Interlukin-17a inhibitors and uses thereof

Abstract

The present disclosure relates generally to compounds that inhibit IL-17A. 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 IL-17A. The disclosure further relates to the use of the compounds for therapy.

Description

Attorney Docket No.: 1537-US-NP / WO-PCT INTERLUKIN-17A INHIBITORS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 575,075, filed on April 5, 2024, the entire contents of which is hereby incorporated by reference in its entirety. FIELD

[0002] The present disclosure relates to compounds that inhibit interlukin-17A (IL-17A). The disclosure further relates to the use of the compounds for the treatment of diseases and / or conditions responsive to IL-17A inhibition. BACKGROUND

[0003] The Interleukin-17 (IL-17) family consists of six cytokines (IL-17A through IL-17F). IL- 17A and IL-17F have the highest sequence homology. IL- 17A can form homodimers with itself (IL-17 AA) or heterodimers with IL-17F (IL-17 AF). IL-17A is a key effector cytokine involved in the pathogenesis of psoriasis and mediates signaling through binding to IL-17 receptors, IL-17 RA and IL-17 RC. IL-17A alone or together with other cytokines such as TNFα mediates pro-inflammatory effects that may induce the psoriasis phenotype.

[0004] IL-17A inhibitors, including secukinumab, ixekizumab, and brodalumab, have been approved for the treatment of psoriasis. These biological IL-17A inhibitors are administered via an injection which can be inconvenient for patients. In addition, biologic treatments are expensive, which limits their availability. Therefore, there is a need for the development of oral and lower-cost IL-17 modulators with desirable potency for the treatment of psoriasis. SUMMARY

[0005] The present disclosure provides compounds useful as IL-17A inhibitors. The disclosure further relates to the use of the compounds for the treatment of diseases and / or conditions through inhibiting IL-17A by said compounds.Attorney Docket No.: 1537-US-NP / WO-PCT

[0006] In one embodiment, provided herein is a compound of Formula (I),or a pharmaceutically acceptable salt thereof, wherein R1is -O-R12a, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R1is substituted with 0 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is substituted with 0 to 4 Z2, which may be the same or different; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2; Cy1is 5-10 membered heterocyclyl or C5-10 cycloalkyl; the heterocyclyl or cycloalkyl of Cy1is additionally substituted with 0 to 2 Z5, which may be the same or different; each Z5is independently oxo, halogen, -OH, C1-3 alkyl, -C(O) R12a, -C(O)O-R12a, C1-3 haloalkyl, C1-3 haloalkyl, or C1-3 haloalkyl; R3is C1-6 alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is substituted with 0 to 4 Z3, which may be the same or different; R4is absent, H, halogen, -CN, C2-4 alkynyl, -NR12aR12b, -OR12a, C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R4is substituted with 0 to 1 -OR12a; each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each substituted with 0 to 4 Z1a, which may be the same or different;Attorney Docket No.: 1537-US-NP / WO-PCT each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 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)-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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally with 0 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10aryl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis substituted with 0 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6- 10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis substituted with 0 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6alkoxy, or -C1-6haloalkoxy; and each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis substituted with 0 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy; wherein the alkoxy of each Z1dis substituted with 0 to 2 Z1e, which may be the same or different; each Z1eis independently -OH or C1-3 alkoxy; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S.Attorney Docket No.: 1537-US-NP / WO-PCT

[0007] In certain embodiments, provided herein is a compound of Formula (I′),or a pharmaceutically acceptable salt thereof, wherein R1is -O-R12a, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R1is optionally substituted with 1 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2; Cy1is 5-10 membered heterocyclyl or C5-10 cycloalkyl; the heterocyclyl or cycloalkyl of Cy1is optionally additionally substituted with 1 to 2 Z5, which may be the same or different; each Z5is independently oxo, halogen, -OH, C1-3 alkyl, -C(O) R12a, -C(O)O-R12a, C1-3 haloalkyl, C1-3 haloalkyl, or C1-3 haloalkyl; R3is C1-6 alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is optionally substituted with 1 to 4 Z3, which may be the same or different; R4is absent, H, halogen, -CN, C2-4 alkynyl, -NR12aR12b, -OR12a, C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R4is optionally substituted with -OR12a; each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each optionally substituted with 1 to 4 Z1a, which may be the same or different;Attorney Docket No.: 1537-US-NP / WO-PCT each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 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)-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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with 1 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis optionally substituted with 1 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6- 10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis optionally substituted with 1 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6alkoxy, or -C1-6haloalkoxy; and each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis optionally substituted with 1 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S.

[0008] 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.Attorney Docket No.: 1537-US-NP / WO-PCT

[0009] 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.

[0010] In some embodiments, the present disclosure provides methods of inhibiting IL-17A 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

[0011] The present disclosure relates to inhibitors of IL-17A. The disclosure also relates to compositions and methods relating to IL-17A inhibitors and the use of such compounds for treatment of diseases and conditions. The disclosure also relates to compositions and methods of treating diseases and / or conditions that include an IL-17A inhibitor in combination with one or more additional therapeutic agents. Definitions and General Parameters

[0012] 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.

[0013] 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.Attorney Docket No.: 1537-US-NP / WO-PCT

[0014] 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.

[0015] A dash”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is 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:.

[0016] 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.

[0017] 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.

[0018] “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.Attorney Docket No.: 1537-US-NP / WO-PCT

[0019] 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.

[0020] “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., C1-3 alkyl). 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-butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., - CH(CH3)2).

[0021] “Alkenyl” refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 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).

[0022] “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., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0023] “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, asAttorney Docket No.: 1537-US-NP / WO-PCT defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0024] “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.

[0025] “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 (C2-6 alkoxyalkyl), 2 to 5 (C2-5 alkoxyalkyl), 2 to 4 (C2-4 alkoxyalkyl), or 2 to 3 (C2-3 alkoxyalkyl). 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 (C4 alkyl), and in other embodiments, n-propoxy (C3 alkoxy) linked to isopropyl (C3 alkyl). 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.

[0026] “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.

[0027] “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-Attorney Docket No.: 1537-US-NP / WO-PCT 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.

[0028] “Cyano” or “carbonitrile” refers to the group -CN.

[0029] “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., C3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0030] “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 system

[0031] “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., bicyclo[2.2.2]octyl). In some embodiments, the bridged ring, ,

[0032] “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),Attorney Docket No.: 1537-US-NP / WO-PCT 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

[0033] “Halogen” or “halo” includes fluoro, chloro, bromo, and iodo.

[0034] “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 C1-4 alkyl 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.

[0035] “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 suitablenumber of carbon atoms, such as C1-6. The alkoxy groups can be substituted with 1, 2, 3, or morehalogens. 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.

[0036] 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,Attorney Docket No.: 1537-US-NP / WO-PCT 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.

[0037] “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 understood 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 toAttorney Docket No.: 1537-US-NP / WO-PCT

[0038] “Hydroxy” or “hydroxyl” refers to the group -OH.

[0039] “Oxo” refers to the group (=O) or (O).

[0040] “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.

[0041] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an -NH2 group 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.

[0042] 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. For example, the term “optionally substituted with 1 to n” of a moeity is equivalent to the term “substituted with 0 to n” of a moiety (i.e., zero to n hydrogen atoms on the designated atom or group may be replaced by that moiety).

[0043] 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,Attorney Docket No.: 1537-US-NP / WO-PCT 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.

[0044] 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 more 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.Attorney Docket No.: 1537-US-NP / WO-PCT

[0045] 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:.

[0046] 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.

[0047] 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 salts 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 organicAttorney Docket No.: 1537-US-NP / WO-PCT 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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 functionalAttorney Docket No.: 1537-US-NP / WO-PCT 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.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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 methods 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).Attorney Docket No.: 1537-US-NP / WO-PCT

[0056] 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.

[0057] 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.

[0058] 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, 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 inAttorney Docket No.: 1537-US-NP / WO-PCT 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.

[0059] 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.

[0060] 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.

[0061] 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.

[0062] 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.Attorney Docket No.: 1537-US-NP / WO-PCT

[0063] “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.

[0064] 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.).

[0065] “IC50” or “EC50” refers to the inhibitory concentration required to achieve 50% of the maximum desired effect.

[0066] “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 or 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 clinicalAttorney Docket No.: 1537-US-NP / WO-PCT symptoms; and / or (iii) relieving the disease, that is, causing the regression of clinical symptoms or the severity thereof.

[0067] “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.

[0068] “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.

[0069] 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 IL- 17A 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.: 1537-US-NP / WO-PCTAttorney Docket No.: 1537-US-NP / WO-PCTAttorney Docket No.: 1537-US-NP / WO-PCT Compounds

[0070] In one embodiment, the present disclosure provides a compound of Formula (I),or a pharmaceutically acceptable salt thereof, wherein R1is -O-R12a, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R1is substituted with 0 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is substituted with 0 to 4 Z2, which may be the same or different; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2; Cy1is 5-10 membered heterocyclyl or C5-10 cycloalkyl; the heterocyclyl or cycloalkyl of Cy1is additionally substituted with 0 to 2 Z5, which may be the same or different; each Z5is independently oxo, halogen, -OH, C1-3 alkyl, -C(O) R12a, -C(O)O-R12a, C1-3 haloalkyl, C1-3 haloalkyl, or C1-3 haloalkyl; R3is C1-6 alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is substituted with 0 to 4 Z3, which may be the same or different; R4is absent, H, halogen, -CN, C2-4 alkynyl, -NR12aR12b, -OR12a, C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R4is substituted with 0 to 1 -OR12a; each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl,Attorney Docket No.: 1537-US-NP / WO-PCT haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each substituted with 0 to 4 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 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)-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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each substituted with 0 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis substituted with 0 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6- 10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis substituted with 0 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6 alkoxy, or -C1-6 haloalkoxy; and each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis substituted with 0 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy, wherein the alkoxy of each Z1dis substituted with 0 to 2 Z1e, which may be the same or different; each Z1eis independently -OH or C1-3 alkoxy; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S.

[0071] In some embodiments, the compound of Formula (I) is a compound of Formula (I′),Attorney Docket No.: 1537-US-NP / WO-PCTor a pharmaceutically acceptable salt thereof, wherein R1is -O-R12a, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R1is optionally substituted with 1 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2; Cy1is 5-10 membered heterocyclyl or C5-10 cycloalkyl; the heterocyclyl or cycloalkyl of Cy1is optionally additionally substituted with 1 to 2 Z5, which may be the same or different; each Z5is independently oxo, halogen, -OH, C1-3 alkyl, -C(O) R12a, -C(O)O-R12a, C1-3 haloalkyl, C1-3 haloalkyl, or C1-3 haloalkyl; R3is C1-6 alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is optionally substituted with 1 to 4 Z3, which may be the same or different; R4is absent, H, halogen, -CN, C2-4 alkynyl, -NR12aR12b, -OR12a, C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R4is optionally substituted with -OR12a; each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each optionally substituted with 1 to 4 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -CN, -O-R12a, -C(O)R12a, -C(O)O-Attorney Docket No.: 1537-US-NP / WO-PCT R12a, -C(O)N(R12a)( R12b), -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), -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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with 1 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis optionally substituted with 1 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6- 10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis optionally substituted with 1 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6 alkoxy, or -C1-6 haloalkoxy; and each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10aryl, or heteroaryl; the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis optionally substituted with 1 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S.

[0072] In some embodiments, the compound of Formula (I) is a compound wherein Cy1is monocyclic. In some embodiments, Cy1is fused bicyclic. In some embodiments, Cy1is bridged bicyclic. In some embodiments, Cy1is spiro bicyclic.

[0073] In some embodiments, the compound of Formula (I) is a compound of Formula (II),Attorney Docket No.: 1537-US-NP / WO-PCTor a pharmaceutically acceptable salt thereof, wherein X1is a bond, or C1-3 alkylene; wherein the C1-3 alkylene of X1is optionally substituted with 1 to 3 C1-6 alkyl, which may be the same or different; X is -NR6a-, -SO2-, -SO2NR6a-, -CO-, -CO(C1-3 alkylene)-, C1-3 alkylene, -O(C1-3 alkylene)-, -N=CR6b-, -NR6a(C1-3 alkylene)-, -NR6aCO-, -NR6aC(O)O-, -NR6aC(O)NR6a-, or - NR6aCO(C1-3 alkylene)-; wherein the alkylene of CO(C1-3 alkylene)-, C1-3 alkylene, -O(C1-3 alkylene)-, -NR6a(C1-3 alkylene)-, or -NR6aCO(C1-3 alkylene)- of X is optionally substituted with 1 to 3 C1-6 alkyl, which may be the same or different; R6ais H, C1-6 alkyl, C1-6 haloalkyl, -C(O) R12a, or -C(O)O-R12a; R6bis -N(R12a)( R12b); X2 is a bond, or C1-3 alkylene; wherein the C1-3 alkylene of X2 is optionally substitutedwith 1 to 3 C1-6 alkyl, which may be the same or different; R1is -O-R12a, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R1is optionally substituted with 1 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; R3is C1-6 alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is optionally substituted with 1 to 4 Z3, which may be the same or different; R4is H, -NR12aR12b, -OR12a, C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R4is optionally substituted with -OR12a; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2; each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -N(R12a)( R12b), -N(R12a)C(O)-R12b, -N(R12a)C(O)O-R12b, -Attorney Docket No.: 1537-US-NP / WO-PCT 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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each optionally substituted with 1 to 4 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 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)-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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with 1 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis optionally substituted with 1 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6alkyl, C1-6haloalkyl, halogen, C3-10cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis optionally substituted with 1 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6 alkoxy, or -C1-6 haloalkoxy; and each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis optionally substituted with 1 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S.Attorney Docket No.: 1537-US-NP / WO-PCT

[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) or (II) is a compound of Formula (IIb),or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, the compound of Formula (I) or (II) is a compound of Formula (IIc),or a pharmaceutically acceptable salt thereof, wherein Z6ais Z6or H.

[0077] In some embodiments, the compound of Formula (I) or (II) is a compound of Formula (IId),Attorney Docket No.: 1537-US-NP / WO-PCT or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the compound of Formula (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X1is a bond. In some embodiments, X1is C1-3 alkylene.

[0079] In some embodiments, the compound of Formula (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X2is a bond. In some embodiments, X2is C1-3 alkylene.

[0080] In some embodiments, the compound of Formula (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein X is C1-3 alkylene, -O(C1-3 alkylene)-, or -NR6a(C1-3 alkylene)-. In some embodiments, X is -CO(C1-3 alkylene)-, -NR6aCO-, or -NR6aCO(C1-3 alkylene)-; wherein the alkylene of -CO(C1-3 alkylene)-, -NR6aCO-, or -NR6aCO(C1-3 alkylene)- is optionally substituted with 1 to 3 C1-6alkyl, which may be the same or different.

[0081] In some embodiments, the compound of Formula (II), (IIa), (IIb), (IIc), or (IId) is aAttorney Docket No.: 1537-US-NP / WO-PCT.Attorney Docket No.: 1537-US-NP / WO-PCT

[0082] In some embodiments, the compound of Formula (II), (IIa), (IIb), (IIc), or (IId) is a

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

[0084] In some embodiments, the compound of Formula (I) is a compound wherein

[0085] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R6ais H or C1-6 alkyl. In some embodiments, R6ais C1-6 haloalkyl.

[0086] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R4is H. In some embodiments, R4is C1-6 alkyl. In some embodiments, R4is -CH3. In some embodiments, R4is C1-6 haloalkyl.

[0087] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), or (IIc) is a compound wherein R2is C1-6 alkyl, C1-6 haloalkyl, or C3-10 cycloalkyl; wherein the alkyl, haloalkyl or cycloalkyl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; andAttorney Docket No.: 1537-US-NP / WO-PCT each Z2is independently -O-R12a, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or phenyl; the cycloalkyl or phenyl of Z2is optionally substituted with 1 to 3 Z1a; R12ais C1-6 alkyl, or C1-6 haloalkyl; and each Z1ais independently halogen or C1-6 alkyl.

[0088] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), or (IIc) is a compound wherein R2is C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; each Z2is independently -O-R12a, C3-6 cycloalkyl, or phenyl; the cycloalkyl or phenyl of Z2is optionally substituted with 1 to 3 Z1a, which may be the same or different; R12ais C1-6 alkyl, or C1-6 haloalkyl; and each Z1ais independently halogen or alkyl.

[0089] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), or (IIc) is acompound wherein R2 is. In some embodiments, R2. In someembodiments, R2is; and Z2is C1-6 alkyl or C1-6 haloalkyl. In some embodiments, R2some embodiments, R2is C1-6 alkyl or C1-6 haloalkyl. In some embodiments,

[0090] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), or (IIc) is a compound wherein R1is heteroaryl optionally substituted with 1 to 4 Z1, which may be the same or different; each Z1is independently halogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl; the alkyl, cycloalkyl of Z1is optionally substituted with 1 to 3 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen or -OR12a; and R12ais H or C1-6 alkyl.Attorney Docket No.: 1537-US-NP / WO-PCT

[0091] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), or (IIc) is a compound wherein R1is . In some emobdiments,someemobdiments, R1is . In some emobdiments, R1is .

[0092] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is heterocyclyl optionally substituted with 1 to 3 Z3, which may be the same or different; and the heterocyclyl of R3is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N or O.

[0093] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound whereinCy2is 4 to 10 membered heterocyclyl; and m is 0, 1, or 2.

[0094] In some embodiments, Cy2is 4 to 10 membered monocyclic heterocyclyl. In some embodiments, Cy2is 5 to 8 membered monocyclic heterocyclyl. In some embodiments, Cy2is 4 to 10 membered bicyclic or tricyclic heterocyclyl. In some embodiments, Cy2is 6 to 10 membered bicyclic or tricyclic heterocyclyl. In some embodiments, Cy2is a heterocyclyl that does include an additional heteroatom. In some embodiments, Cy2is a heterocyclyl that include an additional heteroatom independently N or S.

[0095] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound whereinsome embodiments, m is 0. In some embodiments, m is 1, in some embodiments, m is 2.Attorney Docket No.: 1537-US-NP / WO-PCT

[0096] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is acompound wherein R3 is; and m is 0, 1, or 2. In some embodiments, m is 0. Insome embodiments, m is 1. In some embodiments, m is 3.

[0097] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is -NR12aCOR12b. In some embodiments, R12ais H or C1-6 alkyl; R12bis C1- 6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, or heteroaryl of R12bis optionally with 1 to 3 Z1b, which may be the same or different; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, -OR13a, -N(R13a)( R13b), or -NH- C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl.

[0098] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is -NR12aCOR12b; R12ais H or C1-6alkyl; R12bis C1-6alkyl, or C1-6haloalkyl; wherein the alkyl, or haloalkyl of R12bis optionally with 1 to 3 Z1b, which may be the same or different; each Z1bis independently halogen or -NH-C(O)R13b; and R13bis C1-6 alkyl, or C1-6 haloalkyl.

[0099] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is -NR12aCOR12b; R12bis C1-6 haloalkyl optionally substituted with -NH- C(O)R13b; and R13bis C1-6 alkyl.

[0100] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound whereinsome embodiments,some embodiments,Attorney Docket No.: 1537-US-NP / WO-PCT some embodiments,some embodiments,some embodiments,

[0101] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is -CONR12aR12b. In some embodiments, R12ais H or C1-6 alkyl; R12bis C1- 6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1 to 3 Z1b, which may be the same or different; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl.

[0102] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is -CONHR12b; and R12bis C1-6 haloalkyl.

[0103] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is -COR12a. In some embodiments, R12ais a heterocyclyl optionally substituted with 1 to 3 Z1b, which may be the same or different; the heterocyclyl of R12ais 5 to 6 membered heterocyclyl having one to three heteroatoms each independently N, O, or S; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, -OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl.

[0104] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is -COR12a; R12ais a heterocyclyl optionally substituted with 1 to 3 Z1b, which may be the same or different; the heterocyclyl of R12ais 5 to 6 membered heterocyclyl having one to two N; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl.

[0105] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein R3is heteroaryl optionally substituted with 1 to 4 Z3, which may be the sameAttorney Docket No.: 1537-US-NP / WO-PCT or different. In some embodiments, R3is ; and m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments,

[0106] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein each Z3is independently halo, oxo, phenyl, C3-6 cycloalkyl, C1-6 alkyl, or C1- 6 haloalkyl. In some embodimetns, each Z3is independently oxo, phenyl, C3-6 cycloalkyl, C1-6 alkyl, or C1-6 haloalkyl. In some embodimetns, each Z3is independently halo, oxo, or C1-6 haloalkyl.

[0107] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein Z6is halogen. In some embodiments, Z6is F.

[0108] In some embodiments, the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId) is a compound wherein q is 1. In some embodiments, q is 0.

[0109] In some embodiments, the present disclosure provides a compound disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound having a structure of Examples 1-85, or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the present disclosure provides a racemic mixture comprising the compound of Formula (I), (II), (IIa), (IIb), (IIc), or (IId), 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), or (IId), 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.

[0111] 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, Z2, etc.) to generate a complete compound of Formula (I), (II), (IIa), (IIb), (IIc),Attorney Docket No.: 1537-US-NP / WO-PCT or (IId), 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. Pharmaceutical Compositions and Modes of Administration

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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. IfAttorney Docket No.: 1537-US-NP / WO-PCT 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 amount 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.

[0117] 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.

[0118] 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.

[0119] In some embodiments, the compounds of the present disclosure may also be used as salts with various countercations to yield an orally available formulation.

[0120] 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.

[0121] 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.Attorney Docket No.: 1537-US-NP / WO-PCT

[0122] 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, creams, ointments, aerosols, and the like. In some embodiments, compounds of the present disclosure are administered orally. Method of Treatment

[0123] Disclosed herein are methods of treatment of a disease or disorder in which inhibition of IL-17A is beneficial, the method comprising administering a compound disclosed herein.

[0124] In some embodiments, the disease or disorder is psoriasis, rheumatoid arthritis, spondyloarthritis, multiple sclerosis, psoriatic arthritis, axial spondyloarthritis, ankylosing spondylitis, hidradenitis suppurativa, systemic lupus erythematosus, palmoplantar pustulosis (PPP), atopic dermatitis, asthma, and / or COPD. In some embodiments, the disease or disorder is psoriasis. Dosage

[0125] 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.

[0126] When treating an IL-17A-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 700Attorney Docket No.: 1537-US-NP / WO-PCT 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.

[0127] 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.

[0128] 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

[0129] 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.

[0130] 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.Attorney Docket No.: 1537-US-NP / WO-PCT

[0131] In some embodiments, the additional therapeutic agent is an anti-inflammatory agent, an immunomodulatory agent, or an immunosuppressive agent.

[0132] In some embodiments, the additional therapeutic agent is an anti-TNFα agent, an anti- p40 antibody, or an anti-p19 antibody. Further Embodiments 1. A compound of formula (I′):or a pharmaceutically acceptable salt thereof, wherein R1is -O-R12a, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R1is optionally substituted with 1 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2; Cy1is 5-10 membered heterocyclyl or C5-10cycloalkyl; the heterocyclyl or cycloalkyl of Cy1is optionally additionally substituted with 1 to 2 Z5, which may be the same or different; each Z5is independently oxo, halogen, -OH, C1-3 alkyl, -C(O) R12a, -C(O)O-R12a, C1-3 haloalkyl, C1-3 haloalkyl, or C1-3 haloalkyl; R3is C1-6 alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is optionally substituted with 1 to 4 Z3, which may be the same or different; R4is absent, H, halogen, -CN, C2-4 alkynyl, -NR12aR12b, -OR12a, C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R4is optionally substituted with -OR12a;Attorney Docket No.: 1537-US-NP / WO-PCT each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each optionally substituted with 1 to 4 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, 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)-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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with 1 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis optionally substituted with 1 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6- 10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis optionally substituted with 1 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6 alkoxy, or -C1-6 haloalkoxy; and each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis optionally substituted with 1 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S;Attorney Docket No.: 1537-US-NP / WO-PCT wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S. 2. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Cy1is monocyclic. 3. The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Cy1is fused bicyclic, bridged bicyclic, or spiro bicyclic. 4. The compound of Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein X1is a bond, or C1-3 alkylene; wherein the C1-3 alkylene of X1is optionally substituted with 1 to 3 C1-6 alkyl, which may be the same or different; X is -NR6a-, -SO2-, -SO2NR6a-, -CO-, -CO(C1-3 alkylene)-, C1-3 alkylene, -O(C1-3 alkylene)-, -N=CR6b-, -NR6a(C1-3 alkylene)-, -NR6aCO-, -NR6aC(O)O-, -NR6aC(O)NR6a-, or - NR6aCO(C1-3 alkylene)-; wherein the alkylene of CO(C1-3 alkylene)-, C1-3 alkylene, -O(C1-3alkylene)-, -NR6a(C1-3 alkylene)-, or -NR6aCO(C1-3 alkylene)- of X is optionally substituted with1 to 3 C1-6 alkyl, which may be the same or different; R6ais H, C1-6 alkyl, C1-6 haloalkyl, -C(O) R12a, or -C(O)O-R12a; R6bis -N(R12a)(R12b); X2is a bond, or C1-3 alkylene; wherein the C1-3 alkylene of X2is optionally substituted with 1 to 3 C1-6 alkyl, which may be the same or different; R1is -O-R12a, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R1is optionally substituted with 1 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; R3is C1-6 alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is optionally substituted with 1 to 4 Z3, which may be the same or different;Attorney Docket No.: 1537-US-NP / WO-PCT R4is H, -NR12aR12b, -OR12a, C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R4is optionally substituted with -OR12a; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2; each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each optionally substituted with 1 to 4 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 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)-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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each optionally substituted with 1 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis optionally substituted with 1 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6- 10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis optionally substituted with 1 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6 alkoxy, or -C1-6 haloalkoxy; andAttorney Docket No.: 1537-US-NP / WO-PCT each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis optionally substituted with 1 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy; wherein each heteroaryl is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S; wherein each heterocyclyl is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S. 5. The compound of any one of Embodiments 1, 2, and 4, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIa)6. The compound of any one of Embodiments 1, 2, 4, and 5, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIb)7. The compound of any one of Embodiments 1, 2, and 4-6, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIc); wherein Z6ais Z6or H. 8. The compound of any one of Embodiments 1, 2, and 4-6, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IId)Attorney Docket No.: 1537-US-NP / WO-PCT9. The compound of any one of Embodiments 4-8, or a pharmaceutically acceptable salt thereof, wherein X1is a bond. 10. The compound of any one of Embodiments 4-8, or a pharmaceutically acceptable salt thereof, wherein X1is C1-3 alkylene. 11. The compound of any one of Embodiments 4-10, or a pharmaceutically acceptable salt thereof, wherein X2is a bond. 12. The compound of any one of Embodiments 4-10, or a pharmaceutically acceptable salt thereof, wherein X2is C1-3 alkylene. 13. The compound of any one of Embodiments 4-12, or a pharmaceutically acceptable salt thereof, wherein X is C1-3 alkylene, -O(C1-3 alkylene)-, -NR6a(C1-3 alkylene)-. 14. The compound of any one of Embodiments 4-12, or a pharmaceutically acceptable salt thereof, wherein X is -CO(C1-3 alkylene)-, -NR6aCO-, or -NR6aCO(C1-3 alkylene)-; wherein the alkylene of -CO(C1-3 alkylene)-, -NR6aCO-, or -NR6aCO(C1-3 alkylene)- is optionally substituted with 1 to 3 C1-6 alkyl, which may be the same or different. 15. The compound of any one of Embodiments 4-8, or a pharmaceutically acceptable salt16. The compound of any one of Embodiments 4-6, and 8, or a pharmaceutically acceptableAttorney Docket No.: 1537-US-NP / WO-PCT salt thereof, wherein17. The compound of any one of Embodiments 4-6, and 8, or a pharmaceutically acceptable salt thereof, wherein18. The compound of any one of Embodiments 4-6, and 8, or a pharmaceutically acceptable salt thereof, wherein19. The compound of Embodiment 1 or 3, or a pharmaceutically acceptable salt thereof, wherein20. The compound of any one of Embodiments 4-8, or a pharmaceutically acceptable salt thereof, wherein21. The compound of any one of Embodiments 4-8, or a pharmaceutically acceptable salt thereof, whereinZ5is C1-3 alkyl; and n is 0, 1, or 2. 22. The compound of any one of Embodiments 4-8, or a pharmaceutically acceptable saltAttorney Docket No.: 1537-US-NP / WO-PCT thereof, wherein23. The compound of any one of Embodiments 1-15 and 19-22, or a pharmaceutically acceptable salt thereof, wherein R6ais H or C1-6 alkyl. 24. The compound of any one of Embodiments 1-15 and 19-22, or a pharmaceutically acceptable salt thereof, wherein R6ais C1-6 haloalkyl. 25. The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein R4is H. 26. The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein R4is C1-6 alkyl. 27. The compound of any one of Embodiments 1-24 and 26, or a pharmaceutically acceptable salt thereof, wherein R4is -CH3. 28. The compound of any one of Embodiments 1-24, or a pharmaceutically acceptable salt thereof, wherein R4is C1-6 haloalkyl. 29. The compound of any one of Embodiments 1-7 and 9-28, or a pharmaceutically acceptable salt thereof, wherein R2is C1-6 alkyl, C1-6 haloalkyl, or C3-10 cycloalkyl; wherein the alkyl, haloalkyl or cycloalkyl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; and each Z2is independently -O-R12a, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or phenyl; the cycloalkyl or phenyl of Z2is optionally substituted with 1 to 3 Z1a; R12ais C1-6 alkyl, or C1-6 haloalkyl; and each Z1ais independently halogen or C1-6 alkyl. 30. The compound of any one of Embodiments 1-7 and 9-28, or a pharmaceutically acceptable salt thereof, wherein R2is C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R2is optionally substituted with 1 to 4 Z2, which may be the same or different; each Z2is independently -O-R12a, C3-6 cycloalkyl, or phenyl; the cycloalkyl or phenyl of Z2is optionally substituted with 1 to 3 Z1a, which may be the same or different; R12ais C1-6 alkyl, or C1-6 haloalkyl; and each Z1ais independently halogen or alkyl. 31. The compound of any one of Embodiments 1-7 and 9-28, or a pharmaceuticallyAttorney Docket No.: 1537-US-NP / WO-PCT acceptable salt thereof, wherein R2is. 32. The compound of any one of Embodiments 1-7 and 9-31, or a pharmaceutically acceptable salt thereof, wherein R1is heteroaryl optionally substituted with 1 to 4 Z1, which may be the same or different; each Z1is independently halogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl; the alkyl, cycloalkyl of Z1is optionally substituted with 1 to 3 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen or -OR12a; and R12ais H or C1-6 alkyl. 33. The compound of any one of Embodiments 1-7 and 9-32, or a pharmaceutically acceptable salt thereof, wherein R1is. 34. The compound of any one of Embodiments 1-7 and 9-33, or a pharmaceutically acceptable salt thereof, wherein35. The compound of any one of Embodiments 1-7 and 9-33, or a pharmaceutically acceptable salt thereof, wherein R1is. 36. The compound of any one of Embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is heterocyclyl optionally substituted with 1 to 3 Z3, which may be the same or different; and the heterocyclyl of R3is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N or O. 37. The compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt thereof, whereinCy2is 4 to 10 membered heterocyclyl; andAttorney Docket No.: 1537-US-NP / WO-PCT m is 0, 1, or 2. 38. The compound of Embodiment 37, or a pharmaceutically acceptable salt thereof, wherein Cy2is 4 to 10 membered monocyclic heterocyclyl. 39. The compound of Embodiment 37, or a pharmaceutically acceptable salt thereof, wherein Cy2is 4 to 10 membered bicyclic or tricyclic heterocyclyl. 40. The compound of any one of Embodiments 1-38, or a pharmaceutically acceptable salt thereof, wherein41. The compound of any one of Embodiments 1-37 and 39, or a pharmaceuticallyacceptable salt thereof, wherein R3 is; and m is 0, 1, or 2.42. The compound of any one of Embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is -NR12aCOR12b. 43. The compound of any one of Embodiments 1-35 and 42, or a pharmaceutically acceptable salt thereof, wherein R3is -NR12aCOR12b; R12ais H or C1-6 alkyl; R12bis C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, or heteroaryl of R12bis optionally with 1 to 3 Z1b, which may be the same or different; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl. 44. The compound of any one of Embodiments 1-35 and 42, or a pharmaceutically acceptable salt thereof, wherein R3is -NR12aCOR12b; R12ais H or C1-6 alkyl; R12bis C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl, or haloalkyl of R12bis optionally with 1 to 3 Z1b, which may be the same or different; each Z1bis independently halogen or -NH-C(O)R13b; and R13bis C1-6 alkyl, or C1-6 haloalkyl. 45. The compound of any one of Embodiments 1-35 and 42, or a pharmaceuticallyAttorney Docket No.: 1537-US-NP / WO-PCT acceptable salt thereof, wherein R3is -NHCOR12b; R12bis C1-6 haloalkyl optionally substituted with -NH-C(O)R13b; and R13bis C1-6 alkyl. 46. The compound of any one of Embodiments 1-35, 42, and 43, or a pharmaceutically acceptable salt thereof, wherein47. The compound of any one of Embodiments 1-35, 42, 43, and 46, or a pharmaceutically acceptable salt thereof, wherein48. The compound of any one of Embodiments 1-35, 42, 43, and 46, or a pharmaceutically acceptable salt thereof, wherein49. The compound of any one of Embodiments 1-35, and 42-46, or a pharmaceutically acceptable salt thereof, wherein50. The compound of any one of Embodiments 1-35, and 42-49, or a pharmaceutically acceptable salt thereof, wherein51. The compound of any one of Embodiments 1-35, 42, 43, and 46, or a pharmaceutically acceptable salt thereof, wherein52. The compound of any one of Embodiments 1-35, 42, 43, 46-48, and 51, or aAttorney Docket No.: 1537-US-NP / WO-PCT pharmaceutically acceptable salt thereof, wherein53. The compound of any one of Embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is -CONR12aR12b. 54. The compound of any one of Embodiments 1-35 and 53, or a pharmaceutically acceptable salt thereof, wherein R3is -CONR12aR12b; R12ais H or C1-6 alkyl; R12bis C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1 to 3 Z1b, which may be the same or different; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl. 55. The compound of any one of Embodiments 1-35 and 53, or a pharmaceutically acceptable salt thereof, wherein R3is -CONHR12b; and R12bis C1-6 haloalkyl. 56. The compound of any one of Embodiments 1-36, or a pharmaceutically acceptable salt thereof, wherein R3is -COR12a. 57. The compound of any one of Embodiments 1-35 and 56, or a pharmaceutically acceptable salt thereof, wherein R3is -COR12a; R12ais a heterocyclyl optionally substituted with 1 to 3 Z1b, which may be the same or different; the heterocyclyl of R12ais 5 to 6 membered heterocyclyl having one to three heteroatoms each independently N, O, or S; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6alkyl, or C1-6haloalkyl. 58. The compound of any one of Embodiments 1-35 and 56, or a pharmaceutically acceptable salt thereof, wherein R3is -COR12a; R12ais a heterocyclyl optionally substituted with 1 to 3 Z1b, which may be the same or different; the heterocyclyl of R12ais 5 to 6 membered heterocyclyl having one to two N;Attorney Docket No.: 1537-US-NP / WO-PCT each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl. 59. The compound of any one of Embodiments 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is heteroaryl optionally substituted with 1 to 4 Z3, which may be the same or different. 60. The compound of any one of Embodiments 1-35 and 59, or a pharmaceutically acceptable salt thereof, wherein R3is ; and m is 0, 1, or 2. 61. The compound of any one of Embodiments 1-35, 59, and 60, or a pharmaceutically acceptable salt thereof, wherein R3is. 62. The compound of any one of Embodiments 1-41, 59, and 60, or a pharmaceutically acceptable salt thereof, wherein each Z3is independently halo, oxo, phenyl, C3-6 cycloalkyl, C1-6 alkyl, or C1-6 haloalkyl. 63. The compound of any one of Embodiments 1-15, 19-21, and 23-62, or a pharmaceutically acceptable salt thereof, wherein Z6is halogen. 64. The compound of any one of Embodiments 1-15, 19-21, and 23-632, or a pharmaceutically acceptable salt thereof, wherein Z6is F. 65. The compound of any one of Embodiments 1-15, 19-21, and 23-64, or a pharmaceutically acceptable salt thereof, wherein q is 1. 66. The compound of any one of Embodiments 1-6, 8-15, 19-21, and 23-62, or a pharmaceutically acceptable salt thereof, wherein q is 0. 67. A compound having a structure of Examples 1-85, or a pharmaceutically acceptable salt thereof. 68. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of Embodiments 1-67, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 69. A method of modulating IL-17A in a subject, comprising administering a therapeutically effective amount of a compound of any of embodiments 1-67, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of Embodiment 68, to a subject in need thereof. 70. A method of treating an inflammatory disease or condition comprising administering aAttorney Docket No.: 1537-US-NP / WO-PCT therapeutically effective amount of a compound of any of Embodiments 1-67, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of embodiment 68, to a subject in need thereof. 71. The method of Embodiment 70, wherein the inflammatory disease or condition is psoriasis, psoriatic arthritis, or ankylosing spondylitis. 72. Use of the compound of any one of Embodiments 1-67, or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an IL-17A associated disease or condition. EXAMPLES

