 (0.55 mmol) and diisopropylethylamine (1.11 mmol) in methanol (2 mL) was added (1,1'- bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (0.055 mmol), and the reaction was put under and atmosphere of 60 psi of carbon monoxide and heated to 60 °C for 16 hours. It was cooled to ambient temperature, filtered, concentrated, and purified by flash chromatography on silica (0% to 100% ethyl acetate in hexanes) to yield the product. LCMS (m / z) 386.1.

[0254] Step 2: 6-[(1R)-1-(tert-butoxycarbonylamino)ethyl]-8-methyl-benzofuro[3,2- c]pyridazine-4-carboxylic acid (INT-B9-2) To a solution of INT-B9-1 (0.37 mmol) in 1:1 methanol / methyl THF (2.2 mL) was added 1M aqueous lithium hydroxide (1.1 mmol), at it was stirred at ambient temperature for 1 hour. It was concentrated, diluted with water, and 1.1 mL of 1M hydrochloric acid was added. The solids were collected via filtration to yield the product. LCMS (m / z) 372.3.

[0255] Step 3: tert-butyl N-[(1R)-1-[8-methyl-4- [methyl(phenyl)carbamoyl]benzofuro[3,2-c]pyridazin-6-yl]ethyl]carbamate (INT-B9-3) A screw-cap vial was charged with INT-B9-2 (0.081 mmol), N-methylaniline (0.16 mmol), diisopropylethylamine (0.24 mmol) and dimethylformamide (0.4 mL). To this, HATU (0.16 mmol) was added, and the mixture was stirred at ambient temperature for 2 hours. It was diluted with water and extracted twice with ethyl acetate. The combined extracts were washed twice with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica (0% to 100% methanol in ethyl acetate) to yield the product.Attorney Docket No.: 1542-WO-PCT

[0256] Step 4: 6-[(1R)-1-aminoethyl]-N,8-dimethyl-N-phenyl-benzofuro[3,2-c]pyridazine- 4-carboxamide (INT-B9-4) A screw-cap vial was charged with INT-B9-3 (0.067 mmol), dichloromethane (0.2 mL), and hydrogen chloride in dioxane (4.0M, 0.67 mmol), and the mixture was stirred for 16 hours at ambient temperature. It was concentrated to yield the product without further purification. Procedure I-B10 for the Preparation of INT-B10-2

[0257] Step 1: tert-butyl N-[(1R)-1-[4-(1-bicyclo[1.1.1]pentanyl)-8-methyl-benzofuro[3,2- c]pyridazin-6-yl]ethyl]carbamate (INT-B10-1). A screw-cap vial was charged with (1,2- dimethoxyethane)nickel(II) bromide (0.14 mmol) and 4,4'-di-tert-butyl-N-cyano-[2,2'- bipyridine]-6-carboximidamide (0.14 mmol), then dimethylacetamide (3 mL) was added . It was degassed with argon and stirred for 30 minutes. Another screw-cap vial was charged with INT- A11-2 (0.55 mmol), (1,3-dioxoisoindolin-2-yl)bicyclo[1.1.1]pentane-1-carboxylate (1.38 mmol), and zinc dust (1.66 mmol) and was purged with argon. The nickel catalyst solution was added via syringe, and the mixture was stirred for 20 hours. It was diluted with ethyl acetate and filtered through a plug of celite. The solution was washed with 10% lithium chloride, dried over anhydrous magnesium sulfate, filtered, and concentratedThe residue was purified by flash column chromatography on silica gel (10% to 70% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 394.0.

[0258] Step 2: (1R)-1-[4-(1-bicyclo[1.1.1]pentanyl)-8-methyl-benzofuro[3,2-c]pyridazin- 6-yl]ethanamine (INT-B10-2). To a solution of INT-B10-1 (0.17 mmol) in 1,4-dioxane (1.0 mL) was added HCl (4.0 M in 1,4-dioxane, 0.42 mL) at room temperature. After stirring at room temperature 20 h, the resulting mixture was concentrated under reduced pressure to afford the title compound without further purification. LCMS (m / z) 294.0.

[0259] The following Examples were made using the general route described in Procedure I- B10 and are shown below in Table B10. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B10 and are noted in the last column of Table B10 – “Changes to Procedure I-B10: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize whichAttorney Docket No.: 1542-WO-PCT reagents / starting materials of Procedure I-B10 were replaced with the different reagents / starting materials noted below. Table B10:Procedure I-B11 for the Preparation of INT-B11-2

[0260] Step 1: tert-butyl N-[(1R)-1-[4-(2,2-difluorospiro[3.3]heptan-6-yl)-8-methyl- benzofuro[3,2-c]pyridazin-6-yl]ethyl]carbamate (INT-B11-1). A screw-cap vial was charged with INT-A11-2 (0.11 mmol), 6-bromo-2,2-difluoro-spiro[3.3]heptane (0.13 mmol), [4,4′- bis(1,1-dimethylethyl)-2,2′-bipyridine] nickel (II) dichloride (0.013 mmol), zinc powder (0.46 mmol) tetrabutylammonium iodide (0.11 mmol), phthalimide (0.061 mmol), pyridine (1 drop), and dimethylacetamide (1 mL). It was degassed with argon, sealed, and heated to 60 °C overnight. It was cooled to ambient temperature, concentrated, and purified by flash chromatography on silica gel (0-100% ethyl acetate in hexanes) to yield the title compound. LCMS (m / z) 458.0.

[0261] Step 2: (1R)-1-[4-(2,2-difluorospiro[3.3]heptan-6-yl)-8-methyl-benzofuro[3,2- c]pyridazin-6-yl]ethanamine (INT-B11-2). To a solution of INT-B11-1 (0.054 mmol) in methanol (1.5 mL) was added HCl (4.0 M in 1,4-dioxane, 0.14 mL) at the reaction was heated to 45 °C for 2 hours. It was cooled to ambient temperature, concentrated, and dissolved in ethylAttorney Docket No.: 1542-WO-PCT acetate. It was washed with saturated sodium bicarbonate, and the organics were concentrated to yield the title compound without further purification. LCMS (m / z) 358.1. Procedure I-B12 for the Preparation of INT-B12-2

[0262] Step 1: tert-butyl N-[(1R)-1-(4-cyclobutyl-8-methyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]carbamate (INT-B12-1). A screw-cap vial was charged with INT-A11-2 (0.17 mmol), bromo(cyclobutyl)zinc (0.33 mmol), bis(tri-tert-butylphosphine)palladium(0) (0.017 mmol), and dioxane (4 mL). It was degassed with argon, sealed, and heated to 90 °C for 3 hours. It was cooled to ambient temperature, concentrated, and purified by flash chromatography on silica gel (0-50% methanol in ethyl acetate) to yield the title compound. LCMS (m / z) 382.2.

[0263] Step 2: (1R)-1-(4-cyclobutyl-8-methyl-benzofuro[3,2-c]pyridazin-6-yl)ethanamine (INT-B12-2). A screw-cap vial was charged with INT-B12-1 (0.16 mmol) and HCl (4.0 M in 1,4-dioxane, 1 mL) at the reaction was stirred at ambient temperature for 2 hours. It was concentrated to yield the title compound without further purification. LCMS (m / z) 282.1. Procedure I-B13 for the Preparation of INT-B13-2

[0264] Step 1: tert-butyl N-[(1R)-1-[8-methyl-4-(2-oxo-3-azabicyclo[3.1.1]heptan-3- yl)benzofuro[3,2-b]pyridin-6-yl]ethyl]carbamate (INT-B13-1). A screw-cap vial was charged with INT-A11-2 (0.14 mmol), 3-azabicyclo[3.1.1]heptan-2-one (0.42 mmol), cesium carbonate (0.55 mmol), XantPhos Pd G3 (0.035 mmol), and dioxane (9 mL). It was degassed with argon, sealed, and heated to 100 °C for 12 hours. It was dissolved in ethyl acetate, washed with 10% aqueous lithium chloride, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (10% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 437.2.Attorney Docket No.: 1542-WO-PCT

[0265] Step 2: (R)-3-(6-(1-aminoethyl)-8-methylbenzofuro[3,2-c]pyridazin-4-yl)-3- azabicyclo[3.1.1]heptan-2-one (INT-B13-2). To a solution of INT-B13-1 (0.11 mmol) in 1,4- dioxane (0.57 mL) was added HCl (4.0 M in 1,4-dioxane, 0.29 mL) at room temperature. After stirring at room temperature 20 h, the resulting mixture was concentrated under reduced pressure to afford the title compound without further purification. LCMS (m / z) 337.0.

[0266] The following Examples were made using the general route described in Procedure I- B13 and are shown below in Table B13. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B13 and are noted in the last column of Table B13 – “Changes to Procedure I-B13: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B13 were replaced with the different reagents / starting materials noted below. Table B13:Attorney Docket No.: 1542-WO-PCT Procedure I-B14 for the Preparation of INT-B14-4

[0267] Step 1: (R)-3-(6-(1-((tert-butoxycarbonyl)amino)ethyl)-8-methylbenzofuro[3,2- b]pyridin-4-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (INT-B14-1). INT-A20-8 (0.08 mmol) was taken up in THF (0.8 mL) and aqueous lithium hydroxide (2.0 M, 0.8 mL) was added. The mixture was heated to 50 °C for 1 h. Following this time, the mixture was diluted with ethyl acetate (5 mL) and saturated aqueous ammonium chloride (5 mL). The organic layer was collected and the aqueous phase extracted with ethyl acetate (3 x 2 mL). The combined organic extracts were dried over magnesium sulfate and concentrated in vacuo to afford the title compound which was used without additional purification. LCMS (m / z) 437.1.

[0268] Step 2: tert-Butyl (R)-(1-(4-(3-((acetimidamidooxy)carbonyl)bicyclo[1.1.1]pentan-1- yl)-8-methylbenzofuro[3,2-b]pyridin-6-yl)ethyl)carbamate (INT-B14-2). To a solution of INT-B14-1 (0.08 mmol) in N,N-dimethylformamide (1.0 mL) was added DIPEA (0.28 mmol) followed by (benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate) (0.10 mmol). The mixture was stirred at ambient temperature for 3 h then diluted with ethyl acetate (10 mL) and water (10 mL). The organic phase was collected, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford the title product which was used without additional purification. LCMS (m / z) 493.1.

[0269] Step 3: tert-Butyl (R)-(1-(8-methyl-4-(3-(3-methyl-1,2,4-oxadiazol-5- yl)bicyclo[1.1.1]pentan-1-yl)benzofuro[3,2-b]pyridin-6-yl)ethyl)carbamate (INT-B14-3). To a solution of INT-B14-2 (0.08 mmol) in THF (0.8 mL) was added a solution of tetrabutylammonium fluoride in THF (1.0 M, 0.80 mmol). The mixture was stirred at ambient temperature for 1 h and then additional tetrabutylammonium fluoride in THF (1.0 M, 0.80 mmol) was added and the reaction stirred for 30 min. The mixture was concentrated in vacuo and theAttorney Docket No.: 1542-WO-PCT residue purified by flash column chromatography on silica gel (10% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 475.1.

