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WO2025085560A1 - Lysine acetyltransferase inhibitors - Google Patents

Lysine acetyltransferase inhibitors Download PDF

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Publication number
WO2025085560A1
WO2025085560A1 PCT/US2024/051649 US2024051649W WO2025085560A1 WO 2025085560 A1 WO2025085560 A1 WO 2025085560A1 US 2024051649 W US2024051649 W US 2024051649W WO 2025085560 A1 WO2025085560 A1 WO 2025085560A1
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Prior art keywords
phenyl
methyl
amino
ethyl
acetic acid
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French (fr)
Inventor
Zhihua Ma
Tamara Hopkins
Hua Gao
Christopher John DINSMORE
Benjamin Wesley TROTTER
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Kronos Bio Inc
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Kronos Bio Inc
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Priority to PCT/US2025/010315 priority Critical patent/WO2025147670A1/en
Publication of WO2025085560A1 publication Critical patent/WO2025085560A1/en
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

  • LYSINE ACETYLTRANSFERASE INHIBITORS RELATED APPLICATIONS [0001] This patent application claims the benefit of priority to U.S. Provisional Patent Application No. 63/590,742, filed October 16, 2023, which is incorporated herein by reference in its entirety.
  • BACKGROUND Field [0002] The present disclosure relates to compounds and their use in the treatment of various diseases, including cancer and inflammatory conditions. This disclosure also relates to methods for preparation of the compounds and to pharmaceutical compositions comprising such compounds.
  • Lysine acetyltransferases catalyze the transfer of an acetyl group from acetyl CoA (AcCoA) to the ⁇ -amino group on lysine residues of substrate proteins (Lee, K., Workman, J. Nat Rev Mol Cell Biol 8, 284–295 (2007)). Lysine deacetylases (KDACs) catalyze the removal of the acetyl group. Specific protein domains, including bromodomains, can bind proteins in an acetylation-dependent manner (R. Marmorstein and M.-M. Zhou. Cold Spring Harb Perspect Biol 2014;6:a018762).
  • acetyl group can impact protein function, including protein-protein interactions. This is because the acetyl group on the target lysine residue neutralizes the charge of the lysine ⁇ -amino group which is known to impact chromatin compaction in the nucleus.
  • Emerging evidence highlights a diverse set of cofactors and substrate macromolecules that can be regulated by KATs. In addition to transferring acetyl groups, these proteins can also transfer longer chain acyl groups, including crotonyl (from crotonyl CoA), to lysine resides of substrate proteins (Kaczmarska et al. Nat Chem Biol. 2017 Jan; 13(1): 21– 29).
  • KAT ELP3 The function of longer chain acyl group modification is not well understood and this application will focus on acetyl transferase activity of proteins.
  • the KAT ELP3 is known to acetylate non-protein substrates, including transfer RNAs (Lin, TY., Abbassi, N.E.H., Zakrzewski, K. et al. Nat Commun 10, 625 (2019)), further expanding the biological impact of acetyltransferase function.
  • transfer RNAs Lofi, Zakrzewski, K. et al. Nat Commun 10, 625 (2019)
  • the protein activity and its enzymatic inhibition with CoA-competitive KAT inhibitors (KATi) likely encompasses different acyl chain groups and diverse substrates.
  • the human genome encodes at least 12 KATs, consisting of three subfamilies based on amino acid sequence similarity: MYST family, GNAT family and Orphan family.
  • the human KAT proteins p300 and CREB-binding protein (CBP) are paralogs in the Orphan family of human KATs with well-established roles in gene regulation.
  • the p300 protein is encoded by the E1A Binding Protein (EP300) gene (Uniprot ID: Q09472) that is located on human chromosome 22p13.2.
  • the CBP protein is encoded by the CREBBP gene (Uniprot ID: Q92793) that is located on human chromosome 16p13.
  • p300 and CBP are multidomain proteins that consist of an enzymatic KAT domain and multiple protein-protein interaction domains, including a bromodomain and KIX domain.
  • the KAT domain catalyzes acetylation of histones and non-histone proteins where acetylated histones are associated with actively transcribed regions of the genome.
  • the protein-protein interaction domains aid in localizing p300 or CBP to distinct locations in the genome.
  • compounds provided herein bind to p300 protein on a competition TR-FRET assay of Example B.
  • compounds of Formula (IIIe-1) are provided herein R or a pharmaceutically acceptable salt thereof, wherein: R 1a is hydrogen; R 2b and R 2c are each independently hydrogen; R 3a and R 3b are each independently hydrogen; R 4a is phenyl; R 4b is hydrogen; J is NH; R 5 is -L-R 6 ; L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-; R 6 is aryl substituted with 1 to 3 substituents selected from -CH 2 C(O)H, alkyl, substituted alkyl, cyano, halogen, and R 60 , wherein the aryl is phenyl and the C 1 -C 6 substituted alkyl is C 1 -C 6 alkylene substituted with 1 to 3 R 60 , spiro-connected cycloalkyl or
  • the compound of Formula (IIIe-1) is a compound wherein R 10 is hydrogen. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 10 is halogen. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 10 is fluoro. In some embodiments, the compound of Formula (IIIe- 1) is a compound wherein R 10 is methyl. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 10 is methyl-substituted pyrazole. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 10 is .
  • the compound of Formula (IIIe-1) is a compound wherein R 10 is –(C 1 -C 4 alkyl)COOH. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 10 is –(CH 2 )COOH. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 10 is –(CH 2 ) 2 COOH. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 10 is –(CH 2 ) 3 COOH.
  • the compound of Formula (IIIe-1) is a compound wherein R 6 is phenyl substituted with –(CH 2 )COOH, or phenyl substituted with C 1 -C 6 alkylene substituted with -COOH or cyano and optionally substituted with a spiro-connected C 3 to C 6 cycloalkyl or a spiro-connected 3 to 6 member heterocycloalkyl.
  • the compound of Formula (IIIe-1) is a compound wherein R 6 is phenyl further substituted with one or two methyl.
  • the compound of Formula (IIIe-1) is a compound wherein R 6 is phenyl substituted with cyano or alkyl substituted with cyano. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 6 is In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 6 is In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 6 is In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 6 is In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R 6 is selected from:
  • the compound of Formula (IIIe-1) is a compound wherein R 6 is phenyl substituted with C 1 -C 6 alkylene substituted with -COOH and substituted with a spiro-connected C 3 to C 6 cycloalkyl or a spiro-connected 3 to 6 member heterocycloalkyl.
  • the compound of Formula (IIIe-1) is a compound wherein R 6 is
  • the compound of Formula (IIIe-1) is a compound wherein R 60 is - COOH, cyano, fluoro, methyl, methoxy or -CF3.
  • the compound of Formula (IIIe-1) is a compound wherein R 60 is independently methyl, fluoro or methoxy. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is a compound of Formula (VI-A), or a pharmaceutically acceptable salt thereof: (VI-A). [0014] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is a compound of Formula (VI-A-1), or a pharmaceutically acceptable salt thereof: (VI-A-1). [0015] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is a compound of Formula (VI-A-2), or a pharmaceutically acceptable salt thereof: (VI-A-2).
  • the compound of Formula (IIIe-1) is a compound wherein the N compound is pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is the compound or a pharmaceutically acceptable salt thereof. [0016] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is , or a pharmaceutically acceptable salt thereof. [0017] In some embodiments, a pharmaceutical composition comprising the compound of any one of the compounds disclosed herein and a pharmaceutically acceptable excipient.
  • methods of treating a disease or disorder associated with p300 activity in a subject comprising administering to the subject a therapeutically effective amount of a compound of any one of the compounds disclosed herein or the pharmaceutical composition comprising a compound disclosed herein.
  • DETAILED DESCRIPTION [0019] Provided herein are CBP and p300 KATi with demonstrated anti- proliferative properties in selected cancers, as well as on hematological models. Also provided are methods of treating a subject by administering a therapeutically effective dose of a pharmaceutical composition including the KATi.
  • the compound has a single configuration at that stereocenter, but the configuration is arbitrarily assigned. If the IUPAC name includes the phrase “S and R” or “R and S,” the compound is a mixture of compounds with both R and S configurations at that position. Thus, a single IUPAC name may refer to 1, 2, 4, or more individual compounds.
  • the stereochemistry in the chemical structures assigned at a benzylic stereocenter to R 4a is shown relative to the stereochemistry in the chemical structures at the carbon between the R 7 and A 2 positions of Formula I, but is otherwise arbitrarily assigned.
  • a droplet includes a plurality of such droplets and reference to “the discrete entity” includes reference to one or more discrete entities, and so forth.
  • the claims may be drafted to exclude any element, e.g., any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation.
  • the publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
  • R 1a is hydrogen, -CN, -C 1 -C 6 alkyl, -CO(C 1 -C 6 alkyl), -CO 2 (C 1 -C 6 alkyl), -CONH 2 , -CONH(C 1 -C 6 alkyl), -CON(C 1 -C 6 alkyl) 2 , or -SO 2 (alkyl)
  • R 1b and R 1c are each independently hydrogen, halo, -OH, C 1 -C 6 alkyl, -O-(C 1 -C 6 alkyl), -NH 2 , -
  • a 1 is NR 1a or O. In some embodiments, A 1 is NR 1a .
  • a 2 is NR 2a , O, or S. In some embodiments, A 2 is NR 2a . In some embodiments, A 2 is O. In some embodiments, A 2 is S.
  • W is N.
  • X is CR 9 .
  • Y is CR 10 .
  • Z is CR 11 .
  • Some embodiments relate to a compound, having the structure of Formula (IIe-1) (IIe-1), or a pharmaceutically acceptable salt thereof.
  • Some embodiments relate to a compound, having the structure of Formula (IIe-2) (IIe-2), or a pharmaceutically acceptable salt thereof.
  • Some embodiments relate to a compound, having the structure of Formula (IIIe-1) R1a (IIIe-1), or a pharmaceutically acceptable salt thereof.
  • Some embodiments relate to a compound, having the structure of Formula (IIIe-2) R 1a (IIIe-2), or a pharmaceutically acceptable salt thereof. [0041] Some embodiments relate to a compound, having the structure of Formula (IV-A) or Formula (IV-B):
  • R 4a is phenyl
  • R 6 is optionally substituted aryl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10- membered heterocycloalkyl
  • R 10 is hydrogen, halogen, alkyl optionally substituted with -COOH, or pyrazolyl substituted with alkyl.
  • R 1a is hydrogen.
  • R 1a is -C 1 - C 6 alkyl.
  • R 1a is -CO(C 1 -C 6 alkyl).
  • R 4a and R 4b are each independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 haloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl.
  • R 4a is substituted phenyl. In some embodiments, R 4a is phenyl. In some embodiments, R 4a is optionally substituted C 3 -C 10 cycloalkyl.
  • R 4a is optionally substituted 3- to 10-membered heteroaryl. In some embodiments, R 4a is optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R 4a is optionally substituted C 1 -C 6 alkyl.
  • J is O, NH, or CH 2 . In some embodiments, J is NH.
  • R 5 is L-R 6 .
  • L is optionally substituted C 1 -C 10 alkylene. In some embodiments, L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-.
  • R 6 is optionally substituted phenyl. In some embodiments, R 6 is phenyl substituted with cyano. In some embodiments, R 6 is phenyl substituted with one 1-3 R 60 , where each R 60 is independently selected from alkyl, alkyl substituted with -COOH, alkyl substituted with cycloalkyl and -COOH, alkyl substituted with cyano, or alkyl substituted with alkoxy. In some embodiments, at least one R 60 is – (CH 2 )COOH. In some embodiments, at least one R 60 is cyano or –(CH 2 )CN.
  • R 6 is phenyl or pyridinyl substituted with carboxy and optionally further substituted with alkyl, halogen, haloakyl or alkoxy.
  • R 6 is phenyl substituted with –(C 1 -C 4 alkyl)-COOH and optionally further substituted with one or more of fluoro, methyl or methoxy.
  • R 6 is phenyl substituted with –(spirocyclic cycloaklyl)-COOH or –(spirocyclic heterocycloalkyl)-COOH and optionally further substituted with methyl.
  • R 6 is phenyl substituted with -COOH, –(CH 2 )-COOH or –(CH 2 ) 2 -COOH and optionally further substituted with methyl. [0050] In some embodiments, R 6 is . In some embodiments, R 6 is [0051] In some embodiments, R 6 is wherein R 60 is – (alkyl)COOH. In some embodiments, R 6 is In some embodiments, R 6 is In some embodiments, R 6 is . In some embodiments, R 6 is In some embodiments, R 6 is In some embodiments, R 6 is . In some embodiments, R 6 is . In some embodiments, R 6 is In some embodiments, R 6 is . In some embodiments, R 6 is In some embodiments, R 6 is .
  • R 6 is [0052] In some embodiments, R 6 is wherein R 60 is -CN, - (CH 2 )CN or –(alkyl)COOH. In some embodiments, R 6 is In some embodiments, R 6 is In some embodiments, R 6 is . In some embodiments, R 6 is . [0053] In some embodiments, R 6 is , wherein each R 60 is independently alkyl, haloalkyl, or halogen. In some embodiments, at least one R 60 is methyl optionally substituted with one or more fluoro, or fluoro. In some embodiments, at least one R 60 is -CF 3 . In some embodiments, at least one R 60 is methyl.
  • R 60 is methyl.
  • R 6 is .
  • R 6 is, , .
  • R 6 is .
  • R 6 is phenyl or pyridinyl substituted with one or more methyl, fluoro, -CF 3 methoxy, -O-(C 1 -C 4 alkyl)-COOH, or -(C 1 -C 4 alkyl)-COOH.
  • R 6 is .
  • R 6 is .
  • R 6 is phenyl or pyridinyl substituted with C 1 -C 4 alkyl, C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl; wherein the alkyl is optionally substituted with C 3 -C 10 cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl.
  • R 6 is methyl substituted with a 5- to 6- member heteroaryl. In some embodiments, R 6 is .
  • R 6 is methyl substituted with a 5- to 6- member heterocycloalkyl. In some embodiments, R 6 is . In some embodiments, R 6 is phenyl substituted with a C 3 -C 6 cycloalkyl, a 3- to 6- member heterocycloalkyl, or a 5- to 6- member heteroaryl, each optionally substituted with one or more R 60 . In some embodiments, R 6 is . [0056] In some embodiments, R 6 is optionally substituted C 3 -C 10 cycloalkyl. In some embodiments, R 6 is . [0057] In some embodiments, R 6 is optionally substituted 3- to 10-membered heteroaryl.
  • R 6 is optionally substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl. In some embodiments, R 6 is optionally substituted 3- to 10- memebered heterocycloalkyl. [0058] In some embodiments, R 6 is a fused bicyclic ring system comprising a phenyl or pyridinyl ring fused to a 3 to 6 member heterocycloalkyl or to a C 3 -C 6 cycloalkyl. In some embodiments, R 6 is a dihydroindinene, a dihydroisobenzofuran, or a dihydro cyclopental[b]pyridine.
  • R 6 is , or , or each optionally substituted with alkyl, carboxyl, halogen or haloalkyl.
  • R 6 is a dihydroindinene, a dihydroisobenzofuran, or a dihydro cyclopental[b]pyridine each optionally substituted with -COOH or –(C 1 -C 4 alkyl)COOH.
  • R 6 is , [0059]
  • R 6 is phenyl or pyridinyl substituted with an amide, wherein the amide is optionally substituted with phenyl or a 5- to 6- member heteroaryl.
  • R 6 is .
  • R 6 is an amide optionally substituted with carboxy. In some embodiments, R 6 is . [0061] In some embodiments, R 6 is phenyl or pyridinyl substituted with -O-(C 1 -C 4 alkyl)-COOH. In some embodiments, R 6 is phenyl or pyridinyl substituted with -O-(CH 2 )- COOH, -COOH or -(CH 2 )-COOH.
  • each of R 8 , R 9 , R 10 , and R 11 is independently hydrogen, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -CONH 2 , -CONH(C 1 -C 6 alkyl), -CON(C 1 -C 6 alkyl) 2 , C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q.
  • each of R 8 , R 9 , R 10 , and R 11 is independently selected from the group consisting of hydrogen, halo, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -CN, -CO 2 H, - CO 2 (C 1 -C 6 alkyl), -CONH 2 , -CONH(C 1 -C 6 alkyl), -CON(C 1 -C 6 alkyl) 2 , -SO 2 NH 2 , - SO 2 NH(C 1 -C 6 alkyl), -SO 2 N(C 1 -C 6 alkyl) 2 , C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optional
  • Some embodiments relate to a compound, having the structure of Formula (V-A): wherein R 10 is hydrogen, alkyl optionally substituted with -COOH, or pyrazolyl substituted with alkyl; J is NH; R 5 is -L-R 6 ; L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-; R 6 is substituted phenyl or R 6 is substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl.
  • a compound is a compound of Formula (V-A), wherein R 10 is hydrogen, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is pyridinyl optionally substituted with 1-3 R 60 , as defined above.
  • a compound is a compound of the structure of Formula (V-A), wherein R 10 is a methyl pyrazolyle. In some embodiments, a compound is a compound of the structure of Formula (IV-A), wherein R 10 is . [0070] In some embodiments, a compound is a compound of the structure of Formula (V-A), wherein R 10 is a methyl pyrazolyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or - CH 2 CH(CH 3 )-, and R 6 is as defined above.
  • Some embodiments relate to a compound, having the structure of Formula (V-A), wherein R 10 is methyl pyrazolyl, J is NH, R 5 is -L-R 6 , L is - CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is phenyl substituted with -CN, -(CH 2 )CN, or – (alkyl)COOH and up to two R 60 , as defined above.
  • R 10 is methyl pyrazolyl
  • J is NH
  • R 5 is -L-R 6
  • L is - CH 2 CH 2 - or -CH 2 CH(CH 3 )-
  • R 6 is phenyl substituted with -CN, -(CH 2 )CN, or – (alkyl)COOH and up to two R 60 , as defined above.
  • a compound is a compound of Formula (V-A), wherein R 10 is methyl pyrazolyl, J is NH, R 5 is -L-R 6 , L is - CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is phenyl optionally substituted with –(CH 2 )COOH and 0-2 R 60 , as defined above.
  • a compound is a compound of Formula (V-A), wherein R 10 is methyl pyrazolyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is pyridinyl optionally substituted with 1-3 R 60 , as defined above.
  • a compound is a compound of Formula (V-A), wherein R 10 is methyl pyrazolyl, J is NH, R 5 is - L-R 6 , L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is pyridinyl optionally substituted with – (alkyl)COOH and 0-2 R 60 , as defined above.
  • a compound is a compound of Formula (V-A), wherein R 10 is methyl pyrazolyl, J is NH, R 5 is -L-R 6 , L is - CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is pyridinyl optionally substituted with –(CH 2 )COOH and 0-2 R 60 , as defined above.
  • a compound is a compound of the structure of Formula (V-A), wherein R 10 is a methyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )- , and R 6 is as defined above.
  • Some embodiments relate to a compound, having the structure of Formula (V-A), wherein R 10 is methyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or - CH 2 CH(CH 3 )-, and R 6 is phenyl substituted with -CN, -(CH 2 )CN, or –(alkyl)COOH and up to two R 60 , as defined above.
  • V-A Formula (V-A), wherein R 10 is methyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or - CH 2 CH(CH 3 )-, and R 6 is phenyl substituted with -CN, -(CH 2 )CN, or –(alkyl)COOH and up to two R 60 , as defined above.
  • a compound is a compound of Formula (V- A), wherein R 10 is methyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is phenyl optionally substituted with –(CH 2 )COOH and 0-2 R 60 , as defined above.
  • a compound is a compound of Formula (V-A), wherein R 10 is methyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is pyridinyl optionally substituted with 1-3 R 60 , as defined above.
  • a compound is a compound of Formula (V-A), wherein R 10 is methyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is pyridinyl optionally substituted with –(alkyl)COOH and 0-2 R 60 , as defined above.
  • a compound is a compound of Formula (V-A), wherein R 10 is methyl, J is NH, R 5 is -L-R 6 , L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-, and R 6 is pyridinyl optionally substituted with –(CH 2 )COOH and 0-2 R 60 , as defined above.
  • Some embodiments relate to a compound, having the structure of Formula (VI-A-1) or Formula (VI-A-2): (VI-A-1), (VI-A-2), wherein R 10 and R 6 are as defined above with respect to Formula (VI-A), with the specified absolute or relative stereochemistry.
  • a compound is a compound of Formula (VI-A-1) or Formula (V-A-2), wherein R 10 is hydrogen and R 6 is substituted phenyl as defined above.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is hydrogen and R 6 is phenyl substituted with –(alkyl)COOH, -CN or –(alkyl)CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is hydrogen and R 6 is phenyl substituted with –(CH 2 )COOH, -CN or –(CH 2 )CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is hydrogen and R 6 is phenyl substituted with –(CH 2 )COOH, -CN or –(CH 2 )CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is hydrogen and R 6 is , , , , or .
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is methyl and R 6 is substituted phenyl as defined above.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is methyl and R 6 is phenyl substituted with –(alkyl)COOH, -CN or –(alkyl)CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is methyl and R 6 is phenyl substituted with –(CH 2 )COOH, -CN or –(CH 2 )CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is methyl and R 6 is phenyl substituted with –(CH 2 )COOH, -CN or –(CH 2 )CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is methyl and R 6 is , , , , , , or .
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is and R 6 is substituted phenyl as defined above.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is and R 6 is phenyl substituted with –(alkyl)COOH, - CN or –(alkyl)CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is and R 6 is phenyl substituted with – (CH 2 )COOH, -CN or –(CH 2 )CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is and R 6 is phenyl substituted with –(CH 2 )COOH, -CN or –(CH 2 )CN.
  • a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R 10 is and R 6 is , , , , or .
  • R 10 is hydrogen, halo, -C 1 -C 6 alkyl, or pyrazolyl substituted with 1 substituent Q and Q is methyl.
  • R 10 is hydrogen.
  • R 10 is halo.
  • R 10 is fluoro. In some embodiments, R 10 is . In some embodiments, R 10 is -C 1 -C 6 alkyl. In some embodiments, R 10 is methyl. [0079] In some embodiments, R 6 is pyridinyl substituted with -CN or phenyl substituted with one or more R 60 , wherein one R 60 is C 1 -C 4 alkyl substituted with one or more COOH, cycloalkyl, or heterocycloalkyl, or phenyl substituted with -CH 2 C(O)OR 70 wherein each R 70 is hydrogen.
  • R 6 is phenyl substituted with -CN or phenyl substituted with one or more R 60 , wherein one R 60 is C 1 -C 4 alkyl substituted with one or more COOH, cycloalkyl, or heterocycloalkyl, or phenyl substituted with -CH 2 C(O)OR 70 wherein each R 70 is hydrogen.
  • R 6 is phenyl substituted with -CH 2 C(O)OR 70 , wherein R 70 is hydrogen.
  • R 6 is phenyl substituted with two or more R 60 , wherein one R 60 is C 1 -C 4 alkyl optionally substituted with spirocyclic cycloalkyl.
  • R 6 is phenyl substituted with two or more R 60 , wherein one R 60 is C 1 -C 4 alkyl optionally substituted with spirocyclic heterocycloalkyl. In some embodiments, R 6 is . In some embodiments, R 6 is In some embodiments, R 6 is . [0081] In some embodiments, the compound is the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof.
  • the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. [0082] Also disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure of any one of any one of the compounds described herein. [0083] Also disclosed herein is a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable excipient. Additional Embodiments 1.
  • R 1a is hydrogen; R 2b and R 2c are each independently hydrogen; R 3a and R 3b are each independently hydrogen; R 4a is phenyl; R 4b is hydrogen; J is NH; R 5 is -L-R 6 ; L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-; R 6 is optionally substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl; R 10 is selected from the group consisting of hydrogen, halo, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -CN, -CO 2 H, -CO 2 (C 1 -C 6 alkyl), -CONH 2 , -CONH(C 1 -C 6 alkyl), - CON
  • a linker Since a linker connects two groups, a linker is a diradical group. Connections between groups can also be described by the term “valent”, such as in “monovalent” or “divalent”, which refers to the bond order of the connection.
  • the group -CH 3 is a monovalent group since it can form a single covalent bond with another group, e.g., with -OH to form H 3 COH.
  • the group CH 2 is a divalent group since it can form a double bond with another group, e.g., with an oxygen atom to form formaldehyde (CH 2 O).
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH 3 CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHCH 2 -), sec-butyl ((CH 3 )(CH 3 CH 2 )CH-), t-butyl ((CH 3 ) 3 C-), n-pentyl (CH 3 CH 2 CH 2 CH 2 CH 2 -), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • Alkylene refers to divalent aliphatic hydrocarbyl groups preferably having from 1 to 12 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched. This term includes, by way of example, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH 2 CH 2 CH 2 -), iso-propylene (-CH 2 CH(CH 3 )-), (-C(CH 3 ) 2 CH 2 CH 2 -), (-CH(CH 3 )CH 2 -), and the like.
  • substituted alkenyl refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxy
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C ⁇ CH), and propargyl (-CH 2 C ⁇ CH).
  • substituted alkynyl refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, al
  • Aryl refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thi
  • R is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
  • Cyano or “nitrile” refers to the group –CN.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy,
  • Cycloalkenyl refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
  • Cycloalkynyl refers to non-aromatic cycloalkyl groups having single or multiple rings and having at least one triple bond.
  • Halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.
  • heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic.
  • any heteroatoms in such heteroaryl rings may or may not be bonded to H or a substituent group, e.g., an alkyl group or other substituent as described herein.
  • the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • N ⁇ O N-oxide
  • sulfinyl N-oxide
  • sulfonyl moieties N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thio
  • Heterocycle refers to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or –SO 2 - moieties.
  • any heteroatoms in such heterocyclic rings may or may not be bonded to one or more H or one or more substituent group(s), e.g., an alkyl group or other substituent as described herein.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline,
  • heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,
  • substituted when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
  • Each M + may independently be, for example, an alkali ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R 60 )4; or an alkaline earth ion, such as [Ca 2+ ]0.5, [Mg 2+ ]0.5, or [Ba 2+ ]0.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the present disclosure and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the present disclosure can serve as the counter ion for such divalent alkali earth ions).
  • an alkali ion such as K + , Na + , Li +
  • an ammonium ion such as + N(R 60 )4
  • an alkaline earth ion
  • -NR 80 R 80 is meant to include -NH 2 , -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl and N- morpholinyl.
  • substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R 60 , halo, -O-M + , -OR 70 , -SR 70 , -S – M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO 2 , -N3, -SO 2 R 70 , -SO 3 -M + , -SO 3 R 70 , -OSO 2 R 70 , -OSO 3 -M + , -OSO 3 R 70 , -PO 3 -2 (M + ) 2 , -P(O)(OR 70 )O-M + , -P(O)(OR 70 ) 2 , -C(O)R 70 , -C
  • substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -O-M + , -OR 70 , -SR 70 , -S-M + , -NR 80 R 80 , trihalomethyl, -CF 3 , -CN, -NO, -NO 2 , -S(O) 2 R 70 , -S(O) 2 O-M + , -S(O) 2 OR 70 , -OS(O) 2 R 70 ,
  • a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
  • Two substituents may come together with the atom or atoms to which they are attached to form a ring that is spiro or fused with the rest of the compound.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-.
  • substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
  • salt means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime).
  • Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.
  • salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
  • salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
  • Compounds disclosed herein include all stereoisomers thereof.
  • Stereoisomer and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. [0122] Compounds disclosed herein include all tautomers thereof.
  • pyrazoles imidazoles, benzimidazoles, triazoles, and tetrazoles.
  • the term “or a salt or solvate or stereoisomer thereof” is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of subject compound.
  • Administration and Pharmaceutical Compositions [0124] The disclosed compounds may be used alone or in combination with other treatments. These compounds, when used in combination with other agents, may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). The compounds may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy with another agent in a treatment program.
  • Examples of pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • the compounds of a method and/or composition described herein can be provided via oral administration, rectal administration, transmucosal administration, intestinal administration, enteral administration, topical administration, transdermal administration, intrathecal administration, intraventricular administration, intraperitoneal administration, intranasal administration, intraocular administration and/or parenteral administration.
  • oral administration for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as starch, ge
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient can be mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain, for example, antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0130] In some embodiments unit dosage formulations contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art.
  • the actual dose of the compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • a daily dose may be from about 0.1 mg/kg to about 100 mg/kg or more of body weight, from about 0.25 mg/kg or less to about 50 mg/kg, from about 0.5 mg/kg or less to about 25 mg/kg, from about 1.0 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day or less to about 2000 mg per day or more, from about 70 mg per day to about 1000 mg per day.
  • Some embodiments of the present disclosure include methods of treating a disease or disorder associated with p300 activity in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound as described herein or or a pharmaceutical composition as described herein.
  • Some embodiments relate to a method for treating a disease or condition selected from the group consisting of an inflammatory disorder, an allergic disorder, an autoimmune disease, and a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the compound as described herein or a pharmaceutical composition as described herein to the subject.
  • the disease or condition is a cancer selected from the group consisting of a hematologic malignancy and a solid tumor.
  • the disease or condition is a hematologic malignancy selected from the group consisting of lymphoma, multiple myeloma, or leukemia.
  • the disease or condition is selected from the group consisting of small lymphocytic lymphoma, non-Hodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma, refractory iNHL, mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, lymphoblastic lymphoma, Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes), Nodal marginal zone lymphoma (+/- monocytoid B-cells), Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, cutaneous T-cell lymphoma, extranodal T-cell lymph
  • the disease or condition is selected from the group consisting of systemic lupus erythematosus, myestenia gravis, Goodpasture’s syndrome, glomerulonephritis, hemorrhage, pulmonary hemorrhage, atherosclerosis, rheumatoid arthritis, psoriatic arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis, Behçet disease, autoimmune thyroiditis, Reynaud’s syndrome, acute disseminated encephalomyelitis, chronic idiopathic thrombocytopenic purpura, multiple sclerosis, Sjögren’s syndrome, autoimmune hemolytic anemia, tissue graft rejection, hyperacute rejection of transplanted organs, allograft rejection, graft-versus-host disease, diseases involving leukocyte diapedesis, disease states due to leukocyte dyscrasia and metastasis, granulocyte transfusion
  • R 1a is hydrogen; R 2b and R 2c are each independently hydrogen; R 3a and R 3b are each independently hydrogen; R 4a is phenyl; R 4b is hydrogen; J is NH; R 5 is -L-R 6 ; L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-; R 6 is substituted phenyl; and R 10 is selected from the group consisting of hydrogen, halo, -C 1 -C 6 alkyl, -C 1 - C 6 haloalkyl, -CN, -CO 2 H, -CO 2 (C 1 -C 6 alkyl), -CONH 2 , -CONH(C 1 -C 6 alkyl), - CON(C 1 -C 6 alkyl) 2 , -NH 2 , -NH(C 1 -C 6 alkyl), -N(C 1 -C 6 alkyl) 2 , -OH,
  • Amide intermediates B were constructed by substituted 2-methylpyridin-3- amine A reacting with (S)-3-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid under various amide couple conditions (e.g., T 4 P with TEA in DCM). Amide intermediates B were oxidized with SeO 2 to form aldehyde intermediates C, which were cyclized under basic conditions (e.g., Cs 2 CO 3 in DMF) to generate intermediates D.
  • various amide couple conditions e.g., T 4 P with TEA in DCM.
  • Amide intermediates B were oxidized with SeO 2 to form aldehyde intermediates C, which were cyclized under basic conditions (e.g., Cs 2 CO 3 in DMF) to generate intermediates D.
  • Intermediates D were then reduced under hydrogenation conditions (e.g., PtO 2 , H 2 , with NH 3 -H 2 O) to yield intermediates E, which were pairs of diastereomers and separated via SFC chiral separation to give optically pure diastereomers F1 and F2.
  • F1 and F2 were brought forward separately using same procedures.
  • intermediate amines F1 and F2 were synthesized via the general route as shown below.
  • intermediates E were reduced (e.g., using LAH with TMSCl) to give mixture of F1 and F2, which were then separated via SFC chiral separation. F1 and F2 were brought forward separately using same procedures to give final compounds with different absolute configurations.
  • F2 were brought forward separately using same procedures to give final compounds with different absolute configurations.
  • Optically pure intermediates F2 were reacted with an acid (e.g., HCl in EtOAc) to form deprotected free amine salts (e.g., HCl salts) G, which were converted to final compounds via reductive amination with pre-made aldehydes.
  • an acid e.g., HCl in EtOAc
  • deprotected free amine salts e.g., HCl salts
  • R’ groups needed to be further modified to give desired R’’ groups are needed to be further modified to give desired R’’ groups.
  • Amine intermediates e.g., HCl salts
  • Another alternate approach to make final compounds for bioassay testing Amine intermediates (e.g., HCl salts) G were converted to amides HH by reacting with pre-made carboxlic acids under various known conditions. Amides HH were then reduced to amines to form final compounds for bioassay testing.
  • R’ and R’’ were further modified by chemical transformation as needed.
  • benzyl N-(5-fluoro-2-methylpyridin-3-yl) carbamate [0156] To a stirred solution of 5-fluoro-2-methylpyridin-3-amine (6.15 g, 48.758 mmol, 1 equiv.) and pyridine (77.137 g, 78.872 mL, 0.978 g/mL, 975.153 mmol, 20 equiv.) in DCM (100 mL, 0.488 M, 16.26 Vols) was added benzyl chloroformate (16.635 g, 97.515 mmol, 2 equiv.) at 0 o C. The reaction was stirred at 25 o C for 3 hours under N 2 atmosphere.
  • Step B.3- ⁇ [(benzyloxy) carbonyl] amino ⁇ -5-fluoro-2-methylpyridin-1-ium-1-olate This compound was synthesized using flow chemistry as shown below.
  • Solution 1 benzyl N-(5-fluoro-2-methylpyridin-3-yl) carbamate (20 g, 76.844 mmol, 1 equiv.) in DCE (100 mL, 0.768 M, 5 Vols)
  • Solution 2 m-CPBA (39.001 g, 192.11 mmol, 2.5 equiv.) in DCE (200 mL, 0.384 M, 10 Vols)
  • Solution 1 was pumped by Pump 1 ⁇ S1, P1, 8.765 mL/min ⁇ to flow reactor 1 ⁇ FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL,70 °C ⁇ .
  • the reaction mixture was quenched by sat. aq. NaHCO 3 (600 mL) at 0 °C.
  • the reaction mixture was partitioned between EtOAc (300 m ⁇ 3) and sat. aq. NaHCO 3 (600 mL).
  • the organic phase was separated, washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO@; 220 g SepaFlash@ Silica Flash Column, Eluent of 21 ⁇ 25% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Three reactions were carried out in parallel.
  • Solution 1 benzyl N-[2-(bromomethyl)-5-fluoropyridin-3-yl] carbamate (17 g, 61.53 mmol, 1 equiv.) in DCE (51 mL, 1.207 M, 3 Vols) [0169]
  • Solution 2 PBr 3 (49969.725 mg, 184.604 mmol, 3 equiv.) in DCE (51 mL, 1.207 M, 3 Vols) [0170] Solution 1 was pumped by Pump 1 ⁇ S1, P1, 3.851 mL/min ⁇ to flow reactor 1 ⁇ FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 42.743 mL,50 °C ⁇ .
  • Step H tert-butyl N-[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]carbamate and tert-butyl N-[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl) methyl] carbamate [0189] This reaction was carried over using the flow chemistry as shown below.
  • Solution 1 tert-butyl N-[(S)-(7-fluoro-2-oxo-3,4-dihydro-1H-1,5- naphthyridin-3-yl) (phenyl)methyl] carbamate (2 g, 5.385 mmol, 1 equiv.) in THF (40 mL, 0.135 M, 20 Vols) was added TMSCl (2.106 g, 19.385 mmol, 3.6 equiv.).
  • Solution 2 LiAlH4 (817.421 mg, 2.692 mL, 21.539 mmol, 4 equiv.) in THF (40 mL, 0.135 M, 20 Vols) [0192] The volume of flow reactor 1FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, -10 °C. The residence time of flow reactor 1 was ⁇ FLR1,10 min ⁇ . [0193] The flow rate of Pump1 was adjusted to ⁇ S1, P1, 3.066 mL/min ⁇ for solution 1. [0194] The flow rate of Pump2 was adjusted to ⁇ S2, P2, 3.346 mL/min ⁇ for solution 2.