[0133] Compounds of Formula (I) of the present disclosure (including, e.g., compounds of any one of Formulae (I′), (II), (IIa), (IIb), (IIc), and / or (IIc)) and compounds disclosed herein can be prepared, for example, according to the following schemes. During any of the processes for preparation of the subject compounds, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis,” 4th ed., Wiley, New York 2006. For example, in some embodiments, a protecting group includes a benzyloxycarbonyl group or a tert- butyloxycarbonyl group as an amino-protecting group, and / or a tert-butylmethylsilyl group etc. as a hydroxy-protecting group. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0134] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes, unless otherwise specified, can be run at a temperature from about 0 °C to the reflux temperature of the organic solvent used. Each of variable sites disclosedAttorney Docket No.: 1537-US-NP / WO-PCT in the following schemes is applicable to every functional group in the compounds of Formula (I) (including, e.g., compounds of any one of Formulae (I′), (II), (IIa), (IIb), (IIc), and / or (IIc)) and compounds disclosed herein.

[0135] The embodiments are also directed to processes and intermediates useful for preparing the subject compounds or pharmaceutically acceptable salts thereof. General Reaction Scheme 1:

[0136] Compounds of the Formula (II) and compounds disclosed herein can be prepared according to General Synthetic Scheme 1.

[0137] In accordance with General Synthetic Scheme 1, a compound of the formula (2) may be produced by treating a compound of the formula (1) with tert-butyl carbamate, benzyl carbamate, or diphenylmethanimine in the presence of a suitable metal precatalyst (e.g. XantPhos Pd G3), or alternatively a precatalyst (e.g. Pd2(dba)3) combined with an appropriate ligand (e.g. XantPhos), with an appropriate base (e.g. Cs2CO3) in a suitable solvent (e.g.1,4- dioxane) at elevated temperature (e.g.100 °C). A compound of the formula (2) may beAttorney Docket No.: 1537-US-NP / WO-PCT subsequently treated with appropriate deprotection conditions (e.g. treatment with TFA for G1= NHBoc, treatment with Pd / C catalyst under an atmosphere of hydrogen for G1= NHCbz, or treatment with aqueous hydrochloric acid, citric acid, or hydroxylamine for G1= N=CPh2) to produce a compound of the formula (3). Alternatively, the described deprotection reaction may be carried out as part a work-up sequence following the first step, without isolation of a compound of the formula (2), such that a compound of the formula (3) is prepared directly from a compound of the formula (1). A compound of formula (1) can be purchased or readily synthesized through methods known to those skilled in the art. Additionally, a compound of the formula (3) can be purchased or readily synthesized through methods known to those skilled in the art.

[0138] Compounds of the formula (5) may be prepared by combining a compound of the formula (3) with a carboxylic acid of the formula (4) (e.g. Pg = Boc or Cbz), a suitable amide coupling reagent (e.g. HATU or T3P), and a base (e.g. DIPEA or TEA) in an appropriate solvent (e.g. DMF) at r.t. or elevated temperature. Compounds of the formula (5) can be subsequently treated with appropriate deprotection conditions (e.g. treatment with TFA for Pg = Boc, treatment with Pd / C catalyst under an atmosphere of hydrogen for Pg = Cbz) to produce a compound of the formula (6). Compounds of formula (4) can be purchased or readily synthesized through methods known to those skilled in the art.

[0139] Compounds of the formula (II) may be produced by combining compounds of the formula (6) with carboxylic acids of the formula (7), a suitable amide coupling reagent (e.g. HATU or T3P), and a base (e.g. DIPEA or TEA) in an appropriate solvent (e.g. DMF) at r.t. or elevated temperature. Compounds of formula (7) can be purchased or readily synthesized through methods known to those skilled in the art.

[0140] Further a compound of the present disclosure having a desired functional group at a desired position can be prepared by a suitable combination of the methods above, or a procedure usually carried out in an organic synthesis (for example, alkylation reaction of an amino group, oxidation reaction of an alkylthio group into a sulfoxide group or a sulfone group, converting reaction of an alkoxy group into a hydroxy group, or opposite converting reaction thereof).

[0141] Compounds as described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography (HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversedAttorney Docket No.: 1537-US-NP / WO-PCT phases as well as ionic resins. For example, disclosed compounds can be purified via silica gel chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd ed., ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, E. Stahl (ed.), Springer-Verlag, New York, 1969. Procedures for Some Intermediates and Examples

[0142] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 7th edition, Wiley- Interscience, 2013.)

[0143] Compounds were characterized using standard instrumentation methods. Identification of the compound was carried out by hydrogen nuclear magnetic resonance spectrum (1H-NMR) and mass spectrum (MS).1H-NMR was measured at 400 MHz, unless otherwise specified. In some cases, exchangeable hydrogen could not be clearly observed depending on the compound and measurement conditions. The designation br. or broad, used herein, refers to a broad signal. HPLC preparative chromatography was carried out by a commercially available ODS column in a gradient mode using water / MeCN (containing trifluoroacetic acid) as eluents, unless otherwise specified.

[0144] The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.

[0145] In the following description of the Examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure.

[0146] Representative syntheses of compounds of the present disclosure are described in schemes below, and the particular examples that follow.Attorney Docket No.: 1537-US-NP / WO-PCT

[0147] Step 1. To a stirred solution of (S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanoic acid (6500 mg, 21.4 mmol), methyl 5-amino-2,3-dihydro-1H-indene-1- carboxylate hydrochloride (5000 mg, 22.0 mmol), N,N-diisopropylethylamine (11.2 mL, 64.3 mmol), in DMF (100 mL) was added HATU (5550 mg, 23.6 mmol) in one portion. The mixture was stirred at room temperature for 16h and then diluted with aq.10% LiCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude solid was dissolved in DCM, and to the solution hexanes was added with stirring until a precipitate was observed. The solid was isolated by filtration and concentrated in vacuo to give methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate that was used in step 2 without further purification. ES / MS m / z: 477.3 [M+H]+.

[0148] Step 2. A mixture of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate (6280 mg, 13.2 mmol) and Palladium on carbon (10 wt%) (1400 mg, 1.32 mmol) in EtOH / THF (2:1, 150 mL) was sparged with H2 at room temperature for 20 mins and then stirred for 16h under an atmosphere of H2. The mixture was filtered through a pad of celite, which was rinsed with EtOAc. The eluent was concentrated in vacuo to yield methyl 5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3- dihydro-1H-indene-1-carboxylate which was used without further purification. ES / MS m / z: 343.2 [M+H]+.

[0149] Step 3. To a stirred solution of methyl 5-((S)-2-amino-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate (4520 mg, 13.2 mmol), 1- isopropyl-1H-pyrazole-5-carboxylic acid (4070 mg, 26.4 mmol), and N,N- diisopropylethylamine (9.20 mL, 52.8 mmol), in DMF (100 mL) was added HATU (6210 mg, 26.4 mmol) in one portion. The mixture was stirred at room temperature for 4h and then diluted with aq.10% LiCl and extracted with EtOAc. The combined organic layers were washed withAttorney Docket No.: 1537-US-NP / WO-PCT brine, dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give methyl 5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydro-1H-indene-1-carboxylate ES / MS m / z: 479.8 [M+H]+.

[0150] Step 4. To a solution of methyl 5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole- 5-carboxamido)propanamido)-2,3-dihydro-1H-indene-1-carboxylate (2729 mg, 5.7 mmol) in THF (61 mL) was added aq. LiOH (2 M, 11mmol). The mixture was stirred at room temperature for 16h and then diluted with 1 M HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 5-((S)- 3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-2,3-dihydro- 1H-indene-1-carboxylic acid (I-1) that was used without further purification. ES / MS m / z: 465.3 [M+H]+. Preparation of Intermediate I-2

[0151] 6-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-1-methylisochromane-1-carboxylic acid (I-2) was prepared in analogy to Intermediate I-1 using I-45 in place of methyl 5-amino-2,3-dihydro-1H-indene-1- carboxylate hydrochloride. ES / MS m / z: 495.2 [M+H]+.

[0152] Benzyl (S)-(1,1-dicyclopropyl-3-oxo-3-((5-oxo-5,6,7,8-tetrahydronaphthalen-2- yl)amino)propan-2-yl)carbamate (I-3) was prepared in analogy to Intermediate I-1, step 1 using 6-amino-3,4-dihydronaphthalen-1(2H)-one in place of methyl 5-amino-2,3-dihydro-1H- indene-1-carboxylate hydrochloride. ES / MS m / z: 447.2 [M +H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0153] Step 1. To a stirred solution of (S)-6-bromo-2,3-dihydrobenzofuran-3-amine hydrochloride (10 g, 40 mmol) in DCM was added Boc2O (10.5 g, 48 mmol), triethylamine (12.1 g, 120 mmol), and DMAP (490 mg, 4 mmol). The mixture was stirred at room temperature for 16h. The mixture was filtered and washed with DCM and the organics were concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated NH4Cl, then brine, dried over MgSO4, filtered, and concentrated in vacuo to afford tert-butyl (S)-(6-bromo-2,3- dihydrobenzofuran-3-yl)carbamate which was used without further purification. ES / MS m / z: 315.7 [M+H]+

[0154] Step 2. A mixture of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)carbamate (11 g, 35 mmol), diphenylmethanimine (9.52 g, 52.5 mmol), cesium carbonate (22.8 g, 70 mmol) in 1,4-dioxane (150 mL) was added XantPhos Pd G3 (332 mg, 0.35 mmol). The mixture was sparged with N2 for 5 minutes then heated to 100 °C for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO3 and brine, then concentrated in vacuo. The residue was taken up in THF and 20 mL of 1M HCl was added. The mixture was stirred for 3 hours before adding saturated NaHCO3 and extracting with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl (S)-(6-amino- 2,3-dihydrobenzofuran-3-yl)carbamate which was used without further purification. ES / MS m / z: 251.0 [M+H]+

[0155] Step 3. tert-Butyl ((S)-6-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-2,3-dihydrobenzofuran-3-yl)carbamate was prepared in analogy Intermediate I-1, step 1 using tert-butyl (S)-(6-amino-2,3-dihydrobenzofuran-3- yl)carbamate in place of methyl 5-amino-2,3-dihydro-1H-indene-1-carboxylate hydrochloride. ES / MS m / z: 536.2 [M+H]+Attorney Docket No.: 1537-US-NP / WO-PCT

[0156] Step 4. tert-Butyl ((S)-6-((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3- dihydrobenzofuran-3-yl)carbamate was prepared in analogy to Intermediate I-1, step 2 using Tert-butyl ((S)-6-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3- dihydrobenzofuran-3-yl)carbamate in place of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)- 3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 402.2 [M+H]+

[0157] Step 5. tert-Butyl ((S)-6-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydrobenzofuran-3-yl)carbamate was prepared in analogy to Intermediate I-1, step 3 using tert-butyl ((S)-6-((S)-2-amino-3,3- dicyclopropylpropanamido)-2,3-dihydrobenzofuran-3-yl)carbamate in place of methyl 5-((S)-2- amino-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 538.2 [M+H]+

[0158] Step 6. To a stirred solution tert-butyl ((S)-6-((S)-3,3-dicyclopropyl-2-(1-isopropyl- 1H-pyrazole-5-carboxamido)propanamido)-2,3-dihydrobenzofuran-3-yl)carbamate (7.83 g, 14.6 mmol) in 1,4-dioxanes was added a solution of HCl in 1,4-dixoanes (4M, 50 mL). The mixture was stirred for 3 hours before adding saturated NaHCO3 and extracting with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-((S)-1-(((S)-3-amino-2,3-dihydrobenzofuran-6-yl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-4). ES / MS m / z: 538.2 [M+H]+

[0159] Step 1.2-(tert-Butyl) 1-methyl 5-bromoisoindoline-1,2-dicarboxylate was prepared in analogy to Intermediate I-4, step 1 using methyl 5-bromoisoindoline-1-carboxylate in place of (S)-6-bromo-2,3-dihydrobenzofuran-3-amine hydrochloride. ES / MS m / z: 355.9 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0160] Step 2.2-(tert-Butyl) 1-methyl 5-aminoisoindoline-1,2-dicarboxylate was prepared in analogy to Intermediate I-4, step 2 using 2-(tert-butyl) 1-methyl 5-bromoisoindoline-1,2- dicarboxylate in place of tert-butyl (S)-(6-bromo-2,3-dihydrobenzofuran-3-yl)carbamate. ES / MS m / z: 293.7 [M+H]+.

[0161] Step 3.2-(tert-Butyl) 1-methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)isoindoline-1,2-dicarboxylate was prepared in analogy to Intermediate I-4, step 3 using 2-(tert-butyl) 1-methyl 5-aminoisoindoline-1,2-dicarboxylate in place of tert-butyl (S)-(6-amino-2,3-dihydrobenzofuran-3-yl)carbamate. ES / MS m / z: 578.3 [M+H]+.

[0162] Step 4.2-(tert-Butyl) 1-methyl 5-((S)-2-amino-3,3- dicyclopropylpropanamido)isoindoline-1,2-dicarboxylate was prepared in analogy to Intermediate I-1, step 2 using 2-(tert-butyl) 1-methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)- 3,3-dicyclopropylpropanamido)isoindoline-1,2-dicarboxylate in place of methyl 5-((S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1- carboxylate. ES / MS m / z: 444.3 [M+H]+.

[0163] Step 5.2-(tert-Butyl) 1-methyl 5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H- pyrazole-5-carboxamido)propanamido)isoindoline-1,2-dicarboxylate was prepared in analogy to Intermediate I-4, step 5 using 2-(tert-butyl) 1-methyl 5-((S)-2-amino-3,3- dicyclopropylpropanamido)isoindoline-1,2-dicarboxylate in place of tert-butyl ((S)-6-((S)-2- amino-3,3-dicyclopropylpropanamido)-2,3-dihydrobenzofuran-3-yl)carbamate. ES / MS m / z: 580.2 [M+H]+.

[0164] Step 6.2-(tert-Butoxycarbonyl)-5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H- pyrazole-5-carboxamido)propanamido)isoindoline-1-carboxylic acid was prepared in analogy to Intermediate I-1, step 4 using 2-(tert-butyl) 1-methyl 5-((S)-3,3-dicyclopropyl-2-(1- isopropyl-1H-pyrazole-5-carboxamido)propanamido)isoindoline-1,2-dicarboxylate in place methyl 5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-2,3- dihydro-1H-indene-1-carboxylate (I-5). ES / MS m / z: 566.2 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-6

[0165] 7-Bromo-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (I-6) was prepared in analogy to Intermediate I-4, step 1 using 7-bromo-1,2,3,4- tetrahydroisoquinoline-4-carboxylic acid in place of (S)-6-bromo-2,3-dihydrobenzofuran-3- amine hydrochloride. ES / MS m / z: 355.9 [M+H]+. Preparation of Intermediate I-7

[0166] Step 1. To a stirred solution of (1R)-5-bromoindan-1-amine hydrochloride (10000 mg, 40.2 mmol) and tert-butoxycarbonyl tert-butyl carbonate (10537 mg, 48.3 mmol) in DCM (128 mL) was added TEA (28.0 mL, 201 mmol). The mixture was stirred at room temperature for 16h and then diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give tert-butyl N-[(1R)-5-bromoindan-1-yl]carbamate ES / MS m / z: 313.8 [M+H]+.

[0167] Step 2. To a stirred solution of tert-butyl N-[(1R)-5-bromoindan-1-yl]carbamate (9324 mg, 29.9 mmol), benzyl carbamate (6772 mg, 44.8 mmol), and cesium carbonate (19461 mg, 59.7 mmol) in dioxane was added XPhos Pd G4 (2570 mg, 2.99 mmol) and the mixture was sparged with N2 at room temperature for 10 min. and then heated to 100°C and stirred for 16h. The mixture was cooled to room temperature, diluted with water, and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatographyAttorney Docket No.: 1537-US-NP / WO-PCT eluting with EtOAc in hexanes 0-100% to give tert-butyl N-[(1R)-5- (benzyloxycarbonylamino)indan-1-yl]carbamate ES / MS m / z: 383.2 [M+H]+.

[0168] Step 3. A mixture of tert-butyl N-[(1R)-5-(benzyloxycarbonylamino)indan-1- yl]carbamate (7673 mg, 20.1 mmol) and palladium on carbon (10 wt%) (2135 mg, 2.01 mmol) in EtOH (150 mL) was sparged with H2 at room temperature for 20 min and then stirred for 16h under an atmosphere of H2. The mixture was filtered through a pad of celite, which was rinsed with EtOAc. The eluent was concentrated in vacuo to yield tert-butyl N-[(1R)-5-aminoindan- 1-yl]carbamate which was used without further purification. ES / MS m / z: 249.1 [M+H]+.

[0169] Step 4. To a stirred solution of tert-butyl N-[(1R)-5-aminoindan-1-yl]carbamate (4982 mg, 20.1 mmol), (2R)-2-(benzyloxycarbonylamino)-3,3-dicyclopropyl-propanoic acid (9129 mg, 30.1 mmol), and TEA (5.59 mL, 40.1 mmol) in CH3CN (150 mL) was added HATU (9891 mg, 26.1 mmol) in one portion. The mixture was stirred at room temperature for 16h and then filtered and rinsed with CH3CN. The solid was dried to yield tert-butyl N-[(1R)-5-[[(2S)-2- (benzyloxycarbonylamino)-3,3-dicyclopropyl-propanoyl]amino]indan-1-yl]carbamate which was used without further purification. ES / MS m / z: 534.3 [M+H]+.

[0170] Step 5. A mixture of tert-butyl N-[(1R)-5-[[(2S)-2-(benzyloxycarbonylamino)-3,3- dicyclopropyl-propanoyl]amino]indan-1-yl]carbamate (10707 mg, 20.1 mmol) and palladium on carbon (10 wt%) (2140 mg, 2.01 mmol) in EtOH (142 mL) was sparged with H2 at room temperature for 20 min and then stirred for 16h under an atmosphere of H2. The mixture was filtered through a pad of celite, which was rinsed with EtOAc. The eluent was concentrated in vacuo to yield tert-butyl N-[(1R)-5-[[(2S)-2-amino-3,3-dicyclopropyl- propanoyl]amino]indan-1-yl]carbamate which was used without further purification. ES / MS m / z: 400.1 [M+H]+.

[0171] Step 6. To a stirred solution of tert-butyl N-[(1R)-5-[[(2S)-2-amino-3,3-dicyclopropyl- propanoyl]amino]indan-1-yl]carbamate (8020 mg, 20.1mmol), 2-isopropylpyrazole-3-carboxylic acid (4640 mg, 30.1 mmol), and TEA (5.6 mL, 40.1 mmol) in CH3CN (171 mL) was added HATU (11400 mg, 30.1 mmol) in one portion. The mixture was stirred at room temperature for 16h and then filtered and rinsed with CH3CN. The solid was dried to yield tert-butyl N-[(1R)- 5-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazole-3- carbonyl)amino]propanoyl]amino]indan-1-yl]carbamate which was used without further purification. ES / MS m / z: 536.3 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0172] Step 7. To a stirred solution of tert-butyl N-[(1R)-5-[[(2S)-3,3-dicyclopropyl-2-[(2- isopropylpyrazole-3-carbonyl)amino]propanoyl]amino]indan-1-yl]carbamate (6165 mg, 11.5 mmol) in DCM (50 mL) was added TFA (10 mL). The mixture was stirred at room temperature for 1h and then concentrated in vacuo. The residue was dissolved in DCM (50 mL), washed with saturated NaHCO3 solution, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with MeOH in DCM 0-100% to give N-[(1S)-1-[[(1R)-1-aminoindan-5-yl]carbamoyl]- 2,2-dicyclopropyl-ethyl]-2-isopropyl-pyrazole-3-carboxamide (I-7). ES / MS m / z: 459.3 [M+Na]+. Preparation of Intermediate I-8

[0173] Step 1. To a mixture of 5-bromo-1-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride (600 mg, 2.30 mmol) and tert-butyl (S)-4-(trifluoromethyl)-1,2,3-oxathiazolidine- 3-carboxylate 2,2-dioxide (998 mg, 3.43 mmol) in CH3CN (20 mL) was added triethylamine (0.955 mL, 6.86 mmol). The mixture was stirred at 35 °C for 16h. Additional tert-butyl (S)-4- (trifluoromethyl)-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (998 mg, 3.43 mmol) and triethylamine (0.955 mL, 6.86 mmol) were added to the mixture which was then stirred at 35 °C for 10h. After cooling to room temperature, the mixture was diluted with 2 M NaOH and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give ((2S)-3-((5-bromo-1-methyl-2,3-dihydro-1H-inden-1- yl)amino)-1,1,1-trifluoropropan-2-yl)(tert-butoxycarbonyl)sulfamic acid that was taken to step 2 without further purification ES / MS m / z: 438.2 [M+H, -SO3H]+.

[0174] Step 2. To a solution of ((2S)-3-((5-bromo-1-methyl-2,3-dihydro-1H-inden-1- yl)amino)-1,1,1-trifluoropropan-2-yl)(tert-butoxycarbonyl)sulfamic acid (999 mg, 2.28 mmol) in CH3CN (5 mL) was added 6 M HCl (5 mL) and stirred at room temperature for 3h. The mixture was diluted with 2N NaOH until pH 14 and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give (2S)-N1-(5-bromo-1-Attorney Docket No.: 1537-US-NP / WO-PCT methyl-2,3-dihydro-1H-inden-1-yl)-3,3,3-trifluoropropane-1,2-diamine that was taken to step 3 without further purification. ES / MS m / z: 338.8 [M+H,]+.

[0175] Step 3. To a solution of (2S)-N1-(5-bromo-1-methyl-2,3-dihydro-1H-inden-1-yl)- 3,3,3-trifluoropropane-1,2-diamine (772 mg, 2.28 mmol) in THF (25 mL) was added 1,1'- Carbonyldiimidazole (832 mg, 5.13 mmol). The mixture was stirred at 65 °C for 4h. The mixture was diluted with 2M aq. K2CO3 and the layers separated. The organic layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give (4S)-1-(5-bromo-1-methyl-2,3- dihydro-1H-inden-1-yl)-4-(trifluoromethyl)imidazolidin-2-one (I-8) ES / MS m / z: 364.8 [M+H]+.

[0176] (S)-1-((R)-7-Bromochroman-4-yl)-4-(trifluoromethyl)imidazolidin-2-one (I-9) was prepared in analogy to I-8 using (R)-7-bromochroman-4-amine in place of 5-bromo-1-methyl- 2,3-dihydro-1H-inden-1-amine hydrochloride. ES / MS m / z: 366.9 [M+H]+

[0177] (S)-1-((S)-6-Bromo-2,3-dihydrobenzofuran-3-yl)-4-(trifluoromethyl)imidazolidin- 2-one (I-10) was prepared in analogy to I-8 using (S)-6-bromo-2,3-dihydrobenzofuran-3-amine in place of 5-bromo-1-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride. ES / MS m / z: 351.0 [M+H]+Preparation of Intermediate I-11Attorney Docket No.: 1537-US-NP / WO-PCT

[0178] (R)-1-(5-Bromo-2,3-dihydro-1H-inden-1-yl)-3-(2,2,2-trifluoroethyl)urea (I-11). To a solution of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride (249 mg, 1.00 mmol) in DCM (10 mL) at 0 °C was added a 15% solution of phosgene in toluene (1.43 mL, 2.00 mmol). The mixture was stirred for 30 min before adding Hünig’s base (0.35 mL, 2.04 mmol). The mixture was stirred 15 min then concentrated in vacuo. The crude residue was dissolved in DCM (10 mL), cooled to 0 °C before adding 2,2,2-trifluoroethanamine hydrochloride (339 mg, 2.50 mmol) and Hünig’s base (0.35 mL, 2.04 mmol). The mixture was stirred for 16 h, then filtered to yield a precipitate that was washed with DCM and dried under vacuum to give I-11. ES / MS m / z: 336.9 [M+H]+Preparation of Intermediate I-12

[0179] (S)-1-(6-Bromo-2,3-dihydrobenzofuran-3-yl)-3-(2,2,2-trifluoroethyl)urea (I-12). I- 12 was prepared in analogy to I-11 using (S)-6-bromo-2,3-dihydrobenzofuran-3-amine in place of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride. ES / MS m / z: 340.0 [M+H]+Preparation of Intermediate I-13

[0180] Step 1. To a stirred solution of NaBH3CN (313 mg, 5.0 mmol) in MeOH (7.4 mL) was added ZnCl2 (1.3 mL, 2.5 mmol). The mixture was allowed to stir at room temperature for 10 min. 8-bromo-3,4-dihydro-2H-1-benzoxepin-5-one (300 mg, 1.2 mmol), (2S)-3,3,3- trifluoropropane-1,2-diamine dihydrochloride (500mg, 2.5 mmol), and TEA (0.35 mL, 2.5 mmol) were dissolved in MeOH (3 mL) and added to the stirred solution of NaBH3CN and ZnCl2. The mixture was heated to 60°C and allowed to stir 3h, then concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give (2S)-N1-(8-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)-3,3,3-trifluoro- propane-1,2-diamine. ES / MS m / z: 353.0.

[0181] Step 2. To a stirred solution of (2S)-N1-(8-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5- yl)-3,3,3-trifluoro-propane-1,2-diamine (264 mg, 0.75 mmol) in THF (6.5 mL) was added CDI (242 mg, 1.5 mmol). The mixture was heated to 65°C and allowed to stir 3h, concentrated inAttorney Docket No.: 1537-US-NP / WO-PCT vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give (4S)-1-(8-bromo-2,3,4,5-tetrahydro-1-benzoxepin-5-yl)-4- (trifluoromethyl)imidazolidin-2-one (I-13). ES / MS m / z: 379.0. Preparation of Intermediate I-14

[0182] (S)-1-((R)-5-Bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)-4- (trifluoromethyl)imidazolidin-2-one (I-14) was prepared in analogy to I-13 using 5-bromo-6- fluoro-indan-1-one in place of 8-bromo-3,4-dihydro-2H-1-benzoxepin-5-one. Diastereomers were separated during purification by SiO2 column chromatography eluting with hexanes and ethyl acetate to give the product tentatively assigned as (S)-1-((R)-5-bromo-6-fluoro-2,3- dihydro-1H-inden-1-yl)-4-(trifluoromethyl)imidazolidin-2-one (I-14). Preparation of Intermediate I-15

[0183] Benzyl ((S)-1,1-dicyclopropyl-3-oxo-3-(((R)-5-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-yl)amino)propan-2- yl)carbamate (I-15) was prepared in analogy to I-13 using I-3 in place of 8-bromo-3,4-dihydro- 2H-1-benzoxepin-5-one. Diastereomers were separated during purification by SiO2 column chromatography (eluting with EtOAc in hexanes 0-100%; the product tentatively assigned as benzyl ((S)-1,1-dicyclopropyl-3-oxo-3-(((R)-5-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)-5,6,7,8-tetrahydronaphthalen-2-yl)amino)propan-2-yl)carbamate (I-15) was the second- eluting diastereomer of product). ES / MS m / z: 607.2 [M +Na]+. Preparation of Intermediates I-16 and I-17

[0184] Step 1. (2S)-N1-(5-Bromo-2,3-dihydro-1H-inden-1-yl)-3,3,3-trifluoropropane-1,2- diamine. To a stirred solution of 5-bromo-2,3-dihydro-1H-inden-1-one (150 mg, 0.711 mmol),Attorney Docket No.: 1537-US-NP / WO-PCT (S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (109 mg, 0.853 mmol), triethylamine (0.30 mL, 2.1 mmol), in 1,2-dichlorethane (6 mL) was added titanium tetraisopropoxide (0.42 mL, 1.4 mmol). The mixture was stirred at 50 °C for 5 hours, cooled to room temperature, and then acetic acid (0.20 mL, 3.6 mmol), sodium cyanoborohydride (134 mg, 2.13 mmol) and methanol (0.78 mL, 19.2 mmol) were added. The resulting mixture was stirred at 50 °C for 18 hours, then cooled to room temperature, and saturated aqueous sodium bicarbonate was added. The slurry was filtered through diatomaceous earth, and the filter pad was washed several times with ethyl acetate. The filtered organic phase was separated, and the aqueous phase was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give (2S)-N1-(5-bromo-2,3-dihydro-1H-inden-1-yl)- 3,3,3-trifluoropropane-1,2-diamine which was used without further purification. ES / MS m / z: 325.0.