[0270] Step 4: (R)-1-(8-methyl-4-(3-(3-methyl-1,2,4-oxadiazol-5-yl)bicyclo[1.1.1]pentan- 1-yl)benzofuro[3,2-b]pyridin-6-yl)ethan-1-amine (INT-B14-4). INT-B14-3 (0.08 mmol) was taken up in methanol (0.5 mL) and a solution of HCl in 1,4-dioxane (4 M, 0.5 mL) was added. The reaction was stirred at r.t. for 1.5 h. Following this time, the mixture was concentrated in vacuo and then the residue was taken up in ethyl acetate (10 mL) and washed with saturated aqueous NaHCO3(10 mL). The organic phase was washed with brine, dried over magnesium sulfate and concentrated to dryness. The title product was used in the subsequent step without additional purification. LCMS (m / z) 375.1.

[0271] The following Examples were made using the general route described in Procedure I- B14 and are shown below in Table B14. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure I-B14 and are noted in the last column of Table B14 – “Changes to Procedure I-B14: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure I-B14 were replaced with the different reagents / starting materials noted below. Table B14:Attorney Docket No.: 1542-WO-PCTProcedure F-1 for the Preparation of Ex.1

[0272] Step 1: (R)-2-((1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (INT-F1-1). To a mixture of INT-A10-5 (0.13 mmol), methyl 2- iodobenzoate (0.27 mmol), and cesium carbonate (0.80 mmol) in 1,4-dioxane (1.0 mL) and dimethylacetamide (1.0 mL) was added XantPhos Pd G3 (0.040 mmol) at room temperature. The mixture was purged with argon and vigorously stirred at 100 °C. After 20 h, the resulting mixture was cooled to room temperature, and water (5 mL) and ethyl acetate (5 mL) were added sequentially. The organic layer was washed with aqueous lithium chloride (5.0 %, 5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 70% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 437.0.

[0273] Step 2: (R)-2-((1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.1). To a solution of INT-F1-1 (0.092 mmol) in methanol (0.50 mL) and tetrahydrofuran (0.50 mL) was added aqueous lithium hydroxide (1.0 M, 0.25 mL) at room temperature. The mixture was heated to 70 °C and vigorously stirred for 1 h before cooling down to room temperature. The resulting mixture was acidified with a few drops of TFA and purified by RP-HPLC (30 to 95 % 0.1% TFA in MeCN / 0.1% TFA in H2O). Fractions containing the product were combined and lyophilized to yield Ex.1.1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 8.70 (d, J = 5.1 Hz, 1H), 8.53 (s, 1H), 8.21 – 8.14 (m, 2H), 7.90 (dd, J = 1.8, 0.9 Hz, 1H), 7.84 (d, J = 5.1 Hz, 1H), 7.81 (dd, J = 7.9, 1.7 Hz, 1H), 7.70 – 7.62 (m, 2H), 7.61 – 7.53 (m, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.23 (ddd, J = 8.8, 7.1, 1.8 Hz, 1H), 6.68 (d, J =Attorney Docket No.: 1542-WO-PCT 8.5 Hz, 1H), 6.58 – 6.49 (m, 1H), 5.40 – 5.02 (m, 1H), 2.49 (s, 3H), 1.72 (d, J = 6.7 Hz, 3H). LCMS (m / z) 423.0.

[0274] The following Examples were made using the general route described in Procedure F- 1 and are shown below in Table F1. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure F-1 and are noted in the last column of Table F1 – “Changes to Procedure F-1: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure F-1 were replaced with the different reagents / starting materials noted below. Table F1:Attorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTProcedure F-2 for the Preparation of Ex.48

[0275] Step 1: tert-butyl (R)-2-((1-(8-methyl-4-(pyridin-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoate (INT-F2-1). A mixture of INT-B2-3 (0.059 mmol), tert-butyl 2- iodobenzoate (0.29 mmol), XantPhos Pd G4 (0.015 mmol), and cesium carbonate (0.47 mmol), in dimethylacetamide (0.25 mL) and 1,4-dioxane (0.40 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction was capped and stirred at 100 °C for 24 h. The reaction was cooled, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes, then 0% to 80% MeOH in EtOAc) to afford the title compound. LCMS (m / z) 480.3.

[0276] Step 2: (R)-2-((1-(8-methyl-4-(pyridin-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.48). A solution of INT-F2-1 (0.042 mmol) in acetonitrile (0.4 mL) and a solution of hydrogen chloride in water (6 M, 0.1 mL) was stirred at 60 ° C for 1 h. The reaction was concentrated and purified by RP-HPLC (5 to 98 % 0.1% TFA in MeCN / 0.1% TFA in H2O) Fractions containing the product were combined and lyophilized to yield Ex.48.1H NMR (400 MHz, DMSO-d6) δ 9.37 (d, J = 2.2 Hz, 1H), 8.77 (d, J = 4.9 Hz, 1H), 8.74 (d, J = 5.0 Hz, 1H), 8.65 – 8.58 (m, 1H), 8.52 (s, 1H), 7.93 (d, J = 5.0 Hz, 1H), 7.90 (s, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.73 (dd, J = 8.0, 4.9 Hz, 1H), 7.46 (s, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 6.53 (t, J = 7.5 Hz, 1H), 5.25 – 5.15 (m, 1H), 1.71 (d, J = 6.7 Hz, 3H). LCMS (m / z) 424.2.

[0277] The following Examples were made using the general route described in Procedure F- 2 and are shown below in Table F2. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure F-2 and are noted in the last column of Table F2 – “Changes to Procedure F-2: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure F-2 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table F2:Attorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCT Procedure F-3 for the Preparation of Ex.54

[0278] Step 1: methyl (R)-6-chloro-3-((1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6- yl)ethyl)amino)picolinate (INT-F3-1). A mixture of INT-A10-5 (0.18 mmol), methyl 6-chloro- 3-fluoro-pyridine-2-carboxylate (0.27 mmol), and N,N-diisopropylethylamine (0.91 mmol) in dimethyl sulfoxide (1.0 mL) was purged with argon and vigorously stirred at 100 °C. After 20 h, the resulting mixture was cooled to room temperature, and water (5 mL) and ethyl acetate (5 mL) were added sequentially. The organic layer was washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 80% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 472.2.

[0279] Step 2: (R)-6-chloro-3-((1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6- yl)ethyl)amino)picolinic acid (Ex.54). To a solution of INT-F3-1 (0.11 mmol) in methanol (0.70 mL) and tetrahydrofuran (0.70 mL) was added aqueous lithium hydroxide (1.0 M, 0.25 mL) at room temperature. The mixture was heated to 70 °C and vigorously stirred for 1 h before cooling down to room temperature. The resulting mixture was acidified with a few drops of TFA and purified by RP-HPLC (30 to 95 % 0.1% TFA in MeCN / 0.1% TFA in H2O). Fractions containing the product were combined and lyophilized to yield Ex.54.1H NMR (400 MHz, DMSO) δ 13.04 (s, 1H), 8.70 (d, J = 5.1 Hz, 1H), 8.51 (d, J = 6.8 Hz, 1H), 8.18 – 8.10 (m, 2H), 7.91 (dd, J = 1.8, 0.9 Hz, 1H), 7.83 (d, J = 5.1 Hz, 1H), 7.69 – 7.61 (m, 2H), 7.62 – 7.54 (m, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 9.1 Hz, 1H), 5.23 (t, J = 6.8 Hz, 1H), 2.49 (s, 3H), 1.73 (d, J = 6.7 Hz, 3H). LCMS (m / z) 458.0.

[0280] The following Examples were made using the general route described in Procedure F- 3 and are shown below in Table F3. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure F-3 and are noted in the last column of Table F3 – “Changes to Procedure F-3: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure F-3 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table F3:Attorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTProcedure F-4 for the Preparation of Ex.62

[0281] Step 1: tert-butyl 6-chloro-3-[(8-methyl-4-phenyl-benzofuro[3,2-b]pyridin-6- yl)methylamino]pyridine-2-carboxylate (INT-F4-1) A screw-cap vial was charged consecutively with INT-A1-4 (0.15 mmol), methyl 2-aminobenzoate (0.15 mmol), N,N- dimethylformamide (0.95 mL), and trimethylsilyl chloride (0.37 mmol). The reaction mixture was cooled to 0 °C, and borane-THF complex (1.0 M in THF 0.15 mmol) was added. The flask was sealed and stirred at ambient temperature overnight. The vigorously stirred reaction mixture was treated with water and the mixture was stirred for 20 min. Ethyl acetate was added followed by saturated sodium carbonate solution. The biphasic mixture was kept stirring until the gas evolution had ceased. The layers were separated, and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica (5% to 100% ethyl acetate in hexanes) to yield the product. LCMS (m / z) 500.2.

[0282] Step 2: 6-chloro-3-[(8-methyl-4-phenyl-benzofuro[3,2-b]pyridin-6- yl)methylamino]pyridine-2-carboxylic acid (Ex.62) To a solution of INT-F4-1 (0.088 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL), and it was allowed to stir for 16 h. It was concentrated, diluted with dimethyl sulfoxide, and purified by RP-HPLC (eluting with 0.1% TFA in MeCN / 0.1% TFA in H2O) to yield Ex.62.1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 5.1 Hz, 1H), 8.51 (s, 1H), 8.12 (dd, J = 7.2, 1.8 Hz, 2H), 7.92 (s, 1H), 7.81 (d, J = 5.1 Hz, 1H), 7.62 (dd, J = 8.2, 6.5 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.43 – 7.35 (m, 2H), 4.92 (d, J = 5.0 Hz, 2H), 2.50 (s, 3H). LCMS (m / z) 444.1.

[0283] The following Examples were made using the general route described in Procedure F- 4 and are shown below in Table F4. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure F-4 and are noted in the lastAttorney Docket No.: 1542-WO-PCT column of Table F4 – “Changes to Procedure F-4: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure F-4 were replaced with the different reagents / starting materials noted below. Table F4:Procedure F-5 for the Preparation of Ex.64

[0284] Step 1: methyl 2-[(8-methyl-4-phenyl-benzofuro[3,2-b]pyridin-6- yl)methylamino]benzoate (INT-F5-1) A screw-cap vial was charged consecutively with INT- A1-4 (0.125 mmol), methyl 2-aminobenzoate (0.125 mmol), dimethylformamide (0.8 mL), and trimethylsilyl chloride (0.313 mmol). The reaction mixture was cooled to 0 °C, and borane-THF complex (1.0 M in THF 0.125 mmol) was added. The flask was sealed and stirred at ambient temperature overnight. The vigorously stirred reaction mixture was treated with water and the mixture was stirred for 20 min. Ethyl acetate was added followed by saturated sodium carbonate solution. The biphasic mixture was kept stirring until the gas evolution had ceased. The phases were separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified byAttorney Docket No.: 1542-WO-PCT flash chromatography on silica (5% to 100% ethyl acetate in hexanes) to yield the product. LCMS (m / z) 423.1.