  • Step J.2-[3-(2- ⁇ [(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl] (phenyl)methyl] amino ⁇ ethyl)-4-methylphenyl] propanoic acid [0204] To a stirred solution of (1S)-1-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]-1-phenylmethanamine (45 mg, 0.17 mmol, 1 equiv.) in MeOH (1 mL, 0.17 M, 22.22 Vols) was added AcOH (0.01 g, 0.17 mmol, 1 equiv.) to adjusted pH 5.
  • Step AA 4-(3-chloro-4-methylphenyl)-1,2-oxazole [0208] To a solution of 4-bromo-2-chloro-1-methylbenzene (2 g, 9.73 mmol, 1 equiv.) in THF (20 mL, 0.48 M, 10 Vols) and H 2 O (4 mL, 2.43 M, 2 Vols) were added K 3 PO 4 (6.198 g, 29.2 mmol, 3 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (1.89 g, 9.73 mmol, 1 equiv.) and Catacxium A-Pd-G2 (0.32 g, 0.48 mmol, 0.05 equiv.) under N 2 .
  • reaction was stirred at 80 o C for 1 h under N 2 atmosphere.
  • the reaction mixture was partitioned between EtOAc (20 mL ⁇ 3) and H 2 O (20 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • Step AD 2- ⁇ 3-[(1E)-2-ethoxyethenyl]-4-methylphenyl ⁇ propanoic acid
  • 2-(3-chloro-4-methylphenyl) propanoic acid 800 mg, 4.02 mmol, 1 equiv.
  • 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.03 g, 5.23 mmol, 1.3 equiv.) in H 2 O (2 mL, 2.01 M, 2.5 Vols) and Tol.
  • Step B.4- ⁇ 3-[(1E)-2-ethoxyethenyl]-4-methylphenyl ⁇ -1,2-oxazole [0214] To a solution of 4-(3-chloro-4-methylphenyl)-1,2-oxazole (2 g, 10.32 mmol, 1 equiv) in dioxane (20 mL, 1.03 M, 10 Vols) and H 2 O (6 mL, 3.14 M, 3 Vols), were added K 3 PO 4 (6.57 g, 30.98 mmol, 3 equiv), Catacxium A-Pd-G2 (0.69 g, 0.10 mmol, 0.1 equiv), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.45 g, 12.4 mmol, 1.2 equiv) with N 2 for 3 times.
  • the reaction was stirred at 100 o C for 2 h under N 2 atmosphere. LCMS indicated one main peak with desired mass was detected.
  • the reaction mixture was partitioned between EtOAc (10 mL ⁇ 3) and H 2 O (10 mL). The organic phase was separated, washed with brine (10 mL ⁇ 1), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography. (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 6% Ethyl acetate/Petroleum ethergradient @ 100 mL/min).
  • Step E [3-(2- ⁇ [(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino ⁇ ethyl)-4-methylphenyl]acetic acid (2002A) and [3-(2- ⁇ [(S)-[(3S)- 7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino ⁇ ethyl)-4- methylphenyl]acetic acid (2002B) [0217] To a solution of (1S) 1 (7 fluoro 1,2,3,4 tetrahydro 1,5 naphthyridin 3 yl) 1-phenylmethanamine (40 mg, 0.15 mmol, 1 equiv) in MeOH (1 mL, 0.15 M, 25 Vols) were added AcOH (9.33 mg, 0.15
  • Step A.4-[(1E)-2-ethoxyethenyl]benzoic acid [0220] To a stirred solution of 4-bromobenzoic acid (1 g, 4.97 mmol, 1 equiv.) and 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.18 g, 5.97 mmol, 1.2 equiv.) in dioxane (16 mL, 0.31 M, 16 Vols) and H 2 O (4 mL, 1.24 M, 4 Vols) were added K 2 CO 3 (1.37 g, 9.94 mmol, 2 equiv.) and Pd(dppf)Cl 2 (363.99 mg, 0.49 mmol, 0.1 equiv.).
  • the reaction mixture was purged with N 2 for three times and stirred at 80 °C for 3 h under N 2 .
  • LCMS showed the reactant was consumed completely and desired mass was formed.
  • the mixture was adjusted pH to 3 with aqueous solution of hydrochloric acid (1 mol/L).
  • the reaction mixture was diluted with EtOAc (45 mL) and H 2 O (20 mL).
  • the organic phase was separated, washed with brine (15 mL), dried over [Na 2 SO 4 ], filtered and concentrated under reduced pressure to give a residue.
  • (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (30 mg, 0.12 mmol, 1 equiv.) in MeOH (2 mL, 0.06 M, 66.66 Vols) was added AcOH (0.75 mg, 0.01 mmol, 0.1 equiv.) to adjust pH ⁇ 6, then NaBH 3 CN (23.63 mg, 0.37 mmol, 3 equiv.) was added to the mixture followed by 4-(2-oxoethyl)benzoic acid (21.60 mg, 0.13 mmol, 1.05 equiv
  • reaction was stirred at 0 °C for 1 h. TLC indicated reactant was consumed completely and one new spot formed.
  • the reaction mixture was filtered and the filtrate was purified by Prep.-HPLC column: Phenomenex Luna C1875*30mm*3um; mobile phase: [A: H 2 O (0.1% TFA); B: ACN]; B%: 1.00%-30.00%, 8.00 min.
  • tert-butyl N-[(1S)-3-[(5-bromo-2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate A stirred solution of SeO 2 (4.6 g, 41.44 mmol) in 1,4-Dioxane (60 mL) at 25 °C, warming up to 80 °C, tert-butyl N-[(1S)-3-[(5-bromo-2-methyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate (6 g, 13.81 mmol) was added to above solution at 80 °C, then the mixture was warmed to 110 o C and stirred at 110 o C for 96 h.
  • tert-butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-2-oxo-3,4-dihydro-1H-1,5-naphthyridin- 3-yl]-phenyl-methyl]carbamate [0225] To a suspension of PtO 2 (210.5 mg, 0.93 mmol) in Methanol (300 mL) was added tert-butyl N-[(R)-[2-hydroxy-7-(1-methylpyrazol-4-yl)-1,5-naphthyridin-3-yl]-phenyl- methyl]carbamate (400 mg, 0.93 mmol) under Ar atmosphere.
  • tert-butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]-phenyl-methyl]carbamate [0226] A solution of tert-butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-2-oxo-3,4- dihydro-1H-1,5-naphthyridin-3-yl]-phenyl-methyl]carbamate (350 mg, 0.81 mmol) in THF (10 mL) was purged with N 2 for 3 times at 25 o C.
  • the reaction was stirred at 25 o C for 1 h. LCMS showed starting material was consumed completely and main desired mass was detected.
  • the crude product was purified by Prep.-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10 um; mobile phase: [A: H 2 O 10 mM NH 4 HCO 3 ); B: ACN]; B%: 10.00%-40.00%, 8.00min). Then the crude product was purified by Prep.-HPLC (column: Phenomenex luna C18 100*40 mm*3 um; mobile phase: [A: H 2 O (0.2% FA); B: ACN]; B%: 5.00%-35.00%, 8.00min).
  • Step AB.4-[3-(2-methoxyvinyl)phenyl]isoxazole To a stirred solution of 1-bromo-3-(2-methoxyvinyl)benzene (0.9 g, 4.22 mmol) in THF (20 mL) and Water (5 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (1.24 g, 6.34 mmol), K 3 PO 4 (1.79 g, 8.45 mmol) and Catacxium A-Pd-G 2 (0.14 g, 0.21 mmol).
  • Step C.4-[3-(2-methoxyvinyl)phenyl]isoxazole To a stirred solution of 1-bromo-3-(2-methoxyvinyl)benzene (780 mg, 3.66 mmol) in THF (20 mL) and Water (5 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (785.32 mg, 4.03 mmol), K 3 PO 4 (2.33 g, 10.98 mmol) and Catacxium A-Pd-G 2 (122.39 mg, 0.18 mmol) at 15 o C. The mixture was degassed with N 2 for 3 times.
  • tert-butyl N-[(1S)-3-[(2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl-propyl]carbamate [0243] A solution of SeO 2 (117.07g, 1055.03mmol) in 1,4-Dioxane (5.7L) and heated to 80 o C to stirred for 20 min. Then the mixture was added tert-butyl N-[(1S)-3-[(2- methyl-3-pyridyl)amino]-3-oxo-1-phenyl-propyl]carbamate (75 g, 211.01 mmol). The reaction was warmed to 110 o C and stirred for 12 h.
  • the reaction was divided for six batch (15 g ⁇ 3 + 10 g ⁇ 3). LCMS showed the starting material was consumed completely and the main peak with desired mass was detected.
  • the reaction was filtered with a pad of Celite and washed with EtOAc (300 mL ⁇ 3). The filtrate was concentrated under reduced pressure.
  • the mixture was poured to water (800 mL) and extracted with ethyl acetate (3 ⁇ 500 mL). The organic layer was washed with brine (500 mL), dried over anhydrous Na 2 SO 4 , then filtered and concentrated under reduced pressure.
  • the crude product was purified by Prep.-HPLC (column: Phenomenex luna C18250mm*100mm*15um; mobile phase: [A: H 2 O (0.2%FA); B: ACN]; B%: 35.00%- 65.00%,23.00 min) to get tert-butyl N-[(1S)-3-[(2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate (30 g, 81.21 mmol, 38.47% yield) as a yellow solid.
  • tert-butyl N-[(R)-(2-hydroxy-1,5-naphthyridin-3-yl)-phenyl-methyl]carbamate [0244] To a solution of tert-butyl N-[(1S)-3-[(2-formyl-3-pyridyl)amino]-3-oxo-1- phenyl-propyl]carbamate (30 g, 81.21 mmol) in DMF (300 mL) was added Cs 2 CO 3 (52.92 g, 162.42 mmol) at 0 o C. Then the mixture was warmed to 60 o C and stirred for 2 h.
  • LCMS showed the starting material was consumed completely and the main peak with desired mass was detected.
  • the mixture was poured to water (200 mL) and ethyl acetate (150 mL), then the mixture was washed with water (3 ⁇ 150 mL). Filtered and the filter cake was concentrated under reduced pressure to get tert-butyl N-[(R)-(2-hydroxy-1,5-naphthyridin-3-yl)-phenyl- methyl]carbamate (20 g, 56.91 mmol, 70.08% yield) as a gray solid.
  • Step D tert-butyl N-[(S)-(2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3-yl)-phenyl- methyl]carbamate [0245] To a solution of tert-butyl N-[(R)-(2-hydroxy-1,5-naphthyridin-3-yl)- phenyl-methyl]carbamate (20 g, 56.91 mmol) in Methanol (2400 mL) and THF (2400 mL) was added NH 3 .H 2 O (5 mL, 129.83 mmol) and PtO 2 (5 g, 22.02 mmol).
  • the reaction was degassed with H 2 for 5 times. The reaction was stirred at 80 o C for 24 h under 50 psi. The reaction was for 4 batches (5 g ⁇ 4). LCMS showed ⁇ 17% of the starting material was remained and the main peak with desired mass was detected. The reaction was filtered with a pad of celite and washed with MeOH (100 ml ⁇ 3).
  • Step AA.1-bromo-3-(2-methoxy-1-methyl-vinyl) benzene To a stirred solution of methoxymethyl (triphenyl) phosphonium; chloride (62 g, 180.86 mmol) in THF (500 mL) was added t-BuOK (180.86 mL, 180.86 mmol) (1 M in THF) at 0 °C under N 2 . The mixture was stirred at 0 °C for 1 h, then a solution of 1-(3- bromophenyl) ethanone (18 g, 90.43 mmol) in THF (100 mL) was added to the above solution at 0 °C.
  • Step AB.4-[3-(2-methoxy-1-methyl-vinyl) phenyl] isoxazole [0251] To a stirred solution of 1-bromo-3-(2-methoxy-1-methyl-vinyl)benzene (8 g, 35.23 mmol) in THF (400 mL) and Water (100 mL) were added 4-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl) isoxazole (7.56 g, 38.75 mmol), K 3 PO 4 (22.43 g, 105.68 mmol) and Catacxium A-Pd-G2 (2.36 g, 3.52 mmol).
  • (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine;hydrochloride 35 mg, 0.09 mmol
  • Methanol 1.5 mL
  • TEA 0.02 mL, 0.12 mmol
  • Step A.2-[5-[(E)-2-ethoxyvinyl]-2-fluoro-phenyl]acetic acid [0283] To a stirred solution of 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (2.21 g, 11.16 mmol) in Water (6 mL) and 1,4-Dioxane (30 mL) were added 2- (5-bromo-2-fluoro-phenyl)acetic acid (2 g, 8.58 mmol), Cs 2 CO 3 (5.59 g, 17.16 mmol) and Pd(dppf)Cl 2 (0.63 g, 0.86 mmol).
  • the mixture was degassed with N 2 for 3 times and stirred at 80 °C for 3 h. LCMS showed starting material was consumed completely and main desired mass was detected.
  • the mixture was cooled to room temperature and poured into water (10 mL) and extracted with ethyl acetate (3 ⁇ 10 mL). The organic layer was dried over anhydrous Na 2 SO 4 , then filtered and concentrated under reduced pressure to give a crude product.
  • the crude product was purified by flash column (ISCO 20 g silica, 0-5 % ethyl acetate in petroleum ether, gradient over 40 min).
  • Step A 2-(3-bromo-4-fluoro-phenyl) propanoic acid
  • 2-(3-bromo-4-fluoro-phenyl) acetic acid (2 g, 8.58 mmol) in THF (20 mL) was added NaHMDS (17.16 mL, 17.16 mmol) slowly at 0 o C.
  • the reaction mixture was degassed with N 2 for three times. Then the reaction was stirred at 0 o C for 0.5 h, then the CH 3 I (1.6 mL, 25.75 mmol) was dropwise slowly to the mixture at 0 o C, and the reaction mixture was stirred at 0 o C for 2 h.
  • the reaction was degassed and purged with N 2 for 3 times, and stirred at 80 o C for 12 h under N 2 atmosphere. LCMS showed starting material was remained and one main peak with desired mass was detected.
  • the reaction was cooled to 15 o C. Then the mixture was added into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL ⁇ 3). The combined organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the crude product was purified by flash column (ISCO 20 g silica, 0 - 50% ethyl acetate in petroleum ether, gradient over 20 min).
  • the NaBH 3 CN (77.72 mg, 1.25 mmol) was added to the above solution.
  • the reaction was stirred at 25 o C for 1 h under N 2 .
  • LCMS showed starting material was consumed completely and 26% peak with desired mass was detected.
  • the mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 ⁇ 2 mL). The organic layer was washed with brine (2 mL), dried over anhydrous Na 2 SO 4 , then filtered and concentrated in vacuo.
  • Step A 4-bromo-2-(2-methoxyethenyl)-1-methylbenzene [0296] To a solution of (methoxymethyl)triphenylphosphanium chloride (5.16 g, 15.07 mmol, 1.5 equiv.) and t-BuOK (1.69 g, 15.07 mL, 1 M, 15.07 mmol, 1.5 equiv.) in THF (30 mL, 0.33 M, 15 Vols), the reaction mixture was stirred at 0 °C for 0.5 h under N 2 , 5-bromo- 2-methylbenzaldehyde (2 g, 10.04 mmol, 1 equiv.) were added to the mixture, and the reaction mixture was stirred at 20 °C for 11.5 h under N 2 atmosphere.
  • Step D 2-(4-methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid [0303] This step was synthesized according to the synthetic general procedure.
  • Step A.2-[5-[(E)-2-ethoxyvinyl]-2-methoxy-phenyl] acetic acid A mixture of 2-(5-bromo-2-methoxy-phenyl) acetic acid (2.5 g, 10.2 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.4 g, 12.24 mmol), K 2 CO 3 (4.2 g, 30.6 mmol) and Pd(dppf)Cl 2 (746.42 mg, 1.02 mmol) in 1,4-Dioxane (50 mL) and water (5 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 80 o C for 12 h under N 2 atmosphere.
  • Step C 2-(2-methoxy-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid
  • (S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methanamine 40 mg, 0.17 mmol, 1 equiv.
  • MeOH mL, 0.16 M, 25 Vols
  • AcOH (0.03 g, 0.50 mmol, 3 equiv.
  • 2-(2-methoxy-5-(2-oxoethyl) phenyl) acetic acid 0.04 g, 0.17 mmol, 1 equiv.
  • NaBH 3 CN 0.03 g, 0.50 mmol, 3 equiv.
  • Step A.2-[5-[(E)-2-ethoxyvinyl]-2-methyl-phenyl] acetic acid [0316] To a stirred solution of 2-(5-bromo-2-methyl-phenyl)acetic acid (1000.mg, 4.37 mmol) in 1,4-Dioxane (10 mL) and Water (2 mL) were added 2-[(E)-2-ethoxyvinyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1297.01 mg, 6.55 mmol), K 2 CO 3 (1810.06 mg, 13.1 mmol) and Pd(dppf)Cl 2 (638.86 mg, 0.87 mmol).
  • the suspension was degassed and purged with N 2 for 3 times.
  • the reaction was stirred at 80 o C for 5 h.
  • LC-MS showed reactant 1 was consumed completely and desired mass was formed.
  • the reaction mixture was concentrated under reduced pressure to give a residue.
  • the residue was diluted with H 2 O (50 mL ⁇ 1) and extracted with EtOAc (50 mL ⁇ 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and the filtrate was concentrated under reduced pressure to give a residue.
  • Step C 2-(2-methyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid
  • (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methanamine 35 mg, 0.15 mmol
  • Methanol 1 mL
  • Step A 1-bromo-5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-benzene [0320]
  • Step C 2-[5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-phenyl]acetic acid [0323]
  • TLC indicated reactant 1 was consumed completely and one new spot formed.
  • the mixture acidified pH to 3 with aqueous solution of hydrochloric acid (1mol/L).
  • the reaction mixture was extracted with EtOAc (5 mL ⁇ 3) and H 2 O (10 mL).
  • Step D 2-[2,4-dimethyl-5-(2-oxoethyl)phenyl]acetic acid [0324]
  • a solution of 2-[5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-phenyl]acetic acid (200 mg, 0.85 mmol), HCl (0.3 mL, 3.6 mmol) in CH 3 CN (3 mL) was stirred at 0 o C for 0.5 h. TLC indicated reactant 1 was consumed completely and one new spot formed.
  • the reaction mixture was extracted with EtOAc (5 mL ⁇ 3) and H 2 O (10 mL).
  • Step A 5-[(1E)-2-ethoxyethenyl]-2,4-dimethylpyridine [0328] A mixture of 5-bromo-2,4-dimethylpyridine (1 g, 5.38 mmol, 1 equiv.), 2- [(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 g, 1.37 mL, 0.94 g/mL, 6.45 mmol, 1.2 equiv.), K 2 CO 3 (2.23 g, 16.13 mmol, 3 equiv.) and Pd(dppf)Cl 2 (196.64 mg, 0.27 mmol, 0.05 equiv.) in dioxane (20 mL, 0.27 M, 20 Vols) and H 2 O (5 mL, 1.08 M, 5 Vols) was degassed and purged with N 2 for 3 times, and then the reaction mixture was stirred at 80 o C
  • Step C [2-(4,6-dimethylpyridin-3-yl)ethyl][(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl]amine [0331]
  • (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine 45 mg, 0.19 mmol, 1 equiv.
  • CH 3 COOH 33.88 mg, 0.56 mmol, 3 equiv.
  • 2-(4,6-dimethylpyridin-3-yl)acetaldehyde 56.11 mg, 0.38 mmol, 2 equiv.
  • NaBH 3 CN 23.63 mg, 0.38 mmol, 2
  • Step A.5-fluoro-2-methylpyridin-3-amine A solution of 2-bromo-5-fluoropyridin-3-amine (12.5 g, 65.44 mmol, 1 equiv.), trimethyl-1,3,5,2,4,6-trioxatriborinane (49.29 g, 196.33 mmol, 3 equiv.), Cs 2 CO 3 (53.31 g, 163.61 mmol, 2.5 equiv.) and Ruphos Pd G3 (2.74 g, 3.27 mmol, 0.05 equiv.) in Toluene (150 mL, 0.44 M, 12 Vols) and H 2 O (30 mL, 2.18 M, 2.4 Vols).
  • reaction was stirred at 100 o C for 4 h under N 2 atmosphere. LC-MS showed the reactant was consumed completely and 36% peak with desired mass was formed.
  • the reaction mixture was filtered and the filter cake was rinsed with EtOAc (100 mL ⁇ 2). The reaction mixture was diluted with H 2 O 250 mL and extracted with EtOAc (200 mL ⁇ 3).
  • benzyl N-(5-fluoro-2-methylpyridin-3-yl) carbamate [0335] To a stirred solution of 5-fluoro-2-methylpyridin-3-amine (6.15 g, 48.76 mmol, 1 equiv.) and pyridine (77.14 g, 78.87 mL, 0.98 g/mL, 975.15 mmol, 20 equiv.) in DCM (100 mL, 0.49 M, 16.26 Vols) was added benzyl chloroformate (16.64 g, 97.52 mmol, 2 equiv.) at 0 o C. The reaction was stirred at 25 o C for 3 h under N 2 atmosphere.
  • reaction mixture was quenched by sat. aq. NaHCO 3 (600 mL) at 0 °C.
  • the reaction mixture was partitioned between EtOAc (300 mL ⁇ 3) and sat. aq. NaHCO 3 (600 mL).
  • the organic phase was separated, washed with brine (400 mL), dried over [Na 2 SO 4 ], filtered and concentrated under reduced pressure to give a residue.
  • Solution 1 benzyl N-[2-(bromomethyl)-5-fluoropyridin-3-yl] carbamate (17 g, 61.53 mmol, 1 equiv.) in DCE (51 mL, 1.21 M, 3 Vols) [0349]
  • Solution 2 PBr 3 (49969.73 mg, 184.60 mmol, 3 equiv.) in DCE (51 mL, 1.21 M, 3 Vols) [0350]
  • the solution 1 was pumped by Pump 1 ⁇ S1, P1, 3.851 mL/min ⁇ to flow reactor 1 ⁇ FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 42.743 mL,50 °C ⁇ .
  • Solution 2 LiAlH4 (817.421 mg, 2.692 mL, 21.539 mmol, 4 equiv.) in THF (40 mL, 0.135 M, 20 Vols) [0375] The volume of flow reactor 1FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, -10 °C. The residence time of flow reactor 1 was ⁇ FLR1,10 min ⁇ . [0376] The flow rate of Pump1 was adjusted to ⁇ S1, P1, 3.066 mL/min ⁇ for solution 1. [0377] The flow rate of Pump2 was adjusted to ⁇ S2, P2, 3.346 mL/min ⁇ for solution 2.
  • reaction mixture was concentrated under reduced pressure to get a residue, and the reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (column: Waters Xbridge BEH C18 100*30mm*10 um; mobile phase: [A: H 2 O (10 mM NH 4 HCO 3 ); B: ACN]; B%: 15.00%-50.00%, 8.00min).
  • Step A.2-[5-[(E)-2-ethoxyvinyl]-2-methyl-phenyl]acetic acid [0399] To a mixture of 2-(5-bromo-2-methyl-phenyl)acetic acid (1000 mg, 4.37 mmol) in 1,4-Dioxane (10 mL) and Water (2 mL) were added Pd(dppf)Cl 2 (159.71 mg, 0.22 mmol), K 2 CO 3 (1807.31 mg, 13.1 mmol) and 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1037.6 mg, 5.24 mmol).
  • Step B 2-[2-methyl-5-(2-oxoethyl)phenyl]acetic acid [0401] To a solution of 2-[5-[(E)-2-ethoxyvinyl]-2-methyl-phenyl]acetic acid (100 mg, 0.45 mmol) in MeCN (1 mL) was added HCl (0.08 mL, 1.0 mmol) at 0 o C. The mixture was stirred at 0 o C for 0.5 h. TLC indicated reactant 1 was consumed completely and one new spot formed. The residue was diluted with H 2 O (3 mL) and extracted with EtOAc (3 mL ⁇ 3).
  • Step D [5-(2- ⁇ [(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino ⁇ ethyl)-2-methylphenyl]acetic acid and [5-(2- ⁇ [(S)-[(3R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino ⁇ ethyl)-2- methylphenyl]acetic acid [0403]
  • the residue was purified by SFC separation (basic condition)(column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [A: CO 2 ; B: MeOH(0.1%NH 3 H 2 O)]; B%: 40.00%-40.00%, 14.00min) to give desired compound [5-(2- ⁇ [(S
  • Step A.2-(3-bromophenyl)propanoic acid To a solution of M-bromophenylacetic acid (1 g, 4.65 mmol, 1 equiv.) in THF (10 mL, 0.46 M, 10 Vols) was added NaHMDS (0.54 g, 9.3 mL, 1 M, 9.3 mmol, 2 equiv.) for 0.5 under N 2 atmosphere at 0 o C, then the reaction was added MeI (0.59 g, 0.25 mL, 2.28 g/mL, 4.65 mmol, 1 equiv.). The mixture was stirred at 25 o C for 1 h. TLC indicated reactant was consumed completely and one new spot formed.
  • Step C.2-[3-(2-oxoethyl)phenyl]propanoic acid To a solution of 2- ⁇ 3-[(1E)-2-ethoxyethenyl]phenyl ⁇ propanoic acid (150 mg, 0.68 mmol, 1 equiv.) in CH 3 CN (1 mL, 0.68 M, 6.66 Vols) was added HCl (0.04 g, 0.1 mL, 12 M, 1.2 mmol, 1.76 equiv.), and the reaction mixture was stirred at 0 °C for 0.5 h.
  • Step A ethyl 2-[(4-bromopyridin-2-yl)oxy]-2-methylpropanoate
  • 4-bromopyridin-2-ol 5 g, 28.73 mmol, 1 equiv.
  • CH 3 CN 50 mL, 0.57 M, 10 Vols
  • Cs 2 CO 3 18.72 g, 57.47 mmol, 2 equiv.
  • ethyl ⁇ - bromoisobutyrate 7.28 g, 37.35 mmol, 1.3 equiv.
  • ethyl 2-( ⁇ 4-[(1E)-2-ethoxyethenyl]pyridin-2-yl ⁇ oxy)-2-methylpropanoate [0420] A solution of ethyl 2-[(4-bromopyridin-2-yl)oxy]-2-methylpropanoate (1500 mg, 5.20 mmol, 1 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.54 g, 7.80 mmol, 1.5 equiv.), K 2 CO 3 (2.15 g, 15.61 mmol, 3 equiv.) and Pd(dppf)Cl 2 (380.91 mg, 0.52 mmol, 0.1 equiv.) in dioxane (15 mL, 0.34 M, 10 Vols) and H 2 O (3 mL, 1.73 M, 2 Vols) was stirred at 80 o C for 6
  • Step A.5-[(3-bromophenyl) methyl]-1H-1,2,3,4-tetrazole [0425] To a stirred solution of 2-(3-bromophenyl)acetonitrile (5 g, 25.50 mmol, 1 equiv.) and Et3N . HCl (10.53 g, 76.51 mmol, 3 equiv.) in Tol. (70 mL, 0.36 M, 14 Vols) was added NaN3 (4.41 g, 67.83 mmol, 2.66 equiv.) at 20 o C under N 2 . The reaction was stirred at 100 o C for 12 h under N 2 atmosphere.
  • Step A 5- ⁇ 3-[(1E)-2-ethoxyethenyl]phenyl ⁇ -1H-1,2,3,4-tetrazole
  • 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.64 g, 13.33 mmol, 1.5 equiv.) in dioxane (20 mL, 0.44 M, 10 Vols) and H 2 O (4 mL, 2.22 M, 2 Vols) was added K 2 CO 3 (3684.80 mg, 26.66 mmol, 3 equiv.) and Pd(dppf)Cl 2 (650.26 mg, 0.89 mmol, 0.1 equiv.) with N 2 for 3 times.
  • reaction was stirred at 90 o C for 8 h under N 2 atmosphere. TLC indicated reactant 1 was consumed completely and one new spot formed.
  • the reaction mixture was extracted with EtOAc (30 mL ⁇ 3) and H 2 O (30 mL). The organic phase was separated, washed with brine (20 mL ⁇ 1), dried over [Na 2 SO 4 ], filtered and concentrated under reduced pressure to give a residue and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 17% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • Step C [(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]( ⁇ 2-[3-(1H- 1,2,3,4-tetrazol-5-yl)phenyl]ethyl ⁇ )amine
  • (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (30 mg, 0.125 mmol, 1 equiv.) in CH 3 OH (1 mL, 0.13 M, 33.33 Vols) was added 2-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]acetaldehyde (35.39 mg, 0.19 mmol, 1.5 equiv.) and CH 3 COOH (8 mg, 0.05 mL, 0.13 mmol, 1 equiv.).
  • Step A 5-[(3-bromophenyl) methyl]-1,3-thiazolidine-2,4-dione [0434]
  • 2,4-thiazolidinedione 2.5 g, 21.34 mmol, 1 equiv.
  • THF 40 mL, 0.53 M, 16 Vols
  • n-BuLi 2.73 g, 17.07 mL, 2.5 M, 42.69 mmol, 2 equiv.
  • Step B 5-( ⁇ 3-[(1E)-2-ethoxyethenyl] phenyl ⁇ methyl)-1, 3-thiazolidine-2, 4-dione
  • Step A.3- ⁇ 3-[(1E)-2-ethoxyethenyl]phenyl ⁇ propanoic acid [0440] To a solution of 3-(3-bromophenyl)propanoic acid (1 g, 4.36 mmol, 1 equiv.) in dioxane (10 mL, 0.43 M, 10 Vols) and H 2 O (2 mL, 2.18 M, 2 Vols) were added K 2 CO 3 (1.81 g, 13.09 mmol, 3 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.03 g, 5.23 mmol, 1.2 equiv.) and Pd(dppf)Cl 2 (159.55 mg, 0.21 mmol, 0.05 equiv.) purged with N 2 for 3 times.
  • the reaction was stirred at 100 o C for 12 h under N 2 atmosphere. LC-MS showed the reactant was consumed completely and desired mass was formed.
  • the reaction mixture was diluted between EtOAc (10 mL ⁇ 3) and H 2 O (10 mL). The organic phase was separated, washed with brine (10 mL ⁇ 1), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 100 mL/min).
  • (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine 50 mg, 0.20 mmol, 1 equiv.
  • MeOH MeOH
  • NaBH 3 CN 39.38 mg, 0.62 mmol, 3 equiv.
  • 3-[3-(2-oxoethyl)phenyl]propanoic acid 48.19 mg, 0.25 mmol, 1.2 equiv.).
  • Step A 3- ⁇ 4-[(1E)-2-ethoxyethenyl] phenyl ⁇ propanoic acid
  • the mixture was stirred at 80 °C for 12 h under N 2 .
  • LC-MS showed the reactant was consumed completely and desired mass was detected.
  • the reaction was successful.
  • the mixture acidified pH to 5 with aqueous solution of hydrochloric acid (1mol/L).
  • the reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (50 mL ⁇ 3).
  • Step C 3-[4-(2- ⁇ [(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino ⁇ ethyl)phenyl]propanoic acid
  • (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine 50 mg, 0.21 mmol, 1 equiv.
  • MeOH mL, 0.21 M, 20 Vols
  • Step B ethyl 3-(4-bromopyridin-2-yl) propanoate
  • ethyl 3-(4-bromopyridin-2-yl) prop-2-enoate (2 g, 7.81 mmol, 1 equiv.) in CH 3 OH (20 mL, 0.39 M, 10 Vols) was added NaBH 4 (443.15 mg, 11.71 mmol, 1.5 equiv.) at 0 o C under N 2 and then to the above solution was added CoCl 2 (101.39 mg, 0.78 mmol, 0.1 equiv.). The mixture was stirred at 25 °C for 2 h under N 2 .
  • (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine 25 mg, 0.10 mmol, 1 equiv.
  • MeOH MeOH
  • NaBH 3 CN (19.69 mg, 0.31 mmol, 3 equiv.
  • 3-(2-oxoethyl)benzoic acid 20.57 mg, 0.12 mmol, 1.2 equiv.).
  • Step A.1-bromo-3-(1-methoxyprop-1-en-2-yl)benzene To a solution of (methoxymethyl)triphenylphosphanium chloride (5.16 g, 15.07 mmol, 1.5 equiv.) in THF (30 mL, 0.33 M, 15 Vols) was added t-BuOK (15.07 mL, 1 M, 15.07 mmol, 1.5 equiv.), the mixture was stirred at 0 o C for 1 h, and then the reaction mixture was added M-bromoacetophenone (2 g, 10.04 mmol, 1 equiv.), stirred at 25 °C for 11 h under N 2 atmosphere.
  • [3-(1-oxopropan-2-yl)phenyl]acetic acid [0469] To a solution of [3-(1-methoxyprop-1-en-2-yl)phenyl]acetic acid (300 mg, 1.45 mmol, 1 equiv.) in CH 3 CN (3 mL, 0.48 M, 10 Vols) was added HCl (0.3 mL, 12 M, 3.6 mmol, 2.47 equiv.), and the reaction mixture was stirred at 0 °C for 0.5 h. TLC showed reactant 1 was consumed completely and one new spot formed. The residue was diluted with H 2 O (3 mL) and extracted with ethyl acetate (3 mL ⁇ 3).
  • Step E [3-(1- ⁇ [(S)-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino ⁇ propan-2-yl)phenyl]acetic acid [0470] To a solution of (1S)-1-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl]-1-phenylmethanamine (60 mg, 0.18 mmol, 1 equiv.) in CH 3 OH (1 mL, 0.18 M, 16.66 Vols) were added CH 3 COOH (33.96 mg, 0.56 mmol, 3 equiv.), NaBH 3 CN (35.54 mg, 0.56 mmol, 3 equiv.) and [3-(1-oxopropan-2-yl)phenyl]acetic acid (0.04 g, 0.
  • Step AA 4-bromo-2-(2-methoxyethenyl)-1-methylbenzene
  • (methoxymethyl)triphenylphosphanium chloride 5.16 g, 15.07 mmol, 1.5 equiv.
  • t-BuOK 1.69 g, 15.07 mL, 1 M, 15.07 mmol, 1.5 equiv.
  • THF 30 mL, 0.33 M, 15 Vols
  • the reaction was stirred at 25 o C for 24 h under N 2 atmosphere. LCMS showed the reactant was remained and desired mass was formed. The reaction mixture was concentrated under reduced pressure to get a residue. The reaction mixture was partitioned between EtOAc (1 L ⁇ 3) and sat. aq. NaHCO 3 (1.5 L). The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 20% Ethyl acetate/Petroleum ethergradient @ 150 mL/min).
  • Solution 1 ⁇ benzyl N-[5-bromo-2-(bromomethyl)pyridin-3-yl]carbamate,1 eq, 38 g ⁇ in ⁇ DCE, 300 mL ⁇ [0505]
  • Solution 2 ⁇ PBr3,3 eq, 84.295 g ⁇ in ⁇ DCE, 300 mL ⁇ [0506]
  • the solution 1 was pumped by Pump 1 ⁇ S1, P1, 18.024 mL/min ⁇ to flow reactor 1 ⁇ FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 63.046 mL, 50 °C FLR1, PFA, Dynamic mixer, 1 mL, 50 °C ⁇ .
  • Step G tert-butyl N-[(S)-(7-methyl-2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3- yl)(phenyl)methyl]carbamate
  • a solution of methyl (3S)-2-[(3-amino-5-methylpyridin-2-yl)methyl]-3- [(tert-butoxycarbonyl)amino]-3-phenylpropanoate (1 g, 1.978 mmol, 1 equiv.) in AcOH (10 mL, 0.19 M, 10 Vols), the reaction mixture was stirred at 70 °C for 0.5 h. LC-MS showed Reactant 1 was consumed completely and desired mass was detected.
  • the residence time of flow reactor 1 was ⁇ FLR1,10 min ⁇ .
  • the flow rate of Pump1 was adjusted to ⁇ S1, P1, 4.467 mL/min ⁇ for solution 1.