[0185] Step 2. (S)-1-((S)-5-Bromo-2,3-dihydro-1H-inden-1-yl)-4- (trifluoromethyl)imidazolidin-2-one (I-16) and (S)-1-((R)-5-bromo-2,3-dihydro-1H-inden- 1-yl)-4-(trifluoromethyl)imidazolidin-2-one (I-17). To a stirred solution of (2S)-N1-(5-bromo- 2,3-dihydro-1H-inden-1-yl)-3,3,3-trifluoropropane-1,2-diamine (230 mg, 0.711 mmol) in tetrahydrofuran (10 mL) at 65 °C was added CDI (462 mg, 2.85 mmol). The mixture was stirred at 65 °C for 3 hours, cooled to room temperature, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography with EtOAc in hexanes 0-100% to give the product tentatively assigned as (S)-1-((S)-5-bromo-2,3-dihydro-1H-inden-1-yl)-4- (trifluoromethyl)imidazolidin-2-one (I-16) (ES / MS m / z: 350.9 [M+H]+) as the first-eluting diastereomer and the product tentatively assigned as (S)-1-((R)-5-bromo-2,3-dihydro-1H- inden-1-yl)-4-(trifluoromethyl)imidazolidin-2-one (I-17) (ES / MS m / z: 350.9 [M+H]+) as the second-eluting diastereomer. Preparation of Intermediate I-18

[0186] Step 1. To a solution of 7-bromoisochromane-4-carboxylic acid (500 mg, 1.94 mmol) in methanol (5 mL) at 0 °C was added chlorotrimethylsilane (1.23 mL, 9.72 mmol). The mixture was stirred for 16 h, allowing to warm to room temperature then concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give methyl 6-bromoisochromane-1-carboxylate. ES / MS m / z: 270.9 [M+H]+Attorney Docket No.: 1537-US-NP / WO-PCT

[0187] Step 2. To a solution of methyl 6-bromoisochromane-1-carboxylate (520 mg, 1.92 mmol) in THF (15 mL) at 0 °C was added sodium hydride (147 mg, 3.48 mmol). The mixture was stirred for 1 hour, then iodomethane (0.36 mL, 5.75 mmol) was added and the mixture was stirred for 16 hours, allowing to warm to room temperature. The mixture was cooled to 0 °C before adding saturated NH4Cl and extracting with EtOAc. The combined organic layers were washed with water, then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give methyl 6-bromo-1-methylisochromane-1-carboxylate (I-18). ES / MS m / z: 286.1 [M+H]+Preparation of Intermediate I-19

[0188] In a 40 mL vial, THF (3.5 mL) was cooled to -78°C with stirring and LDA (0.88 mL, 0.88 mmol) was added dropwise. To the cooled mixture of LDA was added a solution of methyl 5-bromoindane-1-carboxylate (150 mg, 0.59 mmol) in THF (1 mL) dropwise over 15 min. The mixture was stirred for 1h then paraformaldehyde (132 mg, 1.5 mmol) was added. The mixture was warmed to 0°C and allowed to stir for 30 min. The mixture was quenched with saturated aq. NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give methyl 5- bromo-1-(hydroxymethyl)indane-1-carboxylate (I-19). ES / MS m / z: 284.9 [M+H]+.

[0189] Step 1. To a stirred solution of 2-(5-chloro-1,3-dihydroisobenzofuran-1-yl)acetic acid (213 mg, 1.00 mmol), 2,2,2-Trifluoroethylamine hydrochloride (149 mg, 1.10 mmol), N,N- diisopropylethylamine (0.52 mL, 3.00 mmol), in DMF (5 mL) was added HATU (282 mg, 1.2 mmol) in one portion. The mixture was stirred at room temperature for 16 h and then diluted with aq.10% LiCl and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purifiedAttorney Docket No.: 1537-US-NP / WO-PCT using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give 2-(5-chloro- 1,3-dihydroisobenzofuran-1-yl)-N-(2,2,2-trifluoroethyl)acetamide. ES / MS m / z: 294.3 [M+H]+.

[0190] Step 2. A mixture of 2-(5-chloro-1,3-dihydroisobenzofuran-1-yl)-N-(2,2,2- trifluoroethyl)acetamide (187 mg, 0.64 mmol), diphenylmethanimine (173 mg, 0.96 mmol), cesium carbonate (415 mg, 1.27 mmol) in 1,4-dioxane (4 mL) was added XantPhos Pd G3 (30 mg, 0.032 mmol). The mixture was sparged with N2 for 5 minutes then heated to 100 °C for 16 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and washed with saturated NaHCO3 and brine, then and concentrated in vacuo. The residue was take up in THF and 20 mL of 1M HCl was added. The mixture was stirred for 3 hours before adding saturated NaHCO3 and extracting with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give 2-(5-amino-1,3-dihydroisobenzofuran-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (I-20), which was used without further purification. ES / MS m / z: 275.0 [M+H]+

[0191] 7-Amino-N-(2,2,2-trifluoroethyl)chromane-4-carboxamide (I-21) was prepared in analogy to I-20 using 7-bromochromane-4-carboxylic acid in place of 2-(5-chloro-1,3- dihydroisobenzofuran-1-yl)acetic acid. ES / MS m / z: 274.4 [M+H]+Preparation of Intermediate I-

[0192] 2-(5-Amino-2,3-dihydro-1H-inden-1-yl)-N-(2,2,2-trifluoroethyl)acetamide (I-22) was prepared in analogy to I-20 using 2-(5-bromo-2,3-dihydro-1H-inden-1-yl)acetic acid in place of 2-(5-chloro-1,3-dihydroisobenzofuran-1-yl)acetic acid.. m / z 273.6 [M+H]+Attorney Docket No.: 1537-US-NP / WO-PCT

[0193] 6-Amino-N-(2,2,2-trifluoroethyl)isochromane-1-carboxamide (I-23) was prepared in analogy to I-20 using 6-bromoisochromane-1-carboxylic acid in place of 2-(5-chloro-1,3- dihydroisobenzofuran-1-yl)acetic acid.. ES / MS m / z: 275.0 [M+H]+Preparation of Intermediate I-

[0194] 5-Amino-1-methyl-N-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-indene-1-carboxamide (I-24) was prepared in analogy to I-20 using 5-bromo-1-methyl-indane-1-carboxylic acid in place of 2-(5-chloro-1,3-dihydroisobenzofuran-1-yl)acetic acid.

[0195] tert-Butyl (5-amino-1-((2,2,2-trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-1- yl)carbamate (I-25) was prepared analogy to I-20 using 5-bromo-1-(tert- butoxycarbonylamino)indane-1-carboxylic acid in place of 2-(5-chloro-1,3- dihydroisobenzofuran-1-yl)acetic acid in step 1 and using 10% aqueous citric acid solution in place of 1M HCl in step 2. ES / MS m / z: 396.1 [M+H]+Preparation of Intermediate I-Attorney Docket No.: 1537-US-NP / WO-PCT

[0196] tert-Butyl 7-amino-4-((2,2,2-trifluoroethyl)carbamoyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate (I-26) was prepared analogy to I-20 using I-6 in place of 2-(5-chloro-1,3- dihydroisobenzofuran-1-yl)acetic acid. ES / MS m / z: 374.0 [M+H]+Preparation of Intermediate I-27

[0197] To a mixture of 6-aminotetralin-1-carboxylic acid (50.0 mg, 0.000261 mol), 2,2,2- trifluoroethanamine (0.129 g, 0.00131 mol), and HATU (0.150 g, 0.000392 mol) in a vial was added DMF (1.86 mL) and Hünigs Base (0.329 mL, 0.00183 mol). The mixture was stirred for 1 h, then water and EtOAc were added. The layers were separated and the organic layer concentrated in vacuo to afford crude product. The crude residue was purified using SiO2 column chromatography eluting with methanol in dichloromethane 0-30% to afford 6-amino-N- (2,2,2-trifluoroethyl)tetralin-1-carboxamide (I-27). ES / MS m / z: 295.1 [M+Na]+.

[0198] Step 1. tert-Butyl (R)-((1-(((5-bromo-2,3-dihydro-1H-inden-1- yl)amino)methyl)cyclopropyl)methyl)carbamate. To a stirred mixture of (R)-5-bromo-2,3- dihydro-1H-inden-1-amine (500 mg, 2.36 mmol) and tert-butyl ((1- formylcyclopropyl)methyl)carbamate (I-61) (470 mg, 2.36 mmol) in dichloromethane (10 mL) was added triethylamine (0.82 mL, 5.9 mmol). The resulting mixture was stirred for 1.5 hours at 40 °C before it was cooled to room temperature and sodium cyanoborohydride (444 mg, 7.07 mmol), methanol (3.8 mL, 94 mmol), and acetic acid (0.67 mL, 12 mmol) were added. The resulting mixture was stirred overnight, 3M aqueous potassium carbonate was added, and the mixture was extracted with dichloromethane. The organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo to provide a crude residue which was purified using SiO2 column chromatography eluting with methanol in dichloromethane 0-20% to give tert-Attorney Docket No.: 1537-US-NP / WO-PCT butyl (R)-((1-(((5-bromo-2,3-dihydro-1H-inden-1- yl)amino)methyl)cyclopropyl)methyl)carbamate. ES / MS m / z: 396.9 [M+H]+.

[0199] Step 2. (R)-N-((1-(Aminomethyl)cyclopropyl)methyl)-5-bromo-2,3-dihydro-1H- inden-1-amine. A mixture of tert-butyl (R)-((1-(((5-bromo-2,3-dihydro-1H-inden-1- yl)amino)methyl)cyclopropyl)methyl)carbamate (824 mg, 2.08 mmol) and trifluoroacetic acid (8 mL) in dichloromethane (10 mL) was stirred for 1 hour before it was concentrated in vacuo, taken up with 3M aqueous potassium carbonate, and extracted with ethyl acetate. The organics were dried over MgSO4, filtered, and concentrated in vacuo to furnish (R)-N-((1- (aminomethyl)cyclopropyl)methyl)-5-bromo-2,3-dihydro-1H-inden-1-amine that was used without further purification. ES / MS m / z: 296.9 [M+H]+.

[0200] Step 3. (R)-5-(5-Bromo-2,3-dihydro-1H-inden-1-yl)-5,7-diazaspiro[2.5]octan-6-one (I-28). CDI (844 mg, 5.21 mmol) was added to a stirred solution of (R)-N-((1- (aminomethyl)cyclopropyl)methyl)-5-bromo-2,3-dihydro-1H-inden-1-amine (615 mg, 2.08 mmol) in tetrahydrofuran (25 mL) at 65 °C. The resulting mixture was stirred for 3 hours before it was cooled to room temperature, concentrated, and purified using SiO2 column chromatography eluting with ethyl acetate in dichloromethane 0-100% to give (R)-5-(5-bromo- 2,3-dihydro-1H-inden-1-yl)-5,7-diazaspiro[2.5]octan-6-one (I-28). ES / MS m / z: 322.4 [M+H]+.

[0201] Step 1. A mixture of 4-bromo-1-fluoro-2-nitrobenzene (150 g, 680 mmol) in DMF (750 mL) was treated with K2CO3 (126 g, 910 mmol) at 0 °C. Dimethyl malonate (147 mL, 1.29 mol) was then added, and the mixture was stirred at r.t. for 16 h. The mixture was diluted with saturated aqueous NH4Cl solution and further diluted with water. The resulting solids were isolated by filtration to afford dimethyl 2-(4-bromo-2-nitrophenyl)malonate. ES / MS m / z: 331.9 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0202] Step 2. A mixture of dimethyl 2-(4-bromo-2-nitrophenyl)malonate (190 g, 570 mmol) in DMF (950 mL) was treated with Cs2CO3 (279 g, 850 mmol) at 0 °C. After stirring for 10 min, iodomethane (162 g, 1.13 mol) was added, and the mixture was stirred for 30 min before being warmed to 15 °C and stirred for an additional 16 h. The mixture was then poured into saturated aqueous NH4Cl, and the resulting solids isolated by filtration to afford dimethyl 2-(4-bromo-2- nitrophenyl)-2-methylmalonate.

[0203] Step 3. A mixture of dimethyl 2-(4-bromo-2-nitrophenyl)-2-methylmalonate (190 g, 540 mmol) in AcOH (1.7 L) was treated with iron powder slowly and with stirring at 100 °C. The mixture was stirred for an additional 3 h at 100 °C, then filtered while hot, washing the filter cake with DCM followed by MeOH. The filtrate was treated with saturated aqueous NaHCO3solution, then extracted three times with DCM. The combined organic layers were washed four times with water, then brine, and concentrated in vacuo to afford methyl 6-bromo-3-methyl-2- oxoindoline-3-carboxylate. ES / MS m / z: 283.9 [M+H]+.

[0204] Step 4. Methyl 6-bromo-3-methyl-2-oxoindoline-3-carboxylate (67.0 g, 235 mmol) was subjected to chiral SFC (Column: OJ-H 250 mm x 50 mm, 10 mm, eluent: 25% MeOH (0.1% NH3·H2O)) to afford two peaks. Fractions corresponding to the first peak were concentrated in vacuo to afford the product tentatively assigned as methyl (R)-6-bromo-3- methyl-2-oxoindoline-3-carboxylate (I-29). ES / MS m / z: 283.9 [M+H]+. Fractions corresponding to the second peak were concentrated in vacuo to afford the product tentatively assigned as methyl (S)-6-bromo-3-methyl-2-oxoindoline-3-carboxylate (I-30). ES / MS m / z: 283.9 [M+H]+. Preparation of Intermediate I-31

[0205] Methyl (S)-6-bromo-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline- 3-carboxylate. To a round bottom flask, I-30 (1500 mg, 0.00528 mol) and K2CO3 (3.65 g, 0.0264 mol) in DMF (15.0 mL) were cooled to 0 °C.2-(Trimethylsilyl)ethoxymethyl chloride (2.64 g, 0.0158 mol) was added dropwise. The mixture was stirred at 0 °C for 30min then allowed to warm to room temperature and stirred for 1hr. To the mixture, EtOAc was added and the resulting solid filtered off. Filtrate was washed with water and concentrated in vacuo. TheAttorney Docket No.: 1537-US-NP / WO-PCT crude residue was purified using SiO2 column chromatography eluting with Ethyl acetate in Hexanes 0-100% to afford product I-31. ES / MS m / z: 436.0 [M+Na]+. Preparation of Intermediate I-32

[0206] Methyl (R)-6-bromo-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline- 3-carboxylate (I-32) was prepared in analogy to I-31 using I-29 in place of I-30. ES / MS m / z: 436.0 [M+Na]+. Preparation of Intermediate I-33

[0207] Methyl (S)-6-bromo-1,3-dimethyl-2-oxoindoline-3-carboxylate (I-33) was prepared in analogy to I-31 using iodomethane in place of 2-(Trimethylsilyl)ethoxymethyl Chloride. ES / MS m / z: 320.0 [M+Na]+.

[0208] Step 1.6-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline-2,3-dione was prepared in analogy to I-31 using 6-bromoindoline-2,3-dione carboxylate in place of methyl (3R)-6-bromo-3-methyl-2-oxo-indoline-3-carboxylate. ES / MS m / z: 378.2 [M+Na]+.

[0209] Step 2: To a vial, 6-bromo-1-(2-trimethylsilylethoxymethyl)indoline-2,3-dione (300 mg, 0.000842 mol) was dissolved in THF (5.00 mL) and cooled to 0 ºC. With stirring, MeMgBr (3400 mmol / L, 0.297 mL, 0.00101 mol) was added. The mixture was stirred for 3h and thenAttorney Docket No.: 1537-US-NP / WO-PCT quenched with sat. aq. NH4Cl and extracted with EtOAc. The combined organic layer was washed with water and brine. Concentrated and purified using SiO2 column chromatography eluting with Hex EtOAc (0-100%) to afford the desired product 6-bromo-3-hydroxy-3-methyl- 1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one. ES / MS m / z: 394.0 [M +Na]+.

[0210] Step 3: To a stirred mixture of 6 -bromo-3-hydroxy-3-methyl-1-(2- trimethylsilylethoxymethyl)indolin-2-one (850 mg, 0.00228 mol) in THF (20 mL) at 0 °C, PBr3 (1000 mmol / L, 2.28 mL, 0.00228 mol) was added. The mixture was then warmed to room temperature and stirred for 1h. The mixture was quenched by addition of H2O and extracted with EtOAc. The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduce pressure. the residue was purified using SiO2column chromatography eluting with (Hexane / ethyl acetate 0 to 100% to afford the product 3,6-dibromo-3-methyl-1-((2- (trimethylsilyl)ethoxy)methyl)indolin-2-one. ES / MS m / z: 456.0 [M +Na]+.

[0211] Step 4: To a vial, 3,6-dibromo-3-methyl-1-(2-trimethylsilylethoxymethyl)indolin-2- one (100 mg, 0.000230 mol) and (2S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride (0.350 g, 0.00174 mol) were charged followed by K2CO3 (0.476 g, 0.00345 mol). CH3CN (3.00 mL) was added and the mixture stirred at room temperature for 16h. The solid was removed by filtration and the eluent concentrated in vacuo, the crude was purified using SiO2 column chromatography eluting with (DCM:MeOH; 0-20%) to afford 3-(((S)-2-amino-3,3,3- trifluoropropyl)amino)-6-bromo-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2- one. ES / MS m / z: 482.1 [M +H]+.

[0212] Step 5 : (S)-6-Bromo-3-methyl-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)- 1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one (I-34) was prepared in analogy to Intermediate I-13, Step-2 using 3-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-6-bromo-3- methyl-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one in place of (2S)-N1-(8-bromo- 2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-3,3,3-trifluoropropane-1,2-diamine. Diastereomers were separated during purification by SiO2 column chromatography (EtOAc in hexanes 0-100%) to give the product tentatively assigned as (S)-6-bromo-3-methyl-3-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one (I-34) as the first-eluting diastereomer. ES / MS m / z: 530.1 [M +H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-35

[0213] Step 1. To a mixture of I-8 (383 mg, 1.05 mmol), Tris(dibenzylideneacetone)dipalladium(0) (96.6 mg, 0.105 mmol), 4,5-Bis(diphenylphosphino)- 9,9-dimethylxanthene (122 mg, 0.211 mmol), diphenylmethanimine (287 mg, 1.58 mmol), and Cs2CO3 (1031 mg, 3.16 mmol) was added 1,4-dioxane (15 mL). The mixture was sparged with Ar and then heated to 100 °C and stirred for 2 h. After cooling to room temperature, the mixture was diluted with sat. aq. NaHCO3 then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give (4S)-1-(5- ((diphenylmethylene)amino)-1-methyl-2,3-dihydro-1H-inden-1-yl)-4- (trifluoromethyl)imidazolidin-2-one. ES / MS m / z: 464.2 [M+H]+.

[0214] Step 2. A mixture of (4S)-1-(5-((diphenylmethylene)amino)-1-methyl-2,3-dihydro-1H- inden-1-yl)-4-(trifluoromethyl)imidazolidin-2-one (339 mg, 0.731 mmol), KOAc (431 mg, 4.39 mmol), hydroxylamine hydrochloride (204 mg, 2.94 mmol) in 1,4-dioxane (9 mL) was stirred at 30 °C for 16h. Upon cooling to room temperature, the mixture was diluted with sat. aq. NaHCO3 then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give (4S)-1-(5-amino-1-methyl-2,3-dihydro-1H-inden-1-yl)-4- (trifluoromethyl)imidazolidin-2-one (I-35) that was used without further purification. ES / MS m / z: 299.9 [M+H]+.

[0215] (S)-6-Amino-3-methyl-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)indolin-2-one (I-36) was prepared in analogy to Intermediate I-20, step 2 using I-34 in place of 2-(5-chloro-1,3-dihydroisobenzofuran-1-yl)-N-(2,2,2- trifluoroethyl)acetamide. ES / MS m / z: 467.2 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-37

[0216] (S)-1-((R)-5-Amino-6-fluoro-2,3-dihydro-1H-inden-1-yl)-4- (trifluoromethyl)imidazolidin-2-one (I-37). To a vial containing I-14 (367 mg, 1.00 mmol), was added diphenylmethanimine (0.252 mL, 1.50 mmol), cesium carbonate (977 mg, 3.00 mmol), XantPhos Pd G3 (47 mg, 0.05 mmol) and 1,4-dioxane (10 mL) and the mixture was heated to 100 °C for 4h. After cooling to room temperature, the mixture was diluted with sat. aq. NaHCO3 then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100%. Evaporation of the appropriate fractions provided a residue which was treated with 1,4-dioxane (20 mL) and 1N HCl (5 mL) for 4h. The mixture was diluted with ethyl acetate and neutralized with 1N NaOH (5 mL). The layers were separated and the aqueous layer further extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to give I-37 that used without further purification. ES / MS m / z: 299.9 [M+H]+. Preparation of Intermediate I-38

[0217] (S)-1-((S)-5-Amino-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethyl)imidazolidin-2- one (I-38) was prepared in analogy to I-37 using I-16 in place of I-14. ES / MS m / z: 286.0[M+H]+. Preparation of Intermediate I-39

[0218] (S)-1-((R)-5-Amino-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethyl)imidazolidin-2- one (I-39). I-39 was prepared in analogy to I-37 using I-17 in place of I-14. ES / MS m / z: 286.0 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-40

[0219] (S)-1-((R)-7-Aminochroman-4-yl)-4-(trifluoromethyl)imidazolidin-2-one (I-40) was prepared in analogy to I-37 using I-9 in place of I-14. ES / MS m / z: 302.0 [M+H]+Preparation of Intermediate I-

[0220] (S)-1-((S)-6-Amino-2,3-dihydrobenzofuran-3-yl)-4-(trifluoromethyl)imidazolidin- 2-one (I-41) was prepared in analogy to I-37 using I-10 in place of I-14. ES / MS m / z: 288.3 [M+H]+Preparation of Intermediate I-42

[0221] (S)-1-((S)-8-Amino-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-4- (trifluoromethyl)imidazolidin-2-one (I-42) was prepared in analogy to I-37 using I-13 in place of I-14. ES / MS m / z: 316.1 [M+H]+Preparation of Intermediate I-43

[0222] (R)-1-(5-Amino-2,3-dihydro-1H-inden-1-yl)-3-(2,2,2-trifluoroethyl)urea (I-43) was prepared in analogy to I-37 using I-11 in place of I-14. ES / MS m / z:[M+H]+Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-44

[0223] (S)-1-(6-Amino-2,3-dihydrobenzofuran-3-yl)-3-(2,2,2-trifluoroethyl)urea (I-44) was prepared in analogy to I-37 using I-12 in place of I-14. ES / MS m / z: 276.0 [M+H]+Preparation of Intermediate I-45

[0224] Methyl 6-amino-1-methylisochromane-1-carboxylate (I-45) was prepared in analogy to I-37 using I-12 in place of I-14. ES / MS m / z: 222.1 [M+H]+Preparation of Intermediate I-46

[0225] Methyl 5-amino-1-(hydroxymethyl)indane-1-carboxylate (I-46) was prepared in analogy to I-37 using I-19 in place of I-14. ES / MS m / z: 222.0 [M+H]+Preparation of Intermediate I-47

[0226] tert-Butyl (5-amino-1-((2,2,2-trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-1- yl)carbamate (I-47) was prepared in analogy to I-37 using I-31 in place of I-14. ES / MS m / z: 351.1 [M+H]+Preparation of Intermediate I-48Attorney Docket No.: 1537-US-NP / WO-PCT

[0227] Methyl (R)-6-amino-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline- 3-carboxylate (I-48) was prepared in analogy to I-37 using I-32 in place of I-14. ES / MS m / z: 351.1 [M+H]+Preparation of Intermediate I-49

[0228] Methyl (S)-6-amino-1,3-dimethyl-2-oxoindoline-3-carboxylate (I-49) was prepared in analogy to I-37 using I-33 in place of I-14. ES / MS m / z: 235.0 [M+H]+Preparation of Intermediate I-50

[0229] (R)-5-(5-Amino-2,3-dihydro-1H-inden-1-yl)-5,7-diazaspiro[2.5]octan-6-one (I-50)was prepared in analogy to I-37 using I-28 in place of I-14. ES / MS m / z: m / z 258.1 [M+H]+of Intermediate I-51

[0230] Step 1. tert-Butyl 7-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-4-((2,2,2-trifluoroethyl)carbamoyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate was prepared in analogy to Intermediate I-1, step 1 using I-26 in place of methyl 5-amino-2,3-dihydro-1H-indene-1-carboxylate hydrochloride. ES / MS m / z: 659.3 [M+H]+.

[0231] Step 2. tert-Butyl 7-((S)-2-amino-3,3-dicyclopropylpropanamido)-4-((2,2,2- trifluoroethyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was prepared inAttorney Docket No.: 1537-US-NP / WO-PCT analogy to Intermediate I-1, step 2 using tert-butyl 7-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-4-((2,2,2-trifluoroethyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)- carboxylate in place of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 525.1 [M+H]+.

[0232] Step 6. tert-Butyl 7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-4-((2,2,2-trifluoroethyl)carbamoyl)-3,4-dihydroisoquinoline- 2(1H)-carboxylate was prepared in analogy to Intermediate I-1, step 3 using tert-butyl 7-((S)- 2-amino-3,3-dicyclopropylpropanamido)-4-((2,2,2-trifluoroethyl)carbamoyl)-3,4- dihydroisoquinoline-2(1H)-carboxylate in place of methyl 5-((S)-2-amino-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate (I-51). ES / MS m / z: 661.3 [M+H]+. Preparation of Intermediate I-52

[0233] 5-[[(2S)-3,3-Dicyclopropyl-2-[(2-isopropylpyrazole-3- carbonyl)amino]propanoyl]amino]-1-(hydroxymethyl)indane-1-carboxylic acid (I-52) was prepared in analogy to I-1 using I-46 in place of methyl 5-amino-2,3-dihydro-1H-indene-1- carboxylate hydrochloride. ES / MS m / z: 495.2 [M+H]+.

[0234] Step 1. Benzyl ((2S)-1,1-dicyclopropyl-3-oxo-3-((1-((2,2,2- trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)carbamate was prepared in analogy to Intermediate I-1, Step 1 using I-25 in place of methyl 5-amino-2,3- dihydro-1H-indene-1-carboxylate hydrochloride. ES / MS m / z: 681.3 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0235] Step 2. tert-Butyl (5-((S)-2-amino-3,3-dicyclopropylpropanamido)-1-((2,2,2- trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-1-yl)carbamate was prepared in analogy to Intermediate I-1, Step 2 using benzyl ((2S)-1,1-dicyclopropyl-3-oxo-3-((1-((2,2,2- trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)carbamate in place of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H- indene-1-carboxylate. ES / MS m / z: 547.2 [M+Na]+.

[0236] Step 3. tert-Butyl (5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-1-((2,2,2-trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-1- yl)carbamate (I-53) was prepared in analogy to Intermediate I-1, step 3 using tert-butyl (5- ((S)-2-amino-3,3-dicyclopropylpropanamido)-1-((2,2,2-trifluoroethyl)carbamoyl)-2,3-dihydro- 1H-inden-1-yl)carbamate in place of methyl 5-((S)-2-amino-3,3-dicyclopropylpropanamido)- 2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 683.3 [M+Na]+. Preparation of Intermediate I-54

[0237] Methyl (S)-6-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline- 3-carboxylate (I-54) was prepared in analogy to Intermediate I-1, Step 1 using I-47 in place of methyl 5-amino-2,3-dihydro-1H-indene-1-carboxylate hydrochloride. ES / MS m / z: 658.3.1 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-55

[0238] Step 1. Methyl (S)-6-((S)-2-amino-3,3-dicyclopropylpropanamido)-3-methyl-2- oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline-3-carboxylate was prepared in analogy to Intermediate I-1, Step 2 using I-54 in place of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)- 3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 524.2 [M+H]+.

[0239] Step 2. Methyl (S)-6-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline- 3-carboxylate (I-55) was prepared in analogy to Intermediate I-1, step 3 using Methyl (S)-6- ((S)-2-amino-3,3-dicyclopropylpropanamido)-3-methyl-2-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)indoline-3-carboxylate in place of methyl 5-((S)-2-amino-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 638.3 [M+H]+. Preparation of Intermediate I-56Attorney Docket No.: 1537-US-NP / WO-PCT

[0240] Step 1. Methyl (R)-6-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline- 3-carboxylate was prepared in analogy to Intermediate I-1, Step 1 using I-48 in place of methyl 5-amino-2,3-dihydro-1H-indene-1-carboxylate hydrochloride. ES / MS m / z: 658.3 [M+Na]+.

[0241] Step 2. Methyl (R)-6-((S)-2-amino-3,3-dicyclopropylpropanamido)-3-methyl-2- oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline-3-carboxylate was prepared in analogy to Intermediate I-1, Step 2 using Methyl (R)-6-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline-3- carboxylate in place of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 502.2 [M+H]+.

[0242] Step 3. Methyl (R)-6-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)indoline- 3-carboxylate (I-56) was prepared in analogy to Intermediate I-1, step 3 using Methyl (R)-6- ((S)-2-amino-3,3-dicyclopropylpropanamido)-3-methyl-2-oxo-1-((2- (trimethylsilyl)ethoxy)methyl)indoline-3-carboxylate in place of methyl 5-((S)-2-amino-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 520.2 [M+H]+. Preparation of Intermediate I-57

[0243] Step 1. Methyl (S)-6-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-1,3-dimethyl-2-oxoindoline-3-carboxylate was prepared in analogy to Intermediate I-1, Step 1 using I-49 in place of methyl 5-amino-2,3-dihydro-1H- indene-1-carboxylate hydrochloride. ES / MS m / z: 520.2xx [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0244] Step 2. Methyl (S)-6-((S)-2-amino-3,3-dicyclopropylpropanamido)-1,3-dimethyl-2- oxoindoline-3-carboxylate was prepared in analogy to Intermediate I-1, Step 2 using methyl (S)-6-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-1,3-dimethyl-2- oxoindoline-3-carboxylate in place of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 386.2 [M+H]+.

[0245] Step 3. Methyl (S)-6-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-1,3-dimethyl-2-oxoindoline-3-carboxylate (I-57) was prepared in analogy to Intermediate I-1, step 3 using methyl (S)-6-((S)-2-amino-3,3- dicyclopropylpropanamido)-1,3-dimethyl-2-oxoindoline-3-carboxylate in place of methyl 5- ((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 522.3 [M+H]+. of Intermediate I-58

[0246] Step 1. Benzyl ((S)-1,1-dicyclopropyl-3-(((S)-3-methyl-2-oxo-3-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-6- yl)amino)-3-oxopropan-2-yl)carbamate was prepared in analogy to Intermediate I-1, Step 1 using I-36 in place of methyl 5-amino-2,3-dihydro-1H-indene-1-carboxylate hydrochloride. ES / MS m / z: 752.3 [M +Na]+.