[0285] Step 2: 2-[(8-methyl-4-phenyl-benzofuro[3,2-b]pyridin-6-yl)methylamino]benzoic acid (Ex.64) To a solution of INT-F5-1 (0.066 mmol) in tetrahydrofuran (0.7 mL) was added 1M aqueous lithium hydroxide (0.27 mmol), and the reaction was allowed to stir at ambient temperature for 4 hours. It was concentrated, diluted with dimethyl sulfoxide, acidified with trifluoroacetic acid, and purified by RP-HPLC (eluting with 0.1% TFA in MeCN / 0.1% TFA in H2O) to yield Ex.64.1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 5.1 Hz, 1H), 8.19 – 8.13 (m, 2H), 7.92 (s, 1H), 7.86 – 7.77 (m, 2H), 7.62 (t, J = 7.5 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.48 (s, 1H), 7.31 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.58 (t, J = 7.5 Hz, 1H), 4.85 (s, 2H), 2.54 (s, 3H). LCMS (m / z) 409.1. Procedure F-6 for the Preparation of Ex.65

[0286] Step 1: (R)-2-((1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzonitrile (INT-F6-1) To a mixture of INT-A10-5 (0.08 mmol), 2- iodobenzonitrile (0.16 mmol), and cesium carbonate (0.66 mmol) in 1,4-dioxane (1.5 mL) and N-N-dimethylacetamide (1.0 mL) was added XantPhos Pd G3 (0.016 mmol) at room temperature. The mixture was sparged with argon and vigorously stirred at 100 °C. After 16 h, the resulting mixture was cooled to room temperature and saturated aqueous sodium bicarbonate (10 mL) and ethyl acetate (10 mL) were added sequentially. The organic layer was collected and the aqueous layer was extracted with ethyl acetate (2 x 5 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (5% to 100% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 403.9.

[0287] Step 2: (R)-N-(1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethyl)-2-(2H- tetrazol-5-yl)aniline (Ex.65) To a solution of INT-F6-1 (0.07 mmol) in N,N- dimethylformamide (1.0 mL) was added sodium azide (0.13 mmol) followed by ammonium chloride (0.13 mmol). The mixture was heated to 110 °C for 2 days. Following this time, theAttorney Docket No.: 1542-WO-PCT mixture was filtered through a syringe filter (washed with 1 mL of N,N-dimethylformamide) and purified directly by RP-HPLC (eluting in 0.1% TFA in MeCN / 0.1% TFA in H2O). Fractions containing the product were combined and lyophilized to yield Ex.65.1H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 5.1 Hz, 1H), 8.28 (br s, 1H), 8.20 – 8.12 (m, 2H), 7.93 – 7.86 (m, 1H), 7.86 – 7.75 (m, 2H), 7.69 – 7.52 (m, 3H), 7.52 – 7.47 (m, 1H), 7.30 – 7.15 (m, 1H), 6.80 (d, J = 8.5 Hz, 1H), 6.77 – 6.66 (m, 1H), 5.44 – 5.17 (m, 1H), 2.47 (s, 3H), 1.80 (d, J = 6.7 Hz, 3H). LCMS (m / z) 446.9. Procedure F-7 for the Preparation of Ex.66

[0288] Step 1: 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (INT-F7-1). To a solution of 7-bromo-1H-benzo[d][1,2,3]triazole (1.5 mmol) in N,N- dimethylformamide (5.0 mL) was added sodium hydride (2.1 mmol) in small portions at 0 °C. The mixture stirred vigorously and allowed to warm to room temperature. After 30 min, (2- (chloromethoxy)ethyl)trimethylsilane (2.0 mmol) was added to the mixture and left to stir. After 2 h, water (20 mL) and dichloromethane (20 mL) were added sequentially. The organic layer was washed with brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (3% to 30% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 329.0.

[0289] Step 2: (R)-N-(1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethyl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-4-amine (INT-F7-2). To a solution of INT-A10-5 (0.10 mmol), INT-F7-1 (0.13 mmol), and XantPhos Pd G3 (0.030 mmol) in 1,4- dioxane (1.0 mL) and N,N-dimethylacetamide (1.0 mL) was added cesium carbonate (0.60 mmol) at room temperature. The mixture was purged with argon gas and vigorously stirred at 100 °C overnight. The resulting mixture was cooled to room temperature, and aqueous lithium chloride (10%, 10 mL) and ethyl acetate (10 mL) were added sequentially. The organic layerAttorney Docket No.: 1542-WO-PCT was washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20% to 70% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 555.0.

[0290] Step 3: (R)-N-(1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethyl)-1H- benzo[d][1,2,3]triazol-4-amine (Ex.66). To a solution of INT-F7-2 (0.050 mmol) in dioxane (2.0 mL) was added HCl (4.0 M in 1,4-dioxane, 0.30 mL). The solution was left to stir at room temperature. After 1 h, the mixture was concentrated under reduced pressure and purified by RP-HPLC (30 to 95 % 0.1% TFA in MeCN / 0.1% TFA in H2O). Fractions containing the product were combined and lyophilized to yield Ex.66.1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 5.1 Hz, 1H), 8.24 – 8.12 (m, 2H), 7.89 – 7.81 (m, 2H), 7.65 (dd, J = 8.3, 6.7 Hz, 2H), 7.61 – 7.53 (m, 2H), 7.06 (t, J = 7.9 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.25 (d, J = 7.7 Hz, 1H), 5.68 – 5.33 (m, 1H), 2.45 (s, 3H), 1.76 (d, J = 6.8 Hz, 3H). LCMS (m / z) 420.0.

[0291] Step 1: (R)-4-fluoro-N-(1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethyl)- 2-(methylsulfonyl)aniline (Ex.67). A mixture of INT-A10-5 (0.067 mmol), 1,4-difluoro-2- methylsulfonylbenzene (0.133 mmol) and cesium carbonate (0.266 mmol) in N,N- dimethylformamide (0.5 mL) was stirred at 100 °C for 16 h. The mixture was then stirred at 140 °C for 24 h. The mixture was cooled to rt and filtered. The filtrate was acidified with a few drops of TFA and purified via RP- HPLC (eluting with 0.1% TFA in MeCN / 0.1% TFA in H2O). Fractions containing product were combined and lyophilized to give Ex.67.1H NMR (400 MHz, Chloroform-d) δ 8.82 (d, J = 5.9 Hz, 1H), 8.29 (s, 1H), 8.11 – 8.02 (m, 2H), 7.88 (d, J = 5.8 Hz, 1H), 7.75 – 7.62 (m, 3H), 7.54 – 7.44 (m, 2H), 7.05 – 6.94 (m, 1H), 6.52 (dd, J = 9.2, 4.0 Hz, 1H), 5.10 – 4.97 (m, 1H), 2.94 (s, 3H), 2.56 (s, 3H), 1.81 (d, J = 6.7 Hz, 3H). LC / MS (m / z) 475.1.

[0292] The following Examples were made using the general route described in Procedure F- 8 and are shown below in Table F8. To prepare the below Examples, different reagents / startingAttorney Docket No.: 1542-WO-PCT materials were used than some of those described in Procedure F-8 and are noted in the last column of Table F8 – “Changes to Procedure F-8: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure F-8 were replaced with the different reagents / starting materials noted below. Table F8:Procedure F-9 for the Preparation of Ex.69

[0293] Step 1: (R)-2-((1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethyl)amino)-N- (methylsulfonyl)benzamide (Ex.69). To a mixture of Ex.1 (0.036 mmol), methanesulfonamide (0.11 mmol), N,N-diisopropylethylamine (0.32 mmol), and 4-dimethylaminopyridine (0.15 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature was added 1-Ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.15 mmol). The mixture was vigorously stirred at room temperature for 12 h. The resulting mixture was acidified with a few drops of TFA and purified by RP-HPLC (30 to 95 % 0.1% TFA in MeCN / 0.1% TFA in H2O). Fractions containing the product were combined and lyophilized to yield Ex.69.1H NMR (400 MHz, DMSO) δ 11.78 (s, 1H), 8.71 (d, J = 5.1 Hz, 1H), 8.47 (s, 1H), 8.23 – 8.16 (m, 2H), 7.93 – 7.87Attorney Docket No.: 1542-WO-PCT (m, 1H), 7.83 (d, J = 5.1 Hz, 1H), 7.75 (dd, J = 8.1, 1.6 Hz, 1H), 7.67 (dd, J = 8.4, 7.0 Hz, 2H), 7.61 – 7.52 (m, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.27 (ddd, J = 8.6, 7.1, 1.6 Hz, 1H), 6.76 (d, J = 8.5 Hz, 1H), 6.60 – 6.52 (m, 1H), 5.23 – 5.17 (m, 1H), 3.33 (s, 3H), 2.49 (s, 3H), 1.73 (d, J = 6.7 Hz, 3H). LCMS (m / z) 500.0. Procedure F-10 for the Preparation of Ex.70

[0294] Step 1: (R)-6-chloro-3-((1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6- yl)ethyl)amino)picolinonitrile (INT-F10-1). A mixture of INT-A10-5 (0.13 mmol), methyl 6- chloro-3-fluoro-pyridine-2-carboxylate (0.32 mmol), and N,N-diisopropylethylamine (1.30 mmol) in dimethyl sulfoxide (1.0 mL) was purged with argon and vigorously stirred at 100 °C. After 20 h, the resulting mixture was cooled to room temperature, and water (5 mL) and ethyl acetate (5 mL) were added sequentially. The organic layer was washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 80% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 439.2.