  • the flow rate of Pump2 was adjusted to ⁇ S2, P2, 1.945 mL/min ⁇ for solution 2.
  • the mixture was collected with a bottle (contained 5 V 10% NaOH aq.), 0 °C.
  • the Pump1 and Pump2 was started at the same time.
  • the reaction mixture was collected after running 10 mins. LCMS showed Reactant 1 was consumed completely and desired mass was detected.
  • the reaction mixture was filtered. The filtrate was concentrated to give a residue.
  • (2S)-2-[3-(1,2-oxazol-4-yl)phenyl]propanoic acid 65.35 mg, 0.30 mmol, 0.9 equiv.
  • (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methanamine 80 mg, 0.33 mmol, 1 equiv.
  • DCM 2 mL, 0.15 M, 30.60 Vols
  • DIPEA 129.61 mg, 0.18 mL, 0.74 g/mL, 1.00 mmol, 3 equiv.
  • Step B [(2S)-2-[3-(1,2-oxazol-4-yl)phenyl]propyl][(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl]amine
  • (2S)-2-[3-(1,2-oxazol-4-yl)phenyl]-N-[(S)-phenyl((3R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]propanamide 50 mg, 0.11 mmol, 1 equiv.
  • Diglyme (2 mL, 0.06 M, 40 Vols) were added BF3.OEt2 (194.19 mg, 0.17 mL, 1.15 g/mL, 1.37 mmol, 12 equiv.) and NaBH 4 (30 mg, 0.79 mmol, 6.95 equiv.) at 0
  • Step A.2-[4-[(E)-2-ethoxyvinyl] phenyl] acetic acid [0543] To a solution of 2-(4-bromophenyl)acetic acid (1000 mg, 4.65 mmol) in 1,4-Dioxane (25 mL) and Water (5 mL) were added Cs 2 CO 3 (3030.18 mg, 9.3 mmol), 2-[(E)- 2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1013.15 mg, 5.12 mmol) and Pd(dppf)Cl 2 (337.44 mg, 0.47 mmol).
  • Table 1 Compounds prepared according to similar procedures as described previously.
  • EXAMPLE B p300 TR-FRET Competition Assay [0550] Exemplary compounds of the disclosure were tested for their potency of binding to p300 protein on a competition TR-FRET assay.
  • Biotinylated p300 protein (a construct covering amino acids 1287-1652, with the following mutations: (i) 1523-1554 deletion, (ii) K1637R, and (iii) M1652G; with N-terminal methionine residue and a C-terminal peptide of the following sequence: CMLVELHTQSQDRFGGSG ⁇ Lys(biotin) ⁇ was preincubated with ten 3.16-fold serial dilutions of a test compound starting at 30 ⁇ M, 10 ⁇ M, 1 ⁇ M, or 100 nM, in duplicates, for 30 min at room temperature.
  • donor fluorophore Eu-W1024 chelate-labeled streptavidin (PerkinElmer) and 1-(6-((2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin- 3-yl)-1H-pyrazol-1-yl)ethyl)amino)-6-oxohexyl)-2-((1E,3E,5E)-5-(3,3-dimethyl-5-sulfonato- 1-(3-sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-3-(4-sulfonatobutyl)- 3H-indol-1-ium-5-sulfonate (the acceptor fluorophore-labeled p300 ligand) were added at final assay concentrations of 1 nM and 40 nM, respectively
  • the final p300 protein concentration in the assay was 2 nM.
  • the mixture was allowed to equilibrate for 30 min at room temperature.
  • the TR-FRET signal was measured using EnVision 2105 multimode plate reader (PerkinElmer) equipped with 337 nm TRF light unit, TRF laser LANCE D407/D630 dual mirror, and two emission filters: APC 665 (665 nm) filter and LANCE laser attenuated Europium (615 nm) filter.
  • the signal was calculated as a ratio of fluorescent intensities at 665 nm and 615 nm.
  • the signal was normalized to no-protein control (100% response) and vehicle control (0% response) and fitted using the four-parameter logistic regression model.
  • IC50 value (defined as a concentration, at which the assay response equaled 50%) was used as a measure of binding affinity of a test compound.
  • the compound may be a compound, or pharmaceutically acceptable salt thereof, selected from: [0554] 2-(2-chloro-5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (3-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b]
  • the compound may be a compound, or pharmaceutically acceptable salt thereof, selected from: 2-(2-methyl-5-(2-(((S)-((R and S)-2- oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((S)-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-methyl-2-(3-(2-(((S)-((S)-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoi

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Abstract

Provided herein are CREB-binding protein (CBP) and p300 lysine acetyltransferase inhibitors (KATi). Also provided are methods of treating a subject by administering a therapeutically effective amount of a pharmaceutical composition including the KATi.

Description

LYSINE ACETYLTRANSFERASE INHIBITORS RELATED APPLICATIONS [0001] This patent application claims the benefit of priority to U.S. Provisional Patent Application No. 63/590,742, filed October 16, 2023, which is incorporated herein by reference in its entirety. BACKGROUND Field [0002] The present disclosure relates to compounds and their use in the treatment of various diseases, including cancer and inflammatory conditions. This disclosure also relates to methods for preparation of the compounds and to pharmaceutical compositions comprising such compounds. Background [0003] Lysine acetylation is a reversible post-translational modification. Lysine acetyltransferases (KATs) catalyze the transfer of an acetyl group from acetyl CoA (AcCoA) to the ε-amino group on lysine residues of substrate proteins (Lee, K., Workman, J. Nat Rev Mol Cell Biol 8, 284–295 (2007)). Lysine deacetylases (KDACs) catalyze the removal of the acetyl group. Specific protein domains, including bromodomains, can bind proteins in an acetylation-dependent manner (R. Marmorstein and M.-M. Zhou. Cold Spring Harb Perspect Biol 2014;6:a018762). The presence or absence of the acetyl group can impact protein function, including protein-protein interactions. This is because the acetyl group on the target lysine residue neutralizes the charge of the lysine ε-amino group which is known to impact chromatin compaction in the nucleus. [0004] Emerging evidence highlights a diverse set of cofactors and substrate macromolecules that can be regulated by KATs. In addition to transferring acetyl groups, these proteins can also transfer longer chain acyl groups, including crotonyl (from crotonyl CoA), to lysine resides of substrate proteins (Kaczmarska et al. Nat Chem Biol. 2017 Jan; 13(1): 21– 29). The function of longer chain acyl group modification is not well understood and this application will focus on acetyl transferase activity of proteins. Similarly, the KAT ELP3 is known to acetylate non-protein substrates, including transfer RNAs (Lin, TY., Abbassi, N.E.H., Zakrzewski, K. et al. Nat Commun 10, 625 (2019)), further expanding the biological impact of acetyltransferase function. The protein activity and its enzymatic inhibition with CoA-competitive KAT inhibitors (KATi) likely encompasses different acyl chain groups and diverse substrates. [0005] The human genome encodes at least 12 KATs, consisting of three subfamilies based on amino acid sequence similarity: MYST family, GNAT family and Orphan family. The human KAT proteins p300 and CREB-binding protein (CBP) are paralogs in the Orphan family of human KATs with well-established roles in gene regulation. [0006] The p300 protein is encoded by the E1A Binding Protein (EP300) gene (Uniprot ID: Q09472) that is located on human chromosome 22p13.2. The CBP protein is encoded by the CREBBP gene (Uniprot ID: Q92793) that is located on human chromosome 16p13. [0007] p300 and CBP are multidomain proteins that consist of an enzymatic KAT domain and multiple protein-protein interaction domains, including a bromodomain and KIX domain. The KAT domain catalyzes acetylation of histones and non-histone proteins where acetylated histones are associated with actively transcribed regions of the genome. The protein-protein interaction domains aid in localizing p300 or CBP to distinct locations in the genome. [0008] There is a continued need to provide compounds that are effective KAT inhibitors having desirable pharmacokinetic properties for use as therapeutics. SUMMARY [0009] In some embodiments, compounds useful KAT inhibitors are provided herein. In some embodiments, compounds provided herein bind to p300 protein on a competition TR-FRET assay of Example B. [0010] In some embodiments, compounds of Formula (IIIe-1) are provided herein R
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is aryl substituted with 1 to 3 substituents selected from -CH2C(O)H, alkyl, substituted alkyl, cyano, halogen, and R60, wherein the aryl is phenyl and the C1-C6 substituted alkyl is C1-C6 alkylene substituted with 1 to 3 R60, spiro-connected cycloalkyl or spiro- connected heterocycloalkyl; R60 is alkyl, cyano, -COOH, halogen, haloalkyl and alkoxy; and R10 is hydrogen, halogen, methyl, methyl-substituted pyrazole, or –(C1-C4 alkyl)COOH or a pharmaceutically acceptable salt thereof. [0011] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is hydrogen. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is halogen. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is fluoro. In some embodiments, the compound of Formula (IIIe- 1) is a compound wherein R10 is methyl. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is methyl-substituted pyrazole. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is . In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is –(C1-C4 alkyl)COOH. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is –(CH2)COOH. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is –(CH2)2COOH. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R10 is –(CH2)3COOH. [0012] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is phenyl substituted with –(CH2)COOH, or phenyl substituted with C1-C6 alkylene substituted with -COOH or cyano and optionally substituted with a spiro-connected C3 to C6 cycloalkyl or a spiro-connected 3 to 6 member heterocycloalkyl. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is phenyl further substituted with one or two methyl. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is phenyl substituted with cyano or alkyl substituted with cyano. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is
Figure imgf000005_0001
In some embodiments, the compound of Formula (IIIe-1) is a
Figure imgf000005_0002
compound wherein R6 is In some
Figure imgf000005_0003
embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is
Figure imgf000006_0001
Figure imgf000006_0003
In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is In some
Figure imgf000006_0004
embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is selected from:
Figure imgf000006_0002
Figure imgf000007_0001
[0013] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is phenyl substituted with C1-C6 alkylene substituted with -COOH and substituted with a spiro-connected C3 to C6 cycloalkyl or a spiro-connected 3 to 6 member heterocycloalkyl. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R6 is
Figure imgf000007_0002
In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R60 is - COOH, cyano, fluoro, methyl, methoxy or -CF3. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein R60 is independently methyl, fluoro or methoxy. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is a compound of Formula (VI-A), or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0001
(VI-A). [0014] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is a compound of Formula (VI-A-1), or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0002
(VI-A-1). [0015] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is a compound of Formula (VI-A-2), or a pharmaceutically acceptable salt thereof:
Figure imgf000008_0003
(VI-A-2). In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the N compound is
Figure imgf000009_0002
Figure imgf000009_0001
pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is the compound
Figure imgf000009_0003
Figure imgf000009_0004
or a pharmaceutically acceptable salt thereof.
Figure imgf000009_0005
[0016] In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is or a pharmaceutically
Figure imgf000010_0001
acceptable salt thereof. In some embodiments, the compound of Formula (IIIe-1) is a compound wherein the compound is , or a pharmaceutically acceptable salt
Figure imgf000010_0002
thereof. [0017] In some embodiments, a pharmaceutical composition comprising the compound of any one of the compounds disclosed herein and a pharmaceutically acceptable excipient. [0018] In some embodiments, methods of treating a disease or disorder associated with p300 activity in a subject are provided, said method comprising administering to the subject a therapeutically effective amount of a compound of any one of the compounds disclosed herein or the pharmaceutical composition comprising a compound disclosed herein. DETAILED DESCRIPTION [0019] Provided herein are CBP and p300 KATi with demonstrated anti- proliferative properties in selected cancers, as well as on hematological models. Also provided are methods of treating a subject by administering a therapeutically effective dose of a pharmaceutical composition including the KATi. [0020] For a given compound as described herein, if the IUPAC name includes the phrase “S or R” or “R or S,” the compound has a single configuration at that stereocenter, but the configuration is arbitrarily assigned. If the IUPAC name includes the phrase “S and R” or “R and S,” the compound is a mixture of compounds with both R and S configurations at that position. Thus, a single IUPAC name may refer to 1, 2, 4, or more individual compounds. [0021] Unless otherwise specified herein, the stereochemistry in the chemical structures assigned at a benzylic stereocenter to R4a (when R4a is phenyl) is shown relative to the stereochemistry in the chemical structures at the carbon between the R7 and A2 positions of Formula I, but is otherwise arbitrarily assigned. In addition, unless otherwise specified herein, the stereochemistry in the chemical structures of the L group methyl substituents was also arbitrarily assigned when L is -(CH2)(CH)(CH3)-. Stereochemistry of substituents in the chemical structures on -(CH2)COOH in R6 are also arbitrarily assigned, unless otherwise indicated. [0022] Before the present disclosure is described in greater detail, it is to be understood that this disclosure is not limited to particular embodiments described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims. [0023] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure. [0024] 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 to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, some potential and exemplary methods and materials may now be described. Any and all publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction. [0025] It must be noted that as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a droplet” includes a plurality of such droplets and reference to “the discrete entity” includes reference to one or more discrete entities, and so forth. [0026] It is further noted that the claims may be drafted to exclude any element, e.g., any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation. [0027] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. To the extent the definition or usage of any term herein conflicts with a definition or usage of a term in an application or reference incorporated by reference herein, the instant application shall control. [0028] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. [0029] Disclosed herein is a compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: A1 is NR1a, O, C
Figure imgf000012_0001
R1bR1c, C(=O), S, SO, or SO2; A2 is NR2a, O, CR2bR2c, C(=O), S, SO, or SO2; R1a is hydrogen, -CN, -C1-C6 alkyl, -CO(C1-C6 alkyl), -CO2(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, or -SO2(alkyl); R1b and R1c are each independently hydrogen, halo, -OH, C1-C6 alkyl, -O-(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO(C1-C6 alkyl), -CO2(C1-C6 alkyl), - CONH2, -CONH(C1-C6 alkyl), or -CON(C1-C6 alkyl)2; R2a is hydrogen, -CN, -C1-C6 alkyl, - CO(C1-C6 alkyl), -CO2(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, or -SO2(alkyl); R2b and R2c are each independently hydrogen, halo, -OH, C1-C6 alkyl, -O-(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -CO(C1-C6 alkyl), -CO2(C1-C6 alkyl), - CONH2, -CONH(C1-C6 alkyl), or -CON(C1-C6 alkyl)2; R3a and R3b are each independently hydrogen, halo, -OH, -CN, C1-C6 alkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or-O-(C1- C6 alkyl); or R3a and R3b taken together are =O; or R3a and R3b together with the carbon atom to which they are attached form an optionally substituted 3- to 10- membered heterocycloalkyl ring or an optionally substituted C3-C10 cycloalkyl ring; R4a and R4b are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, optionally substituted 3- to 10-membered heterocycloalkyl, -CONH2, -CONH(C1-C6 alkyl), or -CON(C1-C6 alkyl)2; or R4a and R4b together with the carbon atom to which they are attached form an optionally substituted 3- to 10- membered heterocycloalkyl ring or an optionally substituted C3-C10 cycloalkyl ring; R5 is -L-R6, -C(O)-, -S(O2)-, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, or-O-(C1-C6 alkyl); R6 is optionally substituted aryl, , , , optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl; R7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl; J is NH, N(C1-C6 alkyl), O, CO, CH2, CH(OH), CHF, CF2, S, SO, or SO2; L is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, or optionally substituted C2-C10 alkynylene; W is N or CR8; X is N or CR9; Y is N or CR10; Z is N or CR11; R8, R9, R10, and R11 are each independently selected from the group consisting of hydrogen, halo, -C1-C6 alkyl, -C1-C6 haloalkyl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), -CON(C1- C6 alkyl)2, -SO2(alkyl), -SO(alkyl), -SO(NH)(alkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), - SO2N(C1-C6 alkyl)2, C6-C10 aryl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10- membered heterocycloalkyl, , , and , wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q; each Q is independently selected from the group consisting of: halo, -CN, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, -(CH2)mNH2, - (CH2)mSO2(optionally substituted C1-C6 alkyl), -C(=O)NH2, -(CH2)mC(=O)NH(optionally substituted C1-C6 alkyl), -(CH2)mC(=O)N(optionally substituted C1-C6 alkyl)2, - (CH2)mC(=O)NH(optionally substituted C6-C10 aryl), -(CH2)mC(=O)NH(optionally substituted 3- to 10- membered heteroaryl), -(CH2)mC(=O)NH(optionally substituted C3-C10 cycloalkyl), -(CH2)mSO2NH(optionally substituted C1-C6 alkyl), optionally substituted C7-C16 arylalkyl, - C(=O)(optionally substituted 3- to 10- membered heterocycloalkyl), - (CH2)mCH(OH)(optionally substituted 3- to 10- membered heteroaryl), optionally substituted 5- to 10- membered heteroaryl-(C1-C6 alkyl), optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 4- to 10- membered heterocycloalkyl-(C1-C6 alkyl), optionally substituted C3-C10 cycloalkyl-(C1-C6 alkyl), optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl; and m is 0 or 1. [0030] In some embodiments, A1 is NR1a or O. In some embodiments, A1 is NR1a. [0031] In some embodiments, A2 is NR2a, O, or S. In some embodiments, A2 is NR2a. In some embodiments, A2 is O. In some embodiments, A2 is S. [0032] In some embodiments, R3a and R3b are each hydrogen. In some embodiments, R3a and R3b taken together are =O. In some embodiments, R3a and R3b together with the carbon atom to which they are attached form an optionally substituted 3- to 10- membered heterocycloalkyl ring or an optionally substituted C3-C10 cycloalkyl ring. [0033] In some embodiments, W is N. [0034] In some embodiments, X is CR9. [0035] In some embodiments, Y is CR10. [0036] In some embodiments, Z is CR11. [0037] Some embodiments relate to a compound, having the structure of Formula (IIe-1)
Figure imgf000015_0001
(IIe-1), or a pharmaceutically acceptable salt thereof. [0038] Some embodiments relate to a compound, having the structure of Formula (IIe-2) (IIe-2), or a pharmaceutically acceptable salt thereof.
Figure imgf000015_0002
[0039] Some embodiments relate to a compound, having the structure of Formula (IIIe-1) R1a (IIIe-1), or a pharmaceutically acceptable salt thereof. [
Figure imgf000015_0003
0040] Some embodiments relate to a compound, having the structure of Formula (IIIe-2) R1a (IIIe-2), or a pharmaceutically acceptable salt thereof.
Figure imgf000015_0004
[0041] Some embodiments relate to a compound, having the structure of Formula (IV-A) or Formula (IV-B):
Figure imgf000015_0005
Figure imgf000016_0001
or a pharmaceutically acceptable salt thereof, wherein R4a is phenyl; R6 is optionally substituted aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10- membered heterocycloalkyl; and R10 is hydrogen, halogen, alkyl optionally substituted with -COOH, or pyrazolyl substituted with alkyl. [0042] In some embodiments, R1a is hydrogen. In some embodiments, R1a is -C1- C6 alkyl. In some embodiments, R1a is -CO(C1-C6 alkyl). [0043] In some embodiments, R4a and R4b are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl. [0044] In some embodiments, R4a is substituted phenyl. In some embodiments, R4a is phenyl. In some embodiments, R4a is optionally substituted C3-C10 cycloalkyl. In some embodiments, R4a is optionally substituted 3- to 10-membered heteroaryl. In some embodiments, R4a is optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R4a is optionally substituted C1-C6 alkyl. [0045] In some embodiments, J is O, NH, or CH2. In some embodiments, J is NH. [0046] In some embodiments, R5 is L-R6. [0047] In some embodiments, L is optionally substituted C1-C10 alkylene. In some embodiments, L is -CH2CH2- or -CH2CH(CH3)-. [0048] In some embodiments, R6 is optionally substituted phenyl. In some embodiments, R6 is phenyl substituted with cyano. In some embodiments, R6 is phenyl substituted with one 1-3 R60, where each R60 is independently selected from alkyl, alkyl substituted with -COOH, alkyl substituted with cycloalkyl and -COOH, alkyl substituted with cyano, or alkyl substituted with alkoxy. In some embodiments, at least one R60 is – (CH2)COOH. In some embodiments, at least one R60 is cyano or –(CH2)CN. [0049] In some embodiments, R6 is phenyl or pyridinyl substituted with carboxy and optionally further substituted with alkyl, halogen, haloakyl or alkoxy. In some embodiments, R6 is phenyl substituted with –(C1-C4 alkyl)-COOH and optionally further substituted with one or more of fluoro, methyl or methoxy. In some embodiments, R6 is phenyl substituted with –(spirocyclic cycloaklyl)-COOH or –(spirocyclic heterocycloalkyl)-COOH and optionally further substituted with methyl. In some embodiments, R6 is phenyl substituted with -COOH, –(CH2)-COOH or –(CH2)2-COOH and optionally further substituted with methyl. [0050] In some embodiments, R6 is
Figure imgf000017_0001
. In some embodiments, R6 is
Figure imgf000017_0002
[0051] In some embodiments, R6 is wherein R60 is –
Figure imgf000017_0003
(alkyl)COOH. In some embodiments, R6 is In some
Figure imgf000017_0004
embodiments, R6 is In some embodiments, R6 is
Figure imgf000018_0001
. In some embodiments, R6 is In some
Figure imgf000018_0002
Figure imgf000018_0003
embodiments, R6 is In some embodiments, R6 is
Figure imgf000018_0004
. In some embodiments, R6 is
Figure imgf000018_0006
. In some embodiments, R6 is In some
Figure imgf000018_0005
Figure imgf000018_0007
embodiments, R6 is . In some embodiments, R6 is
Figure imgf000018_0008
Figure imgf000018_0009
[0052] In some embodiments, R6 is wherein R60 is -CN, -
Figure imgf000018_0010
(CH2)CN or –(alkyl)COOH. In some embodiments, R6 is In some
Figure imgf000018_0011
embodiments, R6 is . In some embodiments, R6 is . In some embodiments, R6 is . [0053] In some embodiments, R6 is , wherein each R60 is independently alkyl, haloalkyl, or halogen. In some embodiments, at least one R60 is methyl optionally substituted with one or more fluoro, or fluoro. In some embodiments, at least one R60 is -CF3. In some embodiments, at least one R60 is methyl. In some embodiments, at least one R60 is methyl. In some embodiments, R6 is . In some embodiments, R6 is, , . In some embodiments, R6 is . [0054] In some embodiments, R6 is phenyl or pyridinyl substituted with one or more methyl, fluoro, -CF3 methoxy, -O-(C1-C4 alkyl)-COOH, or -(C1-C4 alkyl)-COOH. In some embodiments, R6 is . In some embodiments, R6 is . [0055] In some embodiments, R6 is phenyl or pyridinyl substituted with C1-C4 alkyl, C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl; wherein the alkyl is optionally substituted with C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R6 is methyl substituted with a 5- to 6- member heteroaryl. In some embodiments, R6 is . In some embodiments, R6 is methyl substituted with a 5- to 6- member heterocycloalkyl. In some embodiments, R6 is . In some embodiments, R6 is phenyl substituted with a C3-C6 cycloalkyl, a 3- to 6- member heterocycloalkyl, or a 5- to 6- member heteroaryl, each optionally substituted with one or more R60. In some embodiments, R6 is . [0056] In some embodiments, R6 is optionally substituted C3-C10 cycloalkyl. In some embodiments, R6 is . [0057] In some embodiments, R6 is optionally substituted 3- to 10-membered heteroaryl. In some embodiments, R6 is optionally substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl. In some embodiments, R6 is optionally substituted 3- to 10- memebered heterocycloalkyl. [0058] In some embodiments, R6 is a fused bicyclic ring system comprising a phenyl or pyridinyl ring fused to a 3 to 6 member heterocycloalkyl or to a C3-C6 cycloalkyl. In some embodiments, R6 is a dihydroindinene, a dihydroisobenzofuran, or a dihydro cyclopental[b]pyridine. In some embodiments, R6 is , or , or
Figure imgf000020_0001
each optionally substituted with alkyl, carboxyl, halogen or haloalkyl. In some embodiments, R6 is a dihydroindinene, a dihydroisobenzofuran, or a dihydro cyclopental[b]pyridine each optionally substituted with -COOH or –(C1-C4 alkyl)COOH. In some embodiments, R6 is ,
Figure imgf000021_0001
Figure imgf000021_0002
[0059] In some embodiments, R6 is phenyl or pyridinyl substituted with an amide, wherein the amide is optionally substituted with phenyl or a 5- to 6- member heteroaryl. In some embodiments, R6 is . [0060] In some embodiments, R6 is an amide optionally substituted with carboxy. In some embodiments, R6 is . [0061] In some embodiments, R6 is phenyl or pyridinyl substituted with -O-(C1-C4 alkyl)-COOH. In some embodiments, R6 is phenyl or pyridinyl substituted with -O-(CH2)- COOH, -COOH or -(CH2)-COOH. [0062] In some embodiments, each of R8, R9, R10, and R11 is independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C6-C10 aryl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q. [0063] In some embodiments, each of R8, R9, R10, and R11 is independently selected from the group consisting of hydrogen, halo, -C1-C6 alkyl, -C1-C6 haloalkyl, -CN, -CO2H, - CO2(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -SO2NH2, - SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)2, C6-C10 aryl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q. [0064] In some embodiments, each of R9, R10, and R11 is hydrogen. [0065] In some embodiments, R10 is -CONH2, -CONH(C1-C6 alkyl), or -CON(C1- C6 alkyl)2. In some embodiments, R10 is phenyl optionally substituted with 1, 2, or 3 substituents Q. In some embodiments, R10 is 5- to 10-membered heteroaryl optionally substituted with 1, 2, or 3 substituents Q. In some embodiments, R10 is pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, or indolyl, benzimidazolyl, each optionally substituted with 1, 2, or 3 substituents Q. [0066] In some embodiments, each Q is independently selected from the group consisting of: halo, -CN, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, - (CH2)mNH2, -(CH2)mSO2(optionally substituted C1-C6 alkyl), -C(=O)NH2, - (CH2)mC(=O)NH(optionally substituted C1-C6 alkyl), -(CH2)mC(=O)N(optionally substituted C1-C6 alkyl)2, -(CH2)mC(=O)NH(optionally substituted C6-C10 aryl), - (CH2)mSO2NH(optionally substituted C1-C6 alkyl), optionally substituted C7-C16 arylalkyl, - C(=O)(optionally substituted 3- to 10- membered heterocycloalkyl), - (CH2)mCH(OH)(optionally substituted 3- to 10- membered heteroaryl), optionally substituted 5- to 10- membered heteroaryl-(C1-C6 alkyl), optionally substituted 4- to 10- membered heterocycloalkyl-(C1-C6 alkyl), and optionally substituted C3-C10 cycloalkyl-(C1-C6 alkyl). Some embodiments relate to a compound, having the structure of Formula (V-A):
Figure imgf000022_0001
wherein R10 is hydrogen, alkyl optionally substituted with -COOH, or pyrazolyl substituted with alkyl; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is substituted phenyl or R6 is substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl. [0067] In some embodiments, a compound is a compound of the structure of Formula (V-A), wherein R10 is hydrogen, J is NH, R5 is -L-R6, L is -CH2CH2- or - CH2CH(CH3)-, and R6 is as defined above. Some embodiments relate to a compound, having the structure of Formula (V-A), wherein R10 is hydrogen, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is phenyl substituted with -CN, -(CH2)CN, or –(alkyl)COOH and up to two R60, as defined above. In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is hydrogen, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is phenyl optionally substituted with –(CH2)COOH and 0-2 R60, as defined above. [0068] In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is hydrogen, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with 1-3 R60, as defined above. In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is hydrogen, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with –(alkyl)COOH and 0-2 R60, as defined above. In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is hydrogen, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with –(CH2)COOH and 0-2 R60, as defined above. [0069] In some embodiments, a compound is a compound of the structure of Formula (V-A), wherein R10 is a R10 is 5- to 10-membered heteroaryl optionally substituted with 1, 2, or 3 substituents Q. In some embodiments, a compound is a compound of the structure of Formula (V-A), wherein R10 is a methyl pyrazolyle. In some embodiments, a compound is a compound of the structure of Formula (IV-A), wherein R10 is . [0070] In some embodiments, a compound is a compound of the structure of Formula (V-A), wherein R10 is a methyl pyrazolyl, J is NH, R5 is -L-R6, L is -CH2CH2- or - CH2CH(CH3)-, and R6 is as defined above. Some embodiments relate to a compound, having the structure of Formula (V-A), wherein R10 is methyl pyrazolyl, J is NH, R5 is -L-R6, L is - CH2CH2- or -CH2CH(CH3)-, and R6 is phenyl substituted with -CN, -(CH2)CN, or – (alkyl)COOH and up to two R60, as defined above. In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is methyl pyrazolyl, J is NH, R5 is -L-R6, L is - CH2CH2- or -CH2CH(CH3)-, and R6 is phenyl optionally substituted with –(CH2)COOH and 0-2 R60, as defined above. [0071] In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is methyl pyrazolyl, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with 1-3 R60, as defined above. In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is methyl pyrazolyl, J is NH, R5 is - L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with – (alkyl)COOH and 0-2 R60, as defined above. In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is methyl pyrazolyl, J is NH, R5 is -L-R6, L is - CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with –(CH2)COOH and 0-2 R60, as defined above. [0072] In some embodiments, a compound is a compound of the structure of Formula (V-A), wherein R10 is a methyl, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)- , and R6 is as defined above. Some embodiments relate to a compound, having the structure of Formula (V-A), wherein R10 is methyl, J is NH, R5 is -L-R6, L is -CH2CH2- or - CH2CH(CH3)-, and R6 is phenyl substituted with -CN, -(CH2)CN, or –(alkyl)COOH and up to two R60, as defined above. In some embodiments, a compound is a compound of Formula (V- A), wherein R10 is methyl, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is phenyl optionally substituted with –(CH2)COOH and 0-2 R60, as defined above. [0073] In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is methyl, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with 1-3 R60, as defined above. In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is methyl, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with –(alkyl)COOH and 0-2 R60, as defined above. In some embodiments, a compound is a compound of Formula (V-A), wherein R10 is methyl, J is NH, R5 is -L-R6, L is -CH2CH2- or -CH2CH(CH3)-, and R6 is pyridinyl optionally substituted with –(CH2)COOH and 0-2 R60, as defined above. [0074] Some embodiments relate to a compound, having the structure of Formula (VI-A-1) or Formula (VI-A-2): (VI-A-1),
Figure imgf000025_0001
(VI-A-2), wherein R10 and R6 are as defined above with respect to Formula (VI-A), with the specified absolute or relative stereochemistry. [0075] In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (V-A-2), wherein R10 is hydrogen and R6 is substituted phenyl as defined above. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is hydrogen and R6 is phenyl substituted with –(alkyl)COOH, -CN or –(alkyl)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is hydrogen and R6 is phenyl substituted with –(CH2)COOH, -CN or –(CH2)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is hydrogen and R6 is phenyl substituted with –(CH2)COOH, -CN or –(CH2)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is hydrogen and R6 is , , , , or . [0076] In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is methyl and R6 is substituted phenyl as defined above. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is methyl and R6 is phenyl substituted with –(alkyl)COOH, -CN or –(alkyl)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is methyl and R6 is phenyl substituted with –(CH2)COOH, -CN or –(CH2)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is methyl and R6 is phenyl substituted with –(CH2)COOH, -CN or –(CH2)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is methyl and R6 is , , , , , , or . [0077] In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is and R6 is substituted phenyl as defined above. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is and R6 is phenyl substituted with –(alkyl)COOH, - CN or –(alkyl)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is and R6 is phenyl substituted with – (CH2)COOH, -CN or –(CH2)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is and R6 is phenyl substituted with –(CH2)COOH, -CN or –(CH2)CN. In some embodiments, a compound is a compound of Formula (VI-A-1) or Formula (VI-A-2), wherein R10 is and R6 is , , , , or . [0078] In some embodiments, R10 is hydrogen, halo, -C1-C6 alkyl, or pyrazolyl substituted with 1 substituent Q and Q is methyl. In some embodiments, R10 is hydrogen. In some embodiments, R10 is halo. In some embodiments, R10 is fluoro. In some embodiments, R10 is . In some embodiments, R10 is -C1-C6 alkyl. In some embodiments, R10 is methyl. [0079] In some embodiments, R6 is pyridinyl substituted with -CN or phenyl substituted with one or more R60, wherein one R60 is C1-C4 alkyl substituted with one or more COOH, cycloalkyl, or heterocycloalkyl, or phenyl substituted with -CH2C(O)OR70 wherein each R70 is hydrogen. [0080] In some embodiments, R6 is phenyl substituted with -CN or phenyl substituted with one or more R60, wherein one R60 is C1-C4 alkyl substituted with one or more COOH, cycloalkyl, or heterocycloalkyl, or phenyl substituted with -CH2C(O)OR70 wherein each R70 is hydrogen. In some embodiments, R6 is phenyl substituted with -CH2C(O)OR70, wherein R70 is hydrogen. In some embodiments, R6 is phenyl substituted with two or more R60, wherein one R60 is C1-C4 alkyl optionally substituted with spirocyclic cycloalkyl. In some embodiments, R6 is phenyl substituted with two or more R60, wherein one R60 is C1-C4 alkyl optionally substituted with spirocyclic heterocycloalkyl. In some embodiments, R6 is . In some embodiments, R6 is
Figure imgf000028_0002
Figure imgf000028_0001
In some
Figure imgf000029_0001
embodiments, R6 is
Figure imgf000029_0002
Figure imgf000029_0003
. [0081] In some embodiments, the compound is the compound or a pharmaceutically acceptable salt thereof. In some
Figure imgf000029_0005
embodiments, the compound is the compound or a
Figure imgf000029_0004
pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound
Figure imgf000029_0006
, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound
Figure imgf000030_0001
, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is the compound , or a pharmaceutically acceptable salt thereof. [0082] Also disclosed herein is a compound, or a pharmaceutically acceptable salt thereof, having the structure of any one of any one of the compounds described herein. [0083] Also disclosed herein is a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable excipient. Additional Embodiments 1. A compound of Formula (I):
Figure imgf000031_0001