[0247] Step 2. (S)-2-Amino-3,3-dicyclopropyl-N-((S)-3-methyl-2-oxo-3-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-6- yl)propenamide was prepared in analogy to Intermediate I-1, Step 2 using benzyl ((S)-1,1- dicyclopropyl-3-(((S)-3-methyl-2-oxo-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)indolin-6-yl)amino)-3-oxopropan-2-yl)carbamate in place of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H- indene-1-carboxylate. ES / MS m / z: 618.3 [M +Na]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0248] Step 3. N-((S)-1,1-Dicyclopropyl-3-(((S)-3-methyl-2-oxo-3-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-6- yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-58) was prepared in analogy to Intermediate I-1, step 3 using (S)-2-amino-3,3-dicyclopropyl-N-((S)-3-methyl-2- oxo-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)indolin-6-yl)propenamide in place of methyl 5-((S)-2-amino-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 754.3 [M +Na]+. of Intermediate I-59

[0249] Step 1. Methyl 5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)isoindoline-1-carboxylate was prepared in analogy to Intermediate I-7, Step 7 with 2-(tert-butyl) 1-methyl 5-(3,3-dicyclopropyl-2-(1-isopropyl-1H- pyrazole-5-carboxamido)propanamido)isoindoline-1,2-dicarboxylate in place of tert-butyl N- [(1R)-5-[[(2S)-3,3-dicyclopropyl-2-[(2-isopropylpyrazole-3- carbonyl)amino]propanoyl]amino]indan-1-yl]carbamate. ES / MS m / z: 481.5 [M+H]+

[0250] Step 2. A solution of methyl 5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)isoindoline-1-carboxylate (83 mg, 0.17 mmol), formaldehyde (37% solution) (0.08 mL, 1.04 mmol), and potassium carbonate (48 mg, 0.35 mmol) in acetonitrile was stirred for 30 minutes before adding sodium triacetoxyborohydride (110 mg, 0.52 mmol) and acetic acid (104 mg, 1.73 mmol). The mixture was stirred for 3 hours before adding saturated NaHCO3 and extracting with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give methyl 5- ((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-2- methylisoindoline-1-carboxylate. ES / MS m / z: 494.2 [M+H]+Attorney Docket No.: 1537-US-NP / WO-PCT

[0251] Step 3.5-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2-methylisoindoline-1-carboxylic acid (I-59) was prepared in analogy to Intermediate I-1, step 4 using methyl 5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H- pyrazole-5-carboxamido)propanamido)-2-methylisoindoline-1-carboxylate in place of methyl 5- ((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-2,3-dihydro- 1H-indene-1-carboxylate. ES / MS m / z: 479.8 [M+H]+. Preparation of Intermediate I-60

[0252] Step 1. To a solution of (R)-2-amino-2-cyclopropylethan-1-ol (2.41 g, 23.8 mmol) in dichloromethane (12 mL) was added di-tert-butyl dicarbonate (5.20 g, 23.8 mmol), then carefully N,N-diisopropylethylamine (4.8 mL, 20 mmol). The resulting mixture was stirred for two hours, then concentrated in vacuo and purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give tert-butyl (R)-(1-cyclopropyl-2- hydroxyethyl)carbamate. ES / MS m / z: 202.0 [M+H]+.

[0253] Step 2. tert-Butyl (R)-(1-cyclopropyl-2-oxoethyl)carbamate (I-60). To a solution of tert-butyl (R)-(1-cyclopropyl-2-hydroxyethyl)carbamate (1.14 g, 5.65 mmol) in dichloromethane (50 mL) was added Dess-Martin periodinane (4.80 g, 11.3 mmol). The resulting mixture was stirred at room temperature for one hour, then diluted with dichloromethane and washed successively with saturated aqueous sodium bicarbonate and brine. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to furnish a crude residue that was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give tert-butyl (R)-(1-cyclopropyl-2-oxoethyl)carbamate (I-60).1H NMR (400 MHz, Chloroform-d3) δ 9.64 (s, 1H), 5.28 – 4.82 (m, 1H), 3.93 – 3.36 (m, 1H), 1.45 (s, 9H), 0.97 – 0.83 (m, 1H), 0.76 – 0.64 (m, 1H), 0.64 – 0.58 (m, 1H), 0.58 – 0.51 (m, 1H), 0.51 – 0.37 (m, 1H).Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-61

[0254] Step 1. To a solution of (1-(aminomethyl)cyclopropyl)methanol (1.34 g, 13.2 mmol) in dichloromethane (15 mL) was added di-tert-butyl dicarbonate (2.89 g, 13.2 mmol), then carefully N,N-diisopropylethylamine (4.6 mL, 27 mmol). The resulting mixture was stirred for two hours, then concentrated in vacuo and purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give tert-butyl ((1- (hydroxymethyl)cyclopropyl)methyl)carbamate.1H NMR (400 MHz, Chloroform-d) δ 4.96 (s, 1H), 3.38 (d, J = 5.4 Hz, 2H), 3.34 – 3.21 (m, 1H), 3.11 (d, J = 6.5 Hz, 2H), 1.46 (s, 9H), 0.60 – 0.27 (m, 4H).

[0255] Step 2. tert-Butyl ((1-formylcyclopropyl)methyl)carbamate (I-61). To a solution tert-butyl ((1-(hydroxymethyl)cyclopropyl)methyl)carbamate (869 mg, 4.32 mmol) in dichloromethane (20 mL) was added pyridinium chlorochromate (1.07 g, 4.97 mmol). The resulting mixture was stirred at room temperature for three hours, then filtered through a pad of Celite, washing the filter pad several times with ethyl acetate. The filtrate was concentrated in vacuo to furnish a crude residue that was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give tert-butyl ((1-formylcyclopropyl)methyl)carbamate (I-61).1H NMR (400 MHz, Chloroform-d) δ 8.63 (s, 1H), 5.13 (s, 1H), 3.32 (d, J = 6.4 Hz, 2H), 1.43 (s, 9H), 1.32 – 1.12 (m, 4H).Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-62

[0256] Step 1. A mixture of tert-butyl (1-oxo-2,3-dihydro-1H-inden-5-yl)carbamate (1.00 g, 4.04 mmol) and 4-methylbenzenesulfonohydrazide (753 mg, 4.04 mmol) in MeOH (10 mL) was stirred at 60 °C overnight. The mixture was filtered hot to isolate the precipitate, rinsing the solids three times with MeOH (pre-warmed to 60 °C), followed by 10:1 hexanes / EtOAc (r.t.). The solids were dried under an air stream to afford tert-butyl (E)-(1-(2-tosylhydrazineylidene)- 2,3-dihydro-1H-inden-5-yl)carbamate, which was used in subsequent steps without further purification. ES / MS m / z: 416.1 [M+H]+.

[0257] Step 2. A mixture of tert-butyl (E)-(1-(2-tosylhydrazineylidene)-2,3-dihydro-1H- inden-5-yl)carbamate (300 mg, 0.722 mmol), (2-(benzyloxy)-5-fluoropyridin-3-yl)boronic acid (357 mg, 1.44 mmol), and K2CO3 (200 mg, 1.44 mmol) in 1,4-dioxane (6 mL) was stirred at 110 °C for 24 h. The mixture was then cooled to r.t., diluted with water, and extracted three times with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to afford tert-butyl (1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2,3- dihydro-1H-inden-5-yl)carbamate. ES / MS m / z: 457.2 [M+Na]+.

[0258] Step 3. A mixture of tert-butyl (1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2,3-dihydro- 1H-inden-5-yl)carbamate (227 mg, 0.522 mmol) in MeOH (13 mL) was treated with 4 M HCl in 1,4-dioxane (13 mL, 52 mmol) and stirred at r.t. for 1 h. The mixture was then concentrated in vacuo to give 1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2,3-dihydro-1H-inden-5-amine (I-62), which was used in subsequent steps without further purification. ES / MS m / z: 335.2 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT of Intermediate I-63

[0259] Step 1. A mixture of I-62 (194 mg, 0.523 mmol) and (2S)-2-(tert- butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid (169 mg, 0.628 mmol) in DMF (3 mL) was treated with DIPEA (0.273 mL, 1.57 mmol) followed by HATU (249 mg, 0.654 mmol). The mixture was stirred at r.t. for 30 min, then diluted with EtOAc, washed three times with 10% aqueous LiCl solution, then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give tert-butyl ((2S)-1-((1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2,3-dihydro- 1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate. ES / MS m / z: 608.3 [M+Na]+.

[0260] Step 2. A mixture of tert-butyl ((2S)-1-((1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-2,3- dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (244 mg, 0.417 mmol) in MeOH (10 mL) was treated with 4 M HCl in 1,4-dioxane (10 mL, 42 mmol) and stirred at r.t. for 15 min. The mixture was then concentrated in vacuo to give (2S)-2-amino-N-(1- (2-(benzyloxy)-5-fluoropyridin-3-yl)-2,3-dihydro-1H-inden-5-yl)-3,3- dicyclopropylpropanamide (I-63), which was used in subsequent steps without further purification. ES / MS m / z: 486.2 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT of Intermediate I-64

[0261] N-((2S)-1-((1-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-2,3-dihydro-1H-inden-5- yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I- 64). A mixture of I-63 (217 mg, 0.416 mmol) and 1-isopropyl-1H-pyrazole-5-carboxylic acid (70.5 mg, 0.457 mmol) in DMF (3 mL) was treated with DIPEA (0.217 mL, 1.25 mmol) followed by HATU (198 mg, 0.520 mmol). The mixture was stirred at r.t. for 1 h, then diluted with EtOAc, washed three times with 10% aqueous LiCl solution, then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give I-64. ES / MS m / z: 622.3 [M+H]+. of Intermediate I-65

[0262] Step 1. tert-Butyl N-[(1R)-2-[[(1R)-5-bromoindan-1-yl]amino]-1-cyclopropyl-2- oxo-ethyl]carbamate was prepared in analogy Intermediate I-1, step 1 using (1R)-5- bromoindan-1-amine hydrochloride in place of methyl 5-amino-2,3-dihydro-1H-indene-1- carboxylate hydrochloride and (2R)-2-(tert-butoxycarbonylamino)-2-cyclopropyl-acetic acid in place of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid. ES / MS m / z: 410.2 [M+H]+.

[0263] Step 2. To a stirred solution of tert-butyl N-[(1R)-2-[[(1R)-5-bromoindan-1-yl]amino]- 1-cyclopropyl-2-oxo-ethyl]carbamate (2759 mg, 6.74 mmol) in nitromethane (88.7 mL) was added zinc bromide. The mixture was stirred at room temperature for 3h and then concentrated in vacuo, dissolved in EtOAc, washed with saturated aq. NaHCO3 solution, washed withAttorney Docket No.: 1537-US-NP / WO-PCT saturated brine solution, dried over Na2SO4, filtered, concentrated in vacuo to yield (2R)-2- amino-N-[(1R)-5-bromoindan-1-yl]-2-cyclopropyl-acetamide which was used without further purification. ES / MS m / z: 310.1 [M+H]+.

[0264] Step 3. To a stirred solution of (2R)-2-amino-N-[(1R)-5-bromoindan-1-yl]-2- cyclopropyl-acetamide (2084 mg, 6.74 mmol) in DMF (34.2 mL) was added acetic anhydride (1.27 mL, 13.5 mmol) and triethylamine (2.8 mL, 20.2 mmol). The mixture was stirred at room temperature for 3h and then filtered, washed with acetonitrile, allowed to dry to yield (2R)-2- acetamido-N-[(1R)-5-bromoindan-1-yl]-2-cyclopropyl-acetamide which was used without further purification. ES / MS m / z: 352.2 [M+H]+.

[0265] Step 4. To a stirred solution of (2R)-2-acetamido-N-[(1R)-5-bromoindan-1-yl]-2- cyclopropyl-acetamide (250 mg, 0.712 mmol) in dioxane (4.44 mL) was added benzyl carbamate (161 mg, 1.07 mmol), cesium carbonate (464 mg, 1.42 mmol), and XPhos Pd G4 (61.2 mg, 0.07 mmol). The mixture was heated to 100°C overnight, diluted with DCM, washed with water, washed with saturated aq. brine solution, dried over Na2SO4, filtered over celite, concentrated in vacuo to give the crude product. The crude residue was purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give benzyl N-[(1R)-1- [[(2R)-2-acetamido-2-cyclopropyl-acetyl]amino]indan-5-yl]carbamate. ES / MS m / z: 422.2 [M+H]+.

[0266] Step 5. (2R)-2-Acetamido-N-[(1R)-5-aminoindan-1-yl]-2-cyclopropyl-acetamide (I-65) was prepared in analogy Intermediate I-1, step 2 using benzyl N-[(1R)-1-[[(2R)-2- acetamido-2-cyclopropyl-acetyl]amino]indan-5-yl]carbamate in place of 5-((S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1- carboxylate. ES / MS m / z: 288.1 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT of Intermediate I-66

[0267] Step 1. tert-Butyl N-[(1S)-1-[[(1R)-1-[[(2R)-2-acetamido-2-cyclopropyl- acetyl]amino]indan-5-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate was prepared in analogy Intermediate I-1, step 1 using (2R)-2-acetamido-N-[(1R)-5-aminoindan-1-yl]-2- cyclopropyl-acetamide in place of methyl 5-amino-2,3-dihydro-1H-indene-1-carboxylate hydrochloride and (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid in place of (S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid. ES / MS m / z: 288.1 [M+H]+.

[0268] Step 2. (2S)-N-[(1R)-1-[[(2R)-2-Acetamido-2-cyclopropyl-acetyl]amino]indan-5- yl]-2-amino-3,3-dicyclopropyl-propanamide (I-66) was prepared in analogy Intermediate I- 4, step 6 using tert-butyl N-[(1S)-1-[[(1R)-1-[[(2R)-2-acetamido-2-cyclopropyl- acetyl]amino]indan-5-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate in place of tert-butyl ((S)-6-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-2,3- dihydrobenzofuran-3-yl)carbamate. ES / MS m / z: 439.2 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0269] Step 1. tert-Butyl (3R)-4-[[(1R)-5-bromoindan-1-yl]amino]-3-cyclopropyl-4-oxo- butanoate was prepared in analogy Intermediate I-1, step 1 using (1R)-5-bromoindan-1-amine hydrochloride in place of methyl 5-amino-2,3-dihydro-1H-indene-1-carboxylate hydrochloride and (2R)-4-tert-butoxy-2-cyclopropyl-4-oxo-butanoic acid in place of (S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid. ES / MS m / z: 409.4 [M+H]+.

[0270] Step 2. To a stirred solution of tert-butyl (3R)-4-[[(1R)-5-bromoindan-1-yl]amino]-3- cyclopropyl-4-oxo-butanoate (709 mg, 1.74 mmol) in DCM (6.0 mL) was added 4M HCl in dioxane (2.17 mL, 8.68 mmol). The mixture was stirred at room temperature for 2h and concentrated in vacuo to give (3R)-4-[[(1R)-5-bromoindan-1-yl]amino]-3-cyclopropyl-4-oxo- butanoic acid which was used without further purification. ES / MS m / z: 353.9 [M+H]+.

[0271] Step 3. (2R)-4-(Azetidin-1-yl)-N-[(1R)-5-bromoindan-1-yl]-2-cyclopropyl-4-oxo- butanamide (I-67) was prepared in analogy Intermediate I-1, step 1 using azetidine in place of methyl 5-amino-2,3-dihydro-1H-indene-1-carboxylate hydrochloride and (3R)-4-[[(1R)-5- bromoindan-1-yl]amino]-3-cyclopropyl-4-oxo-butanoic acid in place of (S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanoic acid. ES / MS m / z: 392.3 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0272] Step 1. Benzyl N-[(1R)-1-[[(2R)-4-(azetidin-1-yl)-2-cyclopropyl-4-oxo- butanoyl]amino]indan-5-yl]carbamate was prepared in analogy Procedure 3, step 4 using I- 67 in place of benzyl N-[(1R)-1-[[(2R)-2-acetamido-2-cyclopropyl-acetyl]amino]indan-5- yl]carbamate. ES / MS m / z: 462.7 [M+H]+.

[0273] Step 2. (2R)-N-[(1R)-5-Aminoindan-1-yl]-4-(azetidin-1-yl)-2-cyclopropyl-4-oxo- butanamide was prepared in analogy Procedure 3, step 5 using benzyl N-[(1R)-1-[[(2R)-4- (azetidin-1-yl)-2-cyclopropyl-4-oxo-butanoyl]amino]indan-5-yl]carbamate in place of benzyl N- [(1R)-1-[[(2R)-2-acetamido-2-cyclopropyl-acetyl]amino]indan-5-yl]carbamate. ES / MS m / z: 328.1 [M+H]+.

[0274] Step 3. Benzyl N-[(1S)-1-[[(1R)-1-[[(2R)-4-(azetidin-1-yl)-2-cyclopropyl-4-oxo- butanoyl]amino]indan-5-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate was prepared in analogy Procedure 3, step 6 using (2R)-N-[(1R)-5-aminoindan-1-yl]-4-(azetidin-1-yl)-2- cyclopropyl-4-oxo-butanamide in place of (2R)-2-acetamido-N-[(1R)-5-aminoindan-1-yl]-2- cyclopropyl-acetamide and (2S)-2-(benzyloxycarbonylamino)-3,3-dicyclopropyl-propanoic acid in place of (2S)-2-(tert-butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid. ES / MS m / z: 613.3 [M+H]+.

[0275] Step 4. (2R)-N-[(1R)-5-[[(2S)-2-Amino-3,3-dicyclopropyl-propanoyl]amino]indan- 1-yl]-4-(azetidin-1-yl)-2-cyclopropyl-4-oxo-butanamide (I-68) was prepared in analogy Procedure 3, step 5 using benzyl N-[(1S)-1-[[(1R)-1-[[(2R)-4-(azetidin-1-yl)-2-cyclopropyl-4-Attorney Docket No.: 1537-US-NP / WO-PCT oxo-butanoyl]amino]indan-5-yl]carbamoyl]-2,2-dicyclopropyl-ethyl]carbamate in place of benzyl N-[(1R)-1-[[(2R)-2-acetamido-2-cyclopropyl-acetyl]amino]indan-5-yl]carbamate. ES / MS m / z: 479.7 [M+H]+.

[0276] Step 1.2-(tert-Butyl) 4-methyl 7-bromo-3,4-dihydroisoquinoline-2,4(1H)- dicarboxylate was prepared in analogy to Intermediate I-4, step 1 using methyl 7-bromo- 1,2,3,4-tetrahydroisoquinoline-4-carboxylate in place of (S)-6-bromo-2,3-dihydrobenzofuran- 3-aminehydrochloride. ES / MS m / z: 371.9 [M+H]+.

[0277] Step 2.2-(tert-Butyl) 4-methyl 7-amino-3,4-dihydroisoquinoline-2,4(1H)- dicarboxylate was prepared in analogy to Intermediate I-4, step 2 using 2-(tert-butyl) 4- methyl 7-bromo-3,4-dihydroisoquinoline-2,4(1H)-dicarboxylate in place of tert-butyl (S)-(6- bromo-2,3-dihydrobenzofuran-3-yl)carbamate. ES / MS m / z: 307.4 [M+H]+.

[0278] Step 3.2-(tert-Butyl) 4-methyl 7-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-3,4-dihydroisoquinoline-2,4(1H)-dicarboxylate was prepared in analogy to Intermediate I-4, step 3 using 2-(tert-butyl) 4-methyl 7-amino-3,4- dihydroisoquinoline-2,4(1H)-dicarboxylate in place of tert-butyl (S)-(6-amino-2,3- dihydrobenzofuran-3-yl)carbamate. ES / MS m / z: 492.24 [M+H -Boc]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0279] Step 4.2-(tert-Butyl) 4-methyl 7-((S)-2-amino-3,3-dicyclopropylpropanamido)- 3,4-dihydroisoquinoline-2,4(1H)-dicarboxylate was prepared in analogy to Intermediate I-4, step 4 using 2-(tert-butyl) 4-methyl 7-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-3,4-dihydroisoquinoline-2,4(1H)-dicarboxylate in place of benzyl ((S)-1-(((S)-3-((tert-butoxycarbonyl)amino)-2,3-dihydrobenzofuran-6-yl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)carbamate. ES / MS m / z: 458.2 [M+H]+.

[0280] Step 5.2-(tert-Butyl) 4-methyl 7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H- pyrazole-5-carboxamido)propanamido)-3,4-dihydroisoquinoline-2,4(1H)-dicarboxylate was prepared in analogy to Intermediate I-4, step 5 using 2-(tert-butyl) 4-methyl 7-((S)-2- amino-3,3-dicyclopropylpropanamido)-3,4-dihydroisoquinoline-2,4(1H)-dicarboxylate in place of tert-butyl ((S)-6-((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3-dihydrobenzofuran- 3-yl)carbamate. ES / MS m / z: 594.3 [M+H]+.

[0281] Step 6.2-(tert-Butoxycarbonyl)-7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H- pyrazole-5-carboxamido)propanamido)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid was prepared in analogy to Intermediate I-5, step 6 using 2-(tert-butyl) 4-methyl 7-((S)-3,3- dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3,4- dihydroisoquinoline-2,4(1H)-dicarboxylate in place of 2-(tert-butyl) 1-methyl 5-((S)-3,3- dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)isoindoline-1,2- dicarboxylate. ES / MS m / z: 580.2 [M+H]+.

[0282] Step 7. A mixture of 2-(tert-butoxycarbonyl)-7-((S)-3,3-dicyclopropyl-2-(1- isopropyl-1H-pyrazole-5-carboxamido)propanamido)-1,2,3,4-tetrahydroisoquinoline-4- carboxylic acid (1242 mg, 2.12 mmol), diphenylphosphoryl azide (0.914 mL, 4.24 mmol), and triethylamine (0.65 mL, 4.66 mmol) in toluene (20 mL) was stirred at 110 °C for 1.5 h. The mixture was then cooled to r.t., then 1M potassium trimethylsilanolate in THF (4.24 mL, 4.24 mmol) was added and the mixture was stirred for 30 min. Sat. NH4Cl was added, the mixture diluted with water, then 2N NaOH was added. The mixture was then extracted three times with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with MeOH in DCM 0-30% to afford tert-butyl 4-amino-7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole- 5-carboxamido)propanamido)-3,4-dihydroisoquinoline-2(1H)-carboxylate. ES / MS m / z: 551.2 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0283] Step 8. tert-Butyl 4-((R)-2-acetamido-2-cyclopropylacetamido)-7-((S)-3,3- dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3,4- dihydroisoquinoline-2(1H)-carboxylate (I-69) was prepared in analogy to Intermediate I-4, step 3 using (R)-2-acetamido-2-cyclopropylacetic acid in place of 1-isopropyl-1H-pyrazole-5- carboxylic acid. ES / MS m / z: 690.4 [M+H]+. of Intermediate I-70

[0284] Step 1. tert-Butyl 4-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-7-bromo-3,4- dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-13, step 1 using tert-butyl 7-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (prepared as described in J. Org. Chem., 2022, 87, 776-789.) in place of 8-bromo-3,4- dihydrobenzo[b]oxepin-5(2H)-one. ES / MS m / z: 438.0 [M+H]+.

[0285] Step 2. tert-Butyl 7-bromo-4-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-13, step 2 using tert-butyl 4-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-7-bromo-3,4- dihydroisoquinoline-2(1H)-carboxylate in place (2S)-N1-(8-bromo-2,3,4,5- tetrahydrobenzo[b]oxepin-5-yl)-3,3,3-trifluoropropane-1,2-diamine. ES / MS m / z: 465.9 [M+H]+.

[0286] Step 3. tert-Butyl 7-amino-4-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-5, step 2 using tert-butyl 7-bromo-4-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate in place (4S)-1-(8-bromo-2,3,4,5- tetrahydrobenzo[b]oxepin-5-yl)-4-(trifluoromethyl)imidazolidin-2-one. ES / MS m / z: 401.4 [M+H]+.

[0287] Step 4. tert-Butyl 7-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-4-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-5, step 3Attorney Docket No.: 1537-US-NP / WO-PCT using tert-butyl 7-amino-4-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate in place 2-(tert-butyl) 1-methyl 5-aminoisoindoline- 1,2-dicarboxylate. ES / MS m / z: 586.4 [M+H -Boc]+.

[0288] Step 5. tert-Butyl 7-((S)-2-amino-3,3-dicyclopropylpropanamido)-4-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-5, step 4 using tert-butyl 7-((S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-4-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in place of 2-(tert-butyl) 1-methyl 5-aminoisoindoline-1,2-dicarboxylate. ES / MS m / z: 552.2 [M+H]+.

[0289] Step 6. tert-Butyl 7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-4-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate (I-70) was prepared in analogy to Intermediate I-5, step 5 using tert-Butyl 7-((S)-2-amino-3,3-dicyclopropylpropanamido)-4-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate in place 2- (tert-butyl) 1-methyl 5-((S)-2-amino-3,3-dicyclopropylpropanamido)isoindoline-1,2- dicarboxylate. ES / MS m / z: 688.3 [M+H]+. Preparation of Intermediate I-71

[0290] tert-Butyl 7-amino-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (I-71). To a 40 mL vial, tert-butyl 7-bromo-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (prepared as described in J. Org. Chem., 2022, 87, 776-789.) (916 mg, 2.67 mmol), tBuBrettPhos Pd G3 (11 mg, 0.133 mmol), and NaOtBu (359 mg, 3.73 mmol) were charged. To the vial, 0.4 M NH3 in 1,4-dioxane (26.7 mL, 10.7 mmol) was added. The vial was sealed and stirred at 80 °C for 5 h. After cooling to room temperature, the mixture was concentrated and then dissolved in EtOAc and washed with H2O, then dried over MgSO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0- 100% to give I-71. ES / MS m / z: 263.0 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0291] Step 1. tert-Butyl (S)-7-(2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-1, step 1 using I-71 in place of methyl 5-amino-2,3-dihydro-1H- indene-1-carboxylate hydrochloride. ES / MS m / z: 571.2 [M+Na]+.

[0292] Step 2. tert-Butyl (S)-7-(2-amino-3,3-dicyclopropylpropanamido)-4-oxo-3,4- dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-1, step 2 using tert-butyl (S)-7-(2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-4-oxo- 3,4-dihydroisoquinoline-2(1H)-carboxylate in place of methyl 5-((S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1- carboxylate. ES / MS m / z: 414.1 [M+H]+.

[0293] Step 3. tert-Butyl (S)-7-(3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate (I-72) was prepared in analogy to Intermediate I-1, step 3 using tert-butyl (S)-7-(2-amino-3,3- dicyclopropylpropanamido)-4-oxo-3,4-dihydroisoquinoline-2(1H)-carboxylate in place of methyl 5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate (I-51). ES / MS m / z: 550.2 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0294] Step 1. tert-Butyl 4-(((S)-2-amino-3,3,3-trifluoro-2-methylpropyl)amino)-7-((S)- 3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3,4- dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-13, step 1 using I-72 and (2S)-3,3,3-trifluoro-2-methyl-propane-1,2-diamine dihydrochloride in place of 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one and (2S)-3,3,3-trifluoropropane-1,2-diamine dihydrochloride. ES / MS m / z: 676.4 [M+H]+.

[0295] Step 2. tert-Butyl 7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-4-((S)-4-methyl-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)- 3,4-dihydroisoquinoline-2(1H)-carboxylate was prepared in analogy to Intermediate I-13, step 2 using tert-butyl 4-(((S)-2-amino-3,3,3-trifluoro-2-methylpropyl)amino)-7-((S)-3,3- dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3,4- dihydroisoquinoline-2(1H)-carboxylate in place of (2S)-N1-(8-bromo-2,3,4,5- tetrahydrobenzo[b]oxepin-5-yl)-3,3,3-trifluoropropane-1,2-diamine. ES / MS m / z: 702.4 [M+H]+.

[0296] Step 3. N-((2S)-1,1-Dicyclopropyl-3-((4-((S)-4-methyl-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-3- oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-73) was prepared in analogy to Intermediate I-80 using tert-butyl 7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-4-((S)-4-methyl-2-oxo-4-(trifluoromethyl)imidazolidin-1-yl)-3,4- dihydroisoquinoline-2(1H)-carboxylate in place of I-79. ES / MS m / z: 602.9 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-74

[0297] Step 1. A bottle was charged with AcOH (720 mL) followed by 6-bromoindoline-2,3- dione (45.0 g, 199 mmol), malonic acid (22.8 g, 219 mmol), and NaOAc (20.5 g, 248 mmol) under an atmosphere of N2. The mixture was stirred for 6 h at r.t., then an additional quantity of NaOAc (20.5 g, 248 mmol) was added. The resulting mixture was stirred at 120 °C for 16 h. The mixture was concentrated in vacuo, and the resulting residue suspended in water (450 mL). The resulting solids were isolated by filtration, washing with water (3 x 450 mL), and dried at 60 °C for 2 h to afford 7-bromo-2-oxo-1,2-dihydroquinoline-4-carboxylic acid.1H NMR (DMSO-d6, 400 MHz): δ 11.95 (s, 1H), δ 8.11 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 8.8, 2.0 Hz, 1H), 6.74 (s, 1H).

[0298] Step 2. A bottle was charged with AcOH (400 mL) followed by 7-bromo-2-oxo-1,2- dihydroquinoline-4-carboxylic acid (25.0 g, 93.2 mmol) under an atmsosphere of N2. The mixture was then heated to 50-60 °C, and Zn (50.0 g, 746 mmol) was added portion-wise. The mixture was then heated to 130 °C and stirred for 24 h. The mixture was cooled to r.t. and filtered, rinsing with THF. The resulting filtrate was concentrated in vacuo, then treated with sat. aq. NaHCO3, adjusting to pH = 9. The mixture was then extracted three times with DCM. The resulting aqueous phase was acidified to pH = 2-3 with HCl. The resulting solids were isolated by filtration, washed with water (100 mL), and dried at 60 °C for 2 h to afford 7-bromo-2-oxo- 1,2,3,4-tetrahydroquinoline-4-carboxylic acid.1H NMR (DMSO-d6, 400 MHz): δ 12.69 (br.s, 1H), 10.15 (s, 1H), 7.13-7.29 (m, 1H), 7.11-7.13 (m, 1H), 7.02-7.03 (m, 1H), 3.88-3.91 (m, 1H) , 2.61-2.73 (m, 2H).

[0299] Step 3. A bottle was charged with MeOH (240 mL) followed by 7-bromo-2-oxo- 1,2,3,4-tetrahydroquinoline-4-carboxylic acid (8.00 g, 29.6 mmol) and concentrated HCl (4.00 mL, 47.4 mmol) under an atmosphere of N2. The mixture was stirred for 2 h at 75 °C, then concentrated in vacuo. The residue was basified to pH = 9 with sat. aq. NaHCO3 and extractedAttorney Docket No.: 1537-US-NP / WO-PCT three times with EtOAc (100 mL). The combined organic layers were concentrated in vacuo to afford methyl 7-bromo-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate.1H NMR (DMSO-d6, 400 MHz): δ 10.21 (br.s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.13 (dd, J = 8.0, 2.0 Hz, 1H), 7.04 (s, 1H), 4.04-4.06 (m, 1H), 3.59 (s, 3H) , 2.67-2.74 (m, 2H).

[0300] Step 4. A bottle was charged with acetone (180 mL) followed by methyl 7-bromo-2- oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate (6.00 g, 21.1 mmol), Cs2CO3 (8.25 g, 25.3 mmol), and MeI (7.19 g, 50.6 mmol) under an atmosphere of N2. The mixture was stirred at r.t. for 24 h, then filtered. The resulting filtrate was concentrated in vacuo, and the residue further purified by reverse phase MPLC to afford methyl 7-bromo-1-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-4-carboxylate (I-74).1H NMR (DMSO-d6, 400 MHz): δ 7.25-7.28 (m, 3H), 4.05 (t, J = 4.8 Hz, 1H), 3.58 (s, 3H), 3.21 (s, 3H), 2.81 (d, J = 4.8 Hz, 2H). of Intermediate I-75

[0301] Step 1. Methyl 7-amino-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate was prepared in analogy to Intermediate I-5, step 2 using I-74 in place of (4S)-1-(8-bromo- 2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)-4-(trifluoromethyl)imidazolidin-2-one. ES / MS m / z: 235.0 [M+H]+.

[0302] Step 2. Methyl 7-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate was prepared in analogy to Intermediate I-5, step 3 using methyl 7-amino-1-methyl-2-oxo-1,2,3,4- tetrahydroquinoline-4-carboxylate in place of 2-(tert-butyl) 1-methyl 5-aminoisoindoline-1,2- dicarboxylate. ES / MS m / z: 521.2 [M+H]+.

[0303] Step 3. Methyl 7-((S)-2-amino-3,3-dicyclopropylpropanamido)-1-methyl-2-oxo- 1,2,3,4-tetrahydroquinoline-4-carboxylate was prepared in analogy to Intermediate I-5, step 4 using methyl 7-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-1-Attorney Docket No.: 1537-US-NP / WO-PCT methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate in place of 2-(tert-butyl) 1-methyl 5- aminoisoindoline-1,2-dicarboxylate. ES / MS m / z: 386.2 [M+H]+.

[0304] Step 4. Methyl 7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate was prepared in analogy to Intermediate I-5, step 5 using methyl 7-((S)-2-amino-3,3- dicyclopropylpropanamido)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylate in place of 2-(tert-butyl) 1-methyl 5-((S)-2-amino-3,3-dicyclopropylpropanamido)isoindoline-1,2- dicarboxylate. ES / MS m / z: 522.2 [M+H]+.