[0295] Step 2: (R)-6-chloro-N-(1-(8-methyl-4-phenylbenzofuro[3,2-b]pyridin-6-yl)ethyl)- 2-(2H-tetrazol-5-yl)pyridin-3-amine (Ex.70) To a solution of INT-F10-1 (0.046 mmol) in N,N-dimethylformamide (1.0 mL) was added sodium azide (0.11 mmol) followed by ammonium chloride (0.11 mmol). The mixture was heated to 100 °C. After 20 h, the mixture was filtered through a syringe filter (washed with 1 mL of N,N-dimethylformamide) and purified directly by RP-HPLC (eluting in 0.1% TFA in MeCN / 0.1% TFA in H2O). Fractions containing the product were combined and lyophilized to yield Ex.70.1H NMR (400 MHz, DMSO) δ 8.70 (d, J = 5.1 Hz, 1H), 8.29 (d, J = 6.6 Hz, 1H), 8.17 – 8.10 (m, 2H), 7.92 (dd, J = 1.8, 0.9 Hz, 1H), 7.82 (d, J = 5.1 Hz, 1H), 7.64 – 7.60 (m, 2H), 7.59 – 7.46 (m, 2H), 7.37 (s, 2H), 5.33 (p, J = 6.5 Hz, 1H), 2.48 (s, 3H), 1.84 (d, J = 6.7 Hz, 3H). LCMS (m / z) 482.0.Attorney Docket No.: 1542-WO-PCT Procedure F-11 for the Preparation of Ex.71

[0296] Step 1: tert-butyl 6-chloro-3-((1-(8-methyl-4-phenylbenzo[4,5]thieno[3,2- b]pyridin-6-yl)ethyl)amino)picolinate (INT-F11-1) To a solution of INT-A16-4 (0.091 mmol) in N,N-dimethylformamide (1.0 mL) was added tert-butyl 3-amino-6-chloro-pyridine-2- carboxylate (0.28 mmol), and the reaction was sealed and heated to 80 °C for 16 h. It was cooled to ambient temperature, diluted with ethyl acetate, and washed with saturated sodium bicarbonate. It was dried over anhydrous sodium sulfate, filtered, and concentrated. It was purified by flash chromatography on silica gel (5% to 100% ethyl acetate in hexanes) to yield the product.

[0297] Step 2: 6-chloro-3-((1-(8-methyl-4-phenylbenzo[4,5]thieno[3,2-b]pyridin-6- yl)ethyl)amino)picolinic acid (Ex.71) A screw-cap vial was charged with INT-F11-1 (0.09 mmol) and trifluoroacetic acid (1.0 mL), and it was allowed to stir for 16 h. It was concentrated and purified by RP-HPLC (eluting with 0.1% TFA in MeCN / 0.1% TFA in H2O) to yield Ex.71.1H NMR (400 MHz, DMSO-d6) δ 8.81 (d, J = 4.9 Hz, 1H), 8.43 (d, J = 5.4 Hz, 1H), 8.19 (s, 1H), 7.81 (dd, J = 7.4, 1.7 Hz, 2H), 7.69 – 7.52 (m, 5H), 7.29 (d, J = 8.9 Hz, 1H), 6.96 (d, J = 9.0 Hz, 1H), 5.01 (m, 1H), 2.53 (s, 3H), 1.65 (d, J = 6.7 Hz, 3H). LCMS (m / z) 474.1.

[0298] The following Examples were made using the general route described in Procedure F- 11 and are shown below in Table F11. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure F-11 and are noted in the last column of Table F11 – “Changes to Procedure F-11: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure F-11 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table F11:Attorney Docket No.: 1542-WO-PCTProcedure F-12 for the Preparation of Ex.82

[0299] Step 1: 2-(((1R)-1-(8-methyl-4-(tetrahydrofuran-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.82) To a solution of INT-B5-4 (0.078 mmol) in N,N- dimethylformamide (0.23 mL) was added 2-carboxyphenylboronic acid (0.235 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (0.39 mmol) and copper(II) acetate (0.12 mmol), and the reaction was stirred at ambient temperature exposed to the air for 16 hours. It was diluted with dimethylsulfoxide, acidified with trifluoroacetic acid, and purified by RP-HPLC (eluting with 0.1% TFA in MeCN / 0.1% TFA in H2O) to yield Ex.82. LCMS (m / z) 417.2.

[0300] The following Examples were made using the general route described in Procedure F- 12 and are shown below in Table F12. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure F-12 and are noted in the last column of Table F12 – “Changes to Procedure F-12: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure F-12 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table F12:Attorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTProcedure F-13 for the Preparation of Ex.105 and 106

[0301] 2-(((1R)-1-(8-methyl-4-(tetrahydrofuran-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.82) was subjected to SFC (IC column, 30% ethanol) to yield the diastereomers 105 and 106.

[0302] 2-(((R)-1-(8-methyl-4-((S)-tetrahydrofuran-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.105) ES / MS: 417.2 (M+H+). 1H NMR: (400 MHz, DMSO-d6) δ 8.55 (m, 2H), 7.84 – 7.80 (m, 1H), 7.78 (dd, J = 7.9, 1.7 Hz, 1H), 7.45 (d, J = 4.9 Hz, 2H), 7.22 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.67 (d, J = 8.3 Hz, 1H), 6.51 (ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 5.16 (s, 1H), 4.22 (dd, J = 8.2, 7.2 Hz, 1H), 4.06 (td, J = 8.3, 5.1 Hz, 1H), 3.99 – 3.87 (m, 2H), 3.82 (dd, J = 8.3, 7.1 Hz, 1H), 2.54 (m, 1H), 2.46 (s, 3H), 2.23 (dq, J = 12.4, 7.5 Hz, 1H), 1.72 (d, J = 6.8 Hz, 3H).

[0303] 2-(((R)-1-(8-methyl-4-((R)-tetrahydrofuran-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.106) ES / MS: 417.2 (M+H+).Attorney Docket No.: 1542-WO-PCT 1H NMR: (400 MHz, DMSO-d6) δ 8.55 (m, 2H), 7.81 (dd, J = 1.8, 0.9 Hz, 1H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.21 (ddd, J = 8.6, 7.0, 1.7 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.56 – 6.44 (m, 1H), 5.17 (s, 1H), 4.26 (dd, J = 8.1, 7.2 Hz, 1H), 4.02 (td, J = 8.2, 5.1 Hz, 1H), 3.99 – 3.88 (m, 2H), 3.88 – 3.77 (m, 1H), 2.46 (m, 4H), 2.15 (dq, J = 12.4, 7.6 Hz, 1H), 1.71 (d, J = 6.8 Hz, 3H). Procedure F-14 for the Preparation of Ex.107 and 108

[0304] 2-(((1R)-1-(8-methyl-4-(tetrahydrofuran-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.83) was subjected to SFC (IC column, 30% methanol) to yield the diastereomers 107 and 108.

[0305] 2-(((R)-1-(8-methyl-4-((S)-tetrahydro-2H-pyran-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.107) ES / MS: 431.2 (M+H+). 1H NMR: (400 MHz, DMSO-d6) δ 8.55 (d, J = 5.0 Hz, 1H), 8.53 (s, 1H), 7.83 – 7.82 (m, 1H), 7.79 (dd, J = 8.0, 1.7 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1H), 7.44 (d, J = 1.7 Hz, 1H), 7.22 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 6.52 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 5.18 (d, J = 7.0 Hz, 1H), 4.04 (dd, J = 11.1, 4.0 Hz, 1H), 3.98 – 3.83 (m, 1H), 3.73 (t, J = 10.6 Hz, 1H), 3.54 (dt, J = 11.3, 6.9 Hz, 1H), 3.39 (dt, J = 9.7, 4.6 Hz, 1H), 2.45 (s, 3H), 2.08 (q, J = 10.6, 8.3 Hz, 2H), 1.73 (m, 5H).

[0306] 2-(((R)-1-(8-methyl-4-((R)-tetrahydro-2H-pyran-3-yl)benzofuro[3,2-b]pyridin-6- yl)ethyl)amino)benzoic acid (Ex.108) ES / MS: 431.2 (M+H+). 1H NMR: (400 MHz, DMSO-d6) δ 8.55 (m, 2H), 7.82 (d, J = 1.7 Hz, 1H), 7.79 (dd, J = 8.0, 1.7 Hz, 1H), 7.47 (d, J = 5.1 Hz, 1H), 7.44 (d, J = 1.8 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 6.66 (d, J = 8.5 Hz, 1H), 6.51 (t, J = 7.5 Hz, 1H), 5.18 (s, 1H), 4.05 (dd, J = 11.0, 3.9 Hz, 1H), 3.92 (d, J =Attorney Docket No.: 1542-WO-PCT 11.2 Hz, 1H), 3.68 (m, 2H), 3.55 – 3.45 (m, 1H), 3.42 (p, J = 5.5 Hz, 1H), 2.46 (s, 3H), 2.17 – 1.96 (m, 2H), 1.73 (m, 4H). Procedure F-15 for the Preparation of Ex.109 and 110

[0307] 2-(((1R)-1-(8-methyl-4-(2-(trifluoromethyl)cyclopropyl)benzofuro[3,2-c]pyridazin-6- yl)ethyl)amino)benzoic acid (Ex.94) was subjected to SFC (OD-H column, 30% EtOH / NH3) to yield the diastereomers 109 and 110.

[0308] 2-(((R)-1-(8-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)benzofuro[3,2- c]pyridazin-6-yl)ethyl)amino)benzoic acid (Ex.109) ES / MS: 456.1 (M+H+). 1H NMR: (400 MHz, Methanol-d4) δ 9.44 – 9.13 (m, 1H), 8.13 – 7.98 (m, 1H), 7.98 – 7.82 (m, 1H), 7.76 – 7.56 (m, 1H), 7.27 – 7.07 (m, 1H), 6.72 – 6.38 (m, 2H), 5.31 – 5.14 (m, 1H), 2.99 – 2.65 (m, 2H), 2.56 – 2.48 (m, 3H), 1.94 – 1.81 (m, 1H), 1.82 – 1.69 (m, 4H).

[0309] 2-(((R)-1-(8-methyl-4-((1S,2S)-2-(trifluoromethyl)cyclopropyl)benzofuro[3,2- c]pyridazin-6-yl)ethyl)amino)benzoic acid (Ex.110) ES / MS: 456.1 (M+H+). 1H NMR: (400 MHz, Methanol-d4) δ 9.44 – 9.13 (m, 1H), 8.13 – 7.98 (m, 1H), 7.98 – 7.82 (m, 1H), 7.76 – 7.56 (m, 1H), 7.27 – 7.07 (m, 1H), 6.72 – 6.38 (m, 2H), 5.31 – 5.14 (m, 1H), 2.99 – 2.65 (m, 2H), 2.56 – 2.48 (m, 3H), 1.94 – 1.81 (m, 1H), 1.82 – 1.69 (m, 4H). Procedure F-16 for the Preparation of Ex.111 and 112Attorney Docket No.: 1542-WO-PCT

[0310] 2-(((1R)-1-(4-([1,1'-bi(cyclopropan)]-2-yl)-8-methylbenzofuro[3,2-c]pyridazin-6- yl)ethyl)amino)benzoic acid (Ex.95) was subjected to SFC (IC column, 35% EtOH) to yield the diastereomers 111 and 112.