or a pharmaceutically acceptable salt thereof, wherein: A1 is NR1a; A2 is CR2bR2c; R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is optionally substituted C1-C6 haloalkyl, optionally substituted C6-C10 aryl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, optionally substituted 3- to 10-membered heterocycloalkyl, -CONH2, -CONH(C1- C6 alkyl), or -CON(C1-C6 alkyl)2; or R4a and R4b together with the carbon atom to which they are attached form an optionally substituted 3- to 10- membered heterocycloalkyl ring or an optionally substituted C3-C10 cycloalkyl ring; R4b is hydrogen; R5 is -L-R6; R6 is optionally substituted aryl, optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl; J is NH; L is -CH2CH2- or -CH2CH(CH3)-; W is N; X is CH; Y is CR10; Z is CH; R10 is selected from the group consisting of hydrogen, halo, -C1-C6 alkyl, -C1-C6 haloalkyl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -SO2(alkyl), -SO(alkyl), -SO(NH)(alkyl), -SO2NH2, -SO2NH(C1-C6 alkyl), -SO2N(C1- C6 alkyl)2, C6-C10 aryl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, , , and , wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q; each Q is independently selected from the group consisting of: halo, -CN, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, -(CH2)mNH2, - (CH2)mSO2(optionally substituted C1-C6 alkyl), -C(=O)NH2, -(CH2)mC(=O)NH(optionally substituted C1-C6 alkyl), -(CH2)mC(=O)N(optionally substituted C1-C6 alkyl)2, - (CH2)mC(=O)NH(optionally substituted C6-C10 aryl), -(CH2)mC(=O)NH(optionally substituted 3- to 10- membered heteroaryl), -(CH2)mC(=O)NH(optionally substituted C3-C10 cycloalkyl), -(CH2)mSO2NH(optionally substituted C1-C6 alkyl), optionally substituted C7-C16 arylalkyl, - C(=O)(optionally substituted 3- to 10- membered heterocycloalkyl), - (CH2)mCH(OH)(optionally substituted 3- to 10- membered heteroaryl), optionally substituted 5- to 10- membered heteroaryl-(C1-C6 alkyl), optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 4- to 10- membered heterocycloalkyl-(C1-C6 alkyl), optionally substituted C3-C10 cycloalkyl-(C1-C6 alkyl), optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl; and m is 0 or 1. 2. The compound of embodiment 1, wherein R4a is phenyl. 3. The compound of embodiment 2, wherein R10 is hydrogen. 4. The compound of embodiment 2, wherein R10 is methyl. 5. The compound of embodiment 2, wherein R10 is pyrazole and Q is methyl. 6. The compound of any one of embodiments 1-4, wherein R6 is substituted phenyl. 7. The compound of embodiment 6, wherein R6 is phenyl substituted with 1-3 R60. 8. The compound of embodiment 7, wherein at least one R60 is -CH2C(O)OH. 9. The compound of embodiment 7, wherein at least one R60 is cyano. 10. The compound of embodiment 7, wherein at least one R60 is alkyl optionally substituted with -COOH. 11. The compound of embodiment 7, wherein at least one R60 is alkyl optionally substituted with cyano. 12. The compound of any one of embodiments 1-11, wherein L is -CH2CH2. 13. The compound of any one of embodiments 1-11, wherein L is -CH2CH(CH3)-. 14. A pharmaceutical composition comprising the compound of any one of embodiments 1-13, and a pharmaceutically acceptable excipient. 15. The use of a compound of any one of embodiments 1-13, for inhibiting p300 lysine acetyltransferase (KATi). [0084] Provided herein are compounds of Formula (IIIe-1): (IIIe-1), or a pharmaceutically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is optionally substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl; R10 is selected from the group consisting of hydrogen, halo, -C1-C6 alkyl, -C1- C6 haloalkyl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), - CON(C1-C6 alkyl)2, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, optionally substituted C1-C6 alkoxy,-SO2(alkyl), -SO(alkyl), -SO(NH)(alkyl), -SO2NH2, - SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)2, C6-C10 aryl, C3-C10 cycloalkyl, 5- to 10- membered heteroaryl, 4- to 10-membered heterocycloalkyl,
Figure imgf000034_0001
wherein said alkyl, aryl, cycloalkyl, heteroaryl
Figure imgf000034_0002
and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q; each Q is independently selected from the group consisting of: halo, -CN, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, -(CH2)mNH2, - (CH2)mSO2(optionally substituted C1-C6 alkyl), -C(=O)NH2, - (CH2)mC(=O)NH(optionally substituted C1-C6 alkyl), -(CH2)mC(=O)N(optionally substituted C1-C6 alkyl)2, -(CH2)mC(=O)NH(optionally substituted C6-C10 aryl), - (CH2)mC(=O)NH(optionally substituted 3- to 10- membered heteroaryl), - (CH2)mC(=O)NH(optionally substituted C3-C10 cycloalkyl), - (CH2)mSO2NH(optionally substituted C1-C6 alkyl), optionally substituted C7-C16 arylalkyl, -C(=O)(optionally substituted 3- to 10- membered heterocycloalkyl), - (CH2)mCH(OH)(optionally substituted 3- to 10- membered heteroaryl), optionally substituted 5- to 10- membered heteroaryl-(C1-C6 alkyl), optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 4- to 10- membered heterocycloalkyl-(C1-C6 alkyl), optionally substituted C3-C10 cycloalkyl-(C1-C6 alkyl), optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl; and m is 0 or 1; provided that R10 is -CONH2, -CONH(C1-C6 alkyl), or -CON(C1-C6 alkyl)2; or R10 is phenyl optionally substituted with 1, 2, or 3 substituents Q; or R10 is pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, or indolyl, benzimidazolyl, each optionally substituted with 1, 2, or 3 substituents Q. or a pharmaceutically acceptable salt thereof. Definitions [0085] “Linker” and “linking group” are used interchangeably to refer to a group that connects to two groups. Exemplary types of connections include covalent bonds. As used herein, the term “radical”, such as in “monoradical” or “diradical”, refers to the number groups that a group can connect with. For instance, a monoradical group can connect to only a single other group, e.g., the methyl (-CH3) and ethyl (-CH2CH3) groups are monoradical groups. In contrast, the -CH2- and -CH2CH2- groups are diradical groups since they can each connect to two different groups. Since a linker connects two groups, a linker is a diradical group. Connections between groups can also be described by the term “valent”, such as in “monovalent” or “divalent”, which refers to the bond order of the connection. For instance, the group -CH3 is a monovalent group since it can form a single covalent bond with another group, e.g., with -OH to form H3COH. The group =CH2 is a divalent group since it can form a double bond with another group, e.g., with an oxygen atom to form formaldehyde (CH2O). [0086] “Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-). [0087] “Alkylene” refers to divalent aliphatic hydrocarbyl groups preferably having from 1 to 12 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-CH(CH3)CH2-), and the like. [0088] “Substituted alkylene” refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of “substituted” below. [0089] “Alkenyl” refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-1-yl. Included within this term are the cis and trans isomers or mixtures of these isomers. [0090] The term “substituted alkenyl” refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl. [0091] “Alkynyl” refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH), and propargyl (-CH2C≡CH). [0092] The term “substituted alkynyl” refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, - SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, and -SO2-heteroaryl. [0093] “Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl and trihalomethyl. [0094] “Amino” refers to a “-NRARB” group in which RA and RB are each independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non-limiting example includes free amino (i.e., -NH2). [0095] “Aminocarbonyl” refers to a “-(C=O)NRARB” group in which RA and RB are as defined above in the “amino” definition. [0096] “O-carboxy” refers to a “-OC(=O)R” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. [0097] “C-carboxy” refers to a “-C(=O)OR” group in which R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein. A non-limiting example includes carboxyl (i.e., -C(=O)OH). [0098] “Cyano” or “nitrile” refers to the group –CN. [0099] “Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like. [0100] The term “substituted cycloalkyl” refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl. [0101] “Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds. [0102] The term “substituted cycloalkenyl” refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl. [0103] “Cycloalkynyl” refers to non-aromatic cycloalkyl groups having single or multiple rings and having at least one triple bond. [0104] “Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo. [0105] “Heteroaryl” refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic. To satisfy valence requirements, any heteroatoms in such heteroaryl rings may or may not be bonded to H or a substituent group, e.g., an alkyl group or other substituent as described herein. In certain embodiments, the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl. [0106] “Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl” refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In certain embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or –SO2- moieties. To satisfy valence requirements, any heteroatoms in such heterocyclic rings may or may not be bonded to one or more H or one or more substituent group(s), e.g., an alkyl group or other substituent as described herein. [0107] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like. [0108] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle. [0109] “Oxo” refers to the atom (=O). [0110] In addition to the disclosure herein, the term “substituted,” when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below. [0111] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for substituting for one or more hydrogens (any two hydrogens on a single carbon can be replaced with =O, =NR70, =N-OR70, =N2, =S, or a spiro-connected cycloalkyl or heterocycloalkyl) on saturated carbon atoms in the specified group or radical are, unless otherwise specified, -R60, halo, =O, -OR70, -SR70, -NR80R80, trihalomethyl, -CN, -OCN, -CH2CN, -SCN, -NO, -NO2, =N2, -N3, -SO2R70, -CH2SO2R70, -SO2OR70, -OSO2R70, -SO2O-M+, -OSO2O-M+, -OSO2OR70, -P(O)(O-)2(M+)2, -P(O)(OR70)2, -P(O)(OR70)O-M+, -C(O)R70, -C(S)R70, -C(NR70)R70, -C(O)O-M+, -C(O)OR70, -CH2C(O)OR70, -C(S)OR70, -C(O)NR80R80, -SO2NR80R80, -C(NR70)NR80R80, -CH2NR80R80, -OC(O)R70, -OC(S)R70, -OC(O)O-M+, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S) R70, -NR70CO2-M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60 is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, heterocycloalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each optionally substituted with one or more alkyl, halo, hydroxy, oxo, -COOH, cyano, haloalkyl, or alkoxy, each R70 is independently hydrogen or R60; each R80 is independently R70 or alternatively, two R80’s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have -H or C1-C3 alkyl substitution; and each M+ is a counter ion with a net single positive charge. Each M+ may independently be, for example, an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as +N(R60)4; or an alkaline earth ion, such as [Ca2+]0.5, [Mg2+]0.5, or [Ba2+]0.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the present disclosure and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the present disclosure can serve as the counter ion for such divalent alkali earth ions). As specific examples, -NR80R80 is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl and N- morpholinyl. [0112] In addition to the disclosure herein, substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R60, halo, -O-M+, -OR70, -SR70, -S–M+, -NR80R80, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3-M+, -SO3R70, -OSO2R70, -OSO3-M+, -OSO3R70, -PO3 -2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2-M+, -CO2R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OCO2-M+, -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2-M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined, provided that in case of substituted alkene or alkyne, the substituents are not -O-M+, -OR70, -SR70, or -S–M+. [0113] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R60, -O-M+, -OR70, -SR70, -S-M+, -NR80R80, trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R70, -S(O)2O-M+, -S(O)2OR70, -OS(O)2R70, | -OS(O)2O-M+, -OS(O)2OR70, -P(O)(O-)2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70)(OR70), |-C(O)R70, -C(S)R70, -C(NR70)R70, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70C(O)OR70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined. [0114] In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent. [0115] Two substituents may come together with the atom or atoms to which they are attached to form a ring that is spiro or fused with the rest of the compound. [0116] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl. [0117] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-. [0118] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds. [0119] The term “pharmaceutically acceptable salt” means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like. [0120] The term “salt thereof” means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt. [0121] Compounds disclosed herein include all stereoisomers thereof. “Stereoisomer” and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. [0122] Compounds disclosed herein include all tautomers thereof. “Tautomer” refers to alternate forms of a molecule that differ only in electronic bonding of atoms and/or in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible. [0123] It will be appreciated that the term “or a salt or solvate or stereoisomer thereof” is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of subject compound. Administration and Pharmaceutical Compositions [0124] The disclosed compounds may be used alone or in combination with other treatments. These compounds, when used in combination with other agents, may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). The compounds may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy with another agent in a treatment program. [0125] Examples of pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide. [0126] Compositions containing the active ingredient may be in any form suitable for the intended method of administration. In some embodiments, the compounds of a method and/or composition described herein can be provided via oral administration, rectal administration, transmucosal administration, intestinal administration, enteral administration, topical administration, transdermal administration, intrathecal administration, intraventricular administration, intraperitoneal administration, intranasal administration, intraocular administration and/or parenteral administration. [0127] When the compounds are administered via oral administration, for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed. [0128] Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient can be mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil. [0129] Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain, for example, antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0130] In some embodiments unit dosage formulations contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art. [0131] The actual dose of the compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan. In some embodiments, a daily dose may be from about 0.1 mg/kg to about 100 mg/kg or more of body weight, from about 0.25 mg/kg or less to about 50 mg/kg, from about 0.5 mg/kg or less to about 25 mg/kg, from about 1.0 mg/kg to about 10 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day or less to about 2000 mg per day or more, from about 70 mg per day to about 1000 mg per day. Methods of Treatment [0132] Some embodiments of the present disclosure include methods of treating a disease or disorder associated with p300 activity in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound as described herein or or a pharmaceutical composition as described herein. [0133] Some embodiments relate to a method for treating a disease or condition selected from the group consisting of an inflammatory disorder, an allergic disorder, an autoimmune disease, and a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the compound as described herein or a pharmaceutical composition as described herein to the subject. [0134] In some embodiments, the disease or condition is a cancer selected from the group consisting of a hematologic malignancy and a solid tumor. In some embodiments, the disease or condition is a hematologic malignancy selected from the group consisting of lymphoma, multiple myeloma, or leukemia. In some embodiments, the disease or condition is selected from the group consisting of small lymphocytic lymphoma, non-Hodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma, refractory iNHL, mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, lymphoblastic lymphoma, Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes), Nodal marginal zone lymphoma (+/- monocytoid B-cells), Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, cutaneous T-cell lymphoma, extranodal T-cell lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, mycosis fungoides, B-cell lymphoma, diffuse large B-cell lymphoma, Mediastinal large B-cell lymphoma, Intravascular large B-cell lymphoma, Primary effusion lymphoma, small non-cleaved cell lymphoma, Burkitt’s lymphoma, multiple myeloma, plasmacytoma, acute lymphocytic leukemia, T-cell acute lymphoblastic leukemia, B-cell acute lymphoblastic leukemia, B-cell prolymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, juvenile myelomonocytic leukemia, minimal residual disease, hairy cell leukemia, primary myelofibrosis, secondary myelofibrosis, chronic myeloid leukemia, myelodysplastic syndrome, myeloproliferative disease, and Waldestrom’s macroglobulinemia. [0135] In some embodiments, the disease or condition is a solid tumor, wherein the solid tumor is from a cancer selected from the group consisting of pancreatic cancer, urological cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, thyroid cancer, gall bladder cancer, lung cancer (e.g. non-small cell lung cancer, small-cell lung cancer), ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi’s sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, cancers of the adrenal cortex, and ACTH-producing tumors. [0136] In some embodiments, the disease or condition is selected from the group consisting of systemic lupus erythematosus, myestenia gravis, Goodpasture’s syndrome, glomerulonephritis, hemorrhage, pulmonary hemorrhage, atherosclerosis, rheumatoid arthritis, psoriatic arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis, Behçet disease, autoimmune thyroiditis, Reynaud’s syndrome, acute disseminated encephalomyelitis, chronic idiopathic thrombocytopenic purpura, multiple sclerosis, Sjögren’s syndrome, autoimmune hemolytic anemia, tissue graft rejection, hyperacute rejection of transplanted organs, allograft rejection, graft-versus-host disease, diseases involving leukocyte diapedesis, disease states due to leukocyte dyscrasia and metastasis, granulocyte transfusion-associated syndromes, cytokine-induced toxicity, scleroderma, vasculitis, asthma, psoriasis, chronic inflammatory bowel disease, ulcerative colitis, Crohn’s disease, necrotizing enterocolitis, irritable bowel syndrome, dermatomyositis, Addison’s disease, Parkinson’s disease, Alzheimer’s disease, diabetes, type I diabetes mellitus, sepsis, septic shock, endotoxic shock, gram negative sepsis, gram positive sepsis, and toxic shock syndrome, multiple organ injury syndrome secondary to septicemia, trauma, hypovolemic shock, allergic conjunctivitis, vernal conjunctivitis, and thyroid-associated ophthalmopathy, eosinophilic granuloma, eczema, chronic bronchitis, acute respiratory distress syndrome, allergic rhinitis, coryza, hay fever, bronchial asthma, silicosis, pulmonary sarcoidosis, pleurisy, alveolitis, emphysema, pneumonia, bacterial pneumonia, bronchiectasis, and pulmonary oxygen toxicity, reperfusion injury of the myocardium, brain, or extremities, thermal injury, cystic fibrosis, keloid formation or scar tissue formation, fever and myalgias due to infection, and brain or spinal cord injury due to minor trauma, diseases involving leukocyte diapedesis, acute hypersensitivity, delayed hypersensitivity, urticaria, food allergies, skin sunburn, inflammatory pelvic disease, urethritis, uveitis, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, alcoholic hepatitis, gastritis, enteritis, contact dermatitis, atopic dermatitis, gingivitis, appendicitis, pancreatitis, cholocystitis, polycythemia vera, essential thrombocythemia, and polycystic kidney disease. [0137] In some embodiments, the disease or condition is selected from the group consisting of systemic lupus erythematosus, myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis, Sjoegren’s syndrome, psoriasis, autoimmune hemolytic anemia, asthma, ulcerative colitis, Crohn’s disease, irritable bowel disease, and chronic obstructive pulmonary disease. systemic lupus erythematosus, myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis, Sjoegren’s syndrome, psoriasis, autoimmune hemolytic anemia, asthma, ulcerative colitis, Crohn’s disease, irritable bowel disease, and chronic obstructive pulmonary disease. [0138] In some embodiments, the disease or condition is selected from the group consisting of asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, and systemic lupus erythematosus. [0139] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. EXAMPLES General procedures [0140] It will be apparent to the skilled artisan that methods for preparing precursors and functionality related to the compounds claimed herein are generally described in the literature. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds. [0141] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in their entirety) and the like. All the intermediate compounds of the present disclosure were used without further purification unless otherwise specified. [0142] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene and P. Wuts Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), incorporated herein by reference in its entirety. [0143] The following example schemes are provided for the guidance of the reader, and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds. Such methods specifically include solid phase based chemistries, including combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application. [0144] Trademarks used herein are examples only and reflect illustrative materials used at the time of the present disclosure. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the disclosure. [0145] The following abbreviations have the indicated meanings: Aib = aminoisobutyric acid Bn = benzyl Boc = tert-butoxycarbonyl Bu = butyl Dde = 2-Acetyldimedone DIPEA or DIEA = diisopropylethylamine DMF = dimethylformamide DMS = dimethylsulfide dppf = 1,1′-Bis(diphenylphosphino)ferrocene EDC = 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Et = ethyl Fmoc = fluorenylmethoxycarbonyl HATU = hexafluorophosphate azabenzotriazole tetramethyl uranium HBTU = hexafluorophosphate benzotriazole tetramethyl uranium HMDS = hexamethyldisilazane HPLC = high-performance liquid chromatography Me = methyl NaHMDS = sodium hexamethyldisilazide NMR = nuclear magnetic resonance PCC = pyridinium chlorochromate PEG = polyethylene glycol Ph = phenyl RT = room temperature SFC = supercritical fluid chromatography tBu = tert-butyl TFA = trifluoroacetic acid THF = tetrahydrofuran TMS = trimethylsilyl [0146] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above. EXAMPLE A Preparation of compounds of Formula (IIIe-1) with Reaction Scheme A.
Figure imgf000052_0001
or a pharmaceutically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is substituted phenyl; and R10 is selected from the group consisting of hydrogen, halo, -C1-C6 alkyl, -C1- C6 haloalkyl, -CN, -CO2H, -CO2(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), - CON(C1-C6 alkyl)2, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, optionally substituted C1-C6 alkoxy,-SO2(alkyl), -SO(alkyl), -SO(NH)(alkyl), -SO2NH2, - SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)2, C6-C10 aryl, C3-C10 cycloalkyl, 5- to 10- membered heteroaryl, 4- to 10-membered heterocycloalkyl,
Figure imgf000052_0002
, and , wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q; each Q is independently selected from the group consisting of: halo, -CN, -OH, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 haloalkoxy, -(CH2)mNH2, - (CH2)mSO2(optionally substituted C1-C6 alkyl), -C(=O)NH2, - (CH2)mC(=O)NH(optionally substituted C1-C6 alkyl), -(CH2)mC(=O)N(optionally substituted C1-C6 alkyl)2, -(CH2)mC(=O)NH(optionally substituted C6-C10 aryl), - (CH2)mC(=O)NH(optionally substituted 3- to 10- membered heteroaryl), - (CH2)mC(=O)NH(optionally substituted C3-C10 cycloalkyl), - (CH2)mSO2NH(optionally substituted C1-C6 alkyl), optionally substituted C7-C16 arylalkyl, -C(=O)(optionally substituted 3- to 10- membered heterocycloalkyl), - (CH2)mCH(OH)(optionally substituted 3- to 10- membered heteroaryl), optionally substituted 5- to 10- membered heteroaryl-(C1-C6 alkyl), optionally substituted C3-C10 cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 4- to 10- membered heterocycloalkyl-(C1-C6 alkyl), optionally substituted C3-C10 cycloalkyl-(C1-C6 alkyl), optionally substituted C6-C10 aryl, and optionally substituted 5- to 10- membered heteroaryl; and m is 0 or 1; [0147] provided that R10 is -CONH2, -CONH(C1-C6 alkyl), or -CON(C1-C6 alkyl)2; or R10 is phenyl optionally substituted with 1, 2, or 3 substituents Q; or R10 is pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, or indolyl, benzimidazolyl, each optionally substituted with 1, 2, or 3 substituents Q. or a pharmaceutically acceptable salt thereof. Scheme A [0148] The key intermediate amines F1 and F2 were synthesized via the general route shown below
Figure imgf000054_0001
[0149] Amide intermediates B were constructed by substituted 2-methylpyridin-3- amine A reacting with (S)-3-((tert-butoxycarbonyl)amino)-3-phenylpropanoic acid under various amide couple conditions (e.g., T4P with TEA in DCM). Amide intermediates B were oxidized with SeO2 to form aldehyde intermediates C, which were cyclized under basic conditions (e.g., Cs2CO3 in DMF) to generate intermediates D. Intermediates D were then reduced under hydrogenation conditions (e.g., PtO2, H2, with NH3-H2O) to yield intermediates E, which were pairs of diastereomers and separated via SFC chiral separation to give optically pure diastereomers F1 and F2. F1 and F2 were brought forward separately using same procedures. [0150] Alternatively, intermediate amines F1 and F2 were synthesized via the general route as shown below.
Figure imgf000055_0001
[0151] Substituted 2-methylpyridin-3-amine A reacted with CbzCl to form the protected amines B, which were oxidized by m-CPBA to generate pyridine N-oxide intermediates CC. intermediates CC were converted to alcohols DD, and the latter reacted with PBr3 to form bromide intermediates EE, which then reacted with deprotonated (S)-3-((tert- butoxycarbonyl)amino)-3-phenylpropanoic acid methyl ester (e.g., by reacting with LiHMDS) to generate intermediates FF, Under hydrogenation conditions, intermediates FF were deprotected to form intermediates GG, which were cyclized under acidic conditions (e.g., HOAc) to yield intermediates E, which were pairs of diastereomers and could be separated via SFC chiral separation to give optically pure diastereomers, which were brought forward separately. Alternatively, intermediates E were reduced (e.g., using LAH with TMSCl) to give mixture of F1 and F2, which were then separated via SFC chiral separation. F1 and F2 were brought forward separately using same procedures to give final compounds with different absolute configurations. [0152] Below is the general approach for synthesizing final compounds for bioassay tests using F2 as an example.
Figure imgf000056_0001
[0153] Optically pure intermediates F2 were reacted with an acid (e.g., HCl in EtOAc) to form deprotected free amine salts (e.g., HCl salts) G, which were converted to final compounds via reductive amination with pre-made aldehydes. In some cases, R’ groups needed to be further modified to give desired R’’ groups. [0154] Below was a general approach to synthesize aldehyde intermediates with carboxylic moiety.
Figure imgf000056_0002
[0155] Another alternate approach to make final compounds for bioassay testing. Amine intermediates (e.g., HCl salts) G were converted to amides HH by reacting with pre-made carboxlic acids under various known conditions. Amides HH were then reduced to amines to form final compounds for bioassay testing. In some cases, R’ and R’’ were further modified by chemical transformation as needed.
Figure imgf000057_0003
EXAMPLE 2 Preparation of Compounds (2S or 2R)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid, Example 2A (2001A )and (2R or 2S)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid, Example 2B (2001B)
Figure imgf000057_0001
Step A. benzyl N-(5-fluoro-2-methylpyridin-3-yl) carbamate
Figure imgf000057_0002
[0156] To a stirred solution of 5-fluoro-2-methylpyridin-3-amine (6.15 g, 48.758 mmol, 1 equiv.) and pyridine (77.137 g, 78.872 mL, 0.978 g/mL, 975.153 mmol, 20 equiv.) in DCM (100 mL, 0.488 M, 16.26 Vols) was added benzyl chloroformate (16.635 g, 97.515 mmol, 2 equiv.) at 0 oC. The reaction was stirred at 25 oC for 3 hours under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate=1/1, Rf = 0.5) indicated reactant was consumed completely and one new spot formed. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was partitioned between EtOAc (150 m × 3) and H2O (300 mL). The organic phase was separated, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@;220 g SepaFlash@ Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Three reactions were carried out in parallel. Compound benzyl N-(5-fluoro-2- methylpyridin-3-yl) carbamate (25 g, 86.449 mmol) was obtained as an off-white solid. LCMS m/z 261.3 [M+H]+. Step B.3-{[(benzyloxy) carbonyl] amino}-5-fluoro-2-methylpyridin-1-ium-1-olate [0157] This compound was synthesized using flow chemistry as shown below. [0158] Solution 1: benzyl N-(5-fluoro-2-methylpyridin-3-yl) carbamate (20 g, 76.844 mmol, 1 equiv.) in DCE (100 mL, 0.768 M, 5 Vols) [0159] Solution 2: m-CPBA (39.001 g, 192.11 mmol, 2.5 equiv.) in DCE (200 mL, 0.384 M, 10 Vols) [0160] Solution 1 was pumped by Pump 1 {S1, P1, 8.765 mL/min} to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL,70 °C}. [0161] The solution 2 was pumped by Pump 2 {S2, P2, 23.293 mL/min to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL,70 °C}. [0162] Pump 1 and Pump 2 started at the same time. [0163] The reaction mixture ran 20 mins. [0164] LC-MS showed the reactant was consumed completely and desired mass was formed. [0165] The reaction mixture was quenched by (500 mL) aq. Na2S2O3 and (500 mL) aq. NaHCO3 at 20 °C. [0166] The reaction mixture was partitioned between EtOAc (800 mL × 3) and (500 mL) sat. aq. Na2S2O3 & (500 mL) sat. aq. NaHCO3. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (800 mL). The resulting solid was collected by filtration, washed with MTBE (300 mL) and dried to give 3-{[(benzyloxy)carbonyl] amino}-5-fluoro-2-methylpyridin-1-ium-1-olate (19.1 g, 65.679 mmol, yield 85.47%) as a pale-yellow solid. LCMS m/z 277.0 [M+H]+. Step C. benzyl N-[5-fluoro-2-(hydroxymethyl) pyridin-3-yl] carbamate
Figure imgf000059_0001
[0167] To a solution of 3-{[(benzyloxy)carbonyl] amino}-5-fluoro-2- methylpyridin-1-ium-1-olate (6.34 g, 22.949 mmol, 1 equiv.) in CHCl3 (65 mL, 0.353 M, 10.252 Vols) was added TFAA (4.82 g, 80 mL, 22.949 mmol, 1 equiv.). The mixture was stirred at 70 °C for 36 hours. LC-MS showed the reactant was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to get a residue. The reaction mixture was quenched by sat. aq. NaHCO3 (600 mL) at 0 °C. The reaction mixture was partitioned between EtOAc (300 m × 3) and sat. aq. NaHCO3 (600 mL). The organic phase was separated, washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 220 g SepaFlash@ Silica Flash Column, Eluent of 21~25% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Three reactions were carried out in parallel. Compound benzyl N-[5-fluoro-2-(hydroxymethyl) pyridin-3-yl] carbamate (17.8 g, 61.209 mmol) was obtained as a pale-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 4.67 (s, 2 H), 5.18 - 5.21 (m, 2 H), 7.31 - 7.50 (m, 5 H), 8.08 (dd, J = 11.07, 2.44 Hz, 1 H), 8.22 (d, J = 2.63 Hz, 1 H) 9.33 (s, 1 H). LCMS m/z 277.1 [M+H]+. Step D. benzyl N-[2-(bromomethyl)-5-fluoropyridin-3-yl] carbamate [0168] Solution 1: benzyl N-[5-fluoro-2-(hydroxymethyl) pyridin-3-yl] carbamate (17 g, 61.53 mmol, 1 equiv.) in DCE (51 mL, 1.207 M, 3 Vols) [0169] Solution 2: PBr3 (49969.725 mg, 184.604 mmol, 3 equiv.) in DCE (51 mL, 1.207 M, 3 Vols) [0170] Solution 1 was pumped by Pump 1 {S1, P1, 3.851 mL/min} to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 42.743 mL,50 °C}. [0171] The solution 2 was pumped by Pump 2 {S2, P2, 4.698 mL/min to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 42.743 mL,50 °C}. [0172] Pump 1 and Pump 2 started at the same time. [0173] Stop collecting the reaction mixture after 20 mins. [0174] TLC (Petroleum ether/Ethyl acetate=3/1, Rf = 0.3) indicated reactant was consumed completely and one new spot formed. [0175] The reaction mixture was quenched by sat. aq. NaHCO3 (100 mL) at 0 °C [0176] The reaction mixture was partitioned between EtOAc (80 mL × 3) and NaHCO3 (100 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 120 g SepaFlash Silica Flash Column, Eluent of 15~20% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound benzyl N-[2-(bromomethyl)-5-fluoropyridin-3-yl] carbamate (13.7 g, 38.37 mmol, yield 62.36%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 4.86 (s, 2 H), 5.17 - 5.28 (m, 2 H), 7.33 - 7.51 (m, 5 H), 8.03 (dd, J = 10.76, 2.63 Hz, 1 H), 8.31 (d, J = 2.75 Hz, 1 H), 9.69 (s, 1 H). Step E. methyl (3S)-2-[(3-{[(benzyloxy) carbonyl] amino}-5-fluoropyridin-2-yl) methyl]-3- [(tert-butoxycarbonyl) amino]-3-phenylpropanoate
Figure imgf000060_0001
[0177] To a solution of methyl (3S)-3-[(tert-butoxycarbonyl) amino]-3- phenylpropanoate (3.85 g, 13.78 mmol, 1 equiv.) in THF (50 mL, 0.276 M, 12.987 Vols) was cooled to -70 °C and then was added LiHMDS (27.565 mL, 1 M, 27.565 mmol, 2 equiv.) under N2. The mixture was stirred at -70 °C for 0.5 h. Then benzyl N-[2-(bromomethyl)-5- fluoropyridin-3-yl] carbamate (4.65 g, 13.71 mmol, 0.995 equiv.) in THF (30 mL, 0.459 M, 7.792 Vols) was added dropwise at -70 °C under N2. The mixture was stirred at -70 °C for 1.5 h under N2. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (100 mL) at 0 oC. The reaction mixture was partitioned between EtOAc (150 mL × 2) and saturated aqueous NH4Cl (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 120 g SepaFlash @ Silica Flash Column, Eluent of 20~28% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound methyl (3S)-2-[(3-{[(benzyloxy)carbonyl] amino}-5-fluoropyridin-2-yl) methyl]-3-[(tert- butoxycarbonyl) amino]-3-phenylpropanoate (6.5 g, 10.9 mmol, yield 78.9%) was obtained as a yellow solid. LCMS m/z 538.3 [M+H]+. Step F. methyl (3S)-2-[(3-amino-5-fluoropyridin-2-yl) methyl]-3-[(tert-butoxycarbonyl) amino]-3-phenylpropanoate
Figure imgf000061_0001
[0178] This reaction was carried over using the flow chemistry as shown below. [0179] A solution of methyl (3S)-2-[(3-{[(benzyloxy)carbonyl] amino}-5- fluoropyridin-2-yl) methyl]-3-[(tert-butoxycarbonyl) amino]-3-phenylpropanoate (13 g, 24.182 mmol, 1 equiv.) in THF (195 mL, 0.124 M, 15 Vols) and MeOH (195 mL, 0.124 M, 15 Vols) was stirred at 20 °C until becoming a clear solution. [0180] The fixed bed {SS, 50 mL, U column} with granular catalyst {5%Pd/Al2O3 (1.00 eq), 50 mL} was heated to 65 °C. [0181] The H2 back pressure regulator was adjusted to {1.7 MPa}. [0182] The above solution was pumped into the fixed bed at a flow rate of {2 mL/min}, and the flow rate of H2 was 90 mL/min. [0183] The fixed bed was washed by extra MeOH:THF=1:1 (200 mL). [0184] The reaction mixture was collected after running 4 h. [0185] LC-MS showed the reactant was consumed completely and desired mass was formed. [0186] The reaction mixture was concentrated under reduced pressure to give a residue. [0187] Compound methyl (3S)-2-[(3-amino-5-fluoropyridin-2-yl) methyl]-3-[(tert- butoxycarbonyl) amino]-3-phenylpropanoate (9.7 g, 24.042 mmol, yield 99.42%) was obtained as a yellow solid. LCMS m/z 404.2 [M+H]+. Step G. tert-butyl N-[(S)-(7-fluoro-2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3-yl) (phenyl)methyl] carbamate
Figure imgf000062_0001
[0188] A solution of methyl (3S)-2-[(3-amino-5-fluoropyridin-2-yl) methyl]-3- [(tert-butoxycarbonyl) amino]-3-phenylpropanoate (9.7 g, 24.042 mmol, 1 equiv.) in AcOH (5.867 g, 20 mL, 24.042 mmol, 1 equiv.) was stirred at 70 °C for 1 h. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was concentrated under reduced pressure to get a residue. The reaction mixture was partitioned between EtOAc (200 mL) and sat. aq. NaHCO3 (150 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Compound tert-butyl N-[(S)-(7-fluoro-2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3- yl) (phenyl)methyl] carbamate (8.5 g, 22.886 mmol, yield 95.18%) was obtained as a pale- yellow solid, a mixture of diastereomers with dr%=68%:32%. LCMS m/z 316.1 [M+H-56]+.