[0305] Step 5.7-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-1-methyl-2-oxo-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (I-75) was prepared in analogy to Intermediate I-5, step 6 using methyl 7-((S)-3,3- dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-1-methyl-2-oxo- 1,2,3,4-tetrahydroquinoline-4-carboxylate in place of 2-(tert-butyl) 1-methyl 5-((S)-3,3- dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)isoindoline-1,2- dicarboxylate. ES / MS m / z: 508.1 [M+H]+. Preparation of Intermediate I-76

[0306] 7-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-1-methyl-2-oxo-N-(2,2,2-trifluoroethyl)-1,2,3,4- tetrahydroquinoline-4-carboxamide (I-76) was prepared by analogy to Intermediate I-69, step 7 using I-75 in place of 2-(tert-butoxycarbonyl)-7-((S)-3,3-dicyclopropyl-2-(1-isopropyl- 1H-pyrazole-5-carboxamido)propanamido)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid. ES / MS m / z: 462.2 [M+H -NH3]+.Attorney Docket No.: 1537-US-NP / WO-PCT of Intermediate I-77

[0307] Step 1. A mixture of 5-aminoindan-1-one (250 mg, 1.70 mmol) and (2S)-2-(tert- butoxycarbonylamino)-3,3-dicyclopropyl-propanoic acid (458 mg, 1.70 mmol) in DCM (3 mL) was treated with DIPEA (0.90 mL, 5.10 mmol) followed by HATU (599 mg, 2.55 mmol). The mixture was stirred at r.t. for 30 min, then diluted with EtOAc, washed three times with 10% aqueous LiCl solution, then brine, dried over Na2SO4, filtered, and concentrated in vacuo. Theresulting crude residue was purified by SiO2 column chromatography eluting with EtOAc inhexanes 0-100% to afford tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[(1-oxoindan- 5-yl)amino]ethyl]carbamate. ES / MS m / z: 399.2 [M+H]+.

[0308] Step 2. tert-butyl N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[(1-oxoindan-5- yl)amino]ethyl]carbamate (423 mg, 1.01 mmol) in DCM (5 mL) was treated with trifluoroacetic acid (0.77 mL, 10.1 mmol) and stirred at r.t. for 15 min. The mixture was then concentrated in vacuo to give (2S)-2-amino-3,3-dicyclopropyl-N-(1-oxoindan-5-yl)propanamide, which was used in subsequent steps without further purification. ES / MS m / z: 299.2 [M+H]+.

[0309] Step 3. To a stirred solution of (2S)-2-amino-3,3-dicyclopropyl-N-(1-oxoindan-5- yl)propanamide (301 mg, 1.01 mmol), 2-isopropylpyrazole-3-carboxylic acid (311 mg, 2.02 mmol), and DIPEA (0.88 mL, 5.04 mmol) in DCM (10 mL) was added HATU (475 mg, 2.02 mmol) in one portion. The mixture was stirred at r.t. for 30 min then diluted with EtOAc, washed three times with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to afford N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[(1-oxoindan-5- yl)amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide. ES / MS m / z: 435.2 [M+H]+.

[0310] Step 4. A mixture of N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[(1-oxoindan-5- yl)amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide (355 mg, 0.776 mmol) and p-Attorney Docket No.: 1537-US-NP / WO-PCT toluenesulfonhydrazide (145 mg, 0.776 mmol) in MeOH (3 mL) was stirred at 60 °C overnight. The mixture was filtered to isolate the precipitate, rinsing the solids with MeOH. The solids were dried in vacuo to afford N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[(1E)-1-(p- tolylsulfonylhydrazono)indan-5-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide (I- 77). ES / MS m / z: 603.2 [M+H]+. of Intermediate I-78

[0311] A mixture of N-[(1S)-1-(dicyclopropylmethyl)-2-oxo-2-[[(1E)-1-(p- tolylsulfonylhydrazono)indan-5-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide (I-77) (550 mg, 0.912 mmol), (5-bromo-2-methoxy-3-pyridyl)boronic acid (317 mg, 1.37 mmol), and K2CO3 (252 mg, 1.82 mmol) in 1,4-dioxane (5 mL) was stirred at 110 °C for 24 h. The mixture was then cooled to r.t., diluted with water, and extracted three times with EtOAc. The combined organic layerswere dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to afford N-[(1S)-1-[[1-(5-bromo-2-methoxy-3-pyridyl)indan-5-yl]carbamoyl]-2,2- dicyclopropyl-ethyl]-2-isopropyl-pyrazole-3-carboxamide (I-78). ES / MS m / z: 608 [M+H]+. of Intermediate I-79

[0312] Step 1. tert-Butyl (S,Z)-7-(3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-4-(2-tosylhydrazineylidene)-3,4-dihydroisoquinoline-2(1H)- carboxylate was prepared in analogy to Intermediate I-62, step 1 using I-72 in place of tert- butyl (1-oxo-2,3-dihydro-1H-inden-5-yl)carbamate.Attorney Docket No.: 1537-US-NP / WO-PCT

[0313] Step 2. tert-Butyl 4-(2-(benzyloxy)-5-fluoropyridin-3-yl)-7-((S)-3,3-dicyclopropyl- 2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-3,4-dihydroisoquinoline-2(1H)- carboxylate (I-79) was prepared in analogy to Intermediate I-62, step 2 using tert-butyl (S,Z)- 7-(3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-4-(2- tosylhydrazineylidene)-3,4-dihydroisoquinoline-2(1H)-carboxylate in place of tert-butyl (E)-(1- (2-tosylhydrazineylidene)-2,3-dihydro-1H-inden-5-yl)carbamate. ES / MS m / z: 737.4 [M+H]+. of Intermediate I-80

[0314] N-((2S)-1-((4-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin- 7-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-80). To a solution of I-79 (40 mg, 0.0543 mmol) in CH3NO2 (2 mL) was charged ZnBr2 (61 mg, 0.271 mmol). The mixture was stirred at room temperature for 2.5 hr and the precipitate was removed by filtration. The crude mixture was diluted with DMF and then filtered through a syringe filter, and purified by RP-HPLC (eluent: MeCN / H2O gradient with 0.1% TFA). Product- containing fractions were combined and lyophilized to afford N-((2S)-1-((4-(2-(benzyloxy)-5- fluoropyridin-3-yl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-3,3-dicyclopropyl-1- oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-80). ES / MS m / z: 638.5 [M+H]+. Preparation of Intermediate

[0315] 2-(Benzyloxy)-3-bromo-5-fluoropyridine (I-81). A mixture of 3-bromo-5- fluoropyridin-2(1H)-one (2.02 g, 10.5 mmol) and silver carbonate (2.90 g, 10.5 mmol) in pentane (20 mL) were treated with benzyl bromide (3.75 mL, 31.6 mmol) dropwise and with stirring. The mixture was stirred at r.t. for 5 days, then diluted with EtOAc and filtered through celite. The resulting filtrate was concentrated in vacuo and the resulting crude residue purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-15% to give I-81. ES / MS m / z: 282.0 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT of Intermediate I-82

[0316] Step 1. tert-Butyl (E)-(1-(2-tosylhydrazineylidene)-2,3-dihydro-1H-inden-5- yl)carbamate (1.00 g, 2.41 mmol), 2-(benzyloxy)-3-bromo-5-fluoropyridine (815 mg, 2.89 mmol), Pd(OAc)2 (27 mg, 120 umol), P(c-Hex)3 (81 mg, 289 umol), and K2CO3 (998 mg, 7.22 mmol) were suspended in DMA, sparged with N2 for 1 min, then stirred at 110 °C for 90 min. The mixture was then cooled to r.t., diluted with EtOAc, and washed three times with 10% aq. LiCl solution followed by brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-45% to afford tert-butyl (3-(2-(benzyloxy)-5- fluoropyridin-3-yl)-1H-inden-6-yl)carbamate. ES / MS m / z: 433.2 [M+H]+.

[0317] Step 2. A mixture of tert-butyl (3-(2-(benzyloxy)-5-fluoropyridin-3-yl)-1H-inden-6- yl)carbamate (240 mg, 555 mmol), triethylammonium bis(catecholato)iodomethylsilicate (541 mg, 1.11 mmol), and 4CzIPN (12 mg, 28 umol) in DMSO (8 mL) was sparged with N2 for 1 min. The mixture was then sealed and irradiated with blue LEDs with stirring for 90 min. The mixture was then diluted with EtOAc, washed twice with 2M aq. NaOH, then water, then brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0- 50% to afford tert-butyl (1a-(2-(benzyloxy)-5-fluoropyridin-3-yl)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-4-yl)carbamate. ES / MS m / z: 469.2 [M+Na]+.

[0318] Step 3.1a-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-4-amine (I-82) was prepared in analogy to Intermediate I-62, step 3 using tert-butyl (1a-(2-(benzyloxy)-5-fluoropyridin-3-yl)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-4-yl)carbamate in place of tert-butyl (1-(2-(benzyloxy)-5- fluoropyridin-3-yl)-2,3-dihydro-1H-inden-5-yl)carbamate. ES / MS m / z: 347.1 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT of Intermediate I-83

[0319] (2S)-2-Amino-N-(1a-(2-(benzyloxy)-5-fluoropyridin-3-yl)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-4-yl)-3,3-dicyclopropylpropanamide (I-83) was prepared in analogy to I-63 using I-82 in place of I-62. ES / MS m / z: m / z 498.2 [M+H]+. of Intermediate I-84

[0320] N-((2S)-1-((1a-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-1,1a,6,6a- tetrahydrocyclopropa[a]inden-4-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1- isopropyl-1H-pyrazole-5-carboxamide (I-84) was prepared in analogy to I-64 using I-83 in place of I-63. ES / MS m / z: m / z 634.3 [M+H]+.

[0321] Step 1. (E)-N'-(5-Bromo-6-fluoro-2,3-dihydro-1H-inden-1-ylidene)-4- methylbenzenesulfonohydrazide was prepared in analogy to Intermediate I-62, step 1 using 5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-one in place of tert-butyl (1-oxo-2,3-dihydro-1H- inden-5-yl)carbamate. ES / MS m / z: 397.0 [M+H]+.

[0322] Step 2.2-(Benzyloxy)-3-(5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl)-5- fluoropyridine was prepared in analog to Intermediate I-62, step 2 using (E)-N'-(5-bromo-6- fluoro-2,3-dihydro-1H-inden-1-ylidene)-4-methylbenzenesulfonohydrazide in place of tert-butyl (E)-(1-(2-tosylhydrazineylidene)-2,3-dihydro-1H-inden-5-yl)carbamate. ES / MS m / z: 416.0 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0323] Step 3.1-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-6-fluoro-2,3-dihydro-1H-inden-5- amine (I-85). A vial was charged with 2-(benzyloxy)-3-(5-bromo-6-fluoro-2,3-dihydro-1H- inden-1-yl)-5-fluoropyridine (342 mg, 781 umol), t-BuBrettPhos Pd G3 (33.4 mg, 39 umol), and NaOt-Bu (105 mg, 1.09 mmol). The headspace was purged with N2, then 0.4M NH3 in 1,4- dioxane (7.8 mL, 3.1 mmol) was added. The mixture was sealed and stirred at 80 °C for 90 min. The mixture was then cooled to r.t., diluted with EtOAc, and filtered through a plug of celite. The resulting filtrate was concentrated in vacuo, and the crude residue purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to afford I-85. ES / MS m / z: 353.1 [M+H]+. of Intermediate I-86

[0324] (2S)-2-Amino-N-(1-(2-(benzyloxy)-5-fluoropyridin-3-yl)-6-fluoro-2,3-dihydro-1H- inden-5-yl)-3,3-dicyclopropylpropanamide (I-86) was prepared in analogy to I-63 using I-85 in place of I-62. ES / MS m / z: m / z 504.2 [M+H]+. of Intermediate I-87

[0325] N-((2S)-1-((1-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-6-fluoro-2,3-dihydro-1H-inden- 5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-87) was prepared in analogy to I-64 using I-86 in place of I-63. ES / MS m / z: m / z 640.3 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-88

[0326] Step 1. A mixture of 6-bromo-1-methyl-indoline-2,3-dione (200 mg, 833 umol), (2- benzyloxy-5-fluoro-3-pyridyl)boronic acid (823 mg, 3.33 mmol), (Acetylacetonato)dicarbonylrhodium(I) (21.5 mg, 83.3 umol), and P(c-Hex)3 (45.7 mg, 167 umol) in 9:1 DME / water (4 mL) was sparged with N2 for 1 min. The mixture was then stirred at 80 °C for 24 h, then cooled to r.t. and diluted with sat. aq. NaHCO3 solution. The mixture was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to afford 3-(2-(benzyloxy)-5- fluoropyridin-3-yl)-6-bromo-3-hydroxy-1-methylindolin-2-one. ES / MS m / z: 443.0 [M+H]+.

[0327] Step 2.6-Aamino-3-(2-(benzyloxy)-5-fluoropyridin-3-yl)-3-hydroxy-1- methylindolin-2-one (I-88) was prepared in analogy to Intermediate I-20, step 2 using 3-(2- (benzyloxy)pyridin-3-yl)-6-bromo-3-hydroxy-1-methylindolin-2-one in place of 2-(5-chloro- 1,3-dihydroisobenzofuran-1-yl)-N-(2,2,2-trifluoroethyl)acetamide. ES / MS m / z: 380.1 [M+H]+. Preparation of Intermediate I-89

[0328] (2S)-2-Amino-N-(3-(2-(benzyloxy)-5-fluoropyridin-3-yl)-3-hydroxy-1-methyl-2- oxoindolin-6-yl)-3,3-dicyclopropylpropanamide (I-89) was prepared in analogy to I-63 using I-88 in place of I-62. ES / MS m / z: 531.2 [M+H]+Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-90

[0329] N-((2S)-1-((3-(2-(Benzyloxy)-5-fluoropyridin-3-yl)-3-hydroxy-1-methyl-2- oxoindolin-6-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (I-90) was prepared in analogy to I-64 using I-89 in place of I-63. ES / MS m / z: 689.3 [M+Na]+. of Intermediate I-91

[0330] Step 1. A mixture of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride (2.00 g, 8.05 mmol) in DMF (16 mL) was treated with DIPEA (7.01 mL, 40.2 mmol), (2R)-2-(tert- butoxycarbonylamino)-2-cyclopropyl-acetic acid (1.91 g, 8.85 mmol), and HATU (2.84 g, 12.1 mmol). The mixture was stirred at r.t. for 150 min, then diluted with water. The resulting solids were isolated by filtration to afford tert-butyl ((R)-2-(((R)-5-bromo-2,3-dihydro-1H-inden-1- yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate, which was used in subsequent steps without further purification. ES / MS m / z: 409.0 [M+H]+.

[0331] Step 2. A pressure flask was charged with tert-butyl ((R)-2-(((R)-5-bromo-2,3- dihydro-1H-inden-1-yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (2.52 g, 5.86 mmol), tBuBrettPhos Pd G3 (250 mg, 293 umol), and NaOt-Bu (788 mg, 8.20 mmol). The headspace was flushed with N2, then 0.4 M NH3 in 1,4-dioxane (59 mL, 23 mmol) was added. The vessel was sealed, and the mixture stirred at 80 °C for 80 min. The mixture was cooled to r.t., diluted with EtOAc, and filtered through a plug of celite. The resulting filtrate was concentrated in vacuo, and the crude residue purified by SiO2 column chromatography eluting with 3:1 EtOAc / EtOH in heptane 0-60% to afford tert-butyl ((R)-2-(((R)-5-amino-2,3-dihydro-1H-inden- 1-yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate (I-91). ES / MS m / z: 346.1 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0332] Step 1. A mixture of I-91 (300 mg, 825 umol) and (2S)-2-(benzyloxycarbonylamino)- 3,3-dicyclopropyl-propanoic acid (300 mg, 990 umol) in MeCN (16.5 mL) was treated with NMI (204 uL, 2.56 mmol) followed by TCFH (347 mg, 1.24 mmol). The mixture was stirred at r.t. for 50 min, then diluted with water. The resulting solids were isolated by filtration to afford tert-butyl ((R)-2-(((R)-5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)- 2,3-dihydro-1H-inden-1-yl)amino)-1-cyclopropyl-2-oxoethyl)carbamate, which was used in subsequent steps without further purification.

[0333] Step 2. A mixture of tert-butyl ((R)-2-(((R)-5-((S)-2-(((benzyloxy)carbonyl)amino)- 3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-inden-1-yl)amino)-1-cyclopropyl-2- oxoethyl)carbamate (520 mg, 824 umol) in nitromethane (10 mL) was treated with ZnBr2 (928 mg, 4.12 mmol). The mixture was stirred with occasional sonication at r.t. for 6 h, then concentrated in vacuo. The resulting residue was taken up in EtOAc / water, and sat. aq. NaHCO3 was added. The resulting solids were isolated by filtration to afford benzyl ((S)-1-(((R)-1-((R)-2- amino-2-cyclopropylacetamido)-2,3-dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1- oxopropan-2-yl)carbamate, which was used in subsequent steps with further purification.

[0334] Step 3. A mixture of benzyl ((S)-1-(((R)-1-((R)-2-amino-2-cyclopropylacetamido)-2,3- dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (437 mg, 824 umol) in DMF (8 mL) was treated with Et3N (575 uL, 4.12 mmol) followed by Ac2O (195 uL, 2.06 mmol). The mixture was stirred at r.t. for 90 min, then diluted with water. The resulting solids were isolated by filtration to afford benzyl ((S)-1-(((R)-1-((R)-2-acetamido-2-Attorney Docket No.: 1537-US-NP / WO-PCT cyclopropylacetamido)-2,3-dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2- yl)carbamate, which was used in subsequent steps without further purification.

[0335] Step 4. A mixture of benzyl ((S)-1-(((R)-1-((R)-2-acetamido-2-cyclopropylacetamido)- 2,3-dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate (472 mg, 824 umol) and Pd / C (10wt% loading, 175 mg, 165 umol) in EtOH (15 mL) was stirred under a H2 atmosphere (balloon) for 3 h. An additional portion of Pd / C (10wt% loading, 175 mg, 165 umol) was added, and the mixture was stirred under a H2 atmosphere (balloon) overnight. The mixture was then filtered, and the resulting filtrate concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with 1:1 MeOH / EtOAc (with 0.5% Et3N) in EtOAc 0-50% to afford (S)-N-((R)-1-((R)-2-acetamido-2-cyclopropylacetamido)- 2,3-dihydro-1H-inden-5-yl)-2-amino-3,3-dicyclopropylpropanamide (I-92). ES / MS m / z: 439.2 [M+H]+.

[0336] Step 1. A mixture of (R)-5-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride (1.00 g, 4.02 mmol) in DMF (8 mL) was treated with DIPEA (3.50 mL, 20.1 mmol) followed by (2S)- 2-(tert-butoxycarbonylamino)-4-methylsulfanyl-butanoic acid (1.10 g, 4.43 mmol) and HATU (1.42 g, 6.04 mmol). The mixture was stirred for 75 min at r.t., then diluted with water. The resulting solids were isolated by filtration, then further purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to afford tert-butyl ((S)-1-(((R)-5-bromo-2,3-dihydro- 1H-inden-1-yl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate. ES / MS m / z: 445.0 [M+H]+.

[0337] Step 2. A mixture of tert-butyl ((S)-1-(((R)-5-bromo-2,3-dihydro-1H-inden-1- yl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (777 mg, 1.67 mmol) in DCM (6.5 mL) was cooled in an ice bath and treated with Me3OBF4 (236 mg, 1.83 mmol) with stirring. The mixture was stirred at ice bath temperature for 30 min, then warmed to r.t. and stirred for an additional 2 h. An additional portion of Me3OBF4 (118 mg, 915 umol) was added, and the mixture was stirred for an additional 3 h. K2CO3 (691 mg, 5.00 mmol) was added, a reflux condenser was attached to the reaction vessel, and the mixture was stirred at 40 °C overnight. The mixture was then cooled to r.t., and treated with MeCN (6.5 mL), followed by Cs2CO3 (1.09Attorney Docket No.: 1537-US-NP / WO-PCT g, 3.33 mmol). The mixture was stirred at 65 °C for 5 h. The mixture was cooled to r.t., diluted with EtOAc, and filtered through celite. The resulting filtrate was concentrated in vacuo, and the crude residue purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-80% to afford tert-butyl ((S)-1-((R)-5-bromo-2,3-dihydro-1H-inden-1-yl)-2-oxopyrrolidin-3- yl)carbamate. ES / MS m / z: 396.9 [M+H]+.

[0338] Step 3. tert-Butyl ((S)-1-((R)-5-amino-2,3-dihydro-1H-inden-1-yl)-2- oxopyrrolidin-3-yl)carbamate (I-93) was prepared in analogy to Intermediate I-91, step 2 using tert-butyl ((S)-1-((R)-5-bromo-2,3-dihydro-1H-inden-1-yl)-2-oxopyrrolidin-3- yl)carbamate in place of tert-butyl ((R)-2-(((R)-5-bromo-2,3-dihydro-1H-inden-1-yl)amino)-1- cyclopropyl-2-oxoethyl)carbamate. ES / MS m / z: 331.9 [M+H]+. of Intermediate I-94

[0339] Step 1. tert-butyl ((S)-1-((R)-5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-inden-1-yl)-2-oxopyrrolidin-3-yl)carbamate was prepared in analogy to Intermediate I-1, step 1 using I-93 in place of methyl 5-amino-2,3- dihydro-1H-indene-1-carboxylate hydrochloride.

[0340] Step 2. tert-butyl ((S)-1-((R)-5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3- dihydro-1H-inden-1-yl)-2-oxopyrrolidin-3-yl)carbamate was prepared in analogy to Intermediate I-1, step 2 using tert-butyl ((S)-1-((R)-5-((S)-2-(((benzyloxy)carbonyl)amino)- 3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-inden-1-yl)-2-oxopyrrolidin-3-yl)carbamate in place of methyl 5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3- dihydro-1H-indene-1-carboxylate.Attorney Docket No.: 1537-US-NP / WO-PCT

[0341] Step 3. tert-Butyl ((S)-1-((R)-5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole- 5-carboxamido)propanamido)-2,3-dihydro-1H-inden-1-yl)-2-oxopyrrolidin-3-yl)carbamate (I-94) was prepared in analogy to Intermediate I-1, step 3 using tert-butyl ((S)-1-((R)-5-((S)-2- amino-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-inden-1-yl)-2-oxopyrrolidin-3- yl)carbamate in place of methyl 5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3-dihydro- 1H-indene-1-carboxylate. ES / MS m / z: 619.3 [M+H]+. Preparation of Intermediate I-95

[0342] Step 1.6-Bromo-3-hydroxy-1,3-dimethylindolin-2-one was prepared in analogy to Intermediate I-34, step 2 using 6-bromo-1-methylindoline-2,3-dione in place of 6-bromo-1-(2- trimethylsilylethoxymethyl)indoline-2,3-dione.

[0343] Step 2.3,6-Dibromo-1,3-dimethylindolin-2-one (I-95) was prepared in analogy to Intermediate I-34, step 3 using 6-bromo-3-hydroxy-1,3-dimethylindolin-2-one in place of 6 - bromo-3-hydroxy-3-methyl-1-(2-trimethylsilylethoxymethyl)indolin-2-one. of Intermediates I-96 and I-97

[0344] Step 1. A mixture of I-95 (500 mg, 1.57 mmol) in MeCN (20.5 mL) was treated with DIPEA (563 uL, 3.13 mmol) followed by tert-butyl N-[(1R)-2-amino-1-methyl-ethyl]carbamate (546 mg, 3.13 mmol). The mixture was stirred at 40 °C overnight, then cooled to r.t., diluted with EtOAc, and washed with water. The organic layer was concentrated and the resulting crude residue purified by SiO2 column chromatography to afford tert-butyl ((2R)-1-((6-bromo-1,3- dimethyl-2-oxoindolin-3-yl)amino)propan-2-yl)carbamate.

[0345] Step 2. A mixture of tert-butyl ((2R)-1-((6-bromo-1,3-dimethyl-2-oxoindolin-3- yl)amino)propan-2-yl)carbamate (400 mg, 970 umol) in DCM (10 mL) was treated with TFA (4 mL). The mixture was stirred for 1 h at r.t., then concentrated in vacuo. The resulting residueAttorney Docket No.: 1537-US-NP / WO-PCT was then dissolved in MeCN (12.7 mL) and treated with DIPEA (1.04 mL, 5.82 mmol) followed by CDI (472 mg, 2.91 mmol). The mixture was stirred at 60 °C for 2 h, then cooled to r.t., diluted with sat. aq. NaHCO3, and extracted three times with EtOAc. The combined organics were concentrated in vacuo, and the resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to afford two peaks. Fractions corresponding to the first peak were concentrated in vacuo to afford the product tentatively assigned as (S)-6-bromo-1,3-dimethyl-3-((R)-4-methyl-2-oxoimidazolidin-1-yl)indolin-2-one (I-96). ES / MS m / z: 338.0 [M+H]+. Fractions corresponding to the second peak were concentrated in vacuo to afford the product tentatively assigned as (R)-6-bromo-1,3-dimethyl- 3-((R)-4-methyl-2-oxoimidazolidin-1-yl)indolin-2-one (I-97). ES / MS m / z: 338.0 [M+H]+. Preparation of Intermediate I-98

[0346] (S)-6-Amino-1,3-dimethyl-3-((R)-4-methyl-2-oxoimidazolidin-1-yl)indolin-2-one (I-98) was prepared in analogy to Intermediate I-20, step 2 using I-96 in place of 2-(5-chloro- 1,3-dihydroisobenzofuran-1-yl)-N-(2,2,2-trifluoroethyl)acetamide and 10% aqueous citric acid solution in place of 1M HCl. Preparation of Intermediates I-99 and I-100

[0347] Step 1.3-(((S)-2-Amino-3,3,3-trifluoropropyl)amino)-6-bromo-1,3-dimethylindolin-2- one was prepared in analogy to Intermediate I-34, step 4 using I-95 in place of 3,6-dibromo-3- methyl-1-(2-trimethylsilylethoxymethyl)indolin-2-one.Attorney Docket No.: 1537-US-NP / WO-PCT

[0348] Step 2. (S)-6-Bromo-1,3-dimethyl-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)indolin-2-one (I-99) and (R)-6-bromo-1,3-dimethyl-3-((S)-2-oxo-4- (trifluoromethyl)imidazolidin-1-yl)indolin-2-one (I-100) were prepared in analogy to Intermediate I-13, step 2 using 3-(((S)-2-amino-3,3,3-trifluoropropyl)amino)-6-bromo-1,3- dimethylindolin-2-one in place of (2S)-N1-(8-bromo-2,3,4,5-tetrahydrobenzo[b]oxepin-5-yl)- 3,3,3-trifluoropropane-1,2-diamine. Diastereomers were separated during purification by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give the product tentatively assigned as (S)-6-bromo-1,3-dimethyl-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)indolin-2-one (I-99) as the first-eluting diastereomer. Preparation of Intermediate I-101

[0349] (S)-6-Amino-1,3-dimethyl-3-((S)-2-oxo-4-(trifluoromethyl)imidazolidin-1- yl)indolin-2-one (I-101) was prepared in analogy to I-20, step 2 using I-99 in place of 2-(5- chloro-1,3-dihydroisobenzofuran-1-yl)-N-(2,2,2-trifluoroethyl)acetamide and 10% aqueous citric acid solution in place of 1M HCl. of Intermediate I-102

[0350] Step 1. A mixture of tert-butyl (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl)carbamate (1.96 g, 6.28 mmol) in DMF (13.1 mL) was treated with NaH (60% dispersion in mineral oil, 404 mg, 8.79 mmol). The mixture was stirred at r.t., then treated dropwise with MeI (469 uL, 7.53 mmol). The mixture was stirred at r.t. for 4 h, then poured into 30 mL of water cooled to 5 °C. The resulting mixture was stirred for 5 min, then the resulting solids were isolated by filtration to afford tert-butyl (R)-(5-bromo-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate. ES / MS m / z: 348.0 [M+Na]+.

[0351] Step 2. tert-Butyl (R)-(5-amino-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (I- 102) was prepared in analogy to I-20, step 2 using tert-butyl (R)-(5-bromo-2,3-dihydro-1H-Attorney Docket No.: 1537-US-NP / WO-PCT inden-1-yl)(methyl)carbamate in place of 2-(5-chloro-1,3-dihydroisobenzofuran-1-yl)-N-(2,2,2- trifluoroethyl)acetamide and using 10% aqueous citric acid solution in place of 1M HCl. ES / MS m / z: 285.1 [M+Na]+.

[0352] Step 1. tert-Butyl ((R)-5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate was prepared in analogy to Intermediate I-1, step 1 using I-102 in place of methyl 5-amino-2,3-dihydro-1H- indene-1-carboxylate hydrochloride. ES / MS m / z: 548.2 [M+H]+.

[0353] Step 2. tert-Butyl ((R)-5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3- dihydro-1H-inden-1-yl)(methyl)carbamate was prepared in analogy to Intermediate I-1, step 2 using tert-butyl ((R)-5-((S)-2-(((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)- 2,3-dihydro-1H-inden-1-yl)(methyl)carbamate in place of methyl 5-((S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1- carboxylate.

[0354] Step 3. tert-Butyl ((R)-5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate was prepared in analogy to Intermediate I-1, step 3 using tert-butyl ((R)-5-((S)-2-amino-3,3- dicyclopropylpropanamido)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate in place of methyl 5-Attorney Docket No.: 1537-US-NP / WO-PCT ((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 572.3 [M+Na]+.

[0355] Step 4. N-((S)-1,1-Dicyclopropyl-3-(((R)-1-(methylamino)-2,3-dihydro-1H-inden- 5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-103). A mixture of tert-butyl ((R)-5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate (252 mg, 458 umol) in MeNO2 (2.4 mL) was treated with ZnBr2 (516 mg, 2.29 mmol) and stirred at r.t. overnight. The mixture was then diluted with sat. aq. NaHCO3 solution and extracted with EtOAc. The combined organics were concentrated in vacuo to afford N-((S)-1,1-dicyclopropyl-3-(((R)-1- (methylamino)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (I-103), which was used for subsequent steps without further purification. of Intermediate I-104

[0356] tert-Butyl (R)-(5-amino-2,3-dihydro-1H-inden-1-yl)(methyl-d3)carbamate (I-104) was prepared in analogy to I-102 using iodomethane-d3 in place of iodomethane. ES / MS m / z: 266.2 [M+H]+. Preparation of Intermediate I-105

[0357] N-((S)-1,1-Dicyclopropyl-3-(((R)-1-((methyl-d3)amino)-2,3-dihydro-1H-inden-5- yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-105) was prepared in analogy to I-103 using I-104 in place of I-102. ES / MS m / z: 475.3 [M+Na]+.Attorney Docket No.: 1537-US-NP / WO-PCT

[0358] Step 1. A mixture of 5-bromo-1-methyl-2,3-dihydro-1H-inden-1-amine hydrochloride (5.00 g, 19.0 mmol) in DCM (61 mL) was treated with Boc2O (4.99 g, 22.9 mmol) followed by Et3N (13.3 mL, 95.2 mmol). The mixture was stirred at r.t. for 16 h, then diluted with water and extracted with DCM. The organic layer was then washed with water followed by brine, dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to afford tert-butyl (5-bromo-1- methyl-2,3-dihydro-1H-inden-1-yl)carbamate. ES / MS m / z: 348.0 [M+Na]+.

[0359] Step 2. A mixture of tert-butyl (5-bromo-1-methyl-2,3-dihydro-1H-inden-1- yl)carbamate (1.00 g, 3.07 mmol), Pd2(dba)3 (140 mg, 153 umol), XantPhos (178 mg, 307 umol), and Cs2CO3 (3.00 g, 9.20 mmol) in 1,4-dioxane (15 mL) was treated with benzophenone imine (611 mg, 3.37 mmol). The mixture was then sparged with N2 for 2 min, the vessel sealed, and the mixture was stirred at 85 °C for 3 h. The mixture was then cooled to r.t. and filtered. The resulting filtrate was concentrated in vacuo. The resulting residue was then purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-50% to afford tert-butyl (5- ((diphenylmethylene)amino)-1-methyl-2,3-dihydro-1H-inden-1-yl)carbamate. ES / MS m / z: 427.9 [M+H]+.

[0360] Step 3. A mixture of tert-butyl (5-((diphenylmethylene)amino)-1-methyl-2,3-dihydro- 1H-inden-1-yl)carbamate (2.20 g, 5.16 mmol), KOAc (3.04 g, 30.9 mmol), and hydroxylamine hydrochloride (1.43 g, 20.6 mmol) in 1,4-dioxane (50 mL) was stirred at 30 °C for 24 h. The mixture was then cooled to r.t., diluted with sat. aq. NaHCO3 solution, and extracted three times with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting residue was further purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-30% to afford tert-butyl (5-amino-1-methyl-2,3-dihydro-1H-inden-1- yl)carbamate (I-106). ES / MS m / z: 285.1 [M+Na]+.Attorney Docket No.: 1537-US-NP / WO-PCT of Intermediates I-107 and I-108

[0361] Step 1. Benzyl ((2S)-1-((1-((tert-butoxycarbonyl)amino)-1-methyl-2,3-dihydro-1H- inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate was prepared in analogy to Intermediate I-1, Step 1 using I-106 in place of methyl 5-amino-2,3-dihydro-1H-indene-1- carboxylate hydrochloride. ES / MS m / z: 370.3 [M+Na]+.