[0311] 2-(((R)-1-(4-((1R,2S)-[1,1'-bi(cyclopropan)]-2-yl)-8-methylbenzofuro[3,2- c]pyridazin-6-yl)ethyl)amino)benzoic acid (Ex.111) ES / MS: 428.1 (M+H+). 1H NMR: (400 MHz, Acetonitrile-d3) δ 8.94 (s, 1H), 7.99 – 7.84 (m, 1H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.18 – 7.03 (m, 1H), 6.56 – 6.40 (m, 2H), 5.20 – 5.02 (m, 1H), 2.39 (s, 3H), 2.15 – 2.05 (m, 1H), 1.80 – 1.70 (m, 1H), 1.64 (d, J = 6.8 Hz, 3H), 1.45 (dt, J = 8.9, 5.2 Hz, 1H), 1.21 – 1.07 (m, 1H), 1.03 – 0.90 (m, 1H), 0.48 – 0.35 (m, 2H), 0.26 – 0.11 (m, 2H).

[0312] 2-(((R)-1-(4-((1S,2%)-[1,1'-bi(cyclopropan)]-2-yl)-8-methylbenzofuro[3,2- c]pyridazin-6-yl)ethyl)amino)benzoic acid (Ex.112) ES / MS: 428.1 (M+H+). 1H NMR: (400 MHz, Acetonitrile-d3) δ 8.97 (s, 1H), 8.04 – 7.87 (m, 1H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.64 – 7.48 (m, 1H), 7.11 (ddd, J = 8.7, 7.1, 1.7 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 6.50 – 6.43 (m, 1H), 5.17 – 4.98 (m, 1H), 2.41 (s, 3H), 2.25 – 2.11 (m, 1H), 1.80 – 1.71 (m, 1H), 1.66 (d, J = 6.8 Hz, 3H), 1.48 (dt, J = 8.9, 5.2 Hz, 1H), 1.22 – 1.12 (m, 1H), 1.07 – 0.93 (m, 1H), 0.52 – 0.35 (m, 2H), 0.30 – 0.14 (m, 2H). Procedure F-17 for the Preparation of Ex.113 and 114

[0313] 2-(((1R)-1-(4-(bicyclo[3.1.0]hexan-1-yl)-8-methylbenzofuro[3,2-c]pyridazin-6- yl)ethyl)amino)benzoic acid (Ex.101) was subjected to SFC (AS-H column, 25% MeOH) to yield the diastereomers 111 and 112.

[0314] 2-(((R)-1-(4-((1R,5R)-bicyclo[3.1.0]hexan-1-yl)-8-methylbenzofuro[3,2- c]pyridazin-6-yl)ethyl)amino)benzoic acid (Ex.113)Attorney Docket No.: 1542-WO-PCT ES / MS: 428.1 (M+H+). 1H NMR: (400 MHz, Acetonitrile-d3) δ 9.16 (s, 1H), 8.00 – 7.91 (m, 1H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.64 – 7.43 (m, 1H), 7.25 – 6.96 (m, 1H), 6.58 – 6.33 (m, 2H), 5.26 – 4.91 (m, 1H), 2.48 – 2.15 (m, 6H), 1.98 – 1.87 (m, 2H), 1.76 (dt, J = 15.1, 7.8 Hz, 1H), 1.66 (d, J = 6.8 Hz, 3H), 1.49 – 1.32 (m, 2H), 1.26 – 1.19 (m, 1H). 2-(((R)-1-(4-((1S,5S)-bicyclo[3.1.0]hexan-1-yl)-8-methylbenzofuro[3,2-c]pyridazin-6- yl)ethyl)amino)benzoic acid (Ex.114) ES / MS: 428.1 (M+H+). 1H NMR: (400 MHz, Acetonitrile-d3) δ 9.16 (s, 1H), 8.00 – 7.91 (m, 1H), 7.78 (dd, J = 8.0, 1.7 Hz, 1H), 7.64 – 7.43 (m, 1H), 7.25 – 6.96 (m, 1H), 6.58 – 6.33 (m, 2H), 5.26 – 4.91 (m, 1H), 2.48 – 2.15 (m, 6H), 1.98 – 1.87 (m, 2H), 1.76 (dt, J = 15.1, 7.8 Hz, 1H), 1.66 (d, J = 6.8 Hz, 3H), 1.49 – 1.32 (m, 2H), 1.26 – 1.19 (m, 1H). Procedure F-18 for the Preparation of Ex.115

[0315] Step 1: methyl 2-[[(1R)-1-[8-methyl-4-(1-methylpyrazol-4-yl)benzofuro[3,2- c]pyridazin-6-yl]ethyl]amino]benzoate (INT-F18-1). A mixture of INT-B1-19 (0.053 mmol), methyl 2-iodobenzoate (0.1 mmol), XantPhos Pd G3 (0.015 mmol), and cesium carbonate (0.32 mmol), in dimethylacetamide (0.25 mL) and 1,4-dioxane (0.40 mL) was degassed by bubbling nitrogen through the mixture for 5 min. The reaction was capped and stirred at 100 °C for 24 h. The reaction was cooled, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 100% ethyl acetate in hexanes, then 0% to 80% MeOH in EtOAc) to afford the title compound. LCMS (m / z) 442.2.

[0316] Step 2: methyl 2-[[(1R)-1-[8-methyl-4-(1-methylpyrazol-4-yl)benzofuro[3,2- c]pyridazin-6-yl]ethyl]amino]benzoate (Ex.115). A solution of INT-F18-1 (0.032 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added a solution of lithium hydroxide in water (1 M, 0.32 mL) was stirred at 80 ° C for 1 h. The reaction was concentrated, then taken up inAttorney Docket No.: 1542-WO-PCT DMSO and acidified with TFA. It was purified by RP-HPLC (5 to 98 % 0.1% TFA in MeCN / 0.1% TFA in H2O) Fractions containing the product were combined and lyophilized to yield Ex.115.1H NMR (400 MHz, DMSO-d6) δ 12.72 (s, 1H), 9.71 (s, 1H), 8.75 (s, 1H), 8.60 (d, J = 7.1 Hz, 1H), 8.49 (s, 1H), 8.05 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.61 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 6.69 (d, J = 8.5 Hz, 1H), 6.54 (t, J = 7.5 Hz, 1H), 5.44 – 5.24 (m, 1H), 4.05 (s, 3H), 1.74 (d, J = 6.7 Hz, 3H). LCMS (m / z) 428.0. Procedure F-19 for the Preparation of Ex.116

[0317] Step 1: methyl 6-chloro-3-[[(1R)-1-(8-methyl-4-phenyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]amino]pyridine-2-carboxylate (INT-F19-1). A mixture of INT-A10-8 (0.20 mmol), methyl 6-chloro-3-fluoro-pyridine-2-carboxylate (0.32 mmol), and N,N-diisopropylethylamine (1.0 mmol) in dimethyl sulfoxide (1.0 mL) was purged with argon and vigorously stirred at 100 °C. After 20 h, the resulting mixture was cooled to room temperature, and water (5 mL) and ethyl acetate (5 mL) were added sequentially. The organic layer was washed with brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10% to 80% ethyl acetate in hexanes) to afford the title compound. LCMS (m / z) 473.0.

[0318] Step 2: methyl 6-chloro-3-[[(1R)-1-(8-methyl-4-phenyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]amino]pyridine-2-carboxylate (INT-F19-2). To a solution of INT-F19-1 (0.10 mmol) in methanol (0.70 mL) and tetrahydrofuran (0.70 mL) was added aqueous lithium hydroxide (1.0 M, 0.25 mL) at room temperature. The mixture was heated to 70 °C and vigorously stirred for 1 h before cooling down to room temperature. The resulting mixture was acidified with a few drops of TFA and purified by RP-HPLC (30 to 95 % 0.1% TFA in MeCN / 0.1% TFA in H2O). FractionsAttorney Docket No.: 1542-WO-PCT containing the product were combined and lyophilized to yield the title compound.1H NMR (400 MHz, DMSO) δ 13.03 (s, 1H), 9.71 (s, 1H), 8.53 (d, J = 6.8 Hz, 1H), 8.28 – 8.20 (m, 2H), 8.12 (t, J = 1.3 Hz, 1H), 7.74 – 7.58 (m, 4H), 7.34 (d, J = 9.0 Hz, 1H), 7.26 (d, J = 9.0 Hz, 1H), 5.25 (p, J = 6.7 Hz, 1H), 2.53 (s, 3H), 1.74 (d, J = 6.7 Hz, 3H). LCMS (m / z) 459.0.

[0319] Step 3: 6-chloro-3-[[(1R)-1-(8-methyl-4-phenyl-benzofuro[3,2-c]pyridazin-6- yl)ethyl]amino]-N-methylsulfonyl-pyridine-2-carboxamide (Ex. 116). To a mixture of INT- F19-2 (0.055 mmol), methanesulfonamide (0.27 mmol), N,N-diisopropylethylamine (022 mmol), and 4-dimethylaminopyridine (0.16 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature was added N,N'-Diisopropylcarbodiimide (0.16 mmol). The mixture was vigorously stirred at room temperature for 12 h. The resulting mixture was acidified with a few drops of TFA and purified by RP-HPLC (30 to 95 % 0.1% TFA in MeCN / 0.1% TFA in H2O). Fractions containing the product were combined and lyophilized to yield the title compound.1H NMR (400 MHz, DMSO) δ 11.16 (s, 1H), 9.69 (s, 1H), 8.58 (d, J = 7.1 Hz, 1H), 8.26 (dd, J = 7.3, 1.7 Hz, 2H), 8.13 (s, 1H), 7.71 (dd, J = 8.4, 6.9 Hz, 2H), 7.66 – 7.59 (m, 2H), 7.46 – 7.35 (m, 2H), 5.44 – 5.13 (m, 1H), 3.31 (s, 3H), 2.53 (s, 3H), 1.76 (d, J = 6.7 Hz, 3H). LCMS (m / z) 536.0.