Step H. tert-butyl N-[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]carbamate and tert-butyl N-[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl) methyl] carbamate
Figure imgf000063_0001
[0189] This reaction was carried over using the flow chemistry as shown below. [0190] Solution 1: tert-butyl N-[(S)-(7-fluoro-2-oxo-3,4-dihydro-1H-1,5- naphthyridin-3-yl) (phenyl)methyl] carbamate (2 g, 5.385 mmol, 1 equiv.) in THF (40 mL, 0.135 M, 20 Vols) was added TMSCl (2.106 g, 19.385 mmol, 3.6 equiv.). [0191] Solution 2: LiAlH4 (817.421 mg, 2.692 mL, 21.539 mmol, 4 equiv.) in THF (40 mL, 0.135 M, 20 Vols) [0192] The volume of flow reactor 1FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, -10 °C. The residence time of flow reactor 1 was {FLR1,10 min}. [0193] The flow rate of Pump1 was adjusted to {S1, P1, 3.066 mL/min} for solution 1. [0194] The flow rate of Pump2 was adjusted to {S2, P2, 3.346 mL/min} for solution 2. [0195] The mixture was collected with a bottle (with 10 mL 10% NaOH aq.) at 0 °C. [0196] Pump1 and Pump2 started at the same time. The reaction mixture was collected after running 10 mins. [0197] Stop collecting the reaction mixture after 25 mins. [0198] TLC (Petroleum ether/Ethyl acetate=2/1, Rf = 0.3 & 0.25) indicated reactant was consumed completely and two new spots formed. [0199] The reaction mixture was quenched by (10 mL) aq.10% NaOH at 0 °C. [0200] The reaction mixture was filtered and concentrated under reduced pressure to give a residue and the residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash Silica Flash Column, Eluent of 6~15% THF/DCM @ 100 mL/min). [0201] Compound tert-butyl N-[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] carbamate (860 mg, 2.165 mmol, yield 40.21%) was obtained as a white solid. de%=99.74% (TLC (Petroleum ether/Ethyl acetate=2/1, Rf = 0.3, peak 1 in SFC, elution polarity: 6% THF/DCM @ 100 mL/min). 1H NMR (400 MHz, CDCl3) δ = 1.30 - 1.56 (m, 9 H), 2.29 - 2.43 (m, 1 H), 2.44 - 2.56 (m, 1 H), 2.56 - 2.70 (m, 1 H), 3.12 - 3.24 (m, 1 H), 3.51 (br d, J = 11.01 Hz, 1 H), 4.00 - 4.17 (m, 1 H), 4.56 (br s, 1 H), 5.01 (br d, J = 8.88 Hz, 1 H), 6.51 (dd, J = 10.07, 2.31 Hz, 1 H), 7.22 (br d, J = 7.13 Hz, 2 H), 7.29 (br d, J = 7.00 Hz, 1 H), 7.31 - 7.39 (m, 2 H), 7.68 (d, J = 2.25 Hz, 1 H). LCMS m/z 358.1 [M+H]+. [0202] Compound tert-butyl N-[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] carbamate (430 mg, 1.107 mmol, yield 20.55%) was obtained as a pale-yellow solid. de%=97.58 (TLC (Petroleum ether/Ethyl acetate=2/1, Rf = 0.25, peak 2 in SFC, elution polarity: 10% THF/DCM @ 100 mL/min). 1H NMR (400 MHz, CDCl3) δ = 1.33 - 1.46 (m, 9 H), 2.23 - 2.42 (m, 1 H), 2.74 - 2.99 (m, 2 H), 3.01 - 3.26 (m, 2 H), 3.80 - 3.98 (m, 1 H), 4.52 - 4.74 (m, 1 H), 4.94 - 5.10 (m, 1 H), 6.48 (br d, J = 9.88 Hz, 1 H), 7.28 - 7.33 (m, 2 H), 7.33 - 7.40 (m, 2 H), 7.74 (d, J = 2.13 Hz, 1 H). LCMS m/z 358.2 [M+H]+ .. Step I. (1S)-1-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-1- phenylmethanamine
Figure imgf000064_0001
[0203] To a solution of tert-butyl N-[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] carbamate (430 mg, 1.203 mmol, 1 equiv.) in HCl (4 M in EtOAc) (6 mL, 0.201 M, 13.953 Vols). The mixture was stirred at 25 °C for 1 h. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was concentrated under reduced pressure to get a residue. Compound (1S)-1-[(3R)-7- fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-1-phenylmethanamine hydrochloride (309 mg, 1.052 mmol, HCl salt, yield 87.43%) was obtained as a white solid. LCMS m/z 258.2 [M+H]+. Step J.2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid
Figure imgf000065_0001
[0204] To a stirred solution of (1S)-1-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]-1-phenylmethanamine (45 mg, 0.17 mmol, 1 equiv.) in MeOH (1 mL, 0.17 M, 22.22 Vols) was added AcOH (0.01 g, 0.17 mmol, 1 equiv.) to adjusted pH=5. Then 2-[4- methyl-3-(2-oxoethyl) phenyl] propanoic acid (0.036 g, 0.17 mmol, 1 equiv.) and NaBH3CN (0.033 g, 0.52 mmol, 3 equiv.) was added into the reaction. The reaction was stirred at 20 oC for 10 mins under N2 atmosphere. TLC indicated reactant was consumed completely and one new spot formed. The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 20 g SepaFlash@Silica Flash Column, Eluent of 0~7% Ethyl acetate/Petroleum ether gradient @ 80 mL/min). Compound 2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid (20 mg, 0.045 mmol, yield 25.55%) was obtained as a yellow solid. LCMS m/z 448.2 [M+H]+ Step K. (2S)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid, Example 2A (2001A) and (2R)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid, Example 2B (2001B)
Figure imgf000066_0001
[0205] 2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid (20 mg, 0.04mmol, 1 equiv.) was purified by SFC (base condition, column: REGIS (s,s) WHELK-O1 (250mm*30mm,5um); mobile phase: [A: CO2; B: MeOH(0.1%NH3H2O)]; B%: 35.00%- 35.00%, 11.00min) Example 2A [0206] Compound (2S or R)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid (10.2 mg, 0.023 mmol, yield 51%) was obtained as white solid. (elution time 7.28 min) (peak 1 in SFC). LCMS m/z 448.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.62 (dd, J = 1.4, 4.6 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.26 - 7.19 (m, 3H), 7.15 - 7.09 (m, 1H), 7.05 - 6.96 (m, 2H), 6.83 (dd, J = 4.6, 8.0 Hz, 1H), 6.69 (dd, J = 1.4, 8.1 Hz, 1H), 5.66 (br s, 1H), 3.38 (br d, J = 8.5 Hz, 1H), 3.03 (br dd, J = 3.3, 16.8 Hz, 1H), 2.84 - 2.76 (m, 1H), 2.76 - 2.55 (m, 4H), 2.46 - 2.31 (m, 2H), 2.05 - 1.92 (m, 1H), 1.44 (d, J = 8.8 Hz, 6H), 1.15 (d, J = 6.9 Hz, 3H) Example 2B [0207] Compound (2R or S)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] amino} ethyl)-4-methylphenyl] propanoic acid (9.1 mg, 0.02 mmol, yield 45.5%) was obtained as white solid. (elution time 8.77 min) (peak 2 in SFC) LCMS m/z 448.2 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ ppm 7.63 (dd, J = 1.3, 4.6 Hz, 1H), 7.35 - 7.29 (m, 4H), 7.26 - 7.22 (m, 1H), 7.14 - 7.09 (m, 1H), 7.03 - 6.95 (m, 2H), 6.84 (dd, J = 4.6, 8.0 Hz, 1H), 6.69 (dd, J = 1.3, 8.0 Hz, 1H), 5.66 (br d, J = 2.1 Hz, 1H), 3.36 (br s, 1H), 3.09 - 3.01 (m, 1H), 2.87 - 2.79 (m, 1H), 2.75 - 2.70 (m, 1H), 2.65 - 2.57 (m, 3H), 2.40 - 2.35 (m, 2H), 2.01 (td, J = 4.1, 5.3 Hz, 1H), 1.43 (s, 6H), 1.17 (d, J = 6.9 Hz, 3H). Step AA 4-(3-chloro-4-methylphenyl)-1,2-oxazole
Figure imgf000067_0001
[0208] To a solution of 4-bromo-2-chloro-1-methylbenzene (2 g, 9.73 mmol, 1 equiv.) in THF (20 mL, 0.48 M, 10 Vols) and H2O (4 mL, 2.43 M, 2 Vols) were added K3PO4 (6.198 g, 29.2 mmol, 3 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (1.89 g, 9.73 mmol, 1 equiv.) and Catacxium A-Pd-G2 (0.32 g, 0.48 mmol, 0.05 equiv.) under N2. The reaction was stirred at 80 oC for 1 h under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate=2/1, Rf = 0.5) indicated reactant was consumed completely and one new spot formed. The reaction mixture was partitioned between EtOAc (20 mL × 3) and H2O (20 mL). The organic phase was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 20 g SepaFlash@ Silica Flash Column, Eluent of 0~17% Ethyl acetate/Petroleum ether gradient @ 80 mL/min) Compound 4-(3-chloro-4- methylphenyl)-1,2-oxazole (1.5 g, 7.74 mmol, yield 79.59%) was obtained as a yellow solid. LCMS m/z 194.0 [M+H]+ Step AB. (3-chloro-4-methylphenyl) acetic acid
Figure imgf000067_0002
[0209] To a solution of 4-(3-chloro-4-methylphenyl)-1,2-oxazole (1.45 g, 7.48 mmol, 1 equiv.) was added in MeOH (10 mL, 0.74 M, 6.89 Vols) and H2O (5 mL, 1.49 M, 3.44 Vols) was added LiOH (0.89 g, 37.44 mmol, 5 equiv.). The mixture was stirred at 60 oC for 12 h. TLC (Petroleum ether/Ethyl acetate=1/1, Rf = 0.5) indicated reactant was consumed completely and one new spot formed. The mixture acidified pH to 6 with aqueous solution of hydrochloric acid (1 mol/L). The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Compound (3-chloro-4-methylphenyl) acetic acid (1.3 g, 7.04 mmol, yield 94.03%) was obtained as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ = 2.26 (s, 3 H), 3.16 (s, 2 H), 7.03 (d, J = 7.63 Hz, 1 H), 7.15 (d, J = 7.75 Hz, 1 H), 7.25 (s, 1 H). LCMS m/z 182.9 [M-H]- (NEG). S
Figure imgf000068_0002
[0210] To a stirred solution of bis((3-chloro-4-methylphenyl) acetic acid) (1.1 g, 2.68 mmol, 1 equiv.) in THF (15 mL, 0.17 M, 13.63 Vols) at 0 °C was added NaHMDS (1.22 g, 6.70 mL, 1 M, 6.70 mmol, 2.5 equiv.) The reaction was continuously stirred at 0 oC over 0.5 hours, MeI (0.57 g, 4.02 mmol, 1.5 equiv.) was added to the mixture under N2. The reaction was allowed to warm to 20 oC and continuously stirred at 20 oC over 1.5 hours under N2. TLC indicated reactant was consumed completely and one new spot formed. The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 20 g SepaFlash@ Silica Flash Column, Eluent of 0~47% Ethyl acetate/Petroleum ether gradient @ 80 mL/min). Compound bis(2-(3-chloro-4-methylphenyl) propanoic acid) (800 mg, 2.01 mmol, yield 75.10%) was obtained as a yellow solid. LCMS m/z 197.0 [M-H]- (NEG). Step AD.2-{3-[(1E)-2-ethoxyethenyl]-4-methylphenyl} propanoic acid
Figure imgf000068_0001
[0211] To a stirred solution 2-(3-chloro-4-methylphenyl) propanoic acid (800 mg, 4.02 mmol, 1 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.03 g, 5.23 mmol, 1.3 equiv.) in H2O (2 mL, 2.01 M, 2.5 Vols) and Tol. (10 mL, 0.40 M, 12.5 Vols) at 20 °C were added Ruphos Pd G3 (0.33 g, 0.40 mmol, 0.1 equiv.) and Cs2CO3 (2.624 g, 8.05 mmol, 2 equiv.). The reaction was allowed to 100 oC over 18 hours. TLC indicated reactant was consumed completely and one new spot formed. The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO@; 20 g SepaFlash@ Silica Flash Column, Eluent of 0~7% Ethyl acetate/Petroleum ethergradient @ 80 mL/min) to give Compound 2-{3-[(1E)-2-ethoxyethenyl]-4- methylphenyl} propanoic acid (650 mg, 2.77 mmol, yield 68.88 %) as a yellow solid. Step .AE 2-[4-methyl-3-(2-oxoethyl) phenyl] propanoic acid
Figure imgf000069_0001
[0212] To a stirred solution of 2-{3-[(1E)-2-ethoxyethenyl]-4-methylphenyl} propanoic acid (200 mg, 0.85 mmol, 1 equiv.) in MeCN (3 mL, 0.28 M, 15 Vols) at 0 oC was added HCl (0.87 g, 2 mL, 12 M, 24 mmol, 28.11 equiv.). The reaction was stirred at 0 oC over 0.5 hour. TLC indicated reactant was consumed completely and one new spot formed. The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. Compound 2-[4-methyl-3-(2- oxoethyl) phenyl] propanoic acid (150 mg, 0.72 mmol, yield 85.20 %) was obtained as a yellow solid. EXAMPLE 3 Preparation of Compound [3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)-4-methylphenyl]acetic acid (2002A) and [3-(2-{[(S)-[(3S)-7- fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}ethyl)-4- methylphenyl]acetic acid (2002B) F
Figure imgf000070_0001
Step A.4-(3-chloro-4-methylphenyl)-1,2-oxazole
Figure imgf000070_0002
[0213] To a solution of 4-bromo-2-chloro-1-methylbenzene (8 g, 38.93 mmol, 1 equiv) in THF (100 mL, 38.93 M, 12.5 Vols) and H2O (30 mL, 12.97 M, 3.75 Vols), were added K3PO4 (24.79 g, 116.8 mmol, 3 equiv), Catacxium A-Pd-G2 (2.60 g, 3.89 mmol, 0.1 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (9.11 g, 46.72 mmol, 1.2 equiv) with N2 for 3 times. The reaction was stirred at 80 oC for 1 h under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate = 5/1, Rf = 0.5) indicated one new spot formed. The reaction mixture was partitioned between EtOAc (100 mL × 3) and H2O (100 mL). The organic phase was separated, washed with brine (100 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to get a residue, and the residue was purified by flash silica gel chromatography(ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~3% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound 4-(3-chloro-4-methylphenyl)-1,2-oxazole (7 g, 34.34 mmol, Yield 88.21%) was obtained as a yellow oil. 1H NMR: (400 MHz, CDCl3), δ = 8.61 (s, 1H), 8.48 (s, 1H), 7.42 (s, 1H), 7.22 (s, 2H), 2.35 (s, 3H). Step B.4-{3-[(1E)-2-ethoxyethenyl]-4-methylphenyl}-1,2-oxazole
Figure imgf000070_0003
[0214] To a solution of 4-(3-chloro-4-methylphenyl)-1,2-oxazole (2 g, 10.32 mmol, 1 equiv) in dioxane (20 mL, 1.03 M, 10 Vols) and H2O (6 mL, 3.14 M, 3 Vols), were added K3PO4 (6.57 g, 30.98 mmol, 3 equiv), Catacxium A-Pd-G2 (0.69 g, 0.10 mmol, 0.1 equiv), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.45 g, 12.4 mmol, 1.2 equiv) with N2 for 3 times. The reaction was stirred at 100 oC for 2 h under N2 atmosphere. LCMS indicated one main peak with desired mass was detected. The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography. (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~6% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound 4-{3-[(1E)-2-ethoxyethenyl]-4-methylphenyl}-1,2- oxazole (970 mg, 3.59 mmol, Yield 34.81%) was obtained as a yellow oil.1H NMR: (400 MHz, DMSO- d6) δ = 9.40 (s, 1H), 9.17 - 9.15 (m, 1H), 7.68 (d, J = 1.5 Hz, 1H), 7.36 (dd, J = 1.6, 7.8 Hz, 1H), 7.19 (d, J = 4.8 Hz, 1H), 7.16 (s, 1H), 5.92 (d, J = 12.8 Hz, 1H), 3.97 - 3.90 (m, 2H), 2.24 (s, 3H), 1.28 (t, J = 7.0 Hz, 3H). LCMS: m/z 228.1 [M-H]- Step C. {3-[(1E)-2-ethoxyethenyl]-4-methylphenyl}acetic acid
Figure imgf000071_0001
[0215] To a solution of 4-{3-[(1E)-2-ethoxyethenyl]-4-methylphenyl}-1,2-oxazole (200 mg, 0.87 mmol, 1 equiv) in MeOH (2 mL, 0.43 M, 10 Vols) and H2O (1 mL, 0.87 M, 5 Vols) was added NaOH (0.17 g, 4.36 mmol, 5 equiv), The mixture was stirred at 100 oC for 12 h. LCMS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was basified pH to 6 with 1M HCl, then partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound {3-[(1E)-2-ethoxyethenyl]-4-methylphenyl}acetic acid (150 mg, 0.54 mmol, Yield 62.45%) was obtained as a yellow oil. LCMS: m/z 219.0 [M-H]- Step D. [4-methyl-3-(2-oxoethyl)phenyl]acetic acid [0216] To a solution of {3-[(1E)-2-ethoxyethenyl]-4-methylphenyl}acetic acid (100 mg, 0.45 mmol, 1 equiv) in MeCN (1 mL, 0.45 M, 10 Vols) was added HCl (0.04 g, 0.1 mL, 12 M, 1.2 mmol, 2.64 equiv). The mixture was stirred at 0 oC for 0.5 h. TLC indicated reactant was consumed completely and one new spot formed. The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound [4-methyl-3-(2-oxoethyl)phenyl]acetic acid (100 mg, 0.52 mmol, Yield 95.49%) was obtained as a yellow oil. Step E [3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)-4-methylphenyl]acetic acid (2002A) and [3-(2-{[(S)-[(3S)- 7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}ethyl)-4- methylphenyl]acetic acid (2002B)
Figure imgf000072_0001
[0217] To a solution of (1S) 1 (7 fluoro 1,2,3,4 tetrahydro 1,5 naphthyridin 3 yl) 1-phenylmethanamine (40 mg, 0.15 mmol, 1 equiv) in MeOH (1 mL, 0.15 M, 25 Vols) were added AcOH (9.33 mg, 0.15 mmol, 1 equiv), NaBH4CN (9.92 mg, 0.15 mmol, 1 equiv) and [4-methyl-3-(2-oxoethyl)phenyl]acetic acid (35.85 mg, 0.18 mmol, 1.2 equiv). The mixture was stirred at 0 oC for 0.5 h. LCMS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was partitioned between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The reaction mixture was concentrated under reduced pressure to get a residue, and the reaction mixture was filtered and the filtrate was purified by prep-HPLC (FA condition; column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 10.00%-40.00%, 8.00min). [0218] Compound [3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl](phenyl)methyl]amino}ethyl)-4-methylphenyl]acetic acid (1.1 mg, 0.003 mmol, Yield 1.206%) was obtained as a white solid.1H NMR: (400 MHz, DMSO-d6) δ = 7.55 (d, J = 2.5 Hz, 1H), 7.34 - 7.28 (m, 4H), 7.26 - 7.21 (m, 1H), 7.01 - 6.97 (m, 1H), 6.94 - 6.90 (m, 2H), 6.55 (dd, J = 2.4, 11.2 Hz, 1H), 6.07 (br s, 1H), 3.45 (br d, J = 8.4 Hz, 2H), 3.40 (br s, 2H), 3.10 (br dd, J = 3.1, 16.4 Hz, 1H), 2.78 (br d, J = 11.9 Hz, 1H), 2.71 - 2.63 (m, 3H), 2.45 - 2.35 (m, 2H), 2.10 (s, 3H), 2.06 - 1.99 (m, 1H). LCMS: m/z 434.2 [M+H]+ de% = 88.2%, (peak 2 in SFC) [0219] Compound [3-(2-{[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl](phenyl)methyl]amino}ethyl)-4-methylphenyl]acetic acid (10.7 mg, 0.025 mmol, Yield 11.86%) was obtained as a white solid. 1H NMR: (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.37 - 7.22 (m, 5H), 7.03 - 6.97 (m, 1H), 6.95 - 6.90 (m, 2H), 6.58 (dd, J = 2.4, 11.2 Hz, 1H), 6.25 (br s, 1H), 3.67 - 3.59 (m, 1H), 3.48 - 3.41 (m, 3H), 2.97 (br t, J = 10.6 Hz, 1H), 2.72 - 2.66 (m, 1H), 2.62 - 2.56 (m, 1H), 2.48 - 2.35 (m, 2H), 2.32 - 2.21 (m, 2H), 2.11 (s, 3H), 2.09 - 2.02 (m, 1H). LCMS: m/z 434.2 [M+H]+ ; de% = 100%, (peak 1 in SFC) . EXAMPLE 4 Preparation of Compound 4-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)benzoic acid; trifluoroacetic acid (2003).
Figure imgf000073_0001
Step A.4-[(1E)-2-ethoxyethenyl]benzoic acid [0220] To a stirred solution of 4-bromobenzoic acid (1 g, 4.97 mmol, 1 equiv.) and 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.18 g, 5.97 mmol, 1.2 equiv.) in dioxane (16 mL, 0.31 M, 16 Vols) and H2O (4 mL, 1.24 M, 4 Vols) were added K2CO3 (1.37 g, 9.94 mmol, 2 equiv.) and Pd(dppf)Cl2 (363.99 mg, 0.49 mmol, 0.1 equiv.). The reaction mixture was purged with N2 for three times and stirred at 80 °C for 3 h under N2. LCMS showed the reactant was consumed completely and desired mass was formed. The mixture was adjusted pH to 3 with aqueous solution of hydrochloric acid (1 mol/L). The reaction mixture was diluted with EtOAc (45 mL) and H2O (20 mL). The organic phase was separated, washed with brine (15 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, DCM/THF = 10/1 to 5/1). Compound 4-[(1E)-2-ethoxyethenyl]benzoic acid (420 mg, 1.96 mmol, 90% purity, yield 39.53%) was obtained as a red solid. Compound 4-[(1E)-2- ethoxyethenyl]benzoic acid (400 mg, 1.66 mmol, 80% purity, yield 33.46%) was obtained as a red solid. LCMS: m/z 191.0 [M-H]- Step B.4-(2-oxoethyl)benzoic acid
Figure imgf000074_0001
[0221] To a solution of 4-[(1E)-2-ethoxyethenyl]benzoic acid (200 mg, 1.04 mmol, 4 equiv.) in MeCN (4 mL, 0.26 M, 20 Vols ) was added HCl (87.50 mg, 0.2 mL, 12 M, 2.4 mmol, 9.22 equiv.), the mixture was stirred at 0 °C for 1 h. TLC indicated reactant was consumed completely and one new spot formed. The reaction mixture was diluted with EtOAc (30 mL) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 4-(2-oxoethyl)benzoic acid (170 mg, 0.93 mmol, yield 89.57%) was obtained as a yellow solid. Step C.4-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)benzoic acid; trifluoroacetic acid [0222] To a solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (30 mg, 0.12 mmol, 1 equiv.) in MeOH (2 mL, 0.06 M, 66.66 Vols) was added AcOH (0.75 mg, 0.01 mmol, 0.1 equiv.) to adjust pH ~ 6, then NaBH3CN (23.63 mg, 0.37 mmol, 3 equiv.) was added to the mixture followed by 4-(2-oxoethyl)benzoic acid (21.60 mg, 0.13 mmol, 1.05 equiv.). The reaction was stirred at 0 °C for 1 h. TLC indicated reactant was consumed completely and one new spot formed. The reaction mixture was filtered and the filtrate was purified by Prep.-HPLC column: Phenomenex Luna C1875*30mm*3um; mobile phase: [A: H2O (0.1% TFA); B: ACN]; B%: 1.00%-30.00%, 8.00 min. Compound 4- (2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]amino}ethyl)benzoic acid; trifluoroacetic acid (34.5 mg, 0.06 mmol, yield 54.50%) was obtained as a white solid. LCMS: m/z 388.2 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 13.22 - 12.58 (m, 1H), 9.80 - 9.19 (m, 2H), 7.91 (br d, J = 5.2 Hz, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.52 - 7.45 (m, 5H), 7.39 (br s, 1H), 7.30 (br s, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.10 - 6.55 (m, 1H), 4.41 (br s, 1H), 3.36 (br d, J = 17.4 Hz, 1H), 3.14 - 2.81 (m, 7H), 2.77 - 2.68 (m, 2H).
EXAMPLE 5 Preparation of Compounds 2-[3-[2-[[(S)-[(3S)-7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl]-phenyl-methyl] amino] ethyl] phenyl] acetic acid, and 2-[3-[2-[[(S)- [(3R)-7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-phenyl- methyl]amino]ethyl]phenyl]acetic acid (2004) (2004A 2004B).
Figure imgf000076_0001
Step A. tert-butyl N-[(1S)-3-[(5-bromo-2-methyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate
Figure imgf000076_0002
[0223] To a stirred solution of (3S)-3-(tert-butoxycarbonylamino)-3-phenyl- propanoic acid (10 g, 37.69 mmol) in DCM (80 mL) was added T4P (61.59 g, 85.54 mmol) (50% in ethyl acetate) and TEA (8.66 g, 85.54 mmol) at 0 °C, after being for 30 min. To a solution of 5-bromo-2-methyl-pyridin-3-amine (8 g, 42.77 mmol) in DCM (10 mL) was added to above solution, then the mixture was stirred at 25 o C for 12 h. LCMS showed starting material was consumed completely and main desired mass was detected. Poured the mixture into the water (1 L), precipitated the white solid, then filtered. The filter cake washed with water (20 mL × 3) and concentrated under reduced pressure to give a crude product. The crude product was triturated with ethyl acetate (50 mL) at 25 °C for 5 min, then filtered to give the product. The product tert-butyl N-[(1S)-3-[(5-bromo-2-methyl-3-pyridyl)amino]-3-oxo-1- phenyl-propyl]carbamate (12 g, 27.63 mmol, 64.60% yield) was obtained as a white solid. tert-butyl N-[(1S)-3-[(5-bromo-2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate A stirred solution of SeO2 (4.6 g, 41.44 mmol) in 1,4-Dioxane (60 mL) at 25 °C, warming up to 80 °C, tert-butyl N-[(1S)-3-[(5-bromo-2-methyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate (6 g, 13.81 mmol) was added to above solution at 80 °C, then the mixture was warmed to 110 oC and stirred at 110 o C for 96 h. LCMS showed 7% of peak with starting material was remained and 43% of peak with desired mass was detected. The mixture filtered, collect the filtrate and concentrated to give the crude product. The crude product was purified by flash column (ISCO 120 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 80 min). TLC (petroleum ether: ethyl acetate =1: 1), Rf = 0.3. The compound tert-butyl N- [(1S)-3-[(5-bromo-2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl-propyl]carbamate (2.5 g, 5.58 mmol, 40.37% yield) was obtained as a yellow solid. Step C. tert-butyl N-[(R)-(7-bromo-2-hydroxy-1,5-naphthyridin-3-yl)-phenyl- methyl]carbamate)
To a solution of tert-butyl N-[(1S)-3-[(5-bromo-2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate (2.5 g, 5.58 mmol) in DMF (25 mL) was added Cs2CO3 (3.63 g, 11.15 mmol) at 25 °C. Then the reaction was stirred at 60 oC for 12 h. LCMS showed starting material was consumed completely and main desired mass was detected. The mixture cooled to room temperature. The mixture was poured into water (20 mL). Then filtered to collect the filter cake wash with water (3 × 5 mL). Concentrated under reduced pressure to give the product. The product tert-butyl N-[(R)-(7-bromo-2-hydroxy-1,5-naphthyridin-3-yl)-phenyl- methyl]carbamate (2.1 g, 4.56 mmol, 81.77% yield) was obtained as a white solid. Step D. tert-butyl N-[(R)-[2-hydroxy-7-(1-methylpyrazol-4-yl)-1,5-naphthyridin-3-yl]- phenyl-methyl]carbamate
Figure imgf000078_0001
[0224] To a stirred solution of tert-butyl N-[(R)-(7-bromo-2-hydroxy-1,5- naphthyridin-3-yl)-phenyl-methyl]carbamate (2.1 g, 4.88 mmol) in 1,4-Dioxane (20 mL) and H2O (4 mL) was added 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (1.22 g, 5.86 mmol), K2CO3 (1.35 g, 9.76 mmol) and Pd(dppf)Cl2 (0.35 g, 0.49 mmol), the mixture was degassed with N2 for 3 times and stirred at 100 o C for 2 h. LCMS showed starting material was consumed completely and main desired mass was detected. The mixture was cooled to room temperature and poured into water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column (ISCO 20 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min). TLC (petroleum ether: ethyl acetate = 0:1, Rf = 0.4). The product tert-butyl N-[(R)-[2- hydroxy-7-(1-methylpyrazol-4-yl)-1,5-naphthyridin-3-yl]-phenyl-methyl]carbamate (1 g, 2.32 mmol, 47.49% yield) was a yellow solid. Step E. tert-butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-2-oxo-3,4-dihydro-1H-1,5-naphthyridin- 3-yl]-phenyl-methyl]carbamate
Figure imgf000079_0001
[0225] To a suspension of PtO2 (210.5 mg, 0.93 mmol) in Methanol (300 mL) was added tert-butyl N-[(R)-[2-hydroxy-7-(1-methylpyrazol-4-yl)-1,5-naphthyridin-3-yl]-phenyl- methyl]carbamate (400 mg, 0.93 mmol) under Ar atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (2 MPa) at 100 oC for 15 h. LCMS showed starting material was remaining 40% and main desired mass was detected. The reaction mixture was filtered through a pad of Celite and the Celite was rinsed with MeOH（ 10 mL × 3). The compound tert-butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-2-oxo-3,4-dihydro- 1H-1,5-naphthyridin-3-yl]-phenyl-methyl]carbamate (350 mg, 0.81 mmol, 87.10% yield) was obtained as a brown solid. Step F. tert-butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]-phenyl-methyl]carbamate
Figure imgf000079_0002
[0226] A solution of tert-butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-2-oxo-3,4- dihydro-1H-1,5-naphthyridin-3-yl]-phenyl-methyl]carbamate (350 mg, 0.81 mmol) in THF (10 mL) was purged with N2 for 3 times at 25 oC. LiBH4 (1.61 mL, 3.23 mmol) (2M in THF) was added dropwise to the mixture at 0 °C. Then the mixture was stirred at 25 oC for 12 h. LCMS showed starting material was consumed completely and main desired mass was detected. The mixture was quenched with MeOH (5 mL) and NH4Cl aq. (5 mL). Then the mixture stirred for 0.5 h at 25 °C. Next the mixture was quenched by 1 M HCl (0.5 mL) and stirred for 12 h at 70 °C. Then the mixture was adjusted by sat. NaHCO3 to pH=7-8 and concentrated under reduced pressure to remove MeOH and THF. The aqueous phase was extracted with EtOAc (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column (ISCO 12 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 50 min). TLC(petroleum ether: ethyl acetate = 0:1，Rf = 0.3). The product tert- butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-phenyl- methyl]carbamate (120 mg, 0.27 mmol, 33.18% yield) was obtained as a creamy-white solid. Step G. hydrogen;(S)-[7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]- phenyl-methanamine;hydrochloride
Figure imgf000080_0001
[0227] To a solution of tert-butyl N-[(S)-[7-(1-methylpyrazol-4-yl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl]-phenyl-methyl]carbamate (120 mg, 0.29 mmol) in Ethyl acetate (0.5 mL) was added HCl/EtOAc (2.72 mL, 5.45 mmol) (2 M) to the mixture at 25 oC. Then the mixture was stirred at 25 o C for 1 h. LCMS showed starting material was consumed completely and main desired mass was detected. The mixture was concentrated under reduced pressure to give a crude product. The crude product hydrogen; (S)-[7-(1-methylpyrazol-4-yl)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-phenyl-methanamine;hydrochloride (120 mg, 0.34 mmol, 117.55% yield) was a pale yellow solid. Step H.2-[3-[2-[[(S)-[(3S)-7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]-phenyl-methyl] amino] ethyl] phenyl] acetic acid and 2-[3-[2-[[(S)-[(3R)-7-(1- methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-phenyl- methyl]amino]ethyl]phenyl]acetic acid
Figure imgf000081_0001
[0228] To a solution of hydrogen;(S)-[7-(1-methylpyrazol-4-yl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl]-phenyl-methanamine;hydrochloride (100 mg, 0.28 mmol) in MeOH (3 mL) was added TEA (1 mL, 7.19 mmol), Sodium cyanoborohydride (115.27 mg, 0.34 mmol), CH3COOH (3.37 mg, 0.06 mmol) and 2-[3-(2-oxoethyl)phenyl]acetic acid (64.91 mg, 0.36 mmol). The reaction was stirred at 25 oC for 1 h. LCMS showed starting material was consumed completely and main desired mass was detected. The reaction was added HCl (1M) to pH=5-6. The mixture was added into water (2 mL) and ethyl acetate (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL × 3). The combined organic phase was dried with anhydrous Na2SO4, filtrated and concentrated in vacuum. The crude product was purified by Prep.-HPLC (column: Waters Xbridge Prep OBD C18150*40 mm*10 um; mobile phase: [A: H2O 10 mM NH4HCO3); B: ACN]; B%: 10.00%-40.00%, 8.00min). Then the crude product was purified by Prep.-HPLC (column: Phenomenex luna C18 100*40 mm*3 um; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 5.00%-35.00%, 8.00min). Compound of 2-[3-[2- [[(S)-[(3S)-7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-phenyl- methyl]amino]ethyl]phenyl]acetic acid (12.3 mg, 0.03 mmol, 9.11% yield) was obtained as a white solid. Compound of 2-[3-[2-[[(S)-[(3R)-7-(1-methylpyrazol-4-yl)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl]-phenyl-methyl]amino]ethyl]phenyl]acetic acid (10.2 mg, 0.02 mmol, 7.56% yield) was obtained as a white solid. [0229] LCMS m/z 482.3 [M+H]+ [0230] 1H NMR: (400 MHz, DMSO-d6) δ = 8.22 (br s, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.71 (s, 1H), 7.41 - 7.19 (m, 5H), 7.19 - 7.12 (m, 1H), 7.09 - 6.94 (m, 3H), 6.85 (s, 1H), 5.85 (br s, 1H), 3.84 (s, 3H), 3.60 (br d, J = 11.0 Hz, 1H), 3.49 (s, 2H), 3.41 - 3.40 (m, 1H), 2.96 (br d, J = 10.4 Hz, 1H), 2.73 - 2.65 (m, 1H), 2.64 - 2.56 (m, 1H), 2.49 - 2.38 (m, 2H), 2.36 - 2.20 (m, 2H), 2.11 - 1.95 (m, 1H) [0231] LCMS m/z 482.3 [M+H] + [0232] 1H NMR: (400 MHz, DMSO-d6) δ = 8.28 (br s, 1H), 8.04 (s, 1H), 7.89 (br s, 1H), 7.73 (s, 1H), 7.44 - 7.20 (m, 5H), 7.20 - 7.12 (m, 1H), 7.12 - 6.90 (m, 3H), 6.84 (s, 1H), 5.71 (br s, 1H), 3.84 (s, 3H), 3.49 (br s, 2H), 3.42 (br d, J = 8.4 Hz, 1H), 3.10 (br d, J = 15.4 Hz, 1H), 2.80 - 2.53 (m, 6H), 2.44 (br s, 1H), 2.04 (br d, J = 4.0 Hz, 1H) Step AA.1-bromo-3-(2-methoxyvinyl)benzene
Figure imgf000082_0001
[0233] To a solution of (Methoxymethyl)triphenylphosphonium chloride (2.78 g, 8.11 mmol) in THF (20 mL) was added t-BuOK (10.81 mL, 10.81 mmol) (1M in THF) at 0 °C -5 °C under N2. The mixture was stirred at 0 °C for 1 h. To a solution of 3-bromobenzaldehyde (1 g, 5.4 mmol) in THF (5 mL) was added dropwise to the mixture at 0 °C ~ 5 °C. The mixture heats up to 25 oC. Then the mixture was stirred at 25 oC for 3 h. TLC (petroleum ether: ethyl acetate = 5:1, Rf = 0.4) showed starting material was consumed completely and one new spot formed. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column (ISCO 40 g silica, 0-20 % ethyl acetate in petroleum ether, gradient over 30 min). TLC (petroleum ehter: ethyl acetate=5:1, Rf = 0.4). Compound 1-bromo-3-(2- methoxyvinyl) benzene (900 mg, 4.22 mmol, 78.15% yield) was obtained as a brown oil.
Step AB.4-[3-(2-methoxyvinyl)phenyl]isoxazole
Figure imgf000083_0002
[0234] To a stirred solution of 1-bromo-3-(2-methoxyvinyl)benzene (0.9 g, 4.22 mmol) in THF (20 mL) and Water (5 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (1.24 g, 6.34 mmol), K3PO4 (1.79 g, 8.45 mmol) and Catacxium A-Pd-G2 (0.14 g, 0.21 mmol). The mixture was degassed with N2 for 3 times and stirred at 80 oC for 3 h. LCMS showed starting material was consumed completely and main desired mass was detected. The mixture was cooled to room temperature and poured into water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column (ISCO 20 g silica, 0-5 % ethyl acetate in petroleum ether, gradient over 40 min). TLC (petroleum ether: ethyl acetate = 10: 1, Rf = 0.5). The product 4- [3-(2-methoxyvinyl)phenyl]isoxazole (600 mg, 2.98 mmol, 70.60% yield) was obtained as a yellow oil. Step AC.2-[3-(2-methoxyvinyl)phenyl]acetic acid
Figure imgf000083_0001
To a stirred solution of 4-[3-(2-methoxyvinyl)phenyl]isoxazole (0.6 g, 2.98mmol) in Methanol (10 mL) was added NaOH (1.19 g, 29.82 mmol) in Water (5 mL) at 25 oC, the reaction heats up to 100 oC and stirred at 100 oC for 12 h. LCMS showed starting material was consumed completely and main desired mass was detected. The mixture pH was adjusted to ~7 by HCl (1M). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried with anhydrous Na2SO4, filtrated and concentrated in vacuum. The crude product 2-[3-(2-methoxyvinyl)phenyl]acetic acid (400 mg, 2.08 mmol, 69.80% yield) was as a yellow oil. Step AD.2-[3-(2-oxoethyl)phenyl]acetic acid [0235] To a stirred solution of 2-[3-(2-methoxyvinyl)phenyl]acetic acid (200 mg, 1.04 mmol) in MeCN (3 mL) was added HCl (0.1 mL, 1.2 mmol) and the mixture was stirred at 0 oC for 10 min. TLC(Petroleum ether : Ethyl acetate = 3 : 1, Rf = 0.5) showed the starting material was consumed completely and new spots was formed. The mixture was added water (1 mL) and extracted with EtOAc (3 × 1 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product 2-[3-(2-oxoethyl)phenyl]acetic acid (160 mg, 0.90 mmol, 86.30% yield) as a pale yellow oil.
EXAMPLE 6 Preparation of Compound 2-[3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl]methyl]amino]ethyl]phenyl]acetic acid (730).