[0362] Step 2. tert-Butyl (5-((S)-2-amino-3,3-dicyclopropylpropanamido)-1-methyl-2,3- dihydro-1H-inden-1-yl)carbamate was prepared in analogy to Intermediate I-1, Step 2 using benzyl ((2S)-1-((1-((tert-butoxycarbonyl)amino)-1-methyl-2,3-dihydro-1H-inden-5-yl)amino)- 3,3-dicyclopropyl-1-oxopropan-2-yl)carbamate in place of methyl 5-((S)-2- (((benzyloxy)carbonyl)amino)-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1- carboxylate. ES / MS m / z: 414.3 [M+H]+.

[0363] Step 3. tert-Butyl (5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-1-methyl-2,3-dihydro-1H-inden-1-yl)carbamate was prepared in analogy to Intermediate 1, Step 3 using tert-butyl (5-((S)-2-amino-3,3- dicyclopropylpropanamido)-1-methyl-2,3-dihydro-1H-inden-1-yl)carbamate in place of methyl 5-((S)-2-amino-3,3-dicyclopropylpropanamido)-2,3-dihydro-1H-indene-1-carboxylate. ES / MS m / z: 572.3 [M+Na]+.

[0364] Step 4. N-((S)-1-(((S)-1-Amino-1-methyl-2,3-dihydro-1H-inden-5-yl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-107) and N- ((S)-1-(((R)-1-amino-1-methyl-2,3-dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1- oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-108) were prepared by analogyAttorney Docket No.: 1537-US-NP / WO-PCT to Intermediate I-103, Step 4 using tert-butyl (5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H- pyrazole-5-carboxamido)propanamido)-1-methyl-2,3-dihydro-1H-inden-1-yl)carbamate in place of tert-butyl ((R)-5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydro-1H-inden-1-yl)(methyl)carbamate. Purification by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% followed by MeOH in DCM 0- 80% afforded two diastereomeric products. Fractions containing the first-eluting product were combined and concentrated in vacuo to afford the product tentatively assigned as N-((S)-1-(((S)- 1-amino-1-methyl-2,3-dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)- 1-isopropyl-1H-pyrazole-5-carboxamide (I-107). Fractions containing the second-eluting product were combined and concentrated in vacuo to afford the product tentatively assigned as N-((S)-1-(((R)-1-amino-1-methyl-2,3-dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1- oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-108).

[0365] N-((S)-1-(((S)-1-Amino-1-methyl-2,3-dihydro-1H-inden-5-yl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-107). ES / MS m / z: 433.2 [M-NH2]+.

[0366] N-((S)-1-(((R)-1-Amino-1-methyl-2,3-dihydro-1H-inden-5-yl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-108). ES / MS m / z: 433.3 [M-NH2]+. Preparation of Intermediate I-109

[0367] Step 1. To a solution of methyl 3,3,3-trifluoro-2-oxopropanoate (50.0 g, 320.39 mmol) in DCM (500.0 mL) was added tert-butyl carbamate (37.5 g, 320.39 mmol) at room temperature, then the mixture was stirred at room temperature for 72 hrs. The mixture was concentrated under reduced pressure to afford methyl 2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoro-2-Attorney Docket No.: 1537-US-NP / WO-PCT hydroxypropanoate.1H NMR (400 MHz, CDCl3): δ 5.73 (brs, 1H), 5.39 (brs, 1H), 3.97 (s, 3H), 1.46 (s, 9H).

[0368] Step 2. To a solution of methyl 2-((tert-butoxycarbonyl)amino)-3,3,3-trifluoro-2- hydroxypropanoate (56.5 g, 206.80 mmol) in anhydrous Et2O (500.0 mL) was added pyridine (49.1 g, 620.40 mmol) at 0 °C. TFAA (65.2 g, 310.20 mmol) was added to the mixture at 0 °C dropwise under N2 atmosphere. Then the mixture was stirred for 1 h at 0 °C, and stirred for a further 16 h at room temperature. The resulting suspension was concentrated under reduced pressure. PE (500.0 mL) was added to the residue, stirred at room temperature for 10 min. the mixture was filtered, and the filter cake was washed with PE (200.0 mL). The filtrate was concentrated under reduced pressure to afford methyl (Z)-2-((tert-butoxycarbonyl)imino)-3,3,3- trifluoropropanoate.1H NMR (400 MHz, CDCl3): δ 3.95 (s, 3H), 1.58 (s, 9H).

[0369] Step 3. To a solution of methyl (Z)-2-((tert-butoxycarbonyl)imino)-3,3,3- trifluoropropanoate (48.8 g, 191.23 mmol) in THF (400.0 mL) was added allylmagnesium bromide (248.6 mL, 248.60 mmol, 1M in THF) at -78oC with N2 protection dropwise. The mixture was stirred at -78oC for 1 hours, then stirred at room temperature for 2 hours. The mixture was quenched with aq. NH4Cl (500.0 mL) and extracted with EA (500.0 mL x 2). The organic layer was washed with brine, dried by Na2SO4 and concentrated, the residue was purified by column chromatography with (PE: EA = 50: 1 to 20: 1) to afford methyl 2-((tert- butoxycarbonyl)amino)-2-(trifluoromethyl)pent-4-enoate.1H NMR (400 MHz, CDCl3): δ 5.67 - 5.58 (m, 1H), 5.44 (brs, 1H), 5.30 -5.19 (m, 2H), 3.95 (s, 3H), 3.42 - 3.38 (m, 1H), 2.83 - 2.77 (m, 1H), 1.47 (s, 9H).

[0370] Step 4. To a mixture of methyl 2-((tert-butoxycarbonyl)amino)-2- (trifluoromethyl)pent-4-enoate (24.0 g, 80.73 mmol) in THF / H2O (200.0 mL / 200.0 mL) was added K2OsO4.2H2O (1.3 g, 4.04 mmol) under Ar protection. The resulting mixture was stirred at 0oC for 10 mins. NaIO4 (40.1 g, 18.57 mmol) was added to the mixture in portions over 10 mins. Then the mixture was stirred at room temperature for 3 h. Water (600.0 mL) was added to the mixture, then extracted with EtOAc (500.0 mL x 2), The EA layer was quenched with aq. Na2SO3 (300.0 mL) and washed by brine, dried over Na2SO4, filtered and concentrated. The crude was purified by column chromatography with (PE: EA = 25: 1 to 10: 1) to afford methyl 2-((tert-butoxycarbonyl)amino)-4-oxo-2-(trifluoromethyl)butanoate (I-109).1H NMR (400 MHz, CDCl3): δ 9.67 (s, 1H), 5.85 (s, 1H), 4.27 (d, J = 18.0 Hz, 1H), 3.88 (s, 3H), 3.27 (d, J = 18.0 Hz, 1H), 1.41 (s, 9H).Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-110

[0371] Step 1. Into a 2 L 3-necked round-bottom flask were added HCOOH (560 mL) at roomtemperature. To the above mixture was added Et3N (830 mL) 0.5 h at 0 °C. The resultingmixture was stirred at 0 °C for additional 0.5 h and slowly added into a solution of 3-bromo-4- fluorobenzaldehyde (1 kg, 4925.866 mmol, 1 equiv) and meldrum's acid (709.95 g, 4925.866 mmol, 1 equiv) in DMF (5 L) under nitrogen atmosphere. The resulting mixture was stirred at 100 °C for additional overnight. The mixture was allowed to cool down to room temperature. The mixture basified to pH 10 with NaOH aq. The resulting mixture was extracted with EtOAc (3 x 5 L). The aqueous layer was acidified to pH 1 with conc. HCl. The resulting mixture was extracted with EtOAc (3 x 5 L). The combined organic layers were washed with brine (5 x 5 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3-(3-bromo-4-fluorophenyl)propanoic acid.1H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H), 7.63 – 7.56 (m, 1H), 7.31 – 7.25 (m, 2H), 2.81 (t, 2H), 2.61 – 2.52 (d, 2H).

[0372] Step 2. To a stirred solution of 3-(3-bromo-4-fluorophenyl)propanoic acid (800 g, 3238.0 mmol, 1 equiv) and DMF (40 mL, 516.9 mmol, 0.16 equiv) in DCM (4 L) was added oxalyl chloride (616.5 g, 4857.1 mmol, 1.50 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. TheAttorney Docket No.: 1537-US-NP / WO-PCT residue was dissolved in DCM (1 L) and was added to a refluxing suspension of AlCl3 (1295.2 g, 9714.1mmol, 3 equiv) in DCM (3 L). The resulting mixture was stirred at 40 °C for 3 h under nitrogen atmosphere. The mixture was then diluted with 1 M HCl aq (3 L) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (1 x 2 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with DCM:EA=1:2 (4 L). The resulting mixture was filtered, the filter cake was washed with DCM (2 x 200 mL). The filtrate was concentrated under reduced pressure to afford 5-bromo-6-fluoro-2,3-dihydroinden-1-one. ES / MS m / z: 228.9 [M+H]+.

[0373] Step 3. To a stirred solution of 5-bromo-6-fluoro-2,3-dihydroinden-1-one (600 g, 2619.5 mmol, 1 equiv) and (3aR)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2- c][1,3,2]oxazaborole (393 mL, 392.9 mmol, 0.15 equiv) in THF (3 L) was added Borane dimethyl sulfide complex (10 M) (367 mL, 3667.4 mmol, 1.40 equiv) dropwise at -5 °C under nitrogen atmosphere. The resulting mixture was stirred at -5 °C for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (3 L). The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (1 x 1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford (S)-5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-ol. ES / MS m / z: 229.0 [M-H]-.

[0374] Step 4. To a stirred solution of (1R)-5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-ol (410 g, 1774.4 mmol, 1 equiv) in DCM (2 L) were added DPPA (683.7 g, 2484.2 mmol, 1.4 equiv) and DBU (405.2 g, 2661.6 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (1 x 1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE (0.5% TEA) to afford (1S)-1-azido-5-bromo-6-fluoro-2,3- dihydro-1H-indene.1H NMR (400 MHz, Chloroform-d) δ 7.44 (d, 1H), 7.12 (d, 1H), 4.86 – 4.73 (m, 1H), 3.11 – 2.96 (m, 1H), 2.88 – 2.76 (m, 1H), 2.54 – 2.46 (m, 1H), 2.20 – 2.11 (m, 1H).

[0375] Step 5. To a stirred solution of (1S)-1-azido-5-bromo-6-fluoro-2,3-dihydro-1H-indene (380 g, 1483.9 mmol, 1 equiv) in methanol (2 L) was added Tin(II) chloride dihydrate (669.7 g, 2967.8 mmol, 2.00 equiv) in portions at 10 °C under nitrogen atmosphere. The resulting mixtureAttorney Docket No.: 1537-US-NP / WO-PCT was stirred at room temperature for 2 h under nitrogen atmosphere. The mixture was then diluted with 2 N NaOH aq (3 L) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with 1 N HCl aq (3 x 1 L). The combined water layers were basified to pH 11 with NaOH aq. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (1 x 1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (1S)-5- bromo-6-fluoro-2,3-dihydro-1H-inden-1-amine.1H NMR (300 MHz, Chloroform-d) δ 7.38 (d, 1H), 7.09 (d, 1H), 4.31 (t, 1H), 2.97 – 2.85 (m, 1H), 2.85 – 2.69 (m, 1H), 2.60 – 2.47 (m, 1H), 1.82 – 1.67 (m, 1H), 1.57 (s, 2H).

[0376] Step 6. To a stirred solution of (1S)-5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-amine (300 g, 1303.9 mmol, 1 equiv) and Et3N (197.9 g, 1955.8 mmol, 1.5 equiv) in DCM (2 L) was added di-tert-butyl dicarbonate (341.5 g, 1564.6 mmol, 1.2 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The resulting mixture was diluted with water (2 L). The resulting mixture was extracted with CH2Cl2 (2 x 1 L). The combined organic layers were washed with brine (2 x 1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with n-Hexane (800 mL). The precipitated solids were collected by filtration and washed with n-Hexane (3 x 200 mL) to afford tert-butyl N-[(1S)-5-bromo-6-fluoro-2,3-dihydro-1H-inden-1-yl]carbamate.1H NMR (300 MHz, Chloroform-d) δ 7.37 (d, 1H), 7.07 (d, 1H), 5.15 – 5.10 (m, 1H), 4.73 (s, 1H), 2.96 – 2.69 (m, 2H), 2.64 – 2.54 (m, 1H), 1.87 – 1.74 (m, 1H), 1.48 (s, 9H).

[0377] Step 7. To a stirred mixture of tert-butyl N-[(1S)-5-bromo-6-fluoro-2,3-dihydro-1H- inden-1-yl]carbamate (220 g, 666.3 mmol, 1 equiv), N,N'-bis({5-methyl-[1,1'-biphenyl]-2- yl})ethanediamide (14.0 g, 33.3 mmol, 0.05 equiv) and K3PO4 (424.3 g, 1998.807 mmol, 3 equiv) in DMSO (2.2 L) were added Ammonium hydroxide (28% in water) (140.1 g, 3997.6 mmol, 6 equiv) and CuI (6.3 g, 33.313 mmol, 0.05 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 24 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (2 L). The resulting mixture was filtered, the filter cake was washed with EA (3 x 500 mL). The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (5 x 1 L), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by neutral alumina column chromatography, eluted with PE / EA (12:1) to afford crude product. TheAttorney Docket No.: 1537-US-NP / WO-PCT residue was purified by trituration with MTBE:hexane=10:1 (1 L) to afford tert-butyl N-[(1S)-5- amino-6-fluoro-2,3-dihydro-1H-inden-1-yl]carbamate.1H NMR (300 MHz, DMSO-d6) δ 7.10 (d, 1H), 6.74 (d, 1H), 6.58 (d, 1H), 4.96 (s, 2H), 4.83 (q, 1H), 2.82 – 2.67 (m, 1H), 2.66 – 2.52 (q, 1H), 2.36 – 2.19 (m, 1H), 1.83 – 1.65 (m, 1H), 1.42 (s, 9H).

[0378] Step 8. N-((S)-1-(((R)-1-Amino-6-fluoro-2,3-dihydro-1H-inden-5-yl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-110) was prepared by analogy to Intermediate I-103 using tert-butyl N-[(1S)-5-amino-6-fluoro-2,3- dihydro-1H-inden-1-yl]carbamate in place of I-102. Preparation of Intermediates I-111

[0379] Step 1. Methyl (1r,3r)-3-((5-bromo-2,3-dihydro-1H-inden-1-yl)amino)-1- fluorocyclobutane-1-carboxylate. To a stirred solution of 5-bromoindan-1-one (420 mg, 2.00 mmol), methyl 3-amino-1-fluoro-cyclobutanecarboxylate (244 mg, 1.66 mmol), and triethylamine (0.46 mL, 3.3 mmol) in methanol (5 mL) was added a separately prepared mixture of sodium cyanoborohydride (417 mg, 6.63 mmol) and zinc chloride solution (1.9 M in 2- methyltetrohydrofuran, 1.74 mL, 3.31 mmol) in methanol (5 mL). The resulting mixture was stirred at 60 °C overnight, concentrated in vacuo, and the residue was taken up in ethyl acetate. The resulting organic phase was washed once with 1M aqueous hydrochloric acid, dried over magnesium sulphate, filtered, and concentrated in vacuo, producing a crude residue which was used without further purification. ES / MS m / z: 343.3 [M+H]+.

[0380] Step 2. (1r,3r)-3-((5-Bromo-2,3-dihydro-1H-inden-1-yl)amino)-1- fluorocyclobutane-1-carboxylic acid To a stirred solution of crude Methyl (1r,3r)-3-((5- bromo-2,3-dihydro-1H-inden-1-yl)amino)-1-fluorocyclobutane-1-carboxylate (567 mg, 1.66 mmol) obtained from the previous step in ethanol (5 mL) at was added a 2.0 M aqueous solution of potassium hydroxide (4.1 mL, 8.3 mmol). The mixture was stirred for one hour at room temperature, then standard acidic workup and concentration provided a crude residue that contained the product. (ES / MS m / z: 327.1 [M+H]+.

[0381] Step 3.4-(5-Bromo-2,3-dihydro-1H-inden-1-yl)-1-fluoro-2,4- diazabicyclo[3.1.1]heptan-3-one (I-111). To a stirred solution of crude (1r,3r)-3-((5-bromo-Attorney Docket No.: 1537-US-NP / WO-PCT 2,3-dihydro-1H-inden-1-yl)amino)-1-fluorocyclobutane-1-carboxylic acid (465 mg, 1.44 mmol) obtained from the previous step in dioxane (5 mL) was added N,N-diisopropylethylamine (0.37 mL, 2.1 mmol) and diphenylphosphoryl azide (507 mg, 1.84 mmol). The resulting mixture was heated to 110 °C, stirred at that temperature overnight, then concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0- 100% to give I-111. ES / MS m / z: 326.8 [M+H]+. Preparation of Intermediate I-112

[0382] (R)-4-(5-Amino-2,3-dihydro-1H-inden-1-yl)-1-fluoro-2,4- diazabicyclo[3.1.1]heptan-3-one (I-112) was prepared in analogy to I-37 using I-111 in place of I-14. of Intermediates I-113

[0383] tert-Butyl (2-(((R)-5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydro-1H-inden-1-yl)amino)-1-(2,2- difluorocyclopropyl)-2-oxoethyl)carbamate (I-113). To a mixture of I-7 (29 mg, 0.066 mmol), in dichloromethane (1 mL) and ethyl acetate (1 mL) was added HATU (38 mg, 0.099 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.3 mmol). The resulting mixture was stirred at room temperature temperature overnight, then concentrated in vacuo. The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc in hexanes 0-100% to give I-113 as a mixture of diastereomers. ES / MS m / z: 669.3 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-114

[0384] Step 1.1-(2-(Benzyloxy)-5-(trifluoromethyl)pyridin-3-yl)-2,3-dihydro-1H-inden-5- amine was prepared by analogy to Intermediate I-62 using [2-benzyloxy-5-(trifluoromethyl)-3- pyridyl]boronic acid in place of (2-(benzyloxy)-5-fluoropyridin-3-yl)boronic acid.

[0385] Step 2. (2S)-2-Amino-N-(1-(2-(benzyloxy)-5-(trifluoromethyl)pyridin-3-yl)-2,3- dihydro-1H-inden-5-yl)-3,3-dicyclopropylpropanamide was prepared by analogy to Intermediate I-63 using 1-(2-(benzyloxy)-5-(trifluoromethyl)pyridin-3-yl)-2,3-dihydro-1H- inden-5-amine in place of I-62.

[0386] Step 3. N-((2S)-1-((1-(2-(Benzyloxy)-5-(trifluoromethyl)pyridin-3-yl)-2,3-dihydro- 1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (I-114) was prepared by analogy to Intermediate I-64 using (2S)-2-amino-N-(1- (2-(benzyloxy)-5-(trifluoromethyl)pyridin-3-yl)-2,3-dihydro-1H-inden-5-yl)-3,3- dicyclopropylpropanamide in place of I-63. ES / MS m / z: 636.3 [M+H]+. Preparation of Intermediate I-115

[0387] N-((2S)-1-((1-(2-(Benzyloxy)pyridin-3-yl)-2,3-dihydro-1H-inden-5-yl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I-115) was prepared by analogy to Intermediate I-114 using (2-benzyloxy-3-pyridyl)boronic acid in place of [2-benzyloxy-5-(trifluoromethyl)-3-pyridyl]boronic acid. ES / MS m / z: 604.3 [M+H]+.Attorney Docket No.: 1537-US-NP / WO-PCT Preparation of Intermediate I-116

[0388] N-((2S)-1-((1-(2-(Benzyloxy)-5-methylpyridin-3-yl)-2,3-dihydro-1H-inden-5- yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I- 116) was prepared by analogy to Intermediate I-114 using (2-benzyloxy-5-methyl-3- pyridyl)boronic acid in place of [2-benzyloxy-5-(trifluoromethyl)-3-pyridyl]boronic acid. Preparation of Intermediate I-117

[0389] N-((2S)-1-((1-(2-(Benzyloxy)-5-chloropyridin-3-yl)-2,3-dihydro-1H-inden-5- yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (I- 117) was prepared by analogy to Intermediate I-114 using (2-benzyloxy-5-chloro-3- pyridyl)boronic acid in place of [2-benzyloxy-5-(trifluoromethyl)-3-pyridyl]boronic acid. Preparation of Intermediate I-118

[0390] tert-Butyl N-[(1R)-1-(methoxymethyl)-2-[methoxy(methyl)amino]-2-oxo- ethyl]carbamate To a solution of (2R)-2-(tert-butoxycarbonylamino)-3-methoxy-propanoic acid (110 mg, 0.5 mmol) in DMF (5 mL) at was added N,O-dimethyldroxylamine hydrochloride (54 mg, 0.55 mmol), N,N-diisoproplyethylamine (0.26 mL, 1.5 mmol), and HATU (141 mg, 0.6 mmol). The mixture was stirred for 3 hours then diluted with EtOAc, washed three times with brine. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo The resulting crude residue was purified by SiO2 column chromatography eluting with EtOAc inAttorney Docket No.: 1537-US-NP / WO-PCT hexanes 0-100% to tert-butyl N-[(1R)-1-(methoxymethyl)-2-[methoxy(methyl)amino]-2-oxo- ethyl]carbamate. ES / MS m / z: 263 [M+H]+. Example Procedures: Procedure 1, Example 1

[0391] N-((2S)-1,1-Dicyclopropyl-3-((1-((2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine- 1-carbonyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 1). To a stirred solution of I-1 (20.0 mg, 0.043 mmol), (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride (12.5 mg, 0.065 mmol), N,N- diisopropylethylamine (0.023 mL, 0.129 mmol), in DMF (1 mL) was added HATU (0.013 mg, 0.054 mmol) in one portion. The mixture was stirred at room temperature for 16h, then diluted with DMSO, filtered through a syringe filter, and purified by RP-HPLC (eluent: MeCN / H2O gradient with 0.1% TFA). Product-containing fractions were combined and lyophilized to afford N-((2S)-1,1-dicyclopropyl-3-((1-((2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine-1- carbonyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole- 5-carboxamide (Example 1) as the trifluoroacetate salt. ES / MS m / z: 604.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.27 – 10.02 (m, 1H), 8.42 (t, J = 7.8 Hz, 1H), 7.65 – 7.44 (m, 2H), 7.45 – 7.17 (m, 1H), 7.12 – 6.87 (m, 2H), 5.60 – 5.29 (m, 2H), 4.87 (dt, J = 68.3, 8.6 Hz, 2H), 4.47 – 4.16 (m, 1H), 4.14 – 3.81 (m, 1H), 3.08 – 2.53 (m, 2H), 2.47 – 2.03 (m, 2H), 1.36 (dd, J = 13.5, 6.6 Hz, 6H), 0.94 – 0.66 (m, 3H), 0.53 – 0.04 (m, 8H). Example 2

[0392] Ethyl 3-(5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydro-1H-indene-1-carboxamido)-4,4,4- trifluorobutanoate (Example 2) was prepared using Procedure 1 with ethyl 3-amino-4,4,4- trifluorobutanoate in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride.Attorney Docket No.: 1537-US-NP / WO-PCT ES / MS m / z: 632.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.08 (d, J = 2.9 Hz, 1H), 8.87 – 8.74 (m, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.60 – 7.45 (m, 2H), 7.43 – 7.26 (m, 1H), 7.09 – 7.01 (m, 1H), 6.92 (d, J = 1.8 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.95 (d, J = 12.2 Hz, 1H), 4.78 (t, J = 8.3 Hz, 1H), 4.23 – 3.95 (m, 2H), 3.85 (q, J = 7.0 Hz, 1H), 3.09 – 2.77 (m, 3H), 2.78 – 2.63 (m, 1H), 2.32 – 2.07 (m, 2H), 1.36 (dd, J = 13.7, 6.6 Hz, 6H), 1.25 – 1.04 (m, 3H), 0.96 – 0.64 (m, 3H), 0.51 – 0.03 (m, 8H). Example 3

[0393] N-((2S)-1,1-Dicyclopropyl-3-((1-(((S)-1,1,1,4,4,4-hexafluorobutan-2- yl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 3) was prepared using Procedure 1 with (2S)-1,1,1,4,4,4- hexafluorobutan-2-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 628.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.09 (d, J = 3.5 Hz, 1H), 8.95 (dd, J = 14.1, 9.1 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.61 – 7.46 (m, 2H), 7.41 – 7.29 (m, 1H), 7.07 (dd, J = 8.3, 4.3 Hz, 1H), 6.92 (d, J = 1.9 Hz, 1H), 5.48 – 5.33 (m, 1H), 5.03 – 4.84 (m, 1H), 4.78 (t, J = 8.3 Hz, 1H), 3.89 (t, J = 7.5 Hz, 1H), 3.11 – 2.64 (m, 4H), 2.30 – 2.13 (m, 2H), 1.36 (dd, J = 13.7, 6.6 Hz, 6H), 0.94 – 0.67 (m, 4H), 0.53 – 0.04 (m, 7H). Example 4

[0394] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-((2-(trifluoromethoxy)ethyl)carbamoyl)- 2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 4) was prepared using Procedure 1 with 2-(trifluoromethoxy)ethan-1-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 576.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 8.48 – 8.32 (m, 2H), 7.58 – 7.47 (m, 2H), 7.40 – 7.26 (m, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.48 – 5.32 (m, 1H), 4.78 (t, JAttorney Docket No.: 1537-US-NP / WO-PCT = 8.3 Hz, 1H), 4.16 – 4.03 (m, 2H), 3.84 (t, J = 7.5 Hz, 1H), 3.51 – 3.30 (m, 2H), 3.06 – 2.71 (m, 2H), 2.29 – 2.10 (m, 2H), 1.36 (dd, J = 13.4, 6.6 Hz, 6H), 0.95 – 0.66 (m, 3H), 0.52 – 0.03 (m, 8H). Example 5

[0395] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-((2,2,2-trifluoro-1-(pyridin-3- yl)ethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 5) was prepared using Procedure 1 with 2,2,2-trifluoro-1- (pyridin-3-yl)ethan-1-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 623.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.08 (m, 1H), 9.53 (d, J = 9.6 Hz, 1H), 8.87 (s, 1H), 8.67 (t, J = 5.0 Hz, 1H), 8.40 (dd, J = 13.1, 8.8 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 7.64 – 7.47 (m, 3H), 7.44 – 7.20 (m, 1H), 7.19 – 6.94 (m, 1H), 6.94 – 6.88 (m, 1H), 6.00 (p, J = 9.2 Hz, 1H), 5.49 – 5.34 (m, 1H), 4.77 (dt, J = 15.9, 8.3 Hz, 1H), 4.06 (t, J = 7.4 Hz, 1H), 2.99 (dd, J = 15.9, 7.7 Hz, 1H), 2.91 – 2.74 (m, 1H), 2.23 m, 2H), 1.36 (dt, J = 14.3, 6.5 Hz, 6H), 0.95 – 0.63 (m, 3H), 0.52 – 0.03 (m, 8H). Example 6

[0396] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-(((S)-2,2,2-trifluoro-1- phenylethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 6) was prepared using Procedure 1 with (S)-2,2,2- trifluoro-1-phenylethan-1-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride ES / MS m / z: 622.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.07 (m, 1H), 9.43 (d, J = 9.6 Hz, 1H), 8.39 (dd, J = 15.1, 8.8 Hz, 1H), 7.71 – 7.12 (m, 9H), 7.02 – 6.88 (m, 1H), 5.80 (h, J = 8.7 Hz, 1H), 5.40 (dp, J = 8.4, 6.6 Hz, 1H), 4.85 – 4.71 (m, 1H), 4.07 (t, J = 7.4Attorney Docket No.: 1537-US-NP / WO-PCT Hz, 1H), 2.98 (dq, J = 16.1, 4.2 Hz, 1H), 2.91 – 2.77 (m, 1H), 2.31 – 2.10 (m, 2H), 1.43 – 1.27 (m, 6H), 1.03 – 0.63 (m, 3H), 0.53 – 0.02 (m, 8H). Example 7

[0397] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((S)-1-(((S)-1,1,1-trifluoro-3-hydroxypropan-2- yl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 7) was prepared using Procedure 1 with (S)-2-amino-3,3,3- trifluoropropan-1-ol in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride ES / MS m / z: 576.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.68 (d, J = 9.1 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 2H), 7.38 (dd, J = 8.2, 1.9 Hz, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.78 (t, J = 8.3 Hz, 1H), 4.56 (dt, J = 14.5, 7.8 Hz, 1H), 3.97 (t, J = 7.7 Hz, 1H), 3.73 (dd, J = 11.5, 5.0 Hz, 1H), 3.64 (dd, J = 11.4, 6.6 Hz, 1H), 3.02 – 2.76 (m, 2H), 2.28 – 2.13 (m, 2H), 1.36 (dd, J = 13.3, 6.6 Hz, 6H), 0.96 – 0.65 (m, 3H), 0.54 – 0.03 (m, 8H). Example 8

[0398] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-(((R)-1,1,1-trifluorobutan-2-yl)carbamoyl)- 2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 8) was prepared using Procedure 1 with (R)-1,1,1-trifluorobutan-2-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride ES / MS m / z: 574.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.59 (d, J = 9.1 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.54 (m, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.35 (m, 1H), 7.12 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.78 (t, J = 8.3 Hz, 1H), 4.51 – 4.30 (m, 1H), 3.93 (q, J = 7.3 Hz, 1H), 3.08 – 2.92 (m, 1H), 2.84 (dt, J = 15.8, 7.9 Hz, 1H), 2.31 – 2.14 (m, 2H), 1.77 (ddp, J = 14.8, 7.4, 3.8 Hz, 1H), 1.58 (ddt, J = 13.9, 10.9, 7.2 Hz, 1H), 1.36 (dd, J = 13.7, 6.6 Hz, 6H), 0.97 – 0.65 (m, 6H), 0.50 – 0.05 (m, 8H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 9

[0399] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-((2,2,2-trifluoro-1-(pyridin-2- yl)ethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 9) was prepared using Procedure 1 with 2,2,2-trifluoro-1- (pyridin-2-yl)ethan-1-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride ES / MS m / z: 623.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.13 – 9.98 (m, 1H), 9.48 – 9.35 (m, 1H), 8.76 – 8.62 (m, 1H), 8.39 (dd, J = 14.9, 8.8 Hz, 1H), 7.93 (td, J = 7.7, 1.8 Hz, 1H), 7.76 – 7.67 (m, 1H), 7.60 – 7.44 (m, 3H), 7.43 – 7.19 (m, 1H), 7.08 (dd, J = 8.6, 2.3 Hz, 1H), 6.96 – 6.87 (m, 1H), 5.92 (h, J = 8.1 Hz, 1H), 5.40 (dp, J = 8.8, 6.6 Hz, 1H), 4.77 (dt, J = 16.4, 8.3 Hz, 1H), 4.22 – 4.12 (m, 1H), 3.05 – 2.75 (m, 2H), 2.30 – 2.10 (m, 2H), 1.40 – 1.30 (m, 6H), 1.00 – 0.65 (m, 3H), 0.52 – 0.03 (m, 8H). Example 10

[0400] N-((2S)-1,1-Dicyclopropyl-3-((1-(3,3-difluoroazetidine-1-carbonyl)-2,3-dihydro- 1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 10) was prepared using Procedure 1 with 3,3-difluoroazetidine hydrochloride in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride ES / MS m / z: 540.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.55 (dd, J = 9.4, 1.9 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.36 (ddd, J = 11.2, 8.3, 2.0 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.93 – 4.68 (m, 3H), 4.34 (t, J = 12.7 Hz, 2H), 4.01 (t, J = 7.6 Hz, 1H), 2.97 (dt, J = 15.0, 6.5 Hz, 1H), 2.83 (ddd, J = 16.0, 10.6, 7.4 Hz, 1H), 2.31 – 2.20 (m, 1H), 2.20 – 2.11 (m, 1H), 1.36 (dd, J = 13.4, 6.6 Hz, 6H), 0.96 – 0.66 (m, 3H), 0.52 – 0.04 (m, 8H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 11