[0320] The following Examples were made using the general route described in Procedure F- 19 and are shown below in Table F19. To prepare the below Examples, different reagents / starting materials were used than some of those described in Procedure F-19 and are noted in the last column of Table F19 – “Changes to Procedure F-19: Different Reagents / Starting Materials”. A person of ordinary skill in the art will readily recognize which reagents / starting materials of Procedure F-19 were replaced with the different reagents / starting materials noted below.Attorney Docket No.: 1542-WO-PCT Table F19:Attorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTBiological Assays and Data

[0321] T-47D cell line was obtained from National Cancer Institute. Cells were maintained in RPMI (Gibco 11875-093) supplemented with 10% Fetal Bovine Serum, (FBS, Hyclone SH30071-03), and 1X PenStrep (PS, Gibco 15140-122). SK-BR-3 cell line was obtained from ATCC (ATCC HTB-30). Cells were maintained in McCoy’s 5A (Gibco 16600-082) supplemented with 10% FBS and 1X PS. Cultures were maintained in a humidified incubator at 37°C under 5% CO2 / 95% air. For compound testing in 0% FBS, T-47D cells were seeded at a density of 20,000 cells per well in 40 µl of RPMI assay media with 10% FBS and 1X PS. SK- BR-3 cells were seeded at a density of 10,000 in 40 µl of McCoy’s 5A assay media with 10% FBS and 1X PS in white 384-well plates (Greiner 781080). Assay plates were incubated in a humidified incubator at 37°C under 5% CO2 / 95% air overnight. The assay plates were washed 2x with 70 µl Dulbecco’s Phosphate-Buffered Saline (DPBS, Gibco 14190-144) with a Biotek washer / dispenser (Biotek EL406) and serum starved with 40 µl RPMI with 1x PS for T-47D cells and 40 µl McCoy’s 5A with 1x PS for SK-BR-3 cells overnight. Compounds dissolved in 0.2 mM or 2 mM stock solutions in DMSO were serially diluted 1:3 in DMSO to generate a 10- point dilution series in 384-well polypropylene plates (Greiner 784201) using Biomek FX (Beckman Coulter Life Sciences).0.4 µl compound was added to the assay plates to final concentrations ranging from 1 µM to 0.051 nM in 0.5% DMSO for T-47D and 10 µM to 0.51 nM in 0.5% DMSO for SK-BR-3.0.5% DMSO alone was used to establish the maximum (MAX) signal and BYL-719 at a final concentration of 1 µM was used as a reference compound for the minimum (MIN) signal. The plates were incubated in a humidified incubator at 37°CAttorney Docket No.: 1542-WO-PCT under 5% CO2 / 95% air for 2 hours. HTRF phospho-AKT (SER473) (Revvity 64AKSPEH) detection reagent (50% 4x lysis buffer, 1.6% blocking reagent, 38% detection buffer, 8.4% water, 1% phosopho-AKT d2 antibody, and 1% phosopho-AKT Eu Cryptate antibody) was prepared during compound treatment. After 2 hours compound treatment, the assay plates were washed with 70 µL DPBS twice and 10 µL of the detection reagent was added. The assay plates were sealed and incubated overnight at room temperature. They were read on a Envision multimode plate reader (PerkinElmer) using standard HTRF settings with two sequential measurements carried out at 620 nm for cryptate emission and at 665 nm for d2 acceptor emission. The values were calculated by the ratio of the two fluorescence intensities 665 nm / 620 nm (acceptor / donor) x 10,000. Compounds were tested in quadruplicate and the values were normalized to the positive and negative controls (as 0% and 100% phospho-AKT (SER473), respectively) and data was fitted using non-linear regression analysis. The EC50 value for each compound was defined as the concentration reducing phospho-AKT (SER473) by 50% (Table 2). Table 2Attorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCTAttorney Docket No.: 1542-WO-PCT* * *

[0322] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0323] Thus, it should be understood that although the present disclosure has been specifically disclosed by preferred embodiments and optional features, modification, improvement and variation of the disclosures embodied therein herein disclosed may be resorted to by those skilled in the art, and that such modifications, improvements and variations are considered to be within the scope of this disclosure. The materials, methods, and examples provided here are representative of preferred embodiments, are exemplary, and are not intended as limitations on the scope of the disclosure.

[0324] The disclosure has been described broadly and generically herein. Each of the narrower species and subgeneric groupings falling within the generic disclosure also form part of the disclosure. This includes the generic description of the disclosure with a proviso or negative limitation removing any subject matter from the genus, regardless of whether or not the excised material is specifically recited herein.

[0325] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0326] It is to be understood that while the disclosure has been described in conjunction with the above embodiments, that the foregoing description and examples are intended to illustrate and not limit the scope of the disclosure. Other aspects, advantages and modifications within the scope of the disclosure will be apparent to those skilled in the art to which the disclosure pertains.

Claims

Attorney Docket No.: 1542-WO-PCT CLAIMS 1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein R1is C6-12 aryl, heteroaryl, C3-12 cycloalkyl, heterocyclyl, C1-6 alkyl, or C1-6 haloalkyl; the aryl, heteroaryl, cycloalkyl, heterocyclyl, haloalkyl, or alkyl of R1is optionally substituted with one to three Z1, which may be the same or different; R2is H, C1-6alkyl, C3-6cycloalkyl, C3-6halocycloalkyl, or C1-6haloalkyl; R3is H, CN, C1-6 alkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkyl; or R2and R3together with the carbon to which they are attached form C3-6 cycloalkyl; Y is N, CH, or CR9; each R4is independently halo, CN, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C3-6 halocycloalkyl, C1-6 alkyl, or C1-6 haloalkyl; R9is halo, C1-6alkyl, or C1-6haloalkyl; each Q, X, X1, or X2is independently N, NH, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N or NH; W is O, NR8, S, SO2, C(=O), or CR6R7; R6is H, halo, CN, C1-6alkyl, or C1-6haloalkyl; R7is H, halo, or C1-6 alkyl; or R6and R7together with the carbon to which they are attached form C3-6 cycloalkyl; each R5is independently halo, oxo, CN, OR12a, -C(O)-N(R12a)(R12b), -N(R12a)C(O)(R12b), -S(O)2R12a, -S(O)2N(R12a)(R12b), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-12 aryl, heteroaryl, C3-12 cycloalkyl, heterocyclyl, or -N(R12a)( R12b); the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl of R5is optionally substituted with one to three Z5, which may be the same or different; or two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form C5-10cycloalkyl, phenyl, 5 or 10 membered heterocyclyl, or 5 or 6 membered heteroaryl; the cycloalkyl, heterocyclyl, phenyl, or the heteroaryl formed from two R5and two adjacent carbons to which they are attached is optionally substituted with one to three Z6, which may be the same or different;Attorney Docket No.: 1542-WO-PCT R8is C1-6alkyl, C1-6haloalkyl, C6-12aryl, heteroaryl, C3-12cycloalkyl, or heterocyclyl; the alkyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z8, which may be the same or different; each Z1, Z5, Z6, or Z8is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6 alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-12 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O-R12a, -C(O)- N(R12a)(R12b), -C(O)N(R12b)S(O)2(R12a), -N(R12a)( R12b), -N(R12a)C(O)-R12b, -N(R12a)C(O)O-R12b, -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -NR12aS(O)2N(R12b)(R12c), - NR12aS(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)( R12b), -S-R12a, -S(O)R12a, - S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)N(R12a)N(R12b)(R12c), -SF5, or - S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z5, Z6, or Z8is each optionally substituted with one to three Z1a, which may be the same or different; each Z1ais independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6alkoxyalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-12 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -CN, -O-R12a, -C(O)R12a, -C(O)O- R12a, -C(O)N(R12a)( R12b), -N(R12a)( R12b), -N(R12a)2(R12b)+, -N(R12a)-C(O)R12b, - N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -N(R12a)S(O)2- N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with one to four Z1b, which may be the same or different; each Z1bis independently C1-9 alkyl, C1-8 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, C3-12cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, - SH, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C2-6 alkenyl), -O(C2-6 alkynyl), -O(C3-15 cycloalkyl), - O(heterocyclyl), -O(C6-10 aryl), -O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C2-6 alkenyl), -NH(C2-6alkynyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), -NH(C6-10aryl), - NH(heteroaryl), -N(C1-9alkyl)2, -N(C1-8haloalkyl)2, -N(C2-6alkenyl)2, -N(C2-6alkynyl)2, -N(C3-15 cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10 aryl)2, -N(heteroaryl)2, -N(C1-9 alkyl)(C1-8 haloalkyl), -N(C1-9alkyl)(C2-6alkenyl), -N(C1-9alkyl)(C2-6alkynyl), -N(C1-9alkyl)(C3-15cycloalkyl), -N(C1-9alkyl)(heterocyclyl), -N(C1-9alkyl)(C6-10aryl), -N(C1-9alkyl)(heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15 cycloalkyl), -C(O)(heterocyclyl), -C(O)(C6-10 aryl), -C(O)(heteroaryl), - C(O)O(C1-9alkyl), -C(O)O(C1-8haloalkyl), -C(O)O(C2-6alkenyl), -C(O)O(C2-6Attorney Docket No.: 1542-WO-PCT alkynyl), -C(O)O(C3-15cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C6-10aryl), - C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C1-9 alkyl), -C(O)NH(C1-8 haloalkyl), -C(O)NH(C2-6 alkenyl), -C(O)NH(C2-6 alkynyl), -C(O)NH(C3-15 cycloalkyl), -C(O)NH(heterocyclyl), - C(O)NH(C6-10aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9alkyl)2, -C(O)N(C1-8haloalkyl)2, -C(O)N(C2-6 alkenyl)2, -C(O)N(C2-6 alkynyl)2, -C(O)N(C3-15 cycloalkyl)2, - C(O)N(heterocyclyl)2, -C(O)N(C6-10 aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C1-9 alkyl), -NHC(O)(C1-8haloalkyl), -NHC(O)(C2-6alkenyl), -NHC(O)(C2-6alkynyl), -NHC(O)(C3-15cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10aryl), -NHC(O)(heteroaryl), - NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkenyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15cycloalkyl), -NHC(O)O(heterocyclyl),-NHC(O)O(C6-10aryl), - NHC(O)O(heteroaryl), -NHC(O)NH(C1-9alkyl), -NHC(O)NH(C1-8haloalkyl), -NHC(O)NH(C2-6 alkenyl), -NHC(O)NH(C2-6 alkynyl), -NHC(O)NH(C3-15 cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(heteroaryl), - NHS(O)(C1-9alkyl), -N(C1-9alkyl)(S(O)(C1-9alkyl), -S(C1-9alkyl), -S(C1-8haloalkyl), -S(C2-6alkenyl), -S(C2-6 alkynyl), -S(C3-15 cycloalkyl), -S(heterocyclyl), -S(C6-10 aryl), -S(heteroaryl), - S(O)N(C1-9 alkyl)2, -S(O)(C1-9 alkyl), -S(O)(C1-8 haloalkyl), -S(O)(C2-6 alkenyl), -S(O)(C2-6 alkynyl), -S(O)(C3-15cycloalkyl), -S(O)(heterocyclyl), -S(O)(C6-10aryl), -S(O)(heteroaryl), - S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10 aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9 alkyl), - S(O)2NH(C1-9alkyl), or -S(O)2N(C1-9alkyl)2; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1bis optionally substituted with one to three C1-9alkyl, C1-8haloalkyl, halogen, -OH, -NH2, -O(C1-9 alkyl), -O(C1-8 haloalkyl), -O(C3-15 cycloalkyl), -O(heterocyclyl), -O(aryl), - O(heteroaryl), -NH(C1-9 alkyl), -NH(C1-8 haloalkyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), - NH(aryl), -NH(heteroaryl), -N(C1-9alkyl)2, -N(C3-15cycloalkyl)2, -NHC(O)(C1-8haloalkyl), -NHC(O)(C3-15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), - NHC(O)(heteroaryl), -NHC(O)O(C1-9 alkyl), -NHC(O)O(C1-8 haloalkyl), -NHC(O)O(C2-6 alkynyl), -NHC(O)O(C3-15cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), - NHC(O)O(heteroaryl), -NHC(O)NH(C1-9alkyl), S(O)2(C1-9alkyl), -S(O)2(C1-8haloalkyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), - S(O)(NH)(C1-9alkyl), -S(O)2NH(C1-9alkyl), or -S(O)2N(C1-9alkyl)2; each R12a, R12b, and R12cis independently H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-15cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each R12a, R12b, and R12cis each optionally substituted with one to four Z1b, which may be the same or different;Attorney Docket No.: 1542-WO-PCT n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is 5 to 12 membered heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 12 membered heterocyclyl having one to four heteroatoms each independently N, O or S.