Figure imgf000085_0001
Step A.1-bromo-3-(2-methoxyvinyl)benzene [0236] To a stirred solution of methoxymethyl(triphenyl)phosphonium;chloride (7.41 g, 21.62 mmol) in THF (70 mL) was added t-BuOK (21.62 mL, 1M in THF, 21.62 mmol) at 0 ℃ under N2. The mixture was stirred at 0 oC for 1 h, then 3-bromobenzaldehyde (2 g, 10.81 mmol) was added to the above solution at 0 oC. The reaction was warmed to 25 oC and stirred for 2 h under N2. TLC(petroleum ether : ethyl acetate = 10:1，Rf = 0.45, KMnO4) showed the starting material was consumed completely and one new spot formed. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 × 20mL). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-5% ethyl acetate in petroleum ether, gradient over 30 min). The eluent was concentrated under reduced pressure to give 1-bromo-3-(2-methoxyvinyl)benzene (2 g, 9.39 mmol, 86.83% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ = 7.93 (t, J = 1.6 Hz, 0.7H), 7.59 (d, J = 8.0 Hz, 0.7H), 7.55 - 7.48 (m, 1.7H), 7.44 - 7.39 (m, 1.7H), 7.32 - 7.28 (m, 2H), 7.20 (d, J = 12.8 Hz, 1H), 6.32 (d, J = 6.8 Hz, 0.7H), 5.89 (d, J = 13.2 Hz, 1H), 5.31 (d, J = 6.8 Hz, 0.7H), 3.96 (s, 2H), 3.85 (s, 3H) Step B.4-[3-(2-methoxyvinyl)phenyl]isoxazole and 1-bromo-3-(2-methoxyvinyl)benzene
Figure imgf000086_0001
[0237] To a stirred solution of 1-bromo-3-(2-methoxyvinyl)benzene (2 g, 9.39 mmol) in THF (20 mL) and Water (5 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (2.2 g, 11.26 mmol), K3PO4 (3.98 g, 18.77 mmol) and Catacxium A-Pd-G2 (627.62 mg, 0.94 mmol) at 15 oC. The mixture was degassed with N2 for 3 times. Then the reaction was warmed to 80 oC and stirred for 3 h under N2. LCMS showed ~33% of the starting material remained and ~40% peak with desired mass was detected. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 20 g silica, 0-10% ethyl acetate in petroleum ether, gradient over 30 min). The eluent was concentrated under reduced pressure to give 4-[3-(2-methoxyvinyl)phenyl]isoxazole (850 mg, 4.22 mmol, 45.01% yield) as a yellow oil. LCMS m/z 202.3 [M+H]+.1H NMR: (400 MHz, CDCl3) δ = 8.58 (d, J = 1.6 Hz, 1.2H), 8.47 (d, J = 1.2 Hz, 1.2H), 7.63 (s, 0.6H), 7.43 (d, J = 7.6 Hz, 0.6H), 7.25 - 7.21 (m, 2.2H), 7.19 - 7.11 (m, 3H), 7.02 (d, J = 13.2 Hz, 1H), 6.12 (d, J = 7.2 Hz, 0.6H), 5.75 (d, J = 13.2 Hz, 1H), 5.16 (d, J = 7.2 Hz, 0.6H), 3.74 (s, 2H), 3.63 (s, 3H). Step C.4-[3-(2-methoxyvinyl)phenyl]isoxazole
Figure imgf000087_0001
[0238] To a stirred solution of 1-bromo-3-(2-methoxyvinyl)benzene (780 mg, 3.66 mmol) in THF (20 mL) and Water (5 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (785.32 mg, 4.03 mmol), K3PO4 (2.33 g, 10.98 mmol) and Catacxium A-Pd-G2 (122.39 mg, 0.18 mmol) at 15 oC. The mixture was degassed with N2 for 3 times. Then the reaction was warmed to 80 oC and stirred for 3 h under N2. LCMS showed starting material was consumed completely and major peak with desired mass was detected. The mixture was cooled to room temperature 25 oC, then was diluted with water (5 mL) and extracted with ethyl acetate (3 × 3 mL). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 12 g silica, 0-10% ethyl acetate in petroleum ether, gradient over 30 min). The eluent was concentrated under reduced pressure to give 4-[3-(2- methoxyvinyl)phenyl]isoxazole (710 mg, 3.53 mmol, 96.39% yield) as a yellow oil. LCMS m/z 202.3 [M+H] +.1H NMR: (400 MHz, CHCl3) δ = 8.58 (d, J = 1.6 Hz, 2H), 8.47 (d, J = 1.6 Hz, 2H), 7.63 (s, 1H), 7.43 (d, J = 7.6 Hz, 1H), 7.26 - 7.20 (m, 3H), 7.19 - 7.11 (m, 4H), 7.02 (d, J = 13.6 Hz, 1H), 6.12 (d, J = 7.2 Hz, 1H), 5.75 (d, J = 12.8 Hz, 1H), 5.16 (d, J = 7.2 Hz, 1H), 3.74 (s, 3H), 3.63 (s, 3H). Step D.2-[3-(2-methoxyvinyl)phenyl]acetic acid
Figure imgf000087_0002
[0239] To a stirred solution of 4-[3-(2-methoxyvinyl)phenyl]isoxazole (710 mg, 3.53 mmol) in Methanol (10 mL) and Water (5 mL) was added NaOH (1.41 g, 35.28 mmol) at 25 oC. The mixture was degassed with N2 for 3 times. Then the reaction was heated to 100 oC and stirred for 12 h. TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.3) showed the starting material was consumed completely and one new spot formed. The reaction was cooled to 25 °C and added dilute hydrochloric acid solution to pH = 5 - 6, then aqueous phase was extracted with ethyl acetate (3 × 5 mL). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give 2-[3-(2- methoxyvinyl)phenyl]acetic acid (700 mg, 3.65 mmol, 103.21% yield) (crude) as a yellow oil. LCMS m/z 191.1 [M-H] - .1H NMR: (400 MHz, CDCl3) δ = 7.52 - 7.46 (m, 2H), 7.27 - 7.19 (m, 3H), 7.18 - 7.13 (m, 2H), 7.09 - 7.02 (m, 3H), 6.14 (d, J = 6.8 Hz, 1H), 5.79 (d, J = 12.8 Hz, 1H), 5.20 (d, J = 6.8 Hz, 1H), 3.78 (s, 3H), 3.68 (s, 3H), 3.62 (d, J = 6.8 Hz, 4H). Step E.2-[3-(2-oxoethyl)phenyl]acetic acid
Figure imgf000088_0001
[0240] To a stirred solution of 2-[3-(2-methoxyvinyl)phenyl]acetic acid (100 mg, 0.52 mmol) in MeCN (1.5 mL) was added HCl (0.08 mL, 0.98 mmol) at 0 oC. The mixture was degassed with N2 for 3 times. The mixture was stirred at 0 oC for 5 min. TLC (petroleum ether : ethyl acetate = 3:1, Rf = 0.2, KMnO4) showed the starting material was consumed completely and one new spot formed. The mixture was added into water (3 mL) and ethyl acetate (3 mL). The aqueous phase was extracted with ethyl acetate (3 mL × 3). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give 2-[3-(2-oxoethyl)phenyl]acetic acid (80 mg, 0.45 mmol, 86.29% yield) (crude) as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ = 9.75 (t, J = 2.4 Hz, 1H), 7.38 - 7.32 (m, 1H), 7.24 (br d, J = 8.0 Hz, 1H), 7.17 - 7.13 (m, 2H), 3.69 (d, J = 2.4 Hz, 2H), 3.66 (s, 2H). Step F.2-[3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]acetic acid
Figure imgf000089_0001
[0241] To a stirred solution of (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (30 mg, 0.13 mmol) in THF (3 mL) was acidified by acetic acid (0.06 mL, 1.05 mmol) until pH~5. NaBH(OAc)3 (53.14 mg, 0.25 mmol) and 2-[3-(2- oxoethyl)phenyl]acetic acid (33.51 mg, 0.19 mmol) were added to above mixture at 25 oC. The mixture was degassed with N2 for 3 times. Then the reaction was stirred at 25 oC for 0.5 h. LCMS showed starting material was consumed completely and ~25% peak with desired mass was detected. The mixture was added into water (3 ml) and DCM (3 ml). The aqueous phase was extracted with DCM (3 ml × 3). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep.-HPLC (Waters Xbridge BEH C18100 * 25 mm * 10 um column; 10%- 40% acetonitrile in a 10mM NH4HCO3 solution, 8 min gradient). After Prep.-HPLC purification, the eluent was lyophilized to give 2-[3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl]methyl]amino]ethyl]phenyl]acetic acid (20.3 mg, 0.05 mmol, 38.35% yield) as a white solid. LCMS m/z 402.2 [M+H] + 1H NMR: (400 MHz, CDCl3) δ = 7.78 (dd, J = 1.2, 4.8 Hz, 1H), 7.47 (s, 1H), 7.38 - 7.33 (m, 2H), 7.33 - 7.27 (m, 4H), 7.19 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.97 (dd, J = 4.8, 8.0 Hz, 1H), 6.78 (dd, J = 0.8, 8.0 Hz, 1H), 3.64 (q, J = 16.8 Hz, 2H), 3.31 (dd, J = 4.4, 16.8 Hz, 1H), 3.15 (d, J = 10.0 Hz, 1H), 2.86 - 2.78 (m, 1H), 2.77 - 2.69 (m, 3H), 2.68 - 2.62 (m, 1H), 2.62 - 2.53 (m, 1H), 2.52 - 2.43 (m, 1H), 2.21 - 2.10 (m, 1H). EXAMPLE 7 Preparation of Compounds 2-[3-[(1R)-1-methyl-2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl]methyl]amino]ethyl]phenyl]acetic acid (762A), and 2-[3-[(1S)-1- methyl-2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]acetic acid (762B).
Figure imgf000090_0001
Step A. tert-butyl N-[(1S)-3-[(2-methyl-3-pyridyl)amino]-3-oxo-1-phenyl-propyl]carbamate
Figure imgf000090_0002
[0242] To a stirred solution of (3S)-3-(tert-butoxycarbonylamino)-3-phenyl- propanoic acid (50 g, 188.46 mmol) in DCM (1000 mL) was added T4P (229.98 mL, 376.92 mmol) and TEA (52.29 mL, 376.92 mmol) at 0 oC, after being for 30 min, to a solution of 2- methylpyridin-3-amine (20.38 g, 188.46 mmol) in DCM (100 mL) was added to above solution, then the mixture was stirred at 25 oC for 12 h. LCMS showed starting material was consumed completely and main desired mass was detected. The mixture was adjusted with Sat. NaHCO3 to pH=7~8. Poured the mixture into the water (1.5 L), the white solid was precipitated, then filtered. The filter cake washed with water (100 ml × 3) and concentrated under reduced pressure to give a residue. The filtrate was extracted with DCM (3 × 150 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to get tert-butyl N-[(1S)-3-[(2-methyl- 3-pyridyl)amino]-3-oxo-1-phenyl-propyl]carbamate (75 g, 211.01 mmol, 111.96% yield) (crude) as a gray solid. LCMS m/z 356.3 [M+H] + 1H NMR: (400 MHz, CDCl3) δ = 8.24 (br s, 1H), 7.95 (br d, J = 7.8 Hz, 1H), 7.79 (br s, 1H), 7.39 - 7.28 (m, 4H), 7.10 (br dd, J = 4.0, 7.8 Hz, 1H), 5.93 (br s, 1H), 5.11 (br d, J = 2.2 Hz, 1H), 2.94 (br s, 2H), 2.43 (br s, 1H), 2.28 (br s, 3H), 1.49 - 1.30 (m, 9H) Step B. tert-butyl N-[(1S)-3-[(2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl-propyl]carbamate
Figure imgf000091_0001
[0243] A solution of SeO2 (117.07g, 1055.03mmol) in 1,4-Dioxane (5.7L) and heated to 80 oC to stirred for 20 min. Then the mixture was added tert-butyl N-[(1S)-3-[(2- methyl-3-pyridyl)amino]-3-oxo-1-phenyl-propyl]carbamate (75 g, 211.01 mmol). The reaction was warmed to 110 oC and stirred for 12 h. The reaction was divided for six batch (15 g × 3 + 10 g × 3). LCMS showed the starting material was consumed completely and the main peak with desired mass was detected. The reaction was filtered with a pad of Celite and washed with EtOAc (300 mL × 3). The filtrate was concentrated under reduced pressure. The mixture was poured to water (800 mL) and extracted with ethyl acetate (3 × 500 mL). The organic layer was washed with brine (500 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by Prep.-HPLC (column: Phenomenex luna C18250mm*100mm*15um; mobile phase: [A: H2O (0.2%FA); B: ACN]; B%: 35.00%- 65.00%,23.00 min) to get tert-butyl N-[(1S)-3-[(2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate (30 g, 81.21 mmol, 38.47% yield) as a yellow solid. LCMS m/z 761.4 [2M+Na] + 1H NMR: (400 MHz, CDCl3) δ = 10.80 (br s, 1H), 9.96 (s, 1H), 8.94 (br d, J = 8.6 Hz, 1H), 8.39 (d, J = 4.2 Hz, 1H), 7.39 (dd, J = 4.4, 8.6 Hz, 1H), 7.32 - 7.22 (m, 4H), 7.21 - 7.13 (m, 1H), 5.67 (br d, J = 80 Hz, 1H), 5.20 - 4.96 (m, 1H), 2.94 (br s, 2H), 1.33 (br s, 9H) Step C. tert-butyl N-[(R)-(2-hydroxy-1,5-naphthyridin-3-yl)-phenyl-methyl]carbamate
Figure imgf000092_0001
[0244] To a solution of tert-butyl N-[(1S)-3-[(2-formyl-3-pyridyl)amino]-3-oxo-1- phenyl-propyl]carbamate (30 g, 81.21 mmol) in DMF (300 mL) was added Cs2CO3 (52.92 g, 162.42 mmol) at 0 oC. Then the mixture was warmed to 60 oC and stirred for 2 h. LCMS showed the starting material was consumed completely and the main peak with desired mass was detected. The mixture was poured to water (200 mL) and ethyl acetate (150 mL), then the mixture was washed with water (3 × 150 mL). Filtered and the filter cake was concentrated under reduced pressure to get tert-butyl N-[(R)-(2-hydroxy-1,5-naphthyridin-3-yl)-phenyl- methyl]carbamate (20 g, 56.91 mmol, 70.08% yield) as a gray solid. LCMS m/z 352.2 [M+H] + 1H NMR: (400 MHz, DMSO-d6) δ = 12.01 (br s, 1H), 8.48 (br d, J = 3.8 Hz, 1H), 8.08 (s, 1H), 7.90 (br d, J = 9.0 Hz, 1H), 7.67 (br d, J = 8.2 Hz, 1H), 7.48 (dd, J = 4.4, 8.3 Hz, 1H), 7.40 - 7.27 (m, 4H), 7.26 - 7.17 (m, 1H), 6.02 (br d, J = 9.0 Hz, 1H), 1.39 (br s, 9H)
Step D. tert-butyl N-[(S)-(2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3-yl)-phenyl- methyl]carbamate
Figure imgf000093_0001
[0245] To a solution of tert-butyl N-[(R)-(2-hydroxy-1,5-naphthyridin-3-yl)- phenyl-methyl]carbamate (20 g, 56.91 mmol) in Methanol (2400 mL) and THF (2400 mL) was added NH3.H2O (5 mL, 129.83 mmol) and PtO2 (5 g, 22.02 mmol). The reaction was degassed with H2 for 5 times. The reaction was stirred at 80 oC for 24 h under 50 psi. The reaction was for 4 batches (5 g × 4). LCMS showed ~17% of the starting material was remained and the main peak with desired mass was detected. The reaction was filtered with a pad of celite and washed with MeOH (100 ml × 3). The filtrate was concentrated under reduced pressure to get tert-butyl N-[(S)-(2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3-yl)-phenyl-methyl]carbamate (18 g, 50.93 mmol, 89.49% yield) LCMS m/z 354.3 [M+H] + Step E. tert-butyl N-[(S)-phenyl-[(3S)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]carbamate/ tert-butyl N-[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]carbamate
Figure imgf000093_0002
[0246] To a solution of tert-butyl N-[(S)-(2-oxo-3,4-dihydro-1H-1,5-naphthyridin- 3-yl)-phenyl-methyl]carbamate (18 g, 50.93 mmol) in THF (150 mL). The reaction was cooled to 0 oC and added LiBH4 (127.33 mL, 254.65 mmol) (2 M in THF). After addition, the reaction was warmed to 25 oC and stirred for 12 h under N2. LCMS showed the starting material was consumed completely and the main peak with desired mass was detected. The mixture was poured Sat. NH4Cl (50 mL) and adjusted with 1M HCl to pH=4~5. The reaction was stirred at 70 oC for 12 h. The mixture was concentrated to remove solvents, then basified by sat.NaHCO3 until pH~8. The mixture was extracted with ethyl acetate (3 × 100 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue (crude product). The crude product was purified by flash column (ISCO 220 g silica, 0~10 % THF in DCM, gradient over 1.5h). Based on TLC (ethyl acetate, Rf = 0.22, 0.20). tert-butyl N-[(S)-phenyl-[(3S)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methyl]carbamate (3.5 g, 10.311 mmol, 19.44% yield) was obtained as a yellow solid. tert-butyl N-[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]carbamate (8 g, 23.57 mmol, 44.44% yield) (5g pure and 3g 45% purity) was obtained as a yellow solid. LCMS m/z 340.3 [M+H] + Step F. (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]methanamine
Figure imgf000094_0001
[0247] To a suspension of tert-butyl N-[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methyl]carbamate (5 g, 14.73 mmol) in Ethyl acetate (10 mL) was added HCl/EtOAc (4M, 50 mL, 100 mmol). The mixture was stirred at 25 oC for 1 h. LCMS showed starting material was consumed completely and main peak with desired mass was detected. The reaction was concentrated to dryness to give the crude. The crude was dissolved with water (20 mL), basified by sat.NaHCO3 until pH~8. The mixture was extracted with CHCl3: i-PrOH (3:1, 20 mL × 6). The organic layer was dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methanamine (3.5 g, 14.63 mmol, 99.29% yield) was obtained as a white solid. LCMS m/z 240.2 [M+H] + Step G.2-[3-[2-[[(S)-[(3S)-5-cyano-1, 2, 3, 4-tetrahydroquinolin-3-yl]-phenyl-methyl] amino] ethyl]-5-fluoro-phenyl] acetic acid
Figure imgf000095_0001
[0248] To a stirred solution of (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (2 g, 8.36 mmol) in DCM (60 mL) was added 2-[3-(1-methyl- 2-oxo-ethyl)phenyl]acetic acid (3.37 g, 17.55 mmol) and NaBH(OAc)3 (0.95 g, 25.07 mmol), the reaction mixture was degassed with N2 for three times, then the reaction was stirred at 15 °C for 2 h under N2. LCMS showed starting material was consumed completely and 27% + 32% peak with desired mass were detected. The mixture was poured into water (40 mL) and extracted with DCM (5 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep.-HPLC (Waters Xbridge BEH C18100 * 30 mm * 10 um; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 23.00%-53.00%, 8.00 min). The compound 2- [3-[(1R)-1-methyl-2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]acetic acid (337.3 mg, 0.79 mmol, 9.40 % yield) was obtained as a white solid. LCMS m/z 416.3 [M+H]+.1H NMR: (400 MHz, DMSO-d6) δ = 7.62 (dd, J = 1.2, 4.6 Hz, 1H), 7.34 - 7.28 (m, 2H), 7.26 - 7.17 (m, 4H), 7.08 - 7.03 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 6.86 (dd, J = 4.8, 8.0 Hz, 1H), 6.71 (dd, J = 6.8, 6.8 Hz, 1H), 5.69 (br s, 1H), 3.50 (s, 2H), 3.37 (d, J = 8.8 Hz, 1H), 3.06 (br dd, J = 3.6, 17.1 Hz, 1H), 2.81 - 2.73 (m, 1H), 2.70 - 2.58 (m, 4H), 2.44 (dd, J = 4.8, 11.6 Hz, 1H), 2.37 - 2.30 (m, 1H), 2.03 - 1.92 (m, 1H), 1.14 (d, J = 6.8 Hz, 3H). [0249] The compound 2-[3-[(1S)-1-methyl-2-[[(S)-phenyl-[(3R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl]methyl]amino]ethyl]phenyl]acetic acid (683.2 mg, 1.54 mmol, 18.45 % yield) was obtained as a white solid. LCMS m/z 416.2 [M+H]+ 1H NMR: (400 MHz, DMSO-d6) δ = 7.65 (d, J = 4.4 Hz, 1H), 7.40 - 7.32 (m, 4H), 7.28 - 7.19 (m, 2H), 7.12 - 7.01 (m, 3H), 6.89 (dd, J = 4.6, 8.0 Hz, 1H), 6.74 (d, J = 8.0 Hz, 1H), 5.75 (br s, 1H), 3.51 (s, 2H), 3.11 (d, J = 3.6 Hz, 1H), 3.09 (br dd, J = 3.8, 16.9 Hz, 1H), 2.86 - 2.75 (m, 1H), 2.72 - 2.57 (m, 3H), 2.43 - 2.32 (m, 2H), 2.07 - 1.96 (m, 1H), 1.18 (d, J = 7.0 Hz, 3H). Step AA.1-bromo-3-(2-methoxy-1-methyl-vinyl) benzene
Figure imgf000096_0001
[0250] To a stirred solution of methoxymethyl (triphenyl) phosphonium; chloride (62 g, 180.86 mmol) in THF (500 mL) was added t-BuOK (180.86 mL, 180.86 mmol) (1 M in THF) at 0 °C under N2. The mixture was stirred at 0 °C for 1 h, then a solution of 1-(3- bromophenyl) ethanone (18 g, 90.43 mmol) in THF (100 mL) was added to the above solution at 0 °C. The reaction was warmed to 25 °C and stirred for 2 h under N2. TLC (Petroleum ether: Ethyl acetate = 1: 0, KMnO4) showed the starting material was remained and one new spot formed. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 80 g silica, 0~3% ethyl acetate in petroleum ether, gradient over 60 min). The eluent was concentrated under reduced pressure to give 1-bromo-3-(2-methoxy-1-methyl- vinyl) benzene (21.1 g, 85.90 mmol, 94.99% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ = 7.78 (t, J = 1.8 Hz, 1H), 7.54 (d, J = 1.6 Hz, 1H), 7.44 (t, J = 1.8 Hz, 1H), 7.37 - 7.28 (m, 4H), 7.24 - 7.20 (m, 1H), 7.19 - 7.13 (m, 2H), 6.44 (s, 1H), 6.16 (d, J = 0.8 Hz, 1H), 3.74 (s, 3H), 3.71 (s, 2H), 1.96 (d, J = 1.2 Hz, 3H), 1.90 (d, J = 1.2 Hz, 2H). Step AB.4-[3-(2-methoxy-1-methyl-vinyl) phenyl] isoxazole
Figure imgf000097_0001
[0251] To a stirred solution of 1-bromo-3-(2-methoxy-1-methyl-vinyl)benzene (8 g, 35.23 mmol) in THF (400 mL) and Water (100 mL) were added 4-(4,4,5,5- tetramethyl- 1,3,2-dioxaborolan-2-yl) isoxazole (7.56 g, 38.75 mmol), K3PO4 (22.43 g, 105.68 mmol) and Catacxium A-Pd-G2 (2.36 g, 3.52 mmol). The mixture was degassed with N2 for 3 times. Then the reaction was warmed to 80 °C and stirred for 3 h under N2. TLC (petroleum ether: ethyl acetate= 10: 1) showed the starting material was remained and one new spot formed. The mixture was cooled to 25 °C, then was diluted with water (300 mL) and extracted with ethyl acetate (3 × 200 mL). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 80 g silica, 0~5% ethyl acetate in petroleum ether, gradient over 40 min). The eluent was concentrated under reduced pressure to give 4-[3-(2-methoxy-1-methyl- vinyl) phenyl] isoxazole (4.8 g, 20.52 mmol, 58.24 % yield) as a yellow oil. LCMS m/z 216.0 [M+H]+ Step AC.2-[3-[2-[[(S)-[(3S)-5-cyano-1, 2, 3, 4-tetrahydroquinolin-3-yl]-phenyl-methyl] amino] ethyl]-5-fluoro-phenyl] acetic acid
Figure imgf000097_0002
[0252] To a stirred solution of 4-[3-(2-methoxy-1-methyl-vinyl) phenyl] isoxazole (3 g, 13.94 mmol) in Methanol (20 mL) and Water (10 mL) was added NaOH (5.57 g, 139.37 mmol). The mixture was degassed with N2 for 3 times. Then the reaction was warmed to 100 °C and stirred for 12 h. TLC (Petroleum ether: ethyl acetate= 3: 1) showed the starting material was consumed completely and one new spot formed. The reaction was concentrated under reduced pressure to give a residue, then was acidified by HCl (1 M) until pH = 5~6. The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give 2- [3-(2-methoxy-1-methyl-vinyl)phenyl]acetic acid (4.3 g, 20.85 mmol, 149.6 % yield) (crude) as a yellow oil. LCMS m/z 224.1 [M+18]+ Step AD.2-[3-(1-methyl-2-oxo-ethyl) phenyl] acetic acid
Figure imgf000098_0001
[0253] To a stirred solution of 2-[3-[(E)-2-methoxy-1-methyl-vinyl] phenyl] acetic acid (4 g, 19.39 mmol) in DCM (30 mL) was added TFA (10 mL, 120 mmol), and the mixture was stirred at 15 °C for 0.5 h under N2 atmosphere. TLC (Petroleum ether: Ethyl acetate =1: 1, KMnO4) showed the starting material was consumed completely and a new spot formed. The reaction mixture was quenched by addition H2O (20 mL) at 0 °C, and then extracted with DCM (3 × 15 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product, the product goes directly to the next step. The compound of 2-[3-(1-methyl-2-oxo-ethyl) phenyl] acetic acid (3.5 g, 18.21 mmol, 93.89 % yield) was obtained as a yellow gum. [0254] 1H NMR: (400 MHz, DMSO-d6) δ = 9.64 (s, 1H), 7.38 - 7.30 (m, 1H), 7.21 (br d, J = 7.8 Hz, 1H), 7.17 - 7.12 (m, 2H), 3.79 (d, J = 7.2 Hz, 1H), 3.59 (s, 2H), 1.34 (d, J = 6.8 Hz, 3H)
EXAMPLE 8 Preparation of Compound 4-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]benzonitrile (744).
Figure imgf000099_0001
Step A.4-(2-oxoethyl)benzonitrile
Figure imgf000099_0002
[0255] To a stirred solution of 4-(2-methoxyvinyl)benzonitrile (130 mg, 0.82 mmol) in MeCN (1.5 mL) was added HCl (0.1 mL, 1.2 mmol) at 25 oC. The mixture was degassed with N2 for 3 times. The mixture was stirred at 25 oC for 30 min. TLC (petroleum ether: ethyl acetate = 3:1, Rf = 0.2, KMnO4) showed the starting material was consumed completely and one new spot formed. The mixture was added into water (5 mL) and ethyl acetate (5 mL). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give 4-(2-oxoethyl)benzonitrile (125 mg, 0.86 mmol, 105.45% yield) (crude) as a yellow oil. [0256] 1H NMR: (400 MHz, CDCl3) δ = 9.80 (t, J = 2.0 Hz, 1H), 7.68 (d, J = 1.6 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 3.82 (s, 2H). Step B.4-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]benzonitrile
Figure imgf000100_0001
[0257] To a srirred solution of hydrogen;(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine;hydrochloride (35 mg, 0.09 mmol) in Methanol (1.5 mL) was added TEA (0.02 mL, 0.12 mmol) until pH~9, and adjusted to pH = 5 with acetic acid (0.02 mL, 0.3 mmol) at 25 oC. 4-(2-oxoethyl)benzonitrile (19.82 mg, 0.14 mmol) and NaBH3CN (11.44 mg, 0.18 mmol) was added to above mixture, then the reaction stirred at 25 oC for 0.5 h. LCMS showed starting material was consumed completely and main peak with the desired mass was detected. The mixture was added into water (3 ml) and DCM (3 ml). The aqueous phase was extracted with DCM (3 ml × 3). The combined organic phase was dried with anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by Prep.-HPLC (Waters Xbridge BEH C18100 * 25 mm * 10 um, column: 30%~60% acetonitrile in a 10mm NH4HCO3 solution, 8 min gradient). After Prep.- HPLC purification, the eluent was lyophilized to give 4-[2-[[(S)-phenyl-[(3R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl]methyl]amino]ethyl]benzonitrile (22.1 mg, 0.06 mmol, 65.88% yield) as a pale yellow solid. LCMS m/z 369.2 [M+H] + [0258] 1H NMR: (400 MHz, CDCl3) δ = 7.89 (dd, J = 1.2, 4.8 Hz, 1H), 7.56 - 7.52 (m, 2H), 7.36 - 7.28 (m, 3H), 7.26 - 7.19 (m, 4H), 6.90 (dd, J = 4.8, 8.0 Hz, 1H), 6.71 (dd, J = 1.2, 8.0 Hz, 1H), 3.63 (br s, 1H), 3.51 (d, J = 8.4 Hz, 1H), 3.21 - 3.15 (m, 1H), 3.01 (br d, J = 10.8 Hz, 1H), 2.88 (dd, J = 9.2, 16.8 Hz, 1H), 2.81 - 2.73 (m, 3H), 2.73 - 2.66 (m, 2H), 2.27 - 2.15 (m, 1H). EXAMPLE 9 Preparation of Compounds (R)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid (2005A), and (S)-2-(3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid (2005B).