[0401] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-(((S)-1,1,1-trifluoropropan-2- yl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 11) was prepared using Procedure 1 with (2S)-1,1,1-trifluoropropan- 2-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 560.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.51 (dd, J = 9.0, 6.8 Hz, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.39 – 7.25 (m, 2H), 7.14 (ddd, J = 31.0, 8.2, 2.0 Hz, 1H), 6.89 (dd, J = 33.9, 8.3 Hz, 1H), 6.71 (t, J = 1.9 Hz, 1H), 5.24 – 5.13 (m, 1H), 4.57 (td, J = 8.4, 8.0, 2.0 Hz, 1H), 4.41 (dp, J = 16.7, 8.3 Hz, 1H), 3.68 (q, J = 7.3 Hz, 1H), 3.12 (t, J = 5.5 Hz, 1H), 2.77 (dt, J = 14.5, 6.7 Hz, 1H), 2.62 (dt, J = 15.9, 8.1 Hz, 1H), 2.10 – 1.87 (m, 2H), 1.21 – 1.00 (m, 8H), 0.70 – 0.44 (m, 3H), 0.27 – -0.07 (m, 7H), -0.12 (t, J = 6.7 Hz, 1H). Example 12

[0402] N-((2S)-1,1-Dicyclopropyl-3-((1-(3,3-difluoropyrrolidine-1-carbonyl)-2,3-dihydro- 1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 12) was prepared using Procedure 1 with 3,3-difluoropyrrolidine in place of (2S,4S)- 4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 554.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.68 – 7.45 (m, 2H), 7.36 (ddd, J = 14.1, 8.1, 2.6 Hz, 1H), 7.05 (dd, J = 8.3, 3.9 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 4.23 (t, J = 7.7 Hz, 1H), 4.20 – 4.10 (m, 1H), 4.02 – 3.85 (m, 1H), 3.76 (t, J = 13.4 Hz, 1H), 3.57 (t, J = 7.5 Hz, 1H), 3.03 – 2.91 (m, 1H), 2.91 – 2.76 (m, 1H), 2.72 – 2.53 (m, 1H), 2.48 – 2.40 (m, 1H), 2.36 – 2.22 (m, 1H), 2.22 – 2.10 (m, 1H), 1.36 (dd, J = 13.4, 6.6 Hz, 6H), 0.94 – 0.67 (m, 4H), 0.51 – 0.14 (m, 6H), 0.12 – 0.05 (m, 1H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 13

[0403] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-(3,3,4,4-tetrafluoropyrrolidine-1-carbonyl)- 2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 13) was prepared using Procedure 1 with 3,3,4,4-tetrafluoropyrrolidine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 590.3 [M+H]+.1H NMR (400 MHz, DMSO-d6). H NMR (400 MHz, DMSO) δ 10.10 (s, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.56 (dd, J = 9.9, 1.9 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.36 (ddd, J = 12.0, 8.2, 2.0 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.5 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 4.54 (h, J = 13.2 Hz, 2H), 4.07 (t, J = 14.1 Hz, 2H), 3.04 – 2.92 (m, 1H), 2.91 – 2.77 (m, 1H), 2.39 – 2.26 (m, 1H), 2.21 – 2.07 (m, 1H), 1.36 (dd, J = 13.5, 6.6 Hz, 6H), 0.94 – 0.67 (m, 4H), 0.49 – 0.24 (m, 4H), 0.24 – 0.14 (m, 3H), 0.13 – 0.05 (m, 1H). Example 14

[0404] N-((2S)-1-((1-((R)-2-Carbamoyl-4,4-difluoropyrrolidine-1-carbonyl)-2,3-dihydro- 1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 14) was prepared using Procedure 1 with (R)-4,4-difluoropyrrolidine- 2-carboxamide in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 597.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.12 – 10.04 (m, 1H), 8.40 (dd, J = 8.9, 2.4 Hz, 1H), 7.78 – 7.01 (m, 6H), 6.92 (d, J = 2.0 Hz, 1H), 5.41 (hept, J = 6.5 Hz, 1H), 4.92 – 4.74 (m, 1H), 4.52 (ddd, J = 11.2, 9.4, 5.1 Hz, 1H), 4.33 (q, J = 11.8 Hz, 1H), 4.25 – 4.06 (m, 1H), 4.01 – 3.86 (m, 1H), 3.79 (q, J = 13.3 Hz, 1H), 3.23 – 2.68 (m, 2H), 2.58 (dd, J = 20.1, 11.4 Hz, 1H), 2.47 – 1.97 (m, 2H), 1.36 (dd, J = 13.4, 6.6 Hz, 6H), 0.94 – 0.67 (m, 4H), 0.58 – 0.03 (m, 7H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 15

[0405] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-((2,2,2-trifluoroethyl)carbamoyl)-2,3- dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 15) was prepared using Procedure 1 with 2,2,2-trifluoroethan-1-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 546.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.59 (t, J = 6.3 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.14 (ddd, J = 18.8, 8.3, 2.0 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 5.19 (p, J = 6.6 Hz, 1H), 4.57 (t, J = 8.3 Hz, 1H), 3.91 – 3.62 (m, 2H), 2.88 – 2.69 (m, 1H), 2.69 – 2.54 (m, 1H), 2.11 – 1.95 (m, 2H), 1.15 (dd, J = 13.5, 6.6 Hz, 6H), 1.03 (s, 1H), 0.75 – 0.45 (m, 3H), 0.23 (t, J = 6.5 Hz, 1H), 0.20 – 0.04 (m, 2H), 0.04 – -0.07 (m, 3H), -0.13 (d, J = 10.6 Hz, 1H). 16 and 17

[0406] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((R)-1-((2,2,2-trifluoroethyl)carbamoyl)-2,3- dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 16) and N-((S)-1,1-dicyclopropyl-3-oxo-3-(((S)-1-((2,2,2- trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 17). Example 15 (22.0 mg, 40.3 mmol) was subjected to chiral SFC (Column: IE 250 mm x 21 mm, 5 mm, eluent: 30% EtOH) to afford two peaks. Fractions corresponding to the first peak were concentrated in vacuo to afford the product tentatively assigned as N-((S)-1,1-dicyclopropyl-3-oxo-3-(((R)-1-((2,2,2- trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 16). Fractions corresponding to the second peak were concentrated in vacuo to afford the product tentatively assigned as N-((S)-1,1-dicyclopropyl-3- oxo-3-(((S)-1-((2,2,2-trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan- 2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 17).Attorney Docket No.: 1537-US-NP / WO-PCT

[0407] Example 16. ES / MS m / z: 546.2 [M+H]+,1H NMR (400 MHz, DMSO-d6). δ 9.88 (s, 1H), 8.59 (t, J = 6.3 Hz, 1H), 8.19 (d, J = 8.9 Hz, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 7.29 (d, J = 2.0 Hz, 1H), 7.14 (ddd, J = 18.8, 8.3, 2.0 Hz, 1H), 6.90 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 2.0 Hz, 1H), 5.19 (p, J = 6.6 Hz, 1H), 4.57 (t, J = 8.3 Hz, 1H), 3.91 – 3.62 (m, 2H), 2.88 – 2.69 (m, 1H), 2.69 – 2.54 (m, 1H), 2.11 – 1.95 (m, 2H), 1.15 (dd, J = 13.5, 6.6 Hz, 6H), 1.03 (s, 1H), 0.75 – 0.45 (m, 3H), 0.23 (t, J = 6.5 Hz, 1H), 0.20 – 0.04 (m, 2H), 0.04 – -0.07 (m, 3H), -0.13 (d, J = 10.6 Hz, 1H).

[0408] Example 17. ES / MS m / z: 546.2 [M+H]+,1H NMR (400 MHz, DMSO-d6). δ 10.09 (s, 1H), 8.79 (t, J = 6.3 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.32 (dd, J = 8.2, 1.9 Hz, 1H), 7.10 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 4.78 (t, J = 8.3 Hz, 1H), 4.06 – 3.86 (m, 3H), 3.03 – 2.93 (m, 1H), 2.88 – 2.78 (m, 1H), 2.30 – 2.14 (m, 2H), 1.40 – 1.31 (m, 6H), 0.91 – 0.68 (m, 3H), 0.49 – 0.14 (m, 7H), 0.13 – 0.06 (m, 1H). Example 18

[0409] N-((2S)-1,1-Dicyclopropyl-3-((1-((S)-3,3-difluoro-2-methylazetidine-1-carbonyl)- 2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 18) was prepared using Procedure 1 with (S)-3,3-difluoro-2- methylazetidine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 554.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 13.2, 1.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.41 – 7.31 (m, 1H), 7.14 – 7.03 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 4.82 – 4.62 (m, 3H), 4.38 – 4.20 (m, 1H), 3.01 – 2.91 (m, 1H), 2.89 – 2.77 (m, 1H), 2.34 – 2.06 (m, 2H), 1.57 – 1.46 (m, 1H), 1.36 (dd, J = 13.4, 6.6 Hz, 8H), 0.92 – 0.68 (m, 3H), 0.49 – 0.14 (m, 7H), 0.13 – 0.05 (m, 1H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 19

[0410] N-((2S)-1,1-Dicyclopropyl-3-((1-(4,4-difluoropiperidine-1-carbonyl)-2,3-dihydro- 1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 19) was prepared using Procedure 1 with 4,4-difluoropiperidine in place of (2S,4S)- 4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 568.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.54 (dd, J = 10.7, 1.9 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.35 (ddd, J = 13.2, 8.2, 2.0 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 4.42 (t, J = 7.7 Hz, 1H), 3.74 (s, 2H), 3.46 (s, 1H), 3.04 – 2.78 (m, 2H), 2.35 – 2.14 (m, 2H), 2.04 (d, J = 42.1 Hz, 5H), 1.36 (dd, J = 13.5, 6.6 Hz, 6H), 1.24 (s, 1H), 0.96 – 0.66 (m, 3H), 0.45 (q, J = 6.1, 5.5 Hz, 1H), 0.40 – 0.26 (m, 2H), 0.19 (dq, J = 10.6, 5.6 Hz, 3H), 0.14 – 0.04 (m, 1H). Example 20

[0411] N-((2S)-1,1-Dicyclopropyl-3-((1-((2,2-difluoropropyl)carbamoyl)-2,3-dihydro-1H- inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 20) was prepared using Procedure 1 with 2,2-difluoropropan-1-amine in place of (2S,4S)-4- fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 542.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.53 (t, J = 6.3 Hz, 1H), 8.40 (d, J = 8.9 Hz, 1H), 7.53 (dd, J = 15.9, 1.9 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.34 (ddd, J = 17.1, 8.2, 2.0 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 4.78 (t, J = 8.3 Hz, 1H), 3.92 (t, J = 7.5 Hz, 1H), 3.63 (ddd, J = 14.4, 6.6, 3.1 Hz, 1H), 3.05 – 2.91 (m, 1H), 2.82 (dt, J = 16.6, 8.1 Hz, 1H), 2.34 – 2.08 (m, 2H), 1.56 (td, J = 19.0, 1.4 Hz, 3H), 1.36 (dd, J = 13.5, 6.6 Hz, 6H), 1.24 (s, 2H), 0.96 – 0.65 (m, 3H), 0.54 – 0.41 (m, 1H), 0.41 – 0.25 (m, 2H), 0.20 (dt, J = 8.8, 5.7 Hz, 3H), 0.09 (d, J = 5.6 Hz, 1H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 21

[0412] N-((2S)-1,1-Dicyclopropyl-3-oxo-3-((1-(((S)-1,1,1-trifluoro-3,3-dimethylbutan-2- yl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 21) was prepared using Procedure 1 with (S)-1,1,1-trifluoro-3,3- dimethylbutan-2-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 602.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.26 – 9.91 (m, 1H), 8.72 – 8.52 (m, 1H), 8.40 (d, J = 8.8 Hz, 1H), 7.55 (J = 22.7 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.40 – 7.25 (m, 1H), 7.11 (J = 44.1, 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 7.1, 6.7 Hz, 1H), 4.78 (t, J = 8.3 Hz, 1H), 4.52 – 4.31 (m, 1H), 4.15 – 4.01 (m, 1H), 3.13 – 2.91 (m, 1H), 2.91 – 2.78 (m, 1H), 2.30 – 2.13 (m, 2H), 1.38 (d, J = 6.6 Hz, 3H), 1.34 (d, J = 6.6 Hz, 3H), 1.10 – 0.94 (m, 9H), 0.93 – 0.66 (m, 3H), 0.51 – 0.40 (m, 1H), 0.40 – 0.32 (m, 2H), 0.32 – 0.25 (m, 1H), 0.25 – 0.14 (m, 3H), 0.14 – 0.04 (m, 1H). Example 22

[0413] tert-Butyl 5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-1-((2,2,2-trifluoroethyl)carbamoyl)isoindoline-2-carboxylate (Example 22) was prepared using Procedure 1 using I-5 in place of I-1 and 2,2,2- trifluoroethan-1-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride ES / MS m / z: 669.3 [M+H]+.1H NMR (400 MHz, DMSO-d6). δ 10.25 (s, 1H), 8.92 (td, J = 6.3, 1.9 Hz, 1H), 8.43 (dd, J = 8.9, 3.3 Hz, 1H), 7.71 – 7.58 (m, 1H), 7.54 – 7.41 (m, 2H), 7.24 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.9 Hz, 1H), 5.31 – 5.25 (m, 1H), 4.78 (t, J = 8.3 Hz, 1H), 4.64 (m, 3H), 4.11 – 3.90 (m, 1H), 3.89 – 3.68 (m, 1H), 1.42 – 1.27 (m, 14H), 0.96 – 0.68 (m, 3H), 0.56 – 0.05 (m, 8H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 23

[0414] 5-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2-methyl-N-(2,2,2-trifluoroethyl)isoindoline-1-carboxamide (Example 23) was prepared using Procedure 1 using I-59 in place of I-1 and 2,2,2- trifluoroethan-1-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 561.3 [M+H]+.1H NMR (400 MHz, DMSO-d6). δ 10.64 – 10.22 (m, 2H), 9.83 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 7.80 (s, 1H), 7.54 (s, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 6.92 (t, J = 1.9 Hz, 1H), 5.47 – 5.31 (m, 1H), 4.86 (s, 1H), 4.78 (t, J = 8.2 Hz, 1H), 4.56 (s, 1H), 4.32 – 3.95 (m, 3H), 2.99 (s, 3H), 1.36 (dd, J = 13.5, 6.6 Hz, 6H), 0.96 – 0.70 (m, 3H), 0.51 – 0.03 (m, 8H). Example 24

[0415] N-((2S)-1,1-Dicyclopropyl-3-((1-(hydroxymethyl)-1-((2,2,2- trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1- isopropyl-1H-pyrazole-5-carboxamide (Example 24) was prepared using Procedure 1 using I-52 in place of I-1 and 2,2,2-trifluoroethan-1-amine in place of (2S,4S)-4-fluoro-2- (trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 576.3 [M+H]+.1H NMR (400 MHz, DMSO-d6). δ 10.09 (s, 1H), 8.39 (d, J = 8.8 Hz, 1H), 8.05 (td, J = 6.4, 3.6 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.33 (dd, J = 8.3, 1.9 Hz, 1H), 7.25 (d, J = 8.4 Hz, 1H), 6.91 (dd, J = 2.0, 0.9 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.78 (t, J = 8.2 Hz, 1H), 3.98 – 3.81 (m, 2H), 3.79 – 3.68 (m, 1H), 3.55 (dd, J = 10.7, 3.0 Hz, 1H), 2.86 (s, 2H), 2.43 (ddd, J = 13.6, 8.9, 6.8 Hz, 1H), 2.11 (dt, J = 13.3, 6.7 Hz, 1H), 1.36 (dd, J = 14.5, 6.6 Hz, 6H), 0.95 – 0.67 (m, 3H), 0.49 – 0.15 (m, 7H), 0.12 (dd, J = 11.3, 6.3 Hz, 1H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 25

[0416] N-((2S)-1,1-Dicyclopropyl-3-((1-methyl-1-((2,2,2- trifluoroethyl)carbamoyl)isochroman-6-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 25) was prepared using Procedure 1 using I-2 in place of I-1 and 2,2,2-trifluoroethan-1-amine in place of (2S,4S)-4-fluoro-2-(trifluoromethyl)pyrrolidine hydrochloride. ES / MS m / z: 576.3 [M+H]+.1H NMR (400 MHz, DMSO-d6). δ 10.11 (s, 1H), 8.53 (t, J = 6.5 Hz, 1H), 8.39 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.38 (s, 2H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.78 (t, J = 8.2 Hz, 1H), 3.93 (m, 2H), 3.89 – 3.75 (m, 2H), 2.86 (dt, J = 16.4, 5.7 Hz, 1H), 2.81 – 2.70 (m, 1H), 1.57 (s, 3H), 1.36 (dd, J = 13.4, 6.6 Hz, 6H), 0.97 – 0.64 (m, 3H), 0.57 – 0.05 (m, 8H).

[0417] 5-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-N-(2,2,2-trifluoroethyl)isoindoline-1-carboxamide (Example 26). To a stirred solution of Example 22 (83 mg, 0.13 mmol) in DCM (1.3 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2h. Work up. then diluted with DMSO, filtered through a syringe filter, and purified by RP-HPLC (eluent: MeCN / H2O gradient with 0.1% TFA). Product-containing fractions were combined and lyophilized to afford 5-((S)- 3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-N-(2,2,2- trifluoroethyl)isoindoline-1-carboxamide (Example 26) as the trifluoroacetate salt. ES / MS m / z: 547.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.40 (s, 1H), 10.00 (s, 1H), 9.61 (t, J = 6.3 Hz, 1H), 9.40 (s, 1H), 8.48 (d, J = 8.6 Hz, 1H), 7.79 (s, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.42 (dd, J = 8.5, 2.1 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.46 (s, 1H), 5.38 (h, J = 6.6 Hz, 1H), 4.78 (t, J = 8.2 Hz, 1H), 4.62 (qd, J = 14.7, 4.4 Hz, 2H), 4.21 – 3.96 (m, 2H), 1.36 (dd, J = 14.3, 6.6 Hz, 6H), 0.99 – 0.69 (m, 3H), 0.56 – 0.03 (m, 8H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 27

[0418] (R)-5-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-N-(2,2,2-trifluoroethyl)isoindoline-1-carboxamide (Example 27). Example 26 (21.4 mg, 39.2 mmol) was subjected to chiral SFC (Column: IG 250 mm x 21 mm, 5 mm, eluent: 30% EtOH) to afford two peaks. Fractions corresponding to the second peak were concentrated in vacuo, diluted with DMSO, filtered through a syringe filter, and purified by RP-HPLC (eluent: MeCN / H2O gradient with 0.1% TFA). Product-containing fractions were combined and lyophilized to afford the product tentatively assigned as (R)-5-((S)-3,3- dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)-N-(2,2,2- trifluoroethyl)isoindoline-1-carboxamide (Example 27) as the trifluoroacetate salt. ES / MS m / z: 573.3 [M+H]+.1H NMR (400 MHz, Methanol-d4) δ 9.98 (s, 1H), 8.02 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 7.30 (s, 1H), 7.24 (d, J = 1.1 Hz, 2H), 6.57 (d, J = 2.1 Hz, 1H), 5.17 (hept, J = 6.7 Hz, 1H), 4.80 (s, 1H), 4.67 (m, 1H), 4.41 (q, J = 5.9 Hz, 1H), 4.35 (d, J = 14.7 Hz, 1H), 4.18 – 4.01 (m, 1H), 3.97 (d, J = 14.8 Hz, 1H), 3.62 (dq, J = 17.3, 8.8 Hz, 1H), 1.30 (m, 2H), 1.23 (t, J = 6.4 Hz, 6H), 0.78 – 0.47 (m, 3H), 0.41 – -0.06 (m, 8H). Example 28

[0419] 7-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-N-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4- carboxamide (Example 28) was prepared using Procedure 2 using I-51 in place of Example 22. ES / MS m / z: 561.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.28 (d, J = 1.7 Hz, 1H), 9.43 (s, 1H), 9.38 (t, J = 6.3 Hz, 1H), 8.75 (s, 1H), 8.44 (d, J = 8.7 Hz, 1H), 7.56 (dd, J = 4.4, 2.1 Hz, 1H), 7.52 – 7.44 (m, 2H), 7.32 (d, J = 8.5 Hz, 1H), 6.92 (t, J = 1.9 Hz, 1H), 5.46 – 5.33 (m, 1H), 4.78 (t, J = 8.2 Hz, 1H), 4.30 (m, 2H), 4.10 – 3.94 (m, 2H), 3.52 (m, 2H), 1.36 (dd, J = 11.9, 6.6 Hz, 6H), 0.95 – 0.68 (m, 3H), 0.55 – 0.03 (m, 8H).Attorney Docket No.: 1537-US-NP / WO-PCT Example 29

[0420] N-((2S)-1-((1-Amino-1-((2,2,2-trifluoroethyl)carbamoyl)-2,3-dihydro-1H-inden-5- yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 29) was prepared using Procedure 2 using I-53 in place of Example 22. ES / MS m / z: 583.3 [M+Na]+.1H NMR (400 MHz, DMSO-d6) δ 10.34 (d, J = 4.3 Hz, 1H), 8.76 – 8.28 (m, 5H), 7.73 (dd, J = 35.2, 1.8 Hz, 1H), 7.55 – 7.40 (m, 2H), 7.19 (dd, J = 8.4, 3.7 Hz, 1H), 6.97 – 6.84 (m, 1H), 5.38 (h, J = 6.6 Hz, 1H), 4.80 (t, J = 8.1 Hz, 1H), 4.08 – 3.79 (m, 1H), 3.27 – 3.00 (m, 2H), 2.72 – 2.55 (m, 1H), 2.43 – 2.28 (m, 1H), 1.36 (dd, J = 13.9, 6.6 Hz, 6H), 0.99 – 0.67 (m, 3H), 0.52 – 0.41 (m, 1H), 0.41 – 0.26 (m, 3H), 0.26 – 0.14 (m, 3H), 0.14 – 0.05 (m, 1H). Procedure 3, 30

[0421] 2-Acetyl-7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-N-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4- carboxamide (Example 30). To a solution of Example 28 (85 mg, 0.151 mmol) and triethylamine (0.04 mL, 0.30 mmol) in DCM (1 mL) at 0 °C was add acetyl chloride (13 mg, 0.17 mmol). The mixture was stirred for 1 hours before adding saturated NH4Cl and extracting with EtOAc. The combined organic layers were washed with saturated NaHCO3, then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude mixture dissolved in DMSO and was filtered through a syringe filter, and purified by RP-HPLC (eluent: MeCN / H2O gradient with 0.1% TFA). Product-containing fractions were combined and lyophilized to afford 2- acetyl-7-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5-carboxamido)propanamido)- N-(2,2,2-trifluoroethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide (Example 30) as the trifluoroacetate salt. ES / MS m / z: 603.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 8.96 – 8.65 (m, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.58 – 7.34 (m, 3H), 7.13 – 6.99 (m, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.79 (t, J = 8.2 Hz, 1H), 4.75 – 4.52 (m,Attorney Docket No.: 1537-US-NP / WO-PCT 1H), 4.45 (dd, J = 17.2, 13.6 Hz, 1H), 4.09 – 3.56 (m, 5H), 2.12 – 1.98 (m, 3H), 1.36 (dd, J = 13.1, 6.6 Hz, 6H), 0.94 – 0.67 (m, 3H), 0.53 – 0.05 (m, 8H). Example 31

[0422] 2-Acetyl-5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-N-(2,2,2-trifluoroethyl)isoindoline-1-carboxamide (Example 31) was prepared using Procedure 3 with Example 27 in place of Example 28. ES / MS m / z: 589.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.22 – 8.77 (m, 1H), 8.50 – 8.41 (m, 1H), 7.78 – 7.62 (m, 1H), 7.58 – 7.44 (m, 2H), 7.36 – 7.21 (m, 1H), 6.92 (d, J = 1.9 Hz, 1H), 5.70 – 5.33 (m, 2H), 4.98 – 4.62 (m, 3H), 4.07 – 3.74 (m, 2H), 2.13 – 1.89 (m, 3H), 1.36 (dd, J = 13.7, 6.6 Hz, 6H), 1.01 – 0.64 (m, 3H), 0.53 – 0.05 (m, 8H).

[0423] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((S)-3-((S)-3,3,3-trifluoro-2- hydroxypropanamido)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 32). To a stirred solution of (S)-3,3,3-trifluoro-2- hydroxypropanoic acid (13 mg, 0.092 mmol) in DMF (1 mL) was added HATU (35 mg, 0.092 mmol) and Triethylamine (13 mL, 0.092 mmol). The mixture was stirred for 10 min and I-4 (20 mg, 0.05 mmol) in DMF (1 mL) was added and the mixture was stirred for 1 h then diluted with DMF, filtered through a syringe filter, and purified by RP-HPLC (eluent: MeCN / H2O gradient with 0.1% TFA). Product-containing fractions were combined and lyophilized to afford N-((S)- 1,1-dicyclopropyl-3-oxo-3-(((S)-3-((S)-3,3,3-trifluoro-2-hydroxypropanamido)-2,3- dihydrobenzofuran-6-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 32) as the trifluoroacetate salt. ES / MS m / z: 564.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.79 (d, J = 7.6 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 1.7 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 7.04 (dd, J = 8.1, 1.8 Hz, 1H), 6.93Attorney Docket No.: 1537-US-NP / WO-PCT (d, J = 2.0 Hz, 1H), 5.52 (td, J = 8.2, 4.9 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 4.78 (t, J = 8.4 Hz, 1H), 4.69 (t, J = 9.2 Hz, 1H), 4.54 (q, J = 7.9 Hz, 1H), 4.32 (dd, J = 9.7, 4.8 Hz, 1H), 1.40 – 1.30 (m, 6H), 0.93 – 0.67 (m, 3H), 0.49 – 0.14 (m, 7H), 0.11 – 0.04 (m, 1H). Example 33

[0424] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((S)-3-((R)-3,3,3-trifluoro-2- hydroxypropanamido)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 33) was prepared using Procedure 4 with (2R)-3,3,3- trifluoro-2-hydroxy-propanoic acid in place of (S)-3,3,3-trifluoro-2-hydroxypropanoic acid. ES / MS m / z: 564.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.80 (d, J = 7.6 Hz, 1H), 8.43 (d, J = 8.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.28 (d, J = 1.7 Hz, 1H), 7.16 (d, J = 8.1 Hz, 1H), 7.05 (dd, J = 8.1, 1.8 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.54 (td, J = 8.2, 4.9 Hz, 1H), 5.41 (p, J = 6.6 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 4.68 (t, J = 9.2 Hz, 1H), 4.54 (q, J = 7.7 Hz, 1H), 4.31 (dd, J = 9.6, 4.9 Hz, 1H), 1.36 (dd, J = 12.5, 6.6 Hz, 6H), 0.87 (ddt, J = 13.4, 8.4, 4.4 Hz, 1H), 0.83 – 0.66 (m, 2H), 0.45 (dtd, J = 11.4, 8.0, 4.4 Hz, 1H), 0.32 (dtdt, J = 21.1, 12.8, 8.7, 3.8 Hz, 2H), 0.19 (dq, J = 10.4, 5.2 Hz, 3H), 0.07 (dt, J = 8.6, 4.7 Hz, 1H).

[0425] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((R)-1-(3,3,3-trifluoropropanamido)-2,3- dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 34). To a stirred solution of 3,3,3-trifluoropropanoic acid (12 mg, 0.092 mmol) in DMF (1 mL) was added HATU (35 mg, 0.092 mmol) and Triethylamine (0.93 mg, 0.092 mmol). The mixture was stirred for 10 min and I-7 (20 mg, 0.05 mmol) in DMF (1 mL) was added and the mixture was stirred for 1 h then diluted with DMF, filtered through a syringe filter, and purified by RP-HPLC (eluent: MeCN / H2O gradient with 0.1% TFA). Product- containing fractions were combined and lyophilized to afford N-((S)-1,1-dicyclopropyl-3-oxo- 3-(((R)-1-(3,3,3-trifluoropropanamido)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-Attorney Docket No.: 1537-US-NP / WO-PCT isopropyl-1H-pyrazole-5-carboxamide (Example 34) as the trifluoroacetate salt. ES / MS m / z: 546.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.13 (s, 1H), 8.59 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.40 (dd, J = 8.2, 1.9 Hz, 1H), 7.12 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 5.23 (q, J = 7.7 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 3.28 (q, J = 11.4 Hz, 2H), 2.91 (ddd, J = 15.9, 8.7, 3.8 Hz, 1H), 2.80 (dt, J = 16.0, 8.1 Hz, 1H), 2.41 (dtd, J = 11.9, 7.8, 3.8 Hz, 1H), 1.76 (dq, J = 12.5, 8.2 Hz, 1H), 1.36 (dd, J = 12.2, 6.6 Hz, 6H), 0.88 (tt, J = 7.9, 3.2 Hz, 1H), 0.79 (q, J = 6.1, 5.1 Hz, 1H), 0.72 (q, J = 8.8 Hz, 1H), 0.45 (q, J = 5.9, 5.1 Hz, 1H), 0.41 – 0.26 (m, 2H), 0.19 (dt, J = 10.0, 5.5 Hz, 3H), 0.08 (q, J = 5.8 Hz, 1H). Example 35

[0426] tert-Butyl (3-(((R)-5-((S)-3,3-dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydro-1H-inden-1-yl)amino)-1,1,1-trifluoro-3- oxopropan-2-yl)carbamate (Example 35) was prepared as a mixture of diastereomers using Procedure 5 with (2S)-2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-propanoic acid in place of 3,3,3-trifluoropropanoic acid, using DCM instead of DMF as solvent, and purified using SiO2 column chromatography eluting with EtOAc in hexanes 0-100% instead of RP-HPLC. ES / MS m / z: 661.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 8.84 (dd, J = 8.2, 4.5 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 8.16 (s, 1H), 7.66 (d, J = 9.6 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.44 – 7.36 (m, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.41 (hept, J = 6.6 Hz, 1H), 5.26 (q, J = 7.9 Hz, 1H), 4.97 (t, J = 8.7 Hz, 1H), 4.80 (t, J = 8.3 Hz, 1H), 3.62 (pd, J = 6.6, 3.9 Hz, 2H), 3.14 (qd, J = 7.3, 4.2 Hz, 2H), 2.99 – 2.73 (m, 2H), 2.42 (dq, J = 9.3, 5.3, 4.8 Hz, 1H), 1.78 (ddd, J = 23.6, 11.9, 6.5 Hz, 1H), 1.44 – 1.30 (m, 10H), 0.93 – 0.66 (m, 3H), 0.48 – 0.14 (m, 7H), 0.08 (q, J = 5.6 Hz, 1H). Example 36Attorney Docket No.: 1537-US-NP / WO-PCT

[0427] N-[(1S)-1-(Dicyclopropylmethyl)-2-oxo-2-[[(1R)-1-[(3,3,3-trifluoro-2,2-dihydroxy- propanoyl)amino]indan-5-yl]amino]ethyl]-2-isopropyl-pyrazole-3-carboxamide (Example 36) was prepared using Procedure 5 with 3,3,3-trifluoro-2,2-dihydroxy-propanoic acid in place of 3,3,3-trifluoropropanoic acid. ES / MS m / z: 578.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H), 7.76 (s, 2H), 7.54 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.0, 1.9 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.41 (p, J = 6.6 Hz, 1H), 5.28 (q, J = 8.2 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 3.02 – 2.87 (m, 1H), 2.78 (dt, J = 16.0, 8.2 Hz, 1H), 2.33 (dtd, J = 11.7, 8.0, 3.2 Hz, 1H), 2.02 (dq, J = 12.3, 8.7 Hz, 1H), 1.36 (dd, J = 12.4, 6.6 Hz, 6H), 0.95 – 0.66 (m, 4H), 0.45 (q, J = 5.9 Hz, 1H), 0.40 – 0.25 (m, 2H), 0.19 (q, J = 6.2 Hz, 3H), 0.14 – 0.02 (m, 1H). Example 37

[0428] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((R)-1-((R)-3,3,3-trifluoro-2- hydroxypropanamido)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 37) was prepared using Procedure 5 with (2R)-3,3,3- trifluoro-2-hydroxy-propanoic acid in place of 3,3,3-trifluoropropanoic acid. ES / MS m / z: 562.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.49 (d, J = 8.5 Hz, 1H), 8.41 (d, J = 8.9 Hz, 1H), 7.56 (d, J = 1.8 Hz, 1H), 7.50 (s, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.41 (p, J = 6.6 Hz, 1H), 5.30 (q, J = 8.0 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 4.55 (q, J = 7.8 Hz, 1H), 2.93 (ddd, J = 16.0, 8.9, 3.4 Hz, 1H), 2.80 (dt, J = 16.1, 8.3 Hz, 1H), 2.36 (dtd, J = 11.7, 8.0, 3.4 Hz, 1H), 1.92 (dq, J = 12.5, 8.5 Hz, 1H), 1.36 (dd, J = 12.3, 6.6 Hz, 6H), 0.96 – 0.66 (m, 3H), 0.44 (p, J = 6.2 Hz, 1H), 0.41 – 0.25 (m, 3H), 0.25 – 0.14 (m, 3H), 0.08 (q, J = 6.0, 5.6 Hz, 1H). Example 38