2. A compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein R1is C6-12 aryl, heteroaryl, C3-12 cycloalkyl, heterocyclyl, C1-6 alkyl, or C1-6 haloalkyl; the aryl, heteroaryl, cycloalkyl, heterocyclyl, haloalkyl, or alkyl of R1is optionally substituted with one to three Z1, which may be the same or different; R2is H, C1-6 alkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkyl; R3is H, CN, C1-6 alkyl, C3-6 cycloalkyl, C3-6 halocycloalkyl, or C1-6 haloalkyl; or R2and R3together with the carbon to which they are attached form C3-6cycloalkyl; Y is N, CH, or CR9; each R4is independently halo, CN, C3-6 cycloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C3-6 halocycloalkyl, C1-6alkyl, or C1-6haloalkyl; R9is halo, C1-6 alkyl, or C1-6 haloalkyl; each Q, X, X1, or X2is independently N, NH, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N or NH; W is O, NR8, S, SO2, C(=O), or CR6R7; R6is H, halo, CN, C1-6 alkyl, or C1-6 haloalkyl; R7is H, halo, or C1-6 alkyl; or R6and R7together with the carbon to which they are attached form C3-6cycloalkyl; each R5is independently halo, oxo, CN, OR12a, -C(O)-N(R12a)(R12b), - S(O)2R12a, -S(O)2N(R12a)(R12b), C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6haloalkoxy, C6-12aryl, heteroaryl, C3-12cycloalkyl, heterocyclyl, or -N(R12a)( R12b); the alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl of R5is optionally substituted with one to three Z5, which may be the same or different;Attorney Docket No.: 1542-WO-PCT or two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form C5-10 cycloalkyl, phenyl, 5 or 10 membered heterocyclyl, or 5 or 6 membered heteroaryl; the cycloalkyl, heterocyclyl, phenyl, or the heteroaryl formed from two R5and two adjacent carbons to which they are attached is optionally substituted with one to three Z6, which may be the same or different; R8is C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, heteroaryl, C3-12 cycloalkyl, or heterocyclyl; the alkyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z8, which may be the same or different; each Z1, Z5, Z6, or Z8is independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-12cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O-R12a, -C(O)- N(R12a)(R12b), -C(O)N(R12b)S(O)2(R12a), -N(R12a)( R12b), -N(R12a)C(O)-R12b, -N(R12a)C(O)O-R12b, -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -NR12aS(O)2N(R12b)(R12c), - NR12aS(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)( R12b), -S-R12a, -S(O)R12a, - S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), -S(O)N(R12a)N(R12b)(R12c), -SF5, or - S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z5, Z6, or Z8is each optionally substituted with one to three Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-12cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -NO2, -CN, -O-R12a, -C(O)R12a, -C(O)O- R12a, -C(O)N(R12a)( R12b), -N(R12a)( R12b), -N(R12a)2(R12b)+, -N(R12a)-C(O)R12b, - N(R12a)C(O)O(R12b), -N(R12a)C(O)N(R12b)(R12c), -N(R12a)S(O)2(R12b), -N(R12a)S(O)2- N(R12b)(R12c), -N(R12a)S(O)2O(R12b), -OC(O)R12a, -OC(O)OR12a, -OC(O)-N(R12a)(R12b), -S-R12a, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with one to four Z1b, which may be the same or different; each Z1bis independently C1-9alkyl, C1-8haloalkyl, C2-6alkenyl, C2-6alkynyl, halogen, C3-12 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NO2, -NH2, -N3, - SH, -O(C1-9alkyl), -O(C1-8haloalkyl), -O(C2-6alkenyl), -O(C2-6alkynyl), -O(C3-15cycloalkyl), - O(heterocyclyl), -O(C6-10aryl), -O(heteroaryl), -NH(C1-9alkyl), -NH(C1-8haloalkyl), -NH(C2-6alkenyl), -NH(C2-6 alkynyl), -NH(C3-15 cycloalkyl), -NH(heterocyclyl), -NH(C6-10 aryl), - NH(heteroaryl), -N(C1-9 alkyl)2, -N(C1-8 haloalkyl)2, -N(C2-6 alkenyl)2, -N(C2-6 alkynyl)2, -N(C3-15cycloalkyl)2, -N(heterocyclyl)2, -N(C6-10aryl)2, -N(heteroaryl)2, -N(C1-9alkyl)(C1-8Attorney Docket No.: 1542-WO-PCT haloalkyl), -N(C1-9alkyl)(C2-6alkenyl), -N(C1-9alkyl)(C2-6alkynyl), -N(C1-9alkyl)(C3-15cycloalkyl), -N(C1-9 alkyl)(heterocyclyl), -N(C1-9 alkyl)(C6-10 aryl), -N(C1-9 alkyl)(heteroaryl), -C(O)(C1-9 alkyl), -C(O)(C1-8 haloalkyl), -C(O)(C2-6 alkenyl), -C(O)(C2-6 alkynyl), -C(O)(C3-15cycloalkyl), -C(O)(heterocyclyl), -C(O)(C6-10aryl), -C(O)(heteroaryl), - C(O)O(C1-9 alkyl), -C(O)O(C1-8 haloalkyl), -C(O)O(C2-6 alkenyl), -C(O)O(C2-6 alkynyl), -C(O)O(C3-15 cycloalkyl), -C(O)O(heterocyclyl), -C(O)O(C6-10 aryl), - C(O)O(heteroaryl), -C(O)NH2, -C(O)NH(C1-9alkyl), -C(O)NH(C1-8haloalkyl), -C(O)NH(C2-6alkenyl), -C(O)NH(C2-6alkynyl), -C(O)NH(C3-15cycloalkyl), -C(O)NH(heterocyclyl), - C(O)NH(C6-10 aryl), -C(O)NH(heteroaryl), -C(O)N(C1-9 alkyl)2, -C(O)N(C1-8 haloalkyl)2, -C(O)N(C2-6alkenyl)2, -C(O)N(C2-6alkynyl)2, -C(O)N(C3-15cycloalkyl)2, - C(O)N(heterocyclyl)2, -C(O)N(C6-10aryl)2, -C(O)N(heteroaryl)2, -NHC(O)(C1-9alkyl), -NHC(O)(C1-8 haloalkyl), -NHC(O)(C2-6 alkenyl), -NHC(O)(C2-6 alkynyl), -NHC(O)(C3- 15 cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(C6-10 aryl), -NHC(O)(heteroaryl), - NHC(O)O(C1-9alkyl), -NHC(O)O(C1-8haloalkyl), -NHC(O)O(C2-6alkenyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl),-NHC(O)O(C6-10 aryl), - NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), -NHC(O)NH(C1-8 haloalkyl), -NHC(O)NH(C2-6alkenyl), -NHC(O)NH(C2-6alkynyl), -NHC(O)NH(C3-15cycloalkyl), -NHC(O)NH(heterocyclyl), -NHC(O)NH(C6-10 aryl), -NHC(O)NH(heteroaryl), - NHS(O)(C1-9 alkyl), -N(C1-9 alkyl)(S(O)(C1-9 alkyl), -S(C1-9 alkyl), -S(C1-8 haloalkyl), -S(C2-6 alkenyl), -S(C2-6alkynyl), -S(C3-15cycloalkyl), -S(heterocyclyl), -S(C6-10aryl), -S(heteroaryl), - S(O)N(C1-9alkyl)2, -S(O)(C1-9alkyl), -S(O)(C1-8haloalkyl), -S(O)(C2-6alkenyl), -S(O)(C2-6alkynyl), -S(O)(C3-15 cycloalkyl), -S(O)(heterocyclyl), -S(O)(C6-10 aryl), -S(O)(heteroaryl), - S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C2-6 alkenyl), -S(O)2(C2-6 alkynyl), -S(O)2(C3-15 cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(C6-10aryl), -S(O)2(heteroaryl), -S(O)(NH)(C1-9alkyl), - S(O)2NH(C1-9 alkyl), or -S(O)2N(C1-9 alkyl)2; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1bis optionally substituted with one to three C1-9 alkyl, C1-8 haloalkyl, halogen, -OH, -NH2, -O(C1-9alkyl), -O(C1-8haloalkyl), -O(C3-15cycloalkyl), -O(heterocyclyl), -O(aryl), - O(heteroaryl), -NH(C1-9alkyl), -NH(C1-8haloalkyl), -NH(C3-15cycloalkyl), -NH(heterocyclyl), - NH(aryl), -NH(heteroaryl), -N(C1-9 alkyl)2, -N(C3-15 cycloalkyl)2, -NHC(O)(C1-8 haloalkyl), -NHC(O)(C3-15cycloalkyl), -NHC(O)(heterocyclyl), -NHC(O)(aryl), - NHC(O)(heteroaryl), -NHC(O)O(C1-9alkyl), -NHC(O)O(C1-8haloalkyl), -NHC(O)O(C2-6alkynyl), -NHC(O)O(C3-15 cycloalkyl), -NHC(O)O(heterocyclyl), -NHC(O)O(aryl), - NHC(O)O(heteroaryl), -NHC(O)NH(C1-9 alkyl), S(O)2(C1-9 alkyl), -S(O)2(C1-8 haloalkyl), -S(O)2(C3-15cycloalkyl), -S(O)2(heterocyclyl), -S(O)2(aryl), -S(O)2(heteroaryl), -Attorney Docket No.: 1542-WO-PCT S(O)(NH)(C1-9alkyl), -S(O)2NH(C1-9alkyl), or -S(O)2N(C1-9alkyl)2; each R12a, R12b, and R12cis independently H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each R12a, R12b, and R12cis each optionally substituted with one to four Z1b, which may be the same or different; n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is 5 to 12 membered heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 12 membered heterocyclyl having one to four heteroatoms each independently N, O or S. 3.The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R1is C6-12 aryl, C3-6 cycloalkyl, 4 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl; the aryl, cycloalkyl, heterocyclyl, or heteroaryl of R1is optionally substituted with one to three Z1, which may be the same or different; R2is H, C1-6 alkyl, or C1-6 haloalkyl; R3is H, CN, C1-6alkyl, or C1-6haloalkyl; Y is N, CH, or CR9; each R4is independently halo, CN, C1-6 alkyl, or C1-6 haloalkyl; R9is halo, C1-6alkyl, or C1-6haloalkyl; each Q, X, X1, or X2is independently N, NH, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N or NH; W is O, S, NR8; each R5is independently halo, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6 alkynyl, C6-12 aryl, 5 to 10 membered heteroaryl, C3-12 cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, C1-6 alkoxy, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6alkoxyalkyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -CN, -O-R12a, - C(O)-R12a, -C(O)O-R12a, -C(O)-N(R12a)(R12b), -C(O)N(R12b)S(O)2(R12a), - N(R12a)( R12b), -N(R12a)C(O)-R12b, -N(R12a)C(O)O-R12b, -N(R12a)S(O)2(R12b), -OC(O)- N(R12a)( R12b), -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; whereinAttorney Docket No.: 1542-WO-PCT the alkyl, haloalkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z5is each optionally substituted with one to three Z1a, which may be the same or different; or two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form C5-10cycloalkyl, phenyl, 5 to 10 membered heterocyclyl, or 5 or 6 membered heteroaryl; R8is C1-6 alkyl, C1-6 haloalkyl, C3-12 cycloalkyl, or heterocyclyl; the alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one to two Z8, which may be the same or different; each Z1is independently C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6alkoxyalkyl, halogen, C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -CN, -O- R12a, -C(O)-N(R12a)(R12b), -C(O)N(R12b)S(O)2(R12a), -N(R12a)( R12b), -N(R12a)C(O)-R12b, - N(R12a)S(O)2(R12b), -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; each Z8is independently C3-15 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkoxyalkyl halogen, C3-15cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, -CN, -O- R12a, -C(O)R12a, -C(O)O-R12a, or -S(O)2R12a; each R12a, R12b, and R12cis independently H, C1-6 alkyl, C3-15 cycloalkyl, heterocyclyl, C6-10aryl, or heteroaryl; and n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is 5 to 12 membered heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 12 membered heterocyclyl having one to four heteroatoms each independently N, O or S. 4.The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):wherein R1is C6-12aryl, C3-6cycloalkyl, 4 to 10 membered heterocyclyl, or 5 to 10 membered heteroaryl; the aryl, cycloalkyl, heterocyclyl, or heteroaryl of R1is optionally substituted withAttorney Docket No.: 1542-WO-PCT one to three Z1, which may be the same or different; each Z1is independently -COOH, halo, oxo, 5 to 10 membered heteroaryl, -C(O)N(R12b)S(O)2(R12a), or -S(O)2R12a; R2is H, C1-6 alkyl, or C1-6 haloalkyl; R3is H, C1-6alkyl, or C1-6haloalkyl; Y is N or CH; each R4is independently halo; each Q, X, X1, or X2is independently N, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N; W is O, S, or NR8; each R5is independently halo, CN, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6haloalkoxy, C2-6alkynyl, C6-12aryl, 5 to 10 membered heteroaryl, C3-12cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, C1-6 alkoxy, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently OH, halo, phenyl, C1-6alkyl, or C1-6haloalkyl; or two R5are attached to two adjacent carbons, and the two R5together with the two adjacent carbons to which they are attached form phenyl, 5 to 10 membered heterocyclyl or 5 to 6 membered heteroaryl; R8is C1-6 alkyl optionally substituted with one to two Z8, which may be the same or different; each Z8is independently cyclopropyl or phenyl; R12ais C1-6alkyl; R12bis H, C1-6alkyl; and n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is heterocyclyl having one to four heteroatoms each independently N, O or S. 5.The compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein R1is C6-12aryl, or 5 to 10 membered heteroaryl; the aryl or heteroaryl of R1is optionally substituted with one to three Z1, which may be the same or different; each Z1is independently - COOH, halo, 5 to 10 membered heteroaryl, or -S(O)2R12a; R2is H, C1-6 alkyl, or C1-6 haloalkyl; R3is H, C1-6alkyl, or C1-6haloalkyl;Attorney Docket No.: 1542-WO-PCT Y is N or CH; each R4is independently halo; each Q, X, X1, or X2is independently N, CH, or CR5, provided that not more than two of Q, X, X1, and X2are N; W is O, or NR8; each R5is independently halo, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C6-12aryl, 5 to 10 membered heteroaryl, C3-6cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently C1-6 alkyl; or two R5are attached to two adjacent carbons, and the two R5together with the two carbons to which they are attached form phenyl or 5 to 10 membered heterocyclyl; R8is C1-6 alkyl optionally substituted with one to two Z8, which may be the same or different; each Z8is independently cyclopropyl or phenyl; R12ais C1-6alkyl; and n is 0, 1, or 2; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to four heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to four heteroatoms each independently N, O or S. 6.The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIa):7.The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIb):(IIb).Attorney Docket No.: 1542-WO-PCT 8.The compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIc):9.The compound of any one claims 1-7, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IId):10.The compound of any one of claims 1-7 and 9, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIe):11.The compound of any one of claims 1-7, 9, and 10, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIf):12.The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X is N. 13.The compound of any one of claims 1-9, or a pharmaceutically acceptable saltAttorney Docket No.: 1542-WO-PCT thereof, wherein X is CH. 14.The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein X1is N. 15.The compound of any one of claims 1-9 and 12-13, or a pharmaceutically acceptable salt thereof, wherein X1is CH. 16.The compound of any one of claims 1-10 and 12-15, or a pharmaceutically acceptable salt thereof, wherein X2is N. 17.The compound of any one of claims 1-10 and 12-15, or a pharmaceutically acceptable salt thereof, wherein X2is CH. 18.The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein W is O. 19.The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein W is NR8. 20.The compound of any one of claims 1-17, or a pharmaceutically acceptable salt thereof, wherein W is NR8; R8is C1-3 alkyl optionally substituted with C3-6 cycloalkyl or phenyl. 21.The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Y is N. 22.The compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, wherein Y is CH. 23.The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein each R4is independently C1-3alkyl or halo. 24.The compound of any one of claims 1-22, or a pharmaceutically acceptable salt thereof, wherein R4is -CH3.Attorney Docket No.: 1542-WO-PCT 25.The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein n is 1. 26.The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R2is H. 27.The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R3is C1-3 alkyl. 28.The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R3is -CH3. 29.The compound of any one of claims 1-7, 9-11, and 18-20, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIf-1):30.The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl, thiazoyl, or pyridyl; the phenyl, thiazoyl, or pyridyl of R1is optionally substituted with one to three Z1, which may be the same or different; each Z1is independently -COOH, halo, 5 to 6 membered heteroaryl, -C(O)N(R12b)S(O)2(R12a), or - S(O)2R12a. 31.The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl, thiazoyl, or pyridyl; the phenyl, thiazoyl, or pyridyl of R1is substituted - COOH; the phenyl or pyridyl of R1is optionally additionally substituted with one or two Z1, which may be the same or different; each Z1is independently halo or -S(O)2R12a; and R12ais C1-3 alkyl.Attorney Docket No.: 1542-WO-PCT 32.The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl; the phenyl of R1is substituted -COOH; the phenyl of R1is optionally additionally substituted with one or two Z1, which may be the same or different; each Z1is independently halo or -S(O)2R12a; and R12ais C1-3 alkyl. 33.The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R1is34.The compound of any one of claims 1-29, or a pharmaceutically acceptable salt35.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein each R5is independently halo, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, 5 to 10 membered heteroaryl, C3-6 cycloalkyl, or 4 to 10 membered heterocyclyl; the alkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl is optionally substituted with one to three Z5, which may be the same or different.Attorney Docket No.: 1542-WO-PCT 36.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein each R5is independently phenyl or 5 to 10 membered heteroaryl; wherein the phenyl or heteroaryl of R5is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently C1-6alkyl, or C1-6haloalkyl. 37.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein each R5is independently phenyl, pyridyl, morpholinyl, pyrimidinyl, pyrazinyl, pyrazolyl; wherein the phenyl, pyridyl, morpholinyl, pyrimidinyl, pyrazinyl, pyrazolyl of R5is optionally substituted with one to three Z5, which may be the same or different; each Z5is independently C1-6alkyl, or C1-6haloalkyl. 38.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt. 39.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein each R5is independently halo, C1-6haloalkyl, or cyclopropyl; the cyclopropyl is optionally substituted with one to three Z5, which may be the same or different. 40.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein each R5is independently 4 to 10 membered heterocyclyl; the heterocyclyl of R5is optionally substituted with one to three Z5, which may be the same or different.Attorney Docket No.: 1542-WO-PCT 41.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt42.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein each R5is independently C3-6 cycloalkyl; the cycloalkyl is optionally substituted with one to three Z5, which may be the same or different. 43.The compound of any one of claims 1-34, or a pharmaceutically acceptable salt44.The compound of any one of claims 1-37, 39, 40 and 42, or a pharmaceutically acceptable salt thereof, wherein each Z5is independently C1-6 alkyl, or C1-6 haloalkyl.