Figure imgf000101_0001
Step A. methyl 2-[3-[(E)-2-ethoxyvinyl]phenyl]propanoate [0259] To a stirred solution of methyl 2-(3-bromophenyl)propanoate (2 g, 8.23 mmol) in 1,4-Dioxane (20 mL) and Water (2 mL) was added 2-[(E)-2-ethoxyvinyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (2.12 g, 10.7 mmol), K2CO3 (3.4 g, 24.68 mmol) and Pd(dppf)Cl2 (601.98 mg, 0.82 mmol). The reaction was degassed and purged with N2 for 3 times, and stirred at 80 oC for 2 h under N2 atmosphere. LCMS showed starting material was consumed completely and main peak with desired mass was detected. The mixture was poured into water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash column (ISCO 40 g silica, 0 - 100% ethyl acetate in petroleum ether, gradient over 30 min). Based on TLC (Petroleum ether: Ethyl acetate = 1 : 1, Rf = 0.5). The compound methyl 2-[3-[(E)-2- ethoxyvinyl]phenyl]propanoate (1.6 g, 6.83 mmol, 83.00% yield). LCMS m/z 235.0 [M+H] + [0260] 1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.28 - 7.21 (m, 1H), 7.19 - 7.13 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 12.8 Hz, 1H), 5.86 (d, J = 13.2 Hz, 1H), 3.93 (q, J = 7.2 Hz, 2H), 3.71 (d, J = 7.2 Hz, 1H), 3.69 (s, 3H), 1.52 (d, J = 7.2 Hz, 3H), 1.37 (t, J = 7.2 Hz, 3H) Step B.2-[3-[(E)-2-ethoxyvinyl]phenyl]propanoic acid
Figure imgf000102_0001
[0261] To a stirred solution of methyl 2-[3-[(E)-2-ethoxyvinyl]phenyl]propanoate (500 mg, 2.13 mmol) in Methanol (2 mL) was added LiOH (256.09 mg, 10.67 mmol) in Water (0.2 mL). The reaction was stirred at 50 oC for 12 h. LCMS showed the starting material was consumed completely and desired product was detected. The reaction mixture was poured into water(3 mL).Then the mixture was adjusted pH ~ 5 by adding citric acid and extracted with Ethyl acetate(2 mL × 3).The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give 2-[3-[(E)-2-ethoxyvinyl]phenyl]propanoic acid (410 mg, 1.86 mmol, 87.22% yield). [0262] LCMS m/z 221.2 [M+H] + Step C.2-[3-(2-oxoethyl)phenyl]propanoic acid
Figure imgf000102_0002
[0263] To a stirred solution of 2-[3-(2-ethoxyvinyl)phenyl]propanoic acid (400 mg, 1.82 mmol) in MeCN (1 mL) was added HCl (0.3 mL, 3.63 mmol). The reaction was stirred at 25 oC for 2 h. TLC (Petroleum ether : Ethyl acetate = 3 : 1, Rf = 0.5) showed the starting material was consumed completely and new spot formed. The mixture was poured into water (5 mL) and extracted with ethyl acetate (3 × 4 mL). The combined organic layers were washed with brine (4 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The compound 2-[3-(2-oxoethyl)phenyl]propanoic acid (330 mg, 1.72 mmol, 94.54% yield) was obtained as a yellow oil. [0264] 1H NMR: (400 MHz, CHLOROFORM-d) δ = 9.67 (t, J = 2.4 Hz, 1H), 7.30 - 7.23 (m, 1H), 7.22 - 7.18 (m, 1H), 7.11 - 7.05 (m, 2H), 3.70 - 3.56 (m, 3H), 1.43 (d, J = 7.2 Hz, 3H) Step D. (R)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid and (S)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid
Figure imgf000103_0001
[0265] Compound was synthesized according to the general procedure. General procedure: [0266] To a solution of (S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methanamine in THF was added dropwise Acetic acid (0.1 eq) to adjust pH=5-6 and added 3-[3-(1-methyl-2-oxo-ethyl)phenyl]oxetane-3-carboxylic acid (1.2 eq), NaBH3CN (1.2 eq). The reaction was stirred at 25 oC for 1 h. LCMS showed the reaction was completed. The mixture was poured to water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude was purified by prep-HPLC to give the 2-(3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid. 2-(3-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid was further purified by SFC separation to give P1 of (R)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid (4.3 mg) as a white solid. LCMS m/z 416.2 [M+H] + [0267] 1H NMR: (400 MHz, DMSO-d6) δ = 7.61 (d, J = 3.6 Hz, 1H), 7.32 - 7.30 (m, 4H), 7.30 - 7.29 (m, 1H), 7.29 - 7.28 (m, 1H), 7.28 - 7.27 (m, 1H), 7.15 - 7.10 (m, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 4.4, 8.0 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 5.74 (s, 1H), 3.63 - 3.55 (m, 1H), 3.15 - 3.11 (m, 1H), 3.15 - 3.11 (m, 1H), 2.75 - 2.65 (m, 2H), 2.65 - 2.55 (m, 3H), 2.43 - 2.36 (m, 2H), 2.10 - 1.95 (m, 1H), 1.31 (d, J = 7.2 Hz, 3H) [0268] P2 of (S)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid (2.6 mg) as a white solid. LCMS m/z 416.2 [M+H] + [0269] 1H NMR: (400 MHz, DMSO-d6) δ = 7.65 (d, J = 3.6 Hz, 1H), 7.32 - 7.30 (m, 4H), 7.30 - 7.29 (m, 1H), 7.29 - 7.28 (m, 1H), 7.28 - 7.27 (m, 2H), 6.97 (d, J = 7.6 Hz, 1H), 6.88 (dd, J = 4.4, 8.0 Hz, 1H), 6.75 (d, J = 4.0 Hz, 1H), 5.73 (s, 1H), 3.63 - 3.55 (m, 1H), 3.15 - 3.11 (m, 1H), 3.15 - 3.11 (m, 1H), 2.75 - 2.65 (m, 2H), 2.65 - 2.55 (m, 3H), 2.50 - 2.45 (m, 2H), 1.91 - 1.90 (m, 1H), 1.31 (d, J = 7.2 Hz, 3H) EXAMPLE 10 Preparation of Compounds 3-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid (2006A), and 3-(3-((R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid (2006B)
Figure imgf000104_0001
Step A. methyl 3-(3-bromophenyl)oxetane-3-carboxylate
Figure imgf000105_0001
[0270] To a solution of 3-(3-bromophenyl)oxetane-3-carboxylic acid (2 g, 7.78 mmol) in Methanol (2 mL) and Toluene (18 mL) was added dropwise (Trimethylsilyl)diazomethane (5.83 mL, 11.67 mmol). The reaction mixture was stirred at 25 oC for 0.3 h. TLC (petroleum ether：ethyl acetate=3:1, Rf = 0.58) showed the starting material was consumed completely and one new spot formed. The mixture was poured water (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by flash column (ISCO 40 g silica, 0-10 % ethyl acetate in petroleum ether, gradient over 20 min) to get methyl 3-(3-bromophenyl)oxetane-3-carboxylate (1.7 g, 6.27 mmol, 80.60% yield) as a pale yellow oil.1H NMR: (400 MHz, CHLOROFORM- d) δ = 7.49 - 7.44 (m, 1H), 7.41 (t, J = 2.0 Hz, 1H), 7.27 - 7.24 (m, 1H), 7.20 - 7.16 (m, 1H), 5.24 (d, J = 6.4 Hz, 2H), 4.98 (d, J = 6.4 Hz, 2H), 3.77 (s, 3H) . Step B. methyl 3-(3-acetylphenyl)oxetane-3-carboxylate
Figure imgf000105_0002
[0271] To a stirred solution of methyl 3-(3-bromophenyl)oxetane-3-carboxylate (1.7 g, 6.27 mmol) in Toluene (30 mL) were added tributyl(1-ethoxyvinyl)stannane (3.18 mL, 9.41 mmol) and Pd(PPh3)2Cl2 (220.06 mg, 0.31 mmol) at 25 oC. The mixture was degassed with N2 for 3 times. Then the reaction was warmed to 100 oC and stirred for 12 h under N2. LCMS showed the starting material was consumed completely and the main peak with desired mass was detected. The reaction was cooled to room temperature and adjusted with TFA to pH = 4. The mixture was stirred at 25 oC for 3h. The mixture was quenched with Sat. KF (50 mL) and extracted with ethyl acetate (3 × 30 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by flash column (ISCO 20 g silica, 0-10 % ethyl acetate in petroleum ether, gradient over 20 min)（TLC petroleum ether : ethyl acetate=5:1, Rf = 0.52) to get methyl 3-(3-acetylphenyl)oxetane-3-carboxylate (460 mg, 1.96 mmol, 31.32% yield) as a colorless oil LCMS m/z 263.2 [M+H+28] + .1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.95 - 7.84 (m, 2H), 7.54 - 7.42 (m, 2H), 5.29 (d, J = 6.4 Hz, 2H), 5.04 (d, J = 6.0 Hz, 2H), 3.77 (s, 3H), 2.63 (s, 3H). Step C. methyl 3-(3-(1-methoxyprop-1-en-2-yl)phenyl)oxetane-3-carboxylate
Figure imgf000106_0001
[0272] To a solution of (methoxymethyl)triphenylphosphonium chloride (1346.32 mg, 3.93mmol) in THF (10 mL) was added t-BuOK (3.93 mL, 1M in THF, 3.93mmol) at 0 oC under N2. The mixture was stirred at 0 oC for 1h. A solution of methyl 3-(3- acetylphenyl)oxetane-3-carboxylate (460 mg, 1.96 mmol) in THF (1 mL) was added to previous mixture at 0 oC. The resulting mixture was stirred at 25 oC for 2 h. TLC (petroleum ether: ethyl acetate = 5 : 1, Rf = 0.45) showed the starting material was consumed completely and one new spot was detected. The mixture was poured into water (30 mL) and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column (ISCO 20 g silica, 0-10 % ethyl acetate in petroleum ether, gradient over 40 min). Compound methyl 3-(3-(1-methoxyprop-1-en-2- yl)phenyl)oxetane-3-carboxylate (360 mg, 1.37 mmol, 69.89% yield) was obtained as a colorless oil. 1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.57 - 7.47 (m, 1H), 7.36 - 7.27 (m, 1H), 7.27 - 7.13 (m, 1H), 7.10 - 7.04 (m, 1H), 6.45 - 6.12 (m, 1H), 5.26 (dd, J = 2.0, 6.4 Hz, 2H), 5.04 (dd, J = 1.6, 6.0 Hz, 2H), 3.78 - 3.68 (m, 6H), 2.01 - 1.91 (m, 3H). Step D.3-[3-[(E)-2-hydroxy-1-methyl-vinyl]phenyl]oxetane-3-carboxylic acid
Figure imgf000107_0001
[0273] To a solution of methyl 3-[3-[(E)-2-methoxy-1-methyl- vinyl]phenyl]oxetane-3-carboxylate (360 mg, 1.37 mmol) in Methanol (2 mL) and THF (2 mL) was added a solution of LiOH (164.34 mg, 6.86 mmol) in Water (2 mL). The reaction was stirred at 50 oC for 1 h. LCMS showed the starting material was consumed completely and the main peak with desired mass was detected. The reaction was added 1M citric acid to adjust pH = 4~5. The mixture was poured water (5 mL) and extracted with ethyl acetate (3 × 2 mL). The organic layer was washed with brine (2 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to get 3-[3-[(E)-2-hydroxy-1-methyl- vinyl]phenyl]oxetane-3-carboxylic acid (300 mg, 1.28 mmol, 93.31% yield) (crude) was obtained as a colorless oil. LCMS m/z 271.3 [M+Na] +. 1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.60 - 7.50 (m, 1H), 7.40 - 7.30 (m, 1H), 7.28 - 7.15 (m, 1H), 7.08 (t, J = 6.0 Hz, 1H), 6.45 - 6.14 (m, 1H), 5.30 (dd, J = 1.6, 6.0 Hz, 2H), 5.09 (d, J = 6.4 Hz, 2H), 3.78 - 3.68 (m, 3H), 2.03 - 1.92 (m, 3H). Step E.3-[3-(1-methyl-2-oxo-ethyl)phenyl]oxetane-3-carboxylic acid
Figure imgf000108_0001
[0274] To a solution of 3-[3-[(E)-2-methoxy-1-methyl-vinyl]phenyl]oxetane-3- carboxylic acid (300 mg, 1.21 mmol) in DCM (5mL) was added TFA (0.5mL, 6.73mmol). The reaction was stirred at 25 oC for 1 h. TLC (petroleum ether：ethyl acetate=1:1, Rf = 0.41, KMnO4) showed the starting material was consumed completely and one new spot was detected. The mixture was poured to water (5 mL) and extracted with dichloromethane (3 × 2 mL). The organic layer was washed with brine (2 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to get 3-[3-(1-methyl-2-oxo- ethyl)phenyl]oxetane-3-carboxylic acid (220 mg, 0.94 mmol, 77.73% yield) (crude) was obtained as a pale yellow gum.1H NMR: (400 MHz, CHLOROFORM-d) δ = 9.69 (s, 1H), 7.47 - 7.37 (m, 1H), 7.20 (br d, J = 7.2 Hz, 2H), 7.10 (s, 1H), 5.28 (d, J = 6.4 Hz, 2H), 5.05 (d, J = 6.4 Hz, 2H), 3.70 (q, J = 7.0 Hz, 1H), 1.46 (d, J = 7.2 Hz, 3H) Step F.3-(3-(1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid
Figure imgf000108_0002
[0275] Compound was synthesized according to the general procedure. [0276] General procedure: To a solution of (S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methanamine (1 eq) in MeOH was added dropwise Acetic acid (0.1 eq) to adjust pH=5-6 and added 3-[3-(1-methyl-2-oxo-ethyl)phenyl]oxetane-3-carboxylic acid (1.2 eq), NaBH3CN (1.2 eq). The reaction was stirred at 25 oC for 1 h. LCMS showed the reaction was complete. The mixture was poured to water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC(column: Waters Xbridge BEH C18 100*25mm*10um;mobile phase: [A: H2O(10mM NH4HCO3);B: ACN];B%: 10.00%-40.00%,8.00min;flow rate:25.00ml/min) to get 3-(3-(1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)oxetane-3- carboxylic acid (40 mg) as a white solid. LCMS m/z 458.4 [M+H] + Step G.3-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid and 3-(3-((R)-1-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)oxetane-3-carboxylic acid
Figure imgf000109_0001
[0277] 3-(3-(1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid (40 mg, 0.09 mmol) was purified by Prep-SFC (column: DAICEL CHIRALPAK IG (250mm*30mm,10um);mobile phase: [A: CO2;B: MeOH(0.1%NH3H2O)];B%: 50.00%-50.00%,10.00min;flow rate:70.00g/min) to give peak 1 3-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid (10.7 mg) as a white solid. [0278] LCMS m/z 458.3 [M+H] + [0279] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.80 (d, J = 4.4 Hz, 1H), 7.49 - 7.27 (m, 8H), 7.15 (br d, J = 7.2 Hz, 1H), 7.05 (dd, J = 5.2, 8.4 Hz, 1H), 6.87 (br d, J = 8.0 Hz, 1H), 5.38 (dd, J = 5.6, 19.6 Hz, 2H), 5.17 (d, J = 6.0 Hz, 1H), 4.96 (d, J = 5.6 Hz, 1H), 3.36 - 3.25 (m, 1H), 3.16 (br dd, J = 4.0, 16.8 Hz, 1H), 3.00 (br s, 1H), 2.72-2.70 (m, 3H), 2.56 - 2.49 (m, 2H), 2.19 - 2.03 (m, 1H), 1.21 (d, J = 6.8 Hz, 3H) [0280] The peak 2 3-(3-((R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid (15.5 mg) as a pale yellow solid. [0281] LCMS m/z 458.2 [M+H] + [0282] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.77 (dd, J = 0.8, 4.8 Hz, 1H), 7.44 - 7.27 (m, 6H), 7.23 (br d, J = 13.2 Hz, 2H), 7.17 (br d, J = 8.0 Hz, 1H), 7.02 (dd, J = 5.2, 8.0 Hz, 1H), 6.82 (dd, J = 0.8, 8.0 Hz, 1H), 5.40 (d, J = 6.0 Hz, 2H), 5.11 (t, J = 6.4 Hz, 2H), 3.03 (br dd, J = 4.0, 17.2 Hz, 1H), 2.93 (br d, J = 10.0 Hz, 1H), 2.81 (br s, 1H), 2.71 - 2.59 (m, 3H), 2.34 - 2.20 (m, 2H), 2.11 - 1.96 (m, 1H), 1.19 (d, J = 7.2 Hz, 3H) EXAMPLE 11 Preparation of Compound 2-[2-fluoro-5-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methyl]amino]ethyl]phenyl]acetic acid (2007).
Figure imgf000110_0001
Step A.2-[5-[(E)-2-ethoxyvinyl]-2-fluoro-phenyl]acetic acid
Figure imgf000110_0002
[0283] To a stirred solution of 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (2.21 g, 11.16 mmol) in Water (6 mL) and 1,4-Dioxane (30 mL) were added 2- (5-bromo-2-fluoro-phenyl)acetic acid (2 g, 8.58 mmol), Cs2CO3 (5.59 g, 17.16 mmol) and Pd(dppf)Cl2 (0.63 g, 0.86 mmol). The mixture was degassed with N2 for 3 times and stirred at 80 ℃ for 3 h. LCMS showed starting material was consumed completely and main desired mass was detected. The mixture was cooled to room temperature and poured into water (10 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layer was dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column (ISCO 20 g silica, 0-5 % ethyl acetate in petroleum ether, gradient over 40 min). The product 2-[5-[(E)-2-ethoxyvinyl]-2-fluoro-phenyl]acetic acid (1.3 g, 5.79 mmol, 67.55% yield) was obtained as a yellow oil. LCMS m/z 242.1 [M+H]+ Step B.2-[2-fluoro-5-(2-oxoethyl)phenyl]acetic acid
Figure imgf000111_0001
[0284] To a solution of 2-[5-[(E)-2-ethoxyvinyl]-2-fluoro-phenyl]acetic acid (100 mg, 0.45 mmol) in DCM (2 mL) was added TFA (0.2 mL, 2.64 mmol). The reaction was stirred at 25 ℃ for 2 h. TLC (petroleum ether: ethyl acetate = 1: 1, Rf = 0.42, KMnO4) showed the starting material was consumed completely and new spot was formed. The reaction mixture was concentrated to dryness to give the crude product and it was directly used for the next reaction. The compound 2-[2-fluoro-5-(2-oxoethyl)phenyl]acetic acid (60 mg, 0.31 mmol, 68.58% yield) was obtained as a yellow oil. Step C.2-[2-fluoro-5-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]acetic acid
Figure imgf000112_0001
[0285] To a stirred solution of (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (50 mg, 0.21 mmol) in THF (2 mL) were added AcOH (0.2 mL, 3.51 mmol), TEA (1 mL, 7.19 mmol), NaBH3CN (15.75 mg, 0.25 mmol) and 2-[2-fluoro- 5-(2-oxoethyl)phenyl]acetic acid (60 mg, 0.31 mmol). The reaction was stirred at 25 ℃ for 1 h under N2. LCMS showed starting material was consumed completely and 28% of desired mass was detected. The reaction was added to citric acid solution to pH = 5. The aqueous phase was extracted with DCM (2 mL × 3). The combined organic phase was dried with anhydrous Na2SO4, filtrated and concentrated in vacuum. The residue was purified by Prep-HPLC (column: Phenomenex Luna C18 75*30mm*3um;mobile phase: [A: H2O(0.1%TFA);B: ACN];B%: 20.00%-40.00%,8.00 min) to give 2-[2-fluoro-5-[2-[[(S)-phenyl-[(3R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl]methyl]amino]ethyl]phenyl]acetic acid (11.6 mg, 0.03 mmol, 13.11% yield) as a white solid. LCMS m/z 420.2 [M+H] + [0286] 1H NMR: (400 MHz, DMSO-d6) δ = 9.58 (s, 2H), 7.89 (d, J = 5.0 Hz, 1H), 7.90 - 7.50 (m, 5H), 7.49 - 7.27 (m, 1H), 7.08 (br d, J = 7.6 Hz, 1H), 7.10 - 7.02 (m, 3H), 4.38 (br d, J = 6.8 Hz, 1H), 3.54 (s, 1H), 3.11 (br d, J = 6.4 Hz, 2H), 2.97 - 2.86 (m, 4H), 2.83 - 2.78 (m, 2H), 2.77 - 2.50 (m, 2H) EXAMPLE 12 Preparation of Compounds (2R)-2-[4-fluoro-3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl]methyl]amino]ethyl]phenyl]propanoic acid (2008A), and (2S)-2-[4- fluoro-3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]propanoic acid (2008B).
Figure imgf000113_0001
Step A.2-(3-bromo-4-fluoro-phenyl) propanoic acid
Figure imgf000113_0002
[0287] To a stirred solution of 2-(3-bromo-4-fluoro-phenyl) acetic acid (2 g, 8.58 mmol) in THF (20 mL) was added NaHMDS (17.16 mL, 17.16 mmol) slowly at 0 oC. The reaction mixture was degassed with N2 for three times. Then the reaction was stirred at 0 oC for 0.5 h, then the CH3I (1.6 mL, 25.75 mmol) was dropwise slowly to the mixture at 0 oC, and the reaction mixture was stirred at 0 oC for 2 h. LCMS showed starting material was consumed completely and one main peak with desired mass was detected. The reaction was quenched with sat.aq NH4Cl (10 mL) at 0 oC and extracted with EtOAc (10 mL × 5). Then the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 2-(3-bromo-4-fluoro-phenyl)propanoic acid (2 g, 8.10 mmol, 94.33% yield) as a pale yellow solid. [0288] 1H NMR: (400 MHz, CHLOROFORM-d) δ = 7.55 (dd, J = 2.2, 6.6 Hz, 1H), 7.31 - 7.24 (m, 1H), 7.15 - 7.06 (m, 1H), 3.74 (q, J = 7.2 Hz, 1H), 1.54 (d, J = 7.2 Hz, 3H) Step B.2-[3-[(E)-2-ethoxyvinyl]-4-fluoro-phenyl] propanoic acid
Figure imgf000114_0001
[0289] To a stirred solution of 2-(3-bromo-4-fluoro-phenyl)propanoic acid (2 g, 8.1 mmol) in 1,4-Dioxane (20 mL) and Water (10 mL) were added 2-[(E)-2-ethoxyvinyl]-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (2.41 g, 12.14 mmol), K2CO3 (3356.27 mg, 24.29 mmol) and Pd(dppf)Cl2 (592.33 mg, 0.81 mmol). The reaction was degassed and purged with N2 for 3 times, and stirred at 80 oC for 12 h under N2 atmosphere. LCMS showed starting material was remained and one main peak with desired mass was detected. The reaction was cooled to 15 oC. Then the mixture was added into water (20 mL). The aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The crude product was purified by flash column (ISCO 20 g silica, 0 - 50% ethyl acetate in petroleum ether, gradient over 20 min). TLC (petroleum ether: ethyl acetate = 3 : 1, Rf = 0.5). Compound 2-[3-[(E)-2-ethoxyvinyl]-4-fluoro-phenyl] propanoic acid (1.7 g, 7.14 mmol, 88.14% yield) was obtained as a yellow oil. Step C.2-[4-fluoro-3-(2-oxoethyl) phenyl] propanoic acid
Figure imgf000114_0002
[0290] To a stirred solution of 2-[3-[(E)-2-ethoxyvinyl]-4-fluoro-phenyl] propanoic acid (350 mg, 1.47 mmol) in MeCN (3 mL) was added HCl (0.24 mL, 2.94 mmol, 12 M). The reaction was stirred at 25 oC for 2 h. TLC (Petroleum ether: Ethyl acetate = 3:1, Rf = 0.5) showed the starting material was consumed completely and new spot formed. The mixture was poured into water (5 mL) and extracted with ethyl acetate (3 × 4 mL). The combined organic layers were washed with brine (4 mL), dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a residue. The compound 2-[4-fluoro- 3-(2-oxoethyl) phenyl]propanoic acid (300 mg, 1.43 mmol, 97.16% yield) was obtained as a yellow oil. Step D.2-[4-fluoro-3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]propanoic acid
Figure imgf000115_0001
[0291] To a stirred solution of (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (100 mg, 0.42 mmol) in THF (1 mL) was added TEA (0.5 mL, 3.56 mmol) and AcOH (0.1 mL, 1.25 mmol). The NaBH3CN (77.72 mg, 1.25 mmol) was added to the above solution. The reaction was stirred at 25 oC for 1 h under N2. LCMS showed starting material was consumed completely and 26% peak with desired mass was detected. The reaction mixture was adjusted by 1 M HCl to pH = 5 at 0 oC. The mixture was diluted with water (3 mL) and extracted with ethyl acetate (3 × 2 mL). The organic layer was washed with brine (2 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (3_Phenomenex Luna C1875 * 30 mm * 3 um; 5-40 % acetonitrile in a 0.1% trifluoroacetic acid solution in water, 15 min gradient). The compound was lyophilized to give 2-[4-fluoro-3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methyl]amino]ethyl]phenyl]propanoic acid (40 mg, 0.09 mmol, 22.08% yield) as a white solid. LCMS m/z 434.3 [M+H] + Step E. (2R)-2-[4-fluoro-3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]propanoic acid and (2S)-2-[4-fluoro-3-[2-[[(S)-phenyl- [(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]methyl]amino]ethyl]phenyl]propanoic acid
Figure imgf000115_0002
[0292] The 2-[4-fluoro-3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methyl]amino]ethyl]phenyl]propanoic acid (40 mg, 0.09 mmol) was separated by prep-SFC (column: (s,s) WHELK-O1 (250 mm * 30 mm, 5 um);mobile phase: [A: Heptane;B: EtOH(0.1% NH3H2O)];B%: 25.00%-25.00%,10.00min) to give P1 (peak 1) of (2R)-2-[4-fluoro-3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]propanoic acid (5.8 mg, 0.01 mmol, 14.35% yield) as a white solid. LCMS m/z 434.2 [M+H]+ [0293] 1H NMR (400 MHz, DMSO-d6) δ = 7.64 (br d, J = 4.4 Hz, 1H), 7.45 - 7.18 (m, 6H), 7.17 - 7.11 (m, 1H), 7.08 - 7.01 (m, 1H), 6.92 (dd, J = 4.8, 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 5.80 (br s, 1H), 3.57 (q, J = 7.2 Hz, 1H), 3.21 (br d, J = 3.6 Hz, 1H), 3.17 (br d, J = 2.8 Hz, 1H), 2.81 - 2.54 (m, 6H), 2.43 - 2.25 (m, 1H), 2.12 - 1.90 (m, 1H), 1.32 (d, J = 7.2 Hz, 3H) [0294] P2 (peak 2) of (2S)-2-[4-fluoro-3-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl]methyl]amino]ethyl]phenyl]propanoic acid (5.5 mg, 0.01 mmol, 13.47% yield) as a pale white solid. LCMS m/z 434.2 [M+H] + [0295] 1H NMR (400 MHz, DMSO-d6) δ = 7.70 (br d, J = 4.0 Hz, 1H), 7.51 - 7.29 (m, 5H), 7.27 (br d, J = 6.8 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.14 - 7.07 (m, 1H), 6.98 (dd, J = 4.8, 8.0 Hz, 1H), 6.86 - 6.80 (m, 1H), 5.86 (br s, 1H), 3.71 (q, J = 6.8 Hz, 1H), 3.27 (br d, J = 4.0 Hz, 1H), 3.22 (br d, J = 3.6 Hz, 1H), 2.84 - 2.66 (m, 5H), 2.65 - 2.58 (m, 2H), 2.25 - 1.96 (m, 1H), 1.38 (d, J = 7.2 Hz, 3H)
EXAMPLE 13 Preparation of Compound 2-(4-methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid, formic acid (2009).
Figure imgf000117_0001
Step A 4-bromo-2-(2-methoxyethenyl)-1-methylbenzene
Figure imgf000117_0002
[0296] To a solution of (methoxymethyl)triphenylphosphanium chloride (5.16 g, 15.07 mmol, 1.5 equiv.) and t-BuOK (1.69 g, 15.07 mL, 1 M, 15.07 mmol, 1.5 equiv.) in THF (30 mL, 0.33 M, 15 Vols), the reaction mixture was stirred at 0 °C for 0.5 h under N2, 5-bromo- 2-methylbenzaldehyde (2 g, 10.04 mmol, 1 equiv.) were added to the mixture, and the reaction mixture was stirred at 20 °C for 11.5 h under N2 atmosphere. TLC showed Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~2% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound 4-bromo-2-(2-methoxyethenyl)-1-methylbenzene (1.9 g, 8.11 mmol, Yield 80.76%) was obtained as a white solid. [0297] 1H NMR: (400 MHz, DMSO-d6) δ = 8.01 - 7.90 (m, 1H), 7.61 - 7.49 (m, 1H), 7.24 - 7.13 (m, 2H), 7.12 - 7.03 (m, 1H), 6.45 - 6.39 (m, 1H), 5.90 - 5.77 (m, 1H), 5.24 (d, J = 7.1 Hz, 1H), 3.80 - 3.73 (m, 1H), 3.70 - 3.61 (m, 2H), 2.25 - 2.16 (m, 3H). [0298] LCMS m/z 227.1 [M+H]+ Step B 4-[3-(2-methoxyethenyl)-4-methylphenyl]-1,2-oxazole
Figure imgf000118_0001
[0299] To a solution of 4-bromo-2-(2-methoxyethenyl)-1-methylbenzene (1.8 g, 7.92 mmol, 1 equiv.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (1.7 g, 8.71 mmol, 1.1 equiv.) in THF (20 mL, 0.40 M, 11.11 Vols) H2O (5 mL, 1.58 M, 2.77 Vols) were added K3PO4 (5.04 g, 23.77 mmol, 3 equiv.) and Catacxium A-Pd-G2 (0.26 g, 0.39 mmol, 0.05 equiv.), and the reaction mixture was stirred at 80 °C for 2 h under N2. TLC showed Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 80 mL/min). Compound 4-[3-(2-methoxyethenyl)-4- methylphenyl]-1,2-oxazole (1.3 g, 5.73 mmol, Yield 72.38%) was obtained as a white solid. LCMS m/z 216.1 [M+H]+ Step C [3-(2-methoxyethenyl)-4-methylphenyl]acetic acid
Figure imgf000118_0002
[0300] To a solution of 4-[3-(2-methoxyethenyl)-4-methylphenyl]-1,2-oxazole (400 mg, 1.85 mmol, 1 equiv.) in MeOH (2 mL, 0.92 M, 5 Vols) and H2O (0.5 mL, 3.71 M, 1.25 Vols) was added NaOH (0.22 g, 5.575 mmol, 3 equiv.), and the reaction mixture was stirred at 100 °C for 12 h under N2 atmosphere. LCMS showed Reactant 1 was consumed completely and desired mass was detected. The reaction mixture was adjusted to pH= 5 by HCl (1 M, in H2O). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated give a residue. Compound [3-(2-methoxyethenyl)-4-methylphenyl]acetic acid (300 mg, 1.29 mmol, Yield 69.66%) was obtained as a white solid. LCMS m/z 205.0 [M-H]- Step D. [4-methyl-3-(2-oxoethyl)phenyl]acetic acid
Figure imgf000119_0001
[0301] To a solution of [3-(2-methoxyethenyl)-4-methylphenyl]acetic acid (300 mg, 1.29 mmol, 1 equiv.) in MeCN (2 mL, 0.64 M, 6.66 Vols) were added HCl (0.044 g, 0.1 mL, 12 M, 1.2 mmol, 0.93 equiv.), and the reaction mixture was stirred at 0 °C for 0.5 h under N2. TLC indicated Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated to give a residue. Compound [4-methyl-3-(2- oxoethyl)phenyl]acetic acid (220 mg, 1.145 mmol, Yield 88.41%) was obtained as a white solid. [0302] Note: The residue was used to the next step directly.
Step D.2-(4-methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid
Figure imgf000120_0001
[0303] This step was synthesized according to the synthetic general procedure. General procedure: [0304] To a solution of (S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methanamine (1 eq) in MeOH was added dropwise Acetic acid (0.1 eq) to adjust pH=5-6 and added 2-(4-methyl-3-(2-oxoethyl)phenyl)acetic acid (1.2 eq), NaBH3CN (1.2 eq). The reaction was stirred at 20 oC for 1 h. LCMS showed the reaction was completed. The mixture was poured to water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (FA condition)(column: Phenomenex luna C18 100*40mm*3 um; mobile phase: [A: H2O(0.2% FA); B: ACN]; B%: 5.00%-35.00%,8.00min; flow rate: 50.00 ml/min) to get 2-(4-methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid, formic acid (38.6 mg) was obtained as a white solid. LCMS m/z 416.2 [M+H]+ [0305] 1H NMR: (400 MHz, DMSO-d6) δ = 8.15 (s, 1H), 7.65 (dd, J = 1.3, 4.6 Hz, 1H), 7.41 - 7.30 (m, 4H), 7.30 - 7.23 (m, 1H), 7.05 - 6.91 (m, 3H), 6.88 (dd, J = 4.6, 8.0 Hz, 1H), 6.74 (dd, J = 1.4, 8.2 Hz, 1H), 5.74 (br s, 1H), 3.50 (br d, J = 8.6 Hz, 1H), 3.44 (s, 2H), 3.16 (br dd, J = 3.4, 16.8 Hz, 1H), 2.81 - 2.54 (m, 5H), 2.48 - 2.36 (m, 2H), 2.12 (s, 3H), 2.08 - 2.02 (m, 1H). EXAMPLE 14 Preparation of Compound [4-methoxy-3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl]amino}ethyl)phenyl]acetic acid; trifluoroacetic acid (2010). Step A. {3-[(1E)-2-ethoxyethenyl]-4-methoxyphenyl}acetic acid
Figure imgf000121_0001
[0306] A solution of (3-bromo-4-methoxyphenyl)acetic acid (2 g, 8.16 mmol, 1 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.94 g, 9.79 mmol, 1.2 equiv.), K2CO3 (3.38 g, 24.48 mmol, 3 equiv.), Pd(dppf)Cl2 (5.97 g, 8.16 mmol, 1 equiv.) in Dioxane (50 mL, 0.16 M, 25 Vols) and H2O (5 mL, 1.63 M, 2.5 Vols) was stirred at 80 oC for 12 h under N2. TLC (Petroleum ether/EtOAc = 3/1, Rf = 0.6) indicated reactant 1 was consumed completely and one major new spot formed. The reaction mixture was filtered and the filtrate was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine (50 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~8% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound {3-[(1E)-2- ethoxyethenyl]-4-methoxyphenyl}acetic acid (1.3 g, 4.57 mmol, yield 55.96%) was obtained as a pale yellow oil. LCMS m/z 237.0 [M+H]+ Step B. [4-methoxy-3-(2-oxoethyl)phenyl]acetic acid [0307] A solution of {3-[(1E)-2-ethoxyethenyl]-4-methoxyphenyl}acetic acid (130 mg, 0.55 mmol, 1 equiv.) in MeCN (2 mL, 0.28 M, 15.39 Vols) was added HCl (0.09 g, 0.2 mL, 12 M, 2.4 mmol, 4.36 equiv.) at 0 oC, the mixture was stirred at 0 oC for 0.5 h. TLC (Petroleum ether/EtOAc = 3/1, Rf = 0.1) indicated reactant 1 was consumed completely and one major new spot formed. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (2 mL × 3). The organic phase was separated, washed with brine (5 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound [4-methoxy-3-(2-oxoethyl)phenyl]acetic acid (100 mg, 0.48 mmol, yield 87.29%) was obtained as a colourless oil. Step C. [4-methoxy-3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)phenyl]acetic acid; trifluoroacetic acid
Figure imgf000122_0001
[0308] A solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methanamine (35 mg, 0.15 mmol, 1 equiv.) in MeOH (1.5 mL, 0.1 M, 42.86 Vols) was added AcOH (17.57 mg, 0.29 mmol, 2 equiv.) adjusted pH to 4~5, then added [4-methoxy-3- (2-oxoethyl)phenyl]acetic acid (45.68 mg, 0.22 mmol, 1.5 equiv.) and NaBH3CN (18.38 mg, 0.29 mmol, 2 equiv.), the mixture was stirred at 25 oC for 0.5 h. [0309] LC-MS showed the reactant was consumed completely and desired mass was detected. [0310] The residue was purified by Prep.-HPLC (TFA condition, column: Phenomenex Luna C1875*30mm*3um; mobile phase: [A: H2O(0.1%TFA); B: ACN]; B%: 5.00%-35.00%, 8.00min). Compound [4-methoxy-3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl)methyl]amino}ethyl)phenyl]acetic acid; trifluoroacetic acid (29.9 mg, 0.06 mmol, yield 37.48%) was obtained as a yellow solid. LCMS m/z 432.2 [M+H]+ [0311] 1H NMR: (400 MHz, DMSO-d6) δ = 12.50 - 11.80 (m, 1H), 9.61 - 9.17 (m, 2H), 7.91 (br d, J = 4.6 Hz, 1H), 7.54 - 7.44 (m, 5H), 7.41 - 7.20 (m, 2H), 7.09 (dd, J = 2.0, 8.4 Hz, 1H), 6.92 (d, J = 2.0 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.41 (br s, 1H), 3.64 (s, 3H), 3.43 (s, 2H), 3.36 (br d, J = 16.8 Hz, 1H), 3.08 (br d, J = 9.8 Hz, 1H), 3.02 - 2.91 (m, 2H), 2.88 - 2.62 (m, 5H) EXAMPLE 15 Preparation of Compound 2-(2-methoxy-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid (2011).
Figure imgf000123_0001
Step A.2-[5-[(E)-2-ethoxyvinyl]-2-methoxy-phenyl] acetic acid
Figure imgf000124_0002
[0312] A mixture of 2-(5-bromo-2-methoxy-phenyl) acetic acid (2.5 g, 10.2 mmol), 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.4 g, 12.24 mmol), K2CO3 (4.2 g, 30.6 mmol) and Pd(dppf)Cl2 (746.42 mg, 1.02 mmol) in 1,4-Dioxane (50 mL) and water (5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 oC for 12 h under N2 atmosphere. LC-MS showed the reactant was consumed completely and desired mass was detected. The reaction was successful. The mixture was acidified pH to 5 with aqueous solution of hydrochloric acid (1mol/L). The mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The organic phase was separated, washed with brine (30 mL). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 40 g SepaFlash@ Silica Flash Column, Eluent of 10~15% Ethyl acetate/Petroleum ether gradient @ 80 mL/min). Compound 2-[5-[(E)-2-ethoxyvinyl]-2- methoxy-phenyl] acetic acid (1.5 g, 5.71 mmol, 56.01% yield) was obtained as white solid. LCMS m/z 235.0 [M-H]- Step B.2-(2-methoxy-5-(2-oxoethyl) phenyl) acetic acid
Figure imgf000124_0001
[ ] o a so ut on o -[ -[( )- -et oxyv ny ]- -met oxy-p eny ] acet c ac (100 mg, 0.42 mmol, 1 equiv.) in CH3CN (2 mL, 0.21 M, 20 Vols) at 0 °C was added HCl (0.1 mL, 0.42 mmol, 1 equiv.). The mixture was stirred at 0 °C for 0.5 h. TLC (Petroleum ether / Ethyl acetate = 2/1, Rf = 0.3) indicated reactant was consumed completely and one new spot formed. The reaction was successful. The mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL × 3). The organic phase was separated, washed with brine (2 mL × 1). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. Compound 2-(2-methoxy-5-(2-oxoethyl) phenyl) acetic acid (70 mg, 0.30 mmol, yield 71.49%) was obtained as a yellow oil. Step C.2-(2-methoxy-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid
Figure imgf000125_0001
[0314] To a solution of (S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methanamine (40 mg, 0.17 mmol, 1 equiv.) in MeOH (1 mL, 0.16 M, 25 Vols) was added AcOH (0.03 g, 0.50 mmol, 3 equiv.), 2-(2-methoxy-5-(2-oxoethyl) phenyl) acetic acid (0.04 g, 0.17 mmol, 1 equiv.) and NaBH3CN (0.03 g, 0.50 mmol, 3 equiv.). The mixture was stirred at 20 °C for 1 h. LC-MS showed the reactant was remained and desired mass was detected. The reaction was successful. The reaction mixture was quenched by addition H2O (1 mL) at 0 °C and the mixture was filtered and the filtrate was purified by Prep.-HPLC (column: Phenomenex Luna C18150*30mm*5um; mobile phase: [water (0.1%TFA)-ACN]; B%: 10% - 50%, 8 min). Compound 2-(2-methoxy-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid (55.3 mg, 0.13 mmol, yield 75.12%) was obtained as a white solid.(TFA salt) LCMS m/z 432.2 [M+H]+ [0315] 1H NMR: (400 MHz, DMSO-d6) δ = 12.44 - 11.88 (m, 1H), 9.60 - 9.26 (m, 1H), 7.92 (d, J = 5.0 Hz, 1H), 7.58 - 7.44 (m, 5H), 7.43 - 7.21 (m, 2H), 6.97 - 6.92 (m, 1H), 6.91 - 6.84 (m, 2H), 4.41 (br s, 1H), 3.70 (s, 3H), 3.42 (s, 2H), 3.36 (br d, J = 17.6 Hz, 1H), 3.09 (br d, J = 9.8 Hz, 1H), 3.04 - 2.85 (m, 3H), 2.83 - 2.64 (m, 4H) EXAMPLE 16 Preparation of Compound 2-(2-methyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid (2012).