[0429] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((R)-1-((S)-3,3,3-trifluoro-2- hydroxypropanamido)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H-Attorney Docket No.: 1537-US-NP / WO-PCT pyrazole-5-carboxamide (Example 38) was prepared using Procedure 5 with (2S)-3,3,3- trifluoro-2-hydroxy-propanoic acid in place of 3,3,3-trifluoropropanoic acid. ES / MS m / z: 562.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.49 (d, J = 8.4 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.56 (s, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 5.29 (q, J = 7.9 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 4.55 (q, J = 7.7 Hz, 1H), 2.93 (ddd, J = 16.1, 8.8, 3.4 Hz, 1H), 2.85 – 2.75 (m, 1H), 2.38 (dtd, J = 11.8, 7.9, 3.4 Hz, 1H), 1.90 (dq, J = 12.6, 8.5 Hz, 1H), 1.41 – 1.32 (m, 6H), 0.92 – 0.68 (m, 3H), 0.49 – 0.14 (m, 7H), 0.13 – 0.05 (m, 1H). Example 39

[0430] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((R)-1-((S)-3,3,3-trifluoro-2-hydroxy-2- methylpropanamido)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 39) was prepared using Procedure 5 with (S)-3,3,3- trifluoro-2-hydroxy-2-methylpropanoic acid in place of 3,3,3-trifluoropropanoic acid. ES / MS m / z: 576.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.21 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 7.05 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 5.27 (q, J = 8.1 Hz, 1H), 4.79 (t, J = 8.4 Hz, 1H), 2.92 (ddd, J = 15.9, 9.0, 3.1 Hz, 1H), 2.78 (dt, J = 16.1, 8.3 Hz, 1H), 2.39 – 2.25 (m, 1H), 1.97 (dq, J = 12.4, 8.7 Hz, 1H), 1.53 (s, 3H), 1.41 – 1.31 (m, 6H), 0.92 – 0.68 (m, 3H), 0.49 – 0.14 (m, 7H), 0.13 – 0.04 (m, 1H). Example 40

[0431] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((R)-1-((R)-3,3,3-trifluoro-2-hydroxy-2- methylpropanamido)-2,3-dihydro-1H-inden-5-yl)amino)propan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 40) was prepared using Procedure 5 with (R)-3,3,3- trifluoro-2-hydroxy-2-methylpropanoic acid in place of 3,3,3-trifluoropropanoic acid. ES / MS m / z: 576.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.40 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.3, 1.9Attorney Docket No.: 1537-US-NP / WO-PCT Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.41 (hept, J = 6.6 Hz, 1H), 5.29 (q, J = 8.2 Hz, 1H), 4.79 (t, J = 8.4 Hz, 1H), 2.93 (ddd, J = 16.0, 8.7, 2.8 Hz, 1H), 2.79 (dt, J = 16.2, 8.4 Hz, 1H), 2.33 (ddt, J = 14.9, 10.0, 7.5 Hz, 1H), 2.01 (dq, J = 12.5, 8.8 Hz, 1H), 1.50 (s, 3H), 1.36 (dd, J = 12.3, 6.6 Hz, 6H), 0.94 – 0.67 (m, 3H), 0.51 – 0.41 (m, 1H), 0.41 – 0.26 (m, 2H), 0.26 – 0.14 (m, 3H), 0.08 (q, J = 6.0, 5.4 Hz, 1H). Example 41

[0432] N-((R)-5-((S)-3,3-Dicyclopropyl-2-(1-isopropyl-1H-pyrazole-5- carboxamido)propanamido)-2,3-dihydro-1H-inden-1-yl)-4-(trifluoromethyl)-1H-pyrazole- 3-carboxamide (Example 41) was prepared using Procedure 5 with 4-(trifluoromethyl)-1H- pyrazole-3-carboxylic acid in place of 3,3,3-trifluoropropanoic acid. ES / MS m / z: 598.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.49 – 8.35 (m, 2H), 7.57 (d, J = 1.9 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.40 – 7.34 (m, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 5.42 (dq, J = 19.7, 7.2, 6.6 Hz, 2H), 4.79 (t, J = 8.3 Hz, 1H), 2.96 (t, J = 11.1 Hz, 1H), 2.82 (q, J = 8.0 Hz, 1H), 2.40 (dt, J = 8.0, 4.0 Hz, 1H), 2.28 (t, J = 7.4 Hz, 1H), 2.04 (dd, J = 12.4, 8.2 Hz, 1H), 1.50 (d, J = 6.2 Hz, 1H), 1.36 (dd, J = 12.4, 6.6 Hz, 6H), 0.98 – 0.62 (m, 2H), 0.51 – 0.25 (m, 3H), 0.25 – 0.13 (m, 3H), 0.09 (q, J = 6.2 Hz, 1H). Example 42

[0433] N-((S)-1,1-Dicyclopropyl-3-(((R)-1-((S)-2,2-difluorocyclopropane-1-carboxamido)- 2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 42) was prepared using Procedure 5 with (R)-2,2- difluorocyclopropane-1-carboxylic acid in place of 3,3,3-trifluoropropanoic acid. ES / MS m / z: 540.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.77 (dd, J = 4.4, 1.4 Hz, 2H), 8.54 (dd, J = 8.4, 1.4 Hz, 2H), 8.43 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 1.9 Hz, 1H), 7.55 – 7.46 (m, 2H), 7.28 (d, J = 8.3 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.62 – 5.26 (m, 1H), 4.96 (q, J = 8.0 Hz, 1H), 4.79 (t, J = 8.4 Hz, 1H), 2.71 – 2.55 (m, 1H), 2.12 – 1.81 (m, 3H),Attorney Docket No.: 1537-US-NP / WO-PCT 1.36 (dd, J = 11.9, 6.6 Hz, 6H), 1.24 (s, 1H), 0.96 – 0.68 (m, 3H), 0.45 (dq, J = 11.8, 7.0, 5.3 Hz, 1H), 0.41 – 0.24 (m, 2H), 0.18 (dq, J = 11.1, 6.2, 5.3 Hz, 2H), 0.07 (d, J = 5.5 Hz, 1H). Example 43

[0434] N-((S)-1,1-Dicyclopropyl-3-(((R)-1-(3,3-difluorocyclobutane-1-carboxamido)-2,3- dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 43) was prepared using Procedure 5 with 3,3-difluorocyclobutane-1-carboxylic acid in place of 3,3,3-trifluoropropanoic acid. ES / MS m / z: 554.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.38 (dd, J = 16.6, 8.5 Hz, 2H), 7.56 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.40 (p, J = 6.6 Hz, 1H), 5.24 (q, J = 7.8 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 2.89 (pd, J = 9.0, 7.6, 2.3 Hz, 2H), 2.84 – 2.61 (m, 3H), 2.38 (dtd, J = 11.8, 7.8, 3.7 Hz, 1H), 1.75 (dq, J = 12.6, 8.4 Hz, 1H), 1.36 (dd, J = 12.3, 6.6 Hz, 6H), 1.24 (s, 1H), 0.67-0.83 (m, 2H), 0.83 – 0.65 (m, 2H), 0.53 – 0.41 (m, 1H), 0.41 – 0.25 (m, 3H), 0.18 (dt, J = 10.2, 5.5 Hz, 3H), 0.07 (dt, J = 8.4, 4.7 Hz, 1H). Example 44

[0435] N-((S)-1,1-Dicyclopropyl-3-(((R)-1-((R)-2,2-difluorocyclopropane-1- carboxamido)-2,3-dihydro-1H-inden-5-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H- pyrazole-5-carboxamide (Example 44) was prepared using Procedure 5 with (S)-2,2- difluorocyclopropane-1-carboxylic acid in place of 3,3,3-trifluoropropanoic acid.1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.64 (d, J = 8.1 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.57 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.39 (dd, J = 8.2, 1.9 Hz, 1H), 7.14 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 5.41 (hept, J = 6.6 Hz, 1H), 5.26 (q, J = 7.6 Hz, 1H), 4.79 (t, J = 8.3 Hz, 1H), 2.93 (ddd, J = 16.0, 8.7, 3.8 Hz, 1H), 2.79 (dt, J = 16.0, 8.1 Hz, 1H), 2.58 (ddd, J = 14.2, 11.0, 7.9 Hz, 1H), 2.41 (dtd, J = 12.1, 7.9, 3.9 Hz, 1H), 1.96 (dq, J = 14.1, 7.4 Hz, 1H), 1.82Attorney Docket No.: 1537-US-NP / WO-PCT (dddd, J = 28.9, 16.1, 11.9, 7.9 Hz, 2H), 1.36 (dd, J = 12.2, 6.6 Hz, 6H), 0.95 – 0.65 (m, 3H), 0.45 (q, J = 5.6 Hz, 1H), 0.41 – 0.25 (m, 2H), 0.25 – 0.14 (m, 3H), 0.14 – 0.03 (m, 1H). Procedure 6, Example 45

[0436] N-((2S)-1-(((1R)-1-(2-Acetamido-3,3,3-trifluoropropanamido)-2,3-dihydro-1H- inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 45). To a vial containing Example 35 (0.05 g, 0.37 mmol) was added DCM (3 mL), TFA (3mL) and the mixture was allowed to stir for 1h. Volatiles were evaporated on a rotary evaporator and DMF (3 mL), triethylamine (0.1 mL), and acetic anhydride (0.1 mL) were added. The mixture was stirred for 3h, filtered through a syringe filter, and purified by RP- HPLC (eluent: MeCN / H2O gradient with 0.1% TFA). Product-containing fractions were combined and lyophilized to afford the product N-((2S)-1-(((1R)-1-(2-acetamido-3,3,3- trifluoropropanamido)-2,3-dihydro-1H-inden-5-yl)amino)-3,3-dicyclopropyl-1-oxopropan- 2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide (Example 45) as a mixture of diastereomers and the trifluoroacetate salt. ES / MS m / z: 603.262 [M+H]+.1H NMR (400 MHz, DMSO-d6; where a difference was observed, * denotes major diastereomer, † denotes minor diastereomer) δ 10.14 (s, 1H), 8.97 (d, J = 8.1 Hz, 1H), 8.88 (dd, J = 9.3, 3.4 Hz, 1H), 8.41 (d, J = 8.8 Hz, 1H), 7.58 (d, J = 1.8 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.43 – 7.37 (m, 1H), 7.13 (d, J = 8.2 Hz,0.25H†), 7.03 (d, J = 8.2 Hz, 0.75H*), 6.93 (d, J = 2.0 Hz, 1H), 5.48 – 5.31 (m, 2H), 5.31 – 5.20 (m, 1H), 4.79 (t, J = 8.3 Hz, 1H), 2.99 – 2.88 (m, 1H), 2.81 (dt, J = 16.1, 8.2 Hz, 1H), 2.42 (qt, J = 7.8, 3.5 Hz, 1H), 1.96 (d, J = 3.9 Hz, 3H), 1.80 (dq, J = 13.1, 9.4, 9.0 Hz, 1H), 1.36 (dd, J = 12.5, 6.6 Hz, 6H), 0.87 (dq, J = 8.1, 4.2, 3.0 Hz, 1H), 0.75 (dq, J = 26.6, 9.1, 7.4 Hz, 2H), 0.45 (q, J = 5.8, 5.3 Hz, 1H), 0.41 – 0.25 (m, 2H), 0.19 (hept, J = 6.7, 6.0 Hz, 3H), 0.08 (q, J = 5.8 Hz, 1H).Attorney Docket No.: 1537-US-NP / WO-PCT

[0437] Step 1. To a solution of Intermediate I-4 (40 mg, 0.91 mmol) and tert-butyl (2- methyl-1-oxopropan-2-yl)carbamate (34 mg, 0.18 mmol) in acetonitrile (1 mL) was added acetic acid (28 mg, 0.46 mmol) and sodium triacetoxyborohydide (58 mg, 0.27 mmol). The mixture was stirred for 16 hours at room temperature and then diluted with 1 M NaOH and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give tert-butyl (1-(((S)-6-((S)-3,3-dicyclopropyl-2-(1-isopropyl- 1H-pyrazole-5-carboxamido)propanamido)-2,3-dihydrobenzofuran-3-yl)amino)-2- methylpropan-2-yl)carbamate that was used in step 2 without further purification. ES / MS m / z: 609.3 [M+H]+

[0438] Step 2. To a stirred mixture of tert-butyl (1-(((S)-6-((S)-3,3-dicyclopropyl-2-(1- isopropyl-1H-pyrazole-5-carboxamido)propanamido)-2,3-dihydrobenzofuran-3-yl)amino)-2- methylpropan-2-yl)carbamate (56 mg mg, 0.93 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (1 mL). The mixture was stirred for 2 hours before adding saturated NaHCO3and extracting with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo to give N-((S)-1-(((S)-3-((2-amino-2- methylpropyl)amino)-2,3-dihydrobenzofuran-6-yl)amino)-3,3-dicyclopropyl-1-oxopropan- 2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide that was used in step 3 without further purification. ES / MS m / z: 509.2 [M+H]+

[0439] Step 3. N-((S)-1,1-Dicyclopropyl-3-(((S)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)- 2,3-dihydrobenzofuran-6-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 46) was prepared in analogy to Intermediate I-8, step 3 using N-((S)-1- (((S)-3-((2-amino-2-methylpropyl)amino)-2,3-dihydrobenzofuran-6-yl)amino)-3,3- dicyclopropyl-1-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5-carboxamide in place of (2S)-N1- (5-bromo-1-methyl-2,3-dihydro-1H-inden-1-yl)-3,3,3-trifluoropropane-1,2-diamine. The crude mixture was filtered through a syringe filter, and purified by RP-HPLC (eluent: MeCN / H2OAttorney Docket No.: 1537-US-NP / WO-PCT gradient with 0.1% TFA). Product-containing fractions were combined and lyophilized to afford N-((S)-1,1-dicyclopropyl-3-(((S)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-2,3- dihydrobenzofuran-6-yl)amino)-3-oxopropan-2-yl)-1-isopropyl-1H-pyrazole-5- carboxamide (Example 46) as the trifluoroacetate salt. ES / MS m / z: 535.3 [M+H]+. NMR (400 MHz, DMSO-d6). δ 10.23 (s, 1H), 8.44 (d, J = 8.7 Hz, 1H), 7.50 (d, J = 1.9 Hz, 1H), 7.38 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.99 (dd, J = 8.1, 1.8 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.67 (s, 1H), 5.51 (dd, J = 8.6, 3.8 Hz, 1H), 5.40 (hept, J = 6.6 Hz, 1H), 4.77 (t, J = 8.3 Hz, 1H), 4.56 (dd, J = 10.1, 8.6 Hz, 1H), 4.36 (dd, J = 10.0, 3.9 Hz, 1H), 2.93 (d, J = 8.4 Hz, 1H), 2.45 (d, J = 8.4 Hz, 1H), 1.36 (dd, J = 14.5, 6.6 Hz, 6H), 1.15 (s, 3H), 1.06 (s, 3H), 0.96 – 0.67 (m, 3H), 0.54 – 0.04 (m, 8H). Example 47

[0440] N-((S)-1,1-Dicyclopropyl-3-oxo-3-(((S)-3-((R)-2-oxo-4-(2,2,2- trifluoroethyl)imidazolidin-1-yl)-2,3-dihydrobenzofuran-6-yl)amino)propan-2-yl)-1- isopropyl-1H-pyrazole-5-carboxamide (...

Claims

1. Attorney Docket No.: 1537-US-NP / WO-PCT CLAIMS 1. A compound of formula (I):or a pharmaceutically acceptable salt thereof, wherein R1is -O-R12a, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R1is substituted with 0 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is substituted with 0 to 4 Z2, which may be the same or different; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2; Cy1is 5-10 membered heterocyclyl or C5-10 cycloalkyl; the heterocyclyl or cycloalkyl of Cy1is additionally substituted with 0 to 2 Z5, which may be the same or different; each Z5is independently oxo, halogen, -OH, C1-3 alkyl, -C(O) R12a, -C(O)O-R12a, C1-3 haloalkyl, C1-3 haloalkyl, or C1-3 haloalkyl; R3is C1-6alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is substituted with 0 to 4 Z3, which may be the same or different; R4is absent, H, halogen, -CN, C2-4 alkynyl, -NR12aR12b, -OR12a, C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R4is substituted with 0 to 1 -OR12a; each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each substituted with 0 to 4 Z1a, which may be the same or different;Attorney Docket No.: 1537-US-NP / WO-PCT each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 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)-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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each substituted with 0 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10aryl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis substituted with 0 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6- 10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis substituted with 0 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6alkoxy, or -C1-6haloalkoxy; and each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis substituted with 0 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy, wherein the alkoxy of each Z1dis substituted with 0 to 2 Z1e, which may be the same or different; each Z1eis independently -OH or C1-3 alkoxy; wherein each heteroaryl unless otherwise specified is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S; wherein each heterocyclyl unless otherwise specified is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy1is monocyclic.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Cy1Attorney Docket No.: 1537-US-NP / WO-PCT is fused bicyclic, bridged bicyclic, or spiro bicyclic.

4. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):or a pharmaceutically acceptable salt thereof, wherein X1is a bond, or C1-3 alkylene; wherein the C1-3 alkylene of X1is substituted with 0 to 3 C1-6 alkyl, which may be the same or different; X is -NR6a-, -SO2-, -SO2NR6a-, -CO-, -CO(C1-3 alkylene)-, C1-3 alkylene, -O(C1-3 alkylene)-, -N=CR6b-, -NR6a(C1-3 alkylene)-, -NR6aCO-, -NR6aC(O)O-, -NR6aC(O)NR6a-, or - NR6aCO(C1-3 alkylene)-; wherein the alkylene of CO(C1-3 alkylene)-, C1-3 alkylene, -O(C1-3 alkylene)-, -NR6a(C1-3 alkylene)-, or -NR6aCO(C1-3 alkylene)- of X is substituted with 0 to 3 C1-6 alkyl, which may be the same or different; R6ais H, C1-6 alkyl, C1-6 haloalkyl, -C(O) R12a, or -C(O)O-R12a; R6bis -N(R12a)( R12b); X2is a bond, or C1-3 alkylene; wherein the C1-3 alkylene of X2is substituted with 0 to 3C1-6 alkyl, which may be the same or different;R1is -O-R12a, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R1is substituted with 0 to 4 Z1, which may be the same or different; R2is C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, C6-10 aryl, heterocyclyl, or heteroaryl; wherein the alkyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl of R2is substituted with 0 to 4 Z2, which may be the same or different; R3is C1-6 alkyl, -NR12aCOR12b, -COR12a, -CONR12aR12b, -N(R12a)C(O)N(R12b)(R12c), heterocyclyl, heteroaryl; wherein the alkyl, heterocyclyl, heteroaryl of R3is substituted with 0 to 4 Z3, which may be the same or different; R4is H, -NR12aR12b, -OR12a, C1-6alkyl, or C1-6haloalkyl; wherein the alkyl of R4is substituted with 0 to 1 -OR12a; each Z6is independently halogen, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxy; q is 0, 1, or 2;Attorney Docket No.: 1537-US-NP / WO-PCT each Z1, Z2, or Z3is independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -NO2, -N3, -CN, -O-R12a, -C(O)-R12a, -C(O)O- R12a, -C(O)-N(R12a)(R12b), -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, -SF5, -S(O)R12a, -S(O)(NH)R12a, -S(O)2R12a, -S(O)2N(R12a)(R12b), or -S(O)(NR12a)R12b; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1, Z2, or Z3is each substituted with 0 to 4 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, 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)-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, cycloalkyl, heterocyclyl, aryl, or heteroaryl of Z1ais each substituted with 0 to 4 Z1b, which may be the same or different; each R12a, R12b, or R12cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of R12a, R12b, or R12cis substituted with 0 to 4 Z1b, which may be the same or different; each Z1bis independently -NR13aCOR13b, -C(O)O- R13a, -C(O)N(R13a)( R13b), -N(R13a)( R13b), -N(R13a)-C(O)R13b, -N(R13a)C(O)O(R13b), - N(R13a)C(O)N(R13b)(R13c), C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6- 10 aryl, heteroaryl, oxo, -OR13a, -CN, -C1-6 alkoxy, -C1-6 haloalkoxy; wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of each of Z1bis substituted with 0 to 4 Z1c, which may be the same or different; each Z1cis independently C1-6 alkyl, C1-6 haloalkyl, halogen, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, heteroaryl, oxo, -OH, -CN, -NH2, -C1-6 alkoxy, or -C1-6 haloalkoxy; and each R13a, R13b, or R13cis independently H, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, heterocyclyl, C6-10 aryl, or heteroaryl; the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl of R13a, R13b, or R13cis substituted with 0 to 4 Z1d, which may be the same or different; each Z1dis independently -OH or C1-3 alkoxy; wherein each heteroaryl is 5 to 10 membered heteroaryl having one to three heteroatoms each independently N, O, or S;Attorney Docket No.: 1537-US-NP / WO-PCT wherein each heterocyclyl is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N, O or S.

5. The compound of any one of claims 1, 2, and 4, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIa)6. The compound of any one of claims 1, 2, 4, and 5, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIb).

7. The compound of any one of claims 1, 2, and 4-6, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IIc); wherein Z6ais Z6or H.

8. The compound of any one of claims 1, 2, and 4-6, or a pharmaceutically acceptable salt thereof, having the structure of Formula (IId)9. The compound of any one of claims 4-8, or a pharmaceutically acceptable salt thereof, wherein X1is a bond.Attorney Docket No.: 1537-US-NP / WO-PCT 10. The compound of any one of claims 4-8, or a pharmaceutically acceptable salt thereof, wherein X1is C1-3 alkylene.

11. The compound of any one of claims 4-10, or a pharmaceutically acceptable salt thereof, wherein X2is a bond.

12. The compound of any one of claims 4-10, or a pharmaceutically acceptable salt thereof, wherein X2is C1-3 alkylene.

13. The compound of any one of claims 4-12, or a pharmaceutically acceptable salt thereof, wherein X is C1-3 alkylene, -O(C1-3 alkylene)-, -NR6a(C1-3 alkylene)-.

14. The compound of any one of claims 4-12, or a pharmaceutically acceptable salt thereof, wherein X is -CO(C1-3alkylene)-, -NR6aCO-, or -NR6aCO(C1-3alkylene)-; wherein the alkylene of -CO(C1-3 alkylene)-, -NR6aCO-, or -NR6aCO(C1-3 alkylene)- is substituted with 0 to 3 C1-6 alkyl, which may be the same or different.

15. The compound of any one of claims 4-8, or a pharmaceutically acceptable salt16. The compound of any one of claims 4-6, and 8, or a pharmaceutically acceptable salt thereof,Attorney Docket No.: 1537-US-NP / WO-PCT 17. The compound of any one of claims 4-6, and 8, or a pharmaceutically acceptable salt thereof, wherein18. The compound of any one of claims 4-6, and 8, or a pharmaceutically acceptable salt thereof, wherein19. The compound of claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein20. The compound of any one of claims 4-8, or a pharmaceutically acceptable salt thereof, wherein21. The compound of any one of claims 4-8, or a pharmaceutically acceptable salt thereof, whereinZ5is C1-3 alkyl; and n is 0, 1, or 2.Attorney Docket No.: 1537-US-NP / WO-PCT 22. The compound of any one of claims 4-8, or a pharmaceutically acceptable salt thereof, wherein23. The compound of any one of claims 1-15 and 19-22, or a pharmaceutically acceptable salt thereof, wherein R6ais H or C1-6 alkyl.

24. The compound of any one of claims 1-15 and 19-22, or a pharmaceutically acceptable salt thereof, wherein R6ais C1-6 haloalkyl.

25. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R4is H.

26. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R4is C1-6 alkyl.

27. The compound of any one of claims 1-24 and 26, or a pharmaceutically acceptable salt thereof, wherein R4is -CH3.

28. The compound of any one of claims 1-24, or a pharmaceutically acceptable salt thereof, wherein R4is C1-6 haloalkyl.

29. The compound of any one of claims 1-7 and 9-28, or a pharmaceutically acceptable salt thereof, wherein R2is C1-6 alkyl, C1-6 haloalkyl, or C3-10 cycloalkyl; wherein the alkyl, haloalkyl or cycloalkyl of R2is substituted with 0 to 4 Z2, which may be the same or different; and each Z2is independently -O-R12a, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or phenyl; the cycloalkyl or phenyl of Z2is substituted with 0 to 3 Z1a; R12ais C1-6 alkyl, or C1-6 haloalkyl; and each Z1ais independently halogen or C1-6 alkyl.

30. The compound of any one of claims 1-7 and 9-28, or a pharmaceutically acceptable salt thereof, wherein R2is C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl of R2is substituted with 0 to 4 Z2, which may be the same or different; each Z2is independently -O-R12a, C3-6 cycloalkyl, or phenyl; the cycloalkyl or phenyl of Z2is substituted with 0 to 3 Z1a, which may be the same or different; R12ais C1-6 alkyl, or C1-6 haloalkyl; andAttorney Docket No.: 1537-US-NP / WO-PCT each Z1ais independently halogen or alkyl.

31. The compound of any one of claims 1-7 and 9-28, or a pharmaceutically acceptable salt thereof, wherein32. The compound of any one of claims 1-7 and 9-31, or a pharmaceutically acceptable salt thereof, wherein R1is heteroaryl substituted with 0 to 4 Z1, which may be the same or different; each Z1is independently halogen, C1-6 alkyl, C1-6 haloalkyl, or C3-6 cycloalkyl; the alkyl, cycloalkyl of Z1is substituted with 0 to 3 Z1a, which may be the same or different; each Z1ais independently C1-6 alkyl, C1-6 haloalkyl, halogen or -OR12a; and R12ais H or C1-6 alkyl.

33. The compound of any one of claims 1-7 and 9-32, or a pharmaceutically acceptable salt thereof, wherein34. The compound of any one of claims 1-7 and 9-33, or a pharmaceutically acceptable salt thereof, wherein35. The compound of any one of claims 1-7 and 9-33, or a pharmaceutically acceptable salt thereof, wherein36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is heterocyclyl substituted with 0 to 3 Z3, which may be the same or different; and the heterocyclyl of R3is 4 to 10 membered heterocyclyl having one to three heteroatoms each independently N or O.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, whereinAttorney Docket No.: 1537-US-NP / WO-PCTCy2is 4 to 10 membered heterocyclyl; and m is 0, 1, or 2.

38. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein Cy2is 4 to 10 membered monocyclic heterocyclyl.

39. The compound of claim 37, or a pharmaceutically acceptable salt thereof, wherein Cy2is 4 to 10 membered bicyclic or tricyclic heterocyclyl.

40. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein41. The compound of any one of claims 1-37 and 39, or a pharmaceutically acceptable saltthereof, wherein42. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is -NR12aCOR12b. 43.The compound of any one of claims 1-35 and 42, or a pharmaceutically acceptable salt thereof, wherein R3is -NR12aCOR12b; R12ais H or C1-6 alkyl; R12bis C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, or heteroaryl of R12bis with 0 to 3 Z1b, which may be the same or different; each Z1bis independently halogen, C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl.

44. The compound of any one of claims 1-35 and 42, or a pharmaceutically acceptable salt thereof, whereinAttorney Docket No.: 1537-US-NP / WO-PCT R3is -NR12aCOR12b; R12ais H or C1-6 alkyl; R12bis C1-6 alkyl, or C1-6 haloalkyl; wherein the alkyl, or haloalkyl of R12bis with 0 to 3 Z1b, which may be the same or different; each Z1bis independently halogen or -NH-C(O)R13b; and R13bis C1-6 alkyl, or C1-6 haloalkyl.

45. The compound of any one of claims 1-35 and 42, or a pharmaceutically acceptable salt thereof, wherein R3is -NHCOR12b; R12bis C1-6haloalkyl substituted with 0 to 1 -NH-C(O)R13b; and R13bis C1-6 alkyl.

46. The compound of any one of claims 1-35, 42, and 43, or a pharmaceutically acceptable salt thereof, wherein47. The compound of any one of claims 1-35, 42, 43, and 46, or a pharmaceutically acceptable salt thereof, wherein48. The compound of any one of claims 1-35, 42, 43, and 46, or a pharmaceutically acceptable salt thereof, wherein49. The compound of any one of claims 1-35, and 42-46, or a pharmaceutically acceptable salt thereof, wherein50. The compound of any one of claims 1-35, and 42-49, or a pharmaceutically acceptable salt thereof, whereinAttorney Docket No.: 1537-US-NP / WO-PCT 51. The compound of any one of claims 1-35, 42, 43, and 46, or a pharmaceutically acceptable salt thereof, wherein52. The compound of any one of claims 1-35, 42, 43, 46-48, and 51, or a pharmaceutically acceptable salt thereof, wherein53. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is -CONR12aR12b.

54. The compound of any one of claims 1-35 and 53, or a pharmaceutically acceptable salt thereof, wherein R3is -CONR12aR12b; R12ais H or C1-6 alkyl; R12bis C1-6 alkyl, C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, phenyl, or heteroaryl is substituted with 0 to 3 Z1b, which may be the same or different; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl.

55. The compound of any one of claims 1-35 and 53, or a pharmaceutically acceptable salt thereof, wherein R3is -CONHR12b; and R12bis C1-6 haloalkyl.

56. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein R3is -COR12a.

57. The compound of any one of claims 1-35 and 56, or a pharmaceutically acceptable salt thereof, wherein R3is -COR12a; R12ais a heterocyclyl substituted with 0 to 3 Z1b, which may be the same or different; the heterocyclyl of R12ais 5 to 6 membered heterocyclyl having one to three heteroatoms each independently N, O, or S;Attorney Docket No.: 1537-US-NP / WO-PCT each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl.

58. The compound of any one of claims 1-35 and 56, or a pharmaceutically acceptable salt thereof, wherein R3is -COR12a; R12ais a heterocyclyl substituted with 0 to 3 Z1b, which may be the same or different; the heterocyclyl of R12ais 5 to 6 membered heterocyclyl having one to two N; each Z1bis independently halogen, C1-6 alkyl, C1-6 haloalkyl, -C(O)O-R13a, - OR13a, -N(R13a)( R13b), or -NH-C(O)R13b; and each R13aor R13bis independently H, C1-6 alkyl, or C1-6 haloalkyl.

59. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein R3is heteroaryl substituted with 0 to 4 Z3, which may be the same or different.

60. The compound of any one of claims 1-35 and 59, or a pharmaceutically acceptable salt thereof, wherein61. The compound of any one of claims 1-35, 59, and 60, or a pharmaceutically acceptable salt thereof, wherein R3is.

62. The compound of any one of claims 1-41, 59, and 60, or a pharmaceutically acceptable salt thereof, wherein each Z3is independently halo, oxo, phenyl, C3-6 cycloalkyl, C1-6 alkyl, or C1-6 haloalkyl.

63. The compound of any one of claims 1-15, 19-21, and 23-62, or a pharmaceutically acceptable salt thereof, wherein Z6is halogen.

64. The compound of any one of claims 1-15, 19-21, and 23-63, or a pharmaceutically acceptable salt thereof, wherein Z6is F.

65. The compound of any one of claims 1-15, 19-21, and 23-64, or a pharmaceutically acceptable salt thereof, wherein q is 1.

66. The compound of any one of claims 1-6, 8-15, 19-21, and 23-62, or a pharmaceutically acceptable salt thereof, wherein q is 0.Attorney Docket No.: 1537-US-NP / WO-PCT 67. A compound having a structure of Examples 1-85, or a pharmaceutically acceptable salt thereof.

68. A compound having a structure of Examples 86-223, or a pharmaceutically acceptable salt thereof.

69. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-68, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

70. A method of modulating IL-17A in a subject, comprising administering a therapeutically effective amount of a compound of any of claims 1-68, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 69, to a subject in need thereof.

71. A method of treating an inflammatory disease or condition comprising administering a therapeutically effective amount of a compound of any of claims 1-68, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 69, to a subject in need thereof.

72. The method of claim 71, wherein the inflammatory disease or condition is psoriasis, psoriatic arthritis, or ankylosing spondylitis.

73. Use of the compound of any one of claims 1-68, or pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of an IL-17A associated disease or condition.