45. The compound of any one of claims 1-9 and 12-34, or a pharmaceutically acceptable salt thereof, wherein two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form 5 or 10 membered heterocyclyl; wherein the heterocyclyl formed from two R5and two adjacent carbons to which they are attached is monocyclic heterocyclyl.Attorney Docket No.: 1542-WO-PCT 46. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein two R5are attached to two adjacent carbons, and the two R5together with the adjacent carbons to which they are attached form 5 or 10 membered heterocyclyl; wherein the heterocyclyl formed from two R5and two adjacent carbons to which they are attached is spiro bicyclic heterocyclyl. 47.A compound having the structure of Example 1-121, or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-47, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 49.A method of treating a PI3Kα-mediated disorder in a subject, comprising administering a therapeutically effective amount of a compound of any of claims 1-47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 45, to a subject in need thereof. 50.A method of treating a proliferative disease in a subject, comprising administering a therapeutically effective amount of a compound of any of claims 1-47, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 48, to a subject in need thereof. 51.The method of claim 50, wherein the proliferative disease is cancer. 52.The method of claim 51, wherein the cancer is breast cancer, endometrium cancer, colon & rectum cancer, lung cancer, bladder cancer, prostate cancer, head & neck cancer, cervix cancer, or melanoma cancer. 53.The method of any one of claims 49-52, wherein the subject has PI3Kα containing at least one of the mutations consisting of H1047R, E542K, E545K, H1047L, and H1047Y. 54.The method of any one of claims 49-53, wherein the subject has PI3Kα containing the mutation of H1047R.Attorney Docket No.: 1542-WO-PCT 55. Use of the compound of any one of claims 1 to 47 or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a PI3Kα associated disease or condition.

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