Figure imgf000126_0001
Step A.2-[5-[(E)-2-ethoxyvinyl]-2-methyl-phenyl] acetic acid [0316] To a stirred solution of 2-(5-bromo-2-methyl-phenyl)acetic acid (1000.mg, 4.37 mmol) in 1,4-Dioxane (10 mL) and Water (2 mL) were added 2-[(E)-2-ethoxyvinyl]- 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1297.01 mg, 6.55 mmol), K2CO3 (1810.06 mg, 13.1 mmol) and Pd(dppf)Cl2 (638.86 mg, 0.87 mmol). The suspension was degassed and purged with N2 for 3 times. The reaction was stirred at 80 oC for 5 h. LC-MS showed reactant 1 was consumed completely and desired mass was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The mixture was adjusted to pH = 5 with 1 M HCl aqueous solution. The residue was diluted with H2O (50 mL × 1) and extracted with EtOAc (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash@ Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound 2-[5-[(E)-2- ethoxyvinyl]-2-methyl-phenyl] acetic acid (620 mg, 2.53 mmol, 58.02% yield) was obtained as a brown oil. LCMS m/z 219.3 [M-H]- Step B.2-[2-methyl-5-(2-oxoethyl) phenyl] acetic acid
Figure imgf000127_0001
[0317] To a stirred solution of 2-[5-[(E)-2-ethoxyvinyl]-2-methyl-phenyl] acetic acid (130 mg, 0.59 mmol) in CH3CN (2 mL) was added HCl (0.15 mL, 1.8 mmol) at 0 oC. The reaction was stirred at 0 oC for 5 mins. TLC (Petroleum ether/Ethyl acetate = 3/1, Rf = 0.3) indicated reactant was consumed completely and one new spot formed. The residue was diluted with H2O (2 mL) and extracted with EtOAc (2 mL × 2). The organic phase was separated, washed with brine (1 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 2-[2-methyl-5-(2-oxoethyl) phenyl] acetic acid (90 mg, 0.46 mmol, 79.33% yield) was obtained as a white oil. Step C.2-(2-methyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid
Figure imgf000127_0002
[0318] To a solution of (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methanamine (35 mg, 0.15 mmol) in Methanol (1 mL) was added AcOH (17.55 mg, 0.29 mmol) to adjusted pH = 5. Then 2-[2-methyl-5-(2-oxoethyl) phenyl] acetic acid (56.22 mg, 0.29 mmol) was added into the reaction. Then NaBH4CN (18.43 mg, 0.29 mmol) was added into the mixture, the mixture was stirred at 20 oC for 10 mins. LC-MS showed the reactant was consumed and desired mass was formed. The reaction mixture was concentrated under reduced pressure to get a residue, and the reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (TFA condition, column: Phenomenex Luna C1875*30mm*3um; mobile phase: [A: H2O (0.1% TFA); B: ACN]; B%: 5.00%-35.00%, 8.00 min). Compound 2-(2-methyl-5- (2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid (35.4 mg, 0.08 mmol, 58.25% yield) was obtained as a white solid(TFA salt). LCMS m/z 416.2 [M+H]+ [0319] 1H NMR: (400 MHz, DMSO-d6) δ = 12.50 - 12.11 (m, 1H), 9.68 - 9.21 (m, 2H), 7.91 (br s, 1H), 7.57 - 7.43 (m, 5H), 7.42 - 7.20 (m, 2H), 7.06 (d, J = 7.8 Hz, 1H), 6.93 - 6.84 (m, 2H), 4.40 (br s, 1H), 3.51 (s, 2H), 3.41 - 3.30 (m, 1H), 3.09 (br d, J = 2.8 Hz, 1H), 3.04 - 2.87 (m, 3H), 2.85 - 2.64 (m, 4H), 2.16 (s, 3H). EXAMPLE 17 Preparation of Compound 2-(2,4-dimethyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid (2013).
Figure imgf000128_0001
Step A 1-bromo-5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-benzene
Figure imgf000128_0002
[0320] A solution of 1,5-dibromo-2,4-dimethyl-benzene (5.0 g, 18.94 mmol), 2- [(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.41 mL, 20.84 mmol) , K2CO3 (5.23g, 37.88 mmol), Pd(dppf)Cl2 (693 mg, 0.95mmol) in 1,4-Dioxane (100 mL) and Water (10mL) was stirred at 80 oC for 12 h. TLC indicated reactant was consumed completely and two new spots formed. The reaction mixture was filtered and the filtrate was dried in vacuum to give a residue. The residue was extracted with EtOAc (50 mL × 3) and H2O (50 mL). The organic phase was separated, washed with brine (100 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to get a residue, and the residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) Compound 1-bromo-5-[(E)-2-ethoxyvinyl]- 2,4-dimethyl-benzene (2.4 g, 8.47 mmol, 44.69% yield) was obtained as a pale-yellow oil. [0321] 1H NMR: (400 MHz, CDCl3) δ = 7.43 (s, 1H), 7.00 (s, 1H), 6.79 (d, J = 12.8 Hz, 1 H), 5.86 (d, J = 12.8 Hz, 1H), 3.92 (q, J = 7.2 Hz, 2 H), 2.21 (s, 3H), 2.33 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H), Step B 4-[5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-phenyl]isoxazole
Figure imgf000129_0001
[0322] A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (917.2 mg, 4.7mmol), 1-bromo-5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-benzene (1.0 g, 3.92mmol) , Catacxium A-Pd-G2 (262.05mg, 0.39mmol), K3PO4 (1.66g, 7.84mmol) in Water (2 mL) and THF (15 mL) was stirred at 80 oC for 4 h. TLC indicated reactant 1 was consumed completely and one major new spot formed. The residue was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound 4-[5-[(E)-2-ethoxyvinyl]-2,4- dimethyl-phenyl]isoxazole (900 mg, 3.33 mmol, 84.94% yield) was obtained as a white solid. Step C 2-[5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-phenyl]acetic acid
Figure imgf000130_0001
[0323] A solution of 4-[5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-phenyl]isoxazole (300 mg, 1.23mmol), NaOH (493.2mg, 12.33mmol) in Methanol (5mL) and Water (2.5mL) was stirred at 100 oC for 12 h. TLC indicated reactant 1 was consumed completely and one new spot formed. The mixture acidified pH to 3 with aqueous solution of hydrochloric acid (1mol/L). The reaction mixture was extracted with EtOAc (5 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give 2-[5-[(E)-2-ethoxyvinyl]-2,4-dimethyl- phenyl]acetic acid (200 mg, 0.85 mmol, 69.23% yield) as a pale yellow oil. Step D.2-[2,4-dimethyl-5-(2-oxoethyl)phenyl]acetic acid
Figure imgf000130_0002
[0324] A solution of 2-[5-[(E)-2-ethoxyvinyl]-2,4-dimethyl-phenyl]acetic acid (200 mg, 0.85 mmol), HCl (0.3 mL, 3.6 mmol) in CH3CN (3 mL) was stirred at 0 oC for 0.5 h. TLC indicated reactant 1 was consumed completely and one new spot formed. The reaction mixture was extracted with EtOAc (5 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give 2-[2,4-dimethyl-5-(2-oxoethyl)phenyl]acetic acid (150 mg, 0.73 mmol, 85.2% yield) as a pale yellow solid. Step E.2-(2,4-dimethyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid
Figure imgf000131_0001
[0325] This step was synthesized according to the synthetic general procedure. General procedure: [0326] To a solution of (S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methanamine (1 eq) in MeOH was added dropwise Acetic acid (0.1 eq) to adjust pH=5-6 and added 2-(2,4-dimethyl-5-(2-oxoethyl)phenyl)acetic acid (1.2 eq), NaBH3CN (1.2 eq). The reaction was stirred at 25 oC for 1 h. LCMS showed the reaction was complete. The mixture was poured to water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (neutral condition) (column: Waters Xbridge BEH C18100*30 mm*10 um; mobile phase: [A: H2O(10 mM NH4HCO3); B: ACN]; B%: 10.00%- 55.00%,8.00 min; flow rate:25.00 ml/min) to get 2-(2,4-dimethyl-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid (19.6 mg) was obtained as a white solid. LCMS m/z 430.3 [M+H]+ [0327] 1H NMR: (400 MHz, DMSO-d6) δ = 7.63 (dd, J = 1.4, 4.6 Hz, 1H), 7.34 - 7.30 (m, 4H), 7.27 - 7.21 (m, 1H), 6.89 - 6.84 (m, 3H), 6.72 (dd, J = 1.4, 8.0 Hz, 1H), 5.71 (br s, 1H), 3.46 - 3.40 (m, 3H), 3.12 (br dd, J = 3.2, 16.8 Hz, 1H), 2.79 - 2.52 (m, 6H), 2.47 - 2.30 (m, 3H), 2.13 (s, 3H), 2.08 (s, 3H), 2.03 (br dd, J = 4.4, 8.8 Hz, 1H). EXAMPLE 18 Preparation of Compound [2-(4,6-dimethylpyridin-3-yl)ethyl][(S)-phenyl((3R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]amine (2014).
Figure imgf000132_0001
Step A 5-[(1E)-2-ethoxyethenyl]-2,4-dimethylpyridine
Figure imgf000132_0002
[0328] A mixture of 5-bromo-2,4-dimethylpyridine (1 g, 5.38 mmol, 1 equiv.), 2- [(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.28 g, 1.37 mL, 0.94 g/mL, 6.45 mmol, 1.2 equiv.), K2CO3 (2.23 g, 16.13 mmol, 3 equiv.) and Pd(dppf)Cl2 (196.64 mg, 0.27 mmol, 0.05 equiv.) in dioxane (20 mL, 0.27 M, 20 Vols) and H2O (5 mL, 1.08 M, 5 Vols) was degassed and purged with N2 for 3 times, and then the reaction mixture was stirred at 80 oC for 12 h under N2 atmosphere. TLC showed Reactant 1was consumed completely and one new spot formed. The reaction mixture was quenched by saturated NH4Cl solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with brine (30 mL × 2), dried over anhydrous Na2SO4, filtered and concentrated give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ethergradient @ 200 mL/min). Compound 5-[(1E)-2-ethoxyethenyl]-2,4-dimethylpyridine (800 mg, 4.33 mmol, Yield 80.62%) was obtained as a yellow oil. [0329] 1H NMR: (400 MHz, DMSO-d6) δ = 8.34 - 8.27 (m, 1H), 7.07 - 6.96 (m, 2H), 5.80 (d, J = 12.8 Hz, 1H), 3.92 - 3.87 (m, 2H), 2.39 - 2.30 (m, 3H), 2.19 (s, 3H), 1.28 - 1.22 (m, 3H) LCMS m/z 178.1 [M+H]+ Step B 2-(4,6-dimethylpyridin-3-yl)acetaldehyde
Figure imgf000133_0001
[0330] To a solution of 5-[(1E)-2-ethoxyethenyl]-2,4-dimethylpyridine (150 mg, 0.85 mmol, 1 equiv.) in MeCN (2 mL, 0.43 M, 13.33 Vols) was added HCl (0.1 mL, 12 M, 1.2 mmol, 1.42 equiv.) at 0 oC, the mixture was stirred at 0 oC for 1 h. TLC showed Reactant 1 was consumed completely and one new spot formed. The reaction mixture was quenched by addition sat. aq. Na2CO3 (3 mL) at 0 °C, and then extracted with EtOAc (2 mL × 3). The combined organic layers were washed with brine (5 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 2-(4,6-dimethylpyridin-3- yl)acetaldehyde (120 mg, 0.80 mmol, Yield 95.04%) was obtained as a colorless oil. Step C [2-(4,6-dimethylpyridin-3-yl)ethyl][(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl]amine
Figure imgf000133_0002
[0331] To a solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (45 mg, 0.19 mmol, 1 equiv.) in CH3OH (1 mL, 0.19 M, 22.22 Vols) was added adjusted pH to 7, then added CH3COOH (33.88 mg, 0.56 mmol, 3 equiv.) adjusted pH to 5~6, then added 2-(4,6-dimethylpyridin-3-yl)acetaldehyde (56.11 mg, 0.38 mmol, 2 equiv.) and NaBH3CN (23.63 mg, 0.38 mmol, 2 equiv.), the mixture was stirred at 25 oC for 0.5 h. LCMS showed Reactant 1 was consumed completely and 36% peak with desired mass was detected. The residue was dissolved in CH3OH (2 mL), and the resulting solution was purified by prep-HPLC (neutral condition, column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 30.00%- 60.00%, 8.00 min; flow rate: 25.00 ml/min). Compound [2-(4,6-dimethylpyridin-3- yl)ethyl][(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]amine (14.7 mg, 0.039 mmol, Yield 20.59%) was obtained as a white solid. [0332] 1H NMR: (400 MHz, DMSO-d6) δ = 8.08 (s, 1H), 7.66 - 7.56 (m, 1H), 7.36 - 7.28 (m, 4H), 7.27 - 7.18 (m, 1H), 7.00 - 6.91 (m, 1H), 6.88 - 6.79 (m, 1H), 6.69 (dd, J = 1.4, 8.0 Hz, 1H), 5.73 - 5.60 (m, 1H), 3.46 (br d, J = 8.0 Hz, 1H), 3.07 (br dd, J = 3.2, 16.8 Hz, 1H), 2.80 - 2.74 (m, 1H), 2.72 - 2.53 (m, 4H), 2.44 - 2.37 (m, 2H), 2.34 (s, 3H), 2.14 - 2.08 (m, 1H), 2.07 (br s, 1H) LCMS m/z 373.2 [M+H]+ EXAMPLE 19 Preparation of Compounds {3-[(2S)-1-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (2015A) and {3- [(2R)-1-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (2015B).
Figure imgf000134_0001
Step A.5-fluoro-2-methylpyridin-3-amine [0333] A solution of 2-bromo-5-fluoropyridin-3-amine (12.5 g, 65.44 mmol, 1 equiv.), trimethyl-1,3,5,2,4,6-trioxatriborinane (49.29 g, 196.33 mmol, 3 equiv.), Cs2CO3 (53.31 g, 163.61 mmol, 2.5 equiv.) and Ruphos Pd G3 (2.74 g, 3.27 mmol, 0.05 equiv.) in Toluene (150 mL, 0.44 M, 12 Vols) and H2O (30 mL, 2.18 M, 2.4 Vols). The reaction was stirred at 100 oC for 4 h under N2 atmosphere. LC-MS showed the reactant was consumed completely and 36% peak with desired mass was formed. The reaction mixture was filtered and the filter cake was rinsed with EtOAc (100 mL × 2). The reaction mixture was diluted with H2O 250 mL and extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine (500 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 220 g SepaFlash@ Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound 5-fluoro-2-methylpyridin-3-amine (14.1 g, 100.61 mmol, yield 153.73%) was obtained as a brown solid. Two reactions were carried out in parallel. [0334] 1H NMR: (400 MHz, DMSO-d6) δ = 7.57 (d, J = 2.6 Hz, 1 H), 6.73 (dd, J = 11.2, 2.57 Hz, 1 H), 5.39 (br s, 2 H), 2.22 (s, 3 H) LCMS m/z 168.2 [M+H]+ Step B. benzyl N-(5-fluoro-2-methylpyridin-3-yl) carbamate
Figure imgf000135_0001
[0335] To a stirred solution of 5-fluoro-2-methylpyridin-3-amine (6.15 g, 48.76 mmol, 1 equiv.) and pyridine (77.14 g, 78.87 mL, 0.98 g/mL, 975.15 mmol, 20 equiv.) in DCM (100 mL, 0.49 M, 16.26 Vols) was added benzyl chloroformate (16.64 g, 97.52 mmol, 2 equiv.) at 0 oC. The reaction was stirred at 25 oC for 3 h under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate=1/1, Rf = 0.5) indicated reactant was consumed completely and one new spot formed. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was diluted with H2O 300 mL and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (200 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 220 g SepaFlash@ Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound benzyl N-(5-fluoro-2-methylpyridin-3-yl) carbamate (25 g, 86.45 mmol) was obtained as an off-white solid. Three reactions were carried out in parallel. [0336] 1H NMR: (400 MHz, DMSO-d6) δ = 9.40 (s, 1 H), 8.21 (d, J = 2.6 Hz, 1 H), 7.84 (dd, J = 10.8, 2.63 Hz, 1 H), 7.48 - 7.28 (m, 5 H), 5.18 (s, 2 H), 2.40 (s, 3 H). LCMS m/z 261.3 [M+H]+ Step C.3-{[(benzyloxy) carbonyl] amino}-5-fluoro-2-methylpyridin-1-ium-1-olate
Figure imgf000136_0001
[0337] Solution 1: benzyl N-(5-fluoro-2-methylpyridin-3-yl) carbamate (20 g, 76.844 mmol, 1 equiv.) in DCE (100 mL, 0.768 M, 5 Vols) [0338] Solution 2: m-CPBA (39.001 g, 192.11 mmol, 2.5 equiv.) in DCE (200 mL, 0.384 M, 10 Vols) [0339] The solution 1 was pumped by Pump 1 {S1, P1, 8.765 mL/min} to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, 70 °C}. [0340] The solution 2 was pumped by Pump 2 {S2, P2, 23.293 mL/min to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, 70 °C}. [0341] The Pump 1 and Pump 2 was started at the same time. [0342] The reaction mixture ran 20 mins. [0343] LC-MS showed the reactant was consumed completely and desired mass was formed. [0344] The reaction mixture was quenched by (500 mL) aq. Na2S2O3 and (500 mL) aq. NaHCO3 at 20 °C. [0345] The reaction mixture was partitioned between EtOAc (800 mL × 3) and (500 mL) sat. aq. Na2S2O3 & (500 mL) sat. aq. NaHCO3. The organic phase was separated, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (800 mL). The resulting solid was collected by filtration, washed with MTBE (300 mL) and dried to give 3-{[(benzyloxy)carbonyl] amino}-5-fluoro-2- methylpyridin-1-ium-1-olate (19.1 g, 65.68 mmol, yield 85.47%) as a pale yellow solid. LCMS m/z 277.0 [M+H]+ Step D. benzyl N-[5-fluoro-2-(hydroxymethyl) pyridin-3-yl] carbamate
Figure imgf000137_0001
[0346] To a solution of 3-{[(benzyloxy)carbonyl] amino}-5-fluoro-2- methylpyridin-1-ium-1-olate (6.34 g, 22.95 mmol, 1 equiv.) in CHCl3 (65 mL, 0.353 M, 10.25 Vols) was added TFAA (4.82 g, 80 mL, 22.95 mmol, 1 equiv.). The mixture was stirred at 70 °C for 36 h. LC-MS showed the reactant was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to get a residue. The reaction mixture was quenched by sat. aq. NaHCO3 (600 mL) at 0 °C. The reaction mixture was partitioned between EtOAc (300 mL × 3) and sat. aq. NaHCO3 (600 mL). The organic phase was separated, washed with brine (400 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO@; 220 g SepaFlash@ Silica Flash Column, Eluent of 21~25% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give Compound benzyl N-[5-fluoro- 2-(hydroxymethyl) pyridin-3-yl] carbamate (17.8 g, 61.21 mmol) as a pale-yellow solid. Three reactions were carried out in parallel. [0347] 1H NMR: (400 MHz, DMSO-d6) δ = 9.33 (s, 1 H), 8.22 (d, J = 2.6 Hz, 1 H), 8.08 (dd, J = 11.1, 2.44 Hz, 1 H), 7.50 - 7.31 (m, 5 H), 5.21 - 5.18 (m, 2 H), 4.67 (s, 2 H). LCMS m/z 277.1 [M+H]+ Step E. benzyl N-[2-(bromomethyl)-5-fluoropyridin-3-yl] carbamate [0348] Solution 1: benzyl N-[5-fluoro-2-(hydroxymethyl) pyridin-3-yl] carbamate (17 g, 61.53 mmol, 1 equiv.) in DCE (51 mL, 1.21 M, 3 Vols) [0349] Solution 2: PBr3 (49969.73 mg, 184.60 mmol, 3 equiv.) in DCE (51 mL, 1.21 M, 3 Vols) [0350] The solution 1 was pumped by Pump 1 {S1, P1, 3.851 mL/min} to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 42.743 mL,50 °C}. [0351] The solution 2 was pumped by Pump 2 {S2, P2, 4.698 mL/min to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 42.743 mL,50 °C}. [0352] The Pump 1 and Pump 2 was started at the same time. [0353] Stop collecting the reaction mixture after 20 mins. [0354] TLC (Petroleum ether/Ethyl acetate=3/1, Rf = 0.3) indicated reactant was consumed completely and one new spot formed. [0355] The reaction mixture was quenched by sat. aq. NaHCO3 (100 mL) at 0 °C [0356] The reaction mixture was partitioned between EtOAc (80 mL × 3) and NaHCO3 (100 mL). The organic phase was separated, washed with brine (50 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 120 g SepaFlash Silica Flash Column, Eluent of 15~20% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound benzyl N-[2-(bromomethyl)-5-fluoropyridin-3-yl] carbamate (13.7 g, 38.37 mmol, yield 62.36%) was obtained as a white solid. [0357] 1H NMR: (400 MHz, DMSO-d6) δ = 9.69 (s, 1 H), 8.31 (d, J = 2.8 Hz, 1 H), 8.03 (dd, J = 10.8, 2.63 Hz, 1 H), 7.51 - 7.33 (m, 5 H), 5.28 - 5.15 (m, 2 H), 4.86 (s, 2 H). [0358] LCMS m/z 339.0/340.9 [M+H]+ Step F. methyl (3S)-2-[(3-{[(benzyloxy) carbonyl] amino}-5-fluoropyridin-2-yl) methyl]-3- [(tert-butoxycarbonyl) amino]-3-phenylpropanoate
Figure imgf000138_0001
[0359] To a solution of methyl (3S)-3-[(tert-butoxycarbonyl) amino]-3- phenylpropanoate (3.85 g, 13.78 mmol, 1 equiv.) in THF (50 mL, 0.28 M, 12.99 Vols) was cooled to -70 °C and then was added LiHMDS (27.57 mL, 1 M, 27.57 mmol, 2 equiv.) under N2. The mixture was stirred at -70 °C for 0.5 h. Then benzyl N-[2-(bromomethyl)-5- fluoropyridin-3-yl] carbamate (4.65 g, 13.71 mmol, 1.0 equiv.) in THF (30 mL, 0.46 M, 7.79 Vols) was added dropwise at -70 °C under N2. The mixture was stirred at -70 °C for 1.5 h under N2. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (100 mL) at 0 oC. The reaction mixture was partitioned between EtOAc (150 mL × 2) and NH4Cl (100 mL). The organic phase was separated, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 120 g SepaFlash @ Silica Flash Column, Eluent of 20~28% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound methyl (3S)-2-[(3- {[(benzyloxy)carbonyl] amino}-5-fluoropyridin-2-yl) methyl]-3-[(tert-butoxycarbonyl) amino]-3-phenylpropanoate (13 g, 21.764 mmol, yield 157.907%) was obtained as a yellow solid. [0360] Two reactions were carried out in parallel. [0361] LCMS m/z 538.3 [M+H]+ [0362] LCMS m/z 538.1 [M+H]+ Step G. methyl (3S)-2-[(3-amino-5-fluoropyridin-2-yl) methyl]-3-[(tert-butoxycarbonyl) amino]-3-phenylpropanoate
Figure imgf000139_0001
[0363] A solution of methyl (3S)-2-[(3-{[(benzyloxy)carbonyl] amino}-5- fluoropyridin-2-yl) methyl]-3-[(tert-butoxycarbonyl) amino]-3-phenylpropanoate (13 g, 24.182 mmol, 1 equiv.) in THF (195 mL, 0.124 M, 15 Vols) and MeOH (195 mL, 0.124 M, 15 Vols) was stirred at 20 °C until becoming a clear solution. [0364] The fixed bed {SS, 50 mL, U column} with granular catalyst {5%Pd/Al2O3 (1.00 eq), 50 mL} was heated to 65 °C. [0365] The H2 back pressure regulator was adjusted to {1.7 MPa}. [0366] The above solution was pumped into the fixed bed at a flow rate of {2 mL/min}, and the flow rate of H2 was 90 mL/min. [0367] The fixed bed was washed by extra MeOH : THF=1:1 (200 mL). [0368] The reaction mixture was collected after running 4 h. [0369] LC-MS showed the reactant was consumed completely and desired mass was formed. [0370] The reaction mixture was concentrated under reduced pressure to give a residue. [0371] Compound methyl (3S)-2-[(3-amino-5-fluoropyridin-2-yl) methyl]-3-[(tert- butoxycarbonyl) amino]-3-phenylpropanoate (9.7 g, 24.042 mmol, yield 99.42%) was obtained as a yellow solid. LCMS m/z 404.2 [M+H]+ Step H. tert-butyl N-[(S)-(7-fluoro-2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3-yl) (phenyl)methyl] carbamate
Figure imgf000140_0001
[0372] A solution of methyl (3S)-2-[(3-amino-5-fluoropyridin-2-yl) methyl]-3- [(tert-butoxycarbonyl) amino]-3-phenylpropanoate (9.7 g, 24.04 mmol, 1 equiv.) in AcOH (5.87 g, 20 mL, 24.04 mmol, 1 equiv.) was stirred at 70 °C for 1 h. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was concentrated under reduced pressure to get a residue. The reaction mixture was partitioned between EtOAc (200 mL) and sat. aq. NaHCO3 (150 mL). The organic phase was separated, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound tert-butyl N-[(S)-(7-fluoro-2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3-yl) (phenyl)methyl] carbamate (8.5 g, 22.89 mmol, yield 95.18%) was obtained as a pale-yellow solid. LCMS m/z 316.1 [M+H-56]+ dr%=68%:32% Step I. tert-butyl N-[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]carbamate tert-butyl N-[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl) methyl] carbamate Flow chemistry
Figure imgf000141_0001
[0373] Solution 1: tert-butyl N-[(S)-(7-fluoro-2-oxo-3,4-dihydro-1H-1,5- naphthyridin-3-yl) (phenyl)methyl] carbamate (2 g, 5.385 mmol, 1 equiv.) in THF (40 mL, 0.135 M, 20 Vols) was added TMSCl (2.106 g, 19.385 mmol, 3.6 equiv.). [0374] Solution 2: LiAlH4 (817.421 mg, 2.692 mL, 21.539 mmol, 4 equiv.) in THF (40 mL, 0.135 M, 20 Vols) [0375] The volume of flow reactor 1FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 64.115 mL, -10 °C. The residence time of flow reactor 1 was {FLR1,10 min}. [0376] The flow rate of Pump1 was adjusted to {S1, P1, 3.066 mL/min} for solution 1. [0377] The flow rate of Pump2 was adjusted to {S2, P2, 3.346 mL/min} for solution 2. [0378] The mixture was collected with a bottle (contained 10 mL 10% NaOH aq.) at 0 °C. [0379] The Pump1 and Pump2 was started at the same time. The reaction mixture was collected after running 10 mins. [0380] Stop collecting the reaction mixture after 25 mins. [0381] TLC (Petroleum ether/Ethyl acetate=2/1, Rf = 0.3 & 0.25) indicated reactant was consumed completely and two new spots formed. [0382] The reaction mixture was quenched by (10 mL) aq.10% NaOH at 0 °C. [0383] The reaction mixture was filtered and concentrated under reduced pressure to give a residue and the residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash Silica Flash Column, Eluent of 6~15% THF/DCM @ 100 mL/min). Compound tert-butyl N-[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl] (phenyl)methyl] carbamate (860 mg, 2.165 mmol, yield 40.21%) was obtained as a white solid. LCMS m/z 358.1 [M+H]+ [0384] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.68 (d, J=2.2 Hz, 1 H), 7.39 - 7.31 (m, 2 H), 7.29 (br d, J=7.0 Hz, 1 H), 7.22 (br d, J=7.1 Hz, 2 H), 6.51 (dd, J=10.1, 2.31 Hz, 1 H), 5.01 (br d, J=8.9 Hz, 1 H), 4.56 (br s, 1 H), 4.17 - 4.00 (m, 1 H), 3.51 (br d, J=11.0 Hz, 1 H), 3.24 - 3.12 (m, 1 H), 2.70 - 2.56 (m, 1 H), 2.56 - 2.44 (m, 1 H), 2.43 - 2.29 (m, 1 H), 1.56 - 1.30 (m, 9 H). LCMS m/z 358.1 [M+H]+ de%=99.74% (TLC (Petroleum ether/Ethyl acetate=2/1, Rf = 0.3, peak 1 in SFC, elution pola-rity: 6% THF/DCM @ 100 mL/min) [0385] Compound tert-butyl N-[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] carbamate (430 mg, 1.107 mmol, yield 20.55%) was obtained as a pale yellow solid. [0386] 1H NMR (400 MHz, CHLOROFORM-d) δ = 7.74 (d, J=2.1 Hz, 1 H), 7.40 - 7.33 (m, 2 H), 7.33 - 7.28 (m, 2 H), 6.48 (br d, J=9.9 Hz, 1 H), 5.10 - 4.94 (m, 1 H), 4.74 - 4.52 (m, 1 H), 3.98 - 3.80 (m, 1 H), 3.26 - 3.01 (m, 2 H), 2.99 - 2.74 (m, 2 H), 2.42 - 2.23 (m, 1 H), 1.46 - 1.33 (m, 9 H). LCMS m/z 358.2 [M+H]+ de%=97.58 [0387] (TLC (Petroleum ether/Ethyl acetate=2/1, Rf = 0.25, peak 2 in SFC, elution polarity: 10% THF/DCM @ 100 mL/min) Step J. (1S)-1-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-1- phenylmethanamine
Figure imgf000142_0001
[0388] To a solution of tert-butyl N-[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl] (phenyl)methyl] carbamate (430 mg, 1.20 mmol, 1 equiv.) in HCl (4 M in EtOAc) (6 mL, 0.20 M, 13.95 Vols). The mixture was stirred at 25 °C for 1 h. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction was successful. The reaction mixture was concentrated under reduced pressure to get a residue. Compound (1S)-1-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-1- phenylmethanamine hydrochloride (309 mg, 1.05 mmol, HCl salt, yield 87.43%) was obtained as a white solid. LCMS m/z 258.2 [M+H]+ Step K. [3-(1-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl)phenyl]acetic acid [0389] To a stirred solution of (1S)-1-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]-1-phenylmethanamine (65 mg, 0.25 mmol, 1 equiv.) in MeOH (1.5 mL, 0.168 M, 23.08 Vols) was added AcOH (45.51 mg, 0.76 mmol, 3 equiv.) to adjusted pH=5. Then [3-(1-oxopropan-2-yl)phenyl]acetic acid (72.83 mg, 0.38 mmol, 1.5 equiv.) was added into the reaction. Then NaBH3CN (31.75 mg, 0.51 mmol, 2 equiv.) was added into the mixture, the mixture was stirred at 20 oC for 0.5 h. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was concentrated under reduced pressure to get a residue, and the reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (column: Waters Xbridge BEH C18 100*30mm*10 um; mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 15.00%-50.00%, 8.00min). Compound [3-(1-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl)phenyl]acetic acid (40 mg, 0.09 mmol, yield 35.80%) was obtained as a white solid. LCMS m/z 434.3 [M+H]+ dr%= 50%:50% Step L. {3-[(2S)-1-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid and {3-[(2R)-1-{[(S)-[(3R)-7- fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}propan-2-
Figure imgf000144_0001
[0390] [3-(1-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl)phenyl]acetic acid (40 mg, 0.1 mmol, 1 equiv.) as a white solid, which was further separated by SFC (column: DAICEL CHIRALPAK ZWIX(+)(250 mm*21mm,5 um); mobile phase: [A: CO2; B: MeOH (0.1%NH3H2O)]; B%: 50.00%-50.00%, 8.00 min). Compound {3-[(2S)-1-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (18.4 mg, 0.04 mmol, yield 46%) was obtained as a white solid. [0391] 1H NMR: (400 MHz, DMSO-d6) δ = 7.54 (d, J = 2.5 Hz, 1 H), 7.37 - 7.27 (m, 4 H), 7.27 - 7.20 (m, 1 H), 7.20 - 7.14 (m, 1 H), 7.08 - 6.96 (m, 3 H), 6.53 (dd, J = 11.2, 2.50 Hz, 1 H), 6.05 (br s, 1 H), 3.49 (s, 2 H), 3.35 (s, 1 H), 3.04 (br dd, J = 16.7, 3.58 Hz, 1 H), 2.83 - 2.52 (m, 5 H), 2.39 - 2.31 (m, 2 H), 2.07 - 1.93 (m, 1 H), 1.15 (d, J = 6.8 Hz, 3 H). LCMS m/z 434.2 [M+H]+ de%=98.48 [0392] Compound {3-[(2R)-1-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (17.7 mg, 0.04 mmol, yield 44.25%) was obtained as a white solid. [0393] 1H NMR: (400 MHz, DMSO-d6) δ = 7.54 (d, J = 2.4 Hz, 1 H), 7.34 - 7.27 (m, 2 H), 7.27 - 7.14 (m, 4 H), 7.05 (d, J = 7.5 Hz, 1 H), 7.03 - 6.95 (m, 2 H), 6.53 (dd, J = 11.2, 2.32 Hz, 1 H), 6.10 - 6.00 (m, 1 H), 3.48 (s, 2 H), 3.37 (d, J = 8.4 Hz, 1 H), 3.03 (br dd, J = 16.6, 3.58 Hz, 1 H), 2.80 - 2.69 (m, 2 H), 2.68 - 2.58 (m, 2 H), 2.43 (dd, J = 11.6, 7.15 Hz, 1 H), 2.37 - 2.29 (m, 1 H), 2.03 - 1.91 (m, 1 H), 1.14 (d, J = 6.9 Hz, 3 H). LCMS m/z 434.3 [M+H]+ de%=96.9 Step AA 1-bromo-3-(1-methoxyprop-1-en-2-yl)benzene
Figure imgf000145_0001
[0394] To a solution of (methoxymethyl)triphenylphosphanium chloride (25.83 g, 75.36 mmol, 1.5 equiv.) in THF (100 mL, 0.50 M, 10 Vols) was added t-BuOK (8.46 g, 75.36 mL, 1 M, 75.36 mmol, 1.5 equiv.) at 0 oC, the mixture was stirred at for 0.5 h, and then was added M-bromoacetophenone (10 g, 50.24 mmol, 1 equiv.) at 0 oC. The mixture was stirred at 25 oC for 11.5 h. TLC (Petroleum ether / Ethyl acetate = 5 / 1, Rf = 0.6) indicated reactant was consumed completely and one new spot formed. The reaction mixture was quenched by addition NH4Cl 200 mL at 0 °C, and then diluted with H2O 100 mL and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (200 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO@; 220 g SepaFlash @ Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound 1-bromo-3-(1- methoxyprop-1-en-2-yl) benzene (11 g, 47.47 mmol, yield 94.49%) was obtained as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ = 7.85 - 7.50 (m, 1H), 7.42 - 7.34 (m, 1H), 7.33 (s, 1H), 7.26 - 7.18 (m, 1H), 6.50 (d, J = 1.2 Hz, 1H), 3.79 (d, J = 14.2 Hz, 3H), 2.04 - 1.95 (m, 3H) Step AB 4-[3-(1-methoxyprop-1-en-2-yl)phenyl]-1,2-oxazole
Figure imgf000145_0002
[0395] To a stirred solution of 1-bromo-3-(1-methoxyprop-1-en-2-yl)benzene (2 g, 8.81 mmol, 1 equiv.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (2.06 g, 10.57 mmol, 1.2 equiv.) in THF (40 mL, 0.22 M, 20 Vols) and H2O (10 mL, 0.88 M, 5 Vols) was added K3PO4 (3.74 g, 17.61 mmol, 2 equiv.) and Catacxium A-Pd-G2 (0.59 g, 0.88 mmol, 0.1 equiv.) at 25 oC under N2. The reaction was stirred at 80 oC over 2 h under N2. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was partitioned between EtOAc (40 mL × 3) and H2O (50 mL × 1). The organic phase was separated, washed with brine (50 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (ISCO@; 80 g SepaFlash @ Silica Flash Column, Eluent of 0~35% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound 4-[3-(1-methoxyprop-1-en-2-yl)phenyl]-1,2- oxazole (1.3 g, 5.86 mmol, yield 66.52%) was obtained as a yellow solid. LCMS m/z 214.0 [M-H]- [0396] 1H NMR: (400 MHz, CDCl3) δ = 8.71 - 8.55 (m, 2H), 7.77 - 7.52 (m, 1H), 7.41 - 7.28 (m, 3H), 6.54 - 6.12 (m, 1H), 3.74 (d, J = 18.5 Hz, 3H), 2.05 - 1.92 (m, 3H). LCMS m/z 216.0 [M+H]+ Step AC [3-(1-methoxyprop-1-en-2-yl) phenyl]acetic acid
Figure imgf000146_0001
[0397] To a stirred solution of 4-[3-(1-methoxyprop-1-en-2-yl) phenyl]-1,2- oxazole (500 mg, 2.32 mmol, 1 equiv.) in MeOH (6 mL, 0.39 M, 12 Vols) and H2O (3 mL, 0.77 M, 6 Vols) at 25 °C NaOH (464.46 mg, 11.61 mmol, 5 equiv.) was added. The reaction was allowed to stirred at 100 oC over 12 h. LC-MS showed the reactant was consumed completely and desired mass was formed. The mixture acidfied pH to 3 with Aqueous solution of hydrochloric acid (1 mol/L). The reaction mixture was partitioned between EtOAc (20 mL × 3) and H2O (20 mL × 1). The organic phase was separated, washed with brine (20 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound [3-(1-methoxyprop-1-en-2-yl) phenyl] acetic acid (520 mg, 2.42 mmol, yield 104.20%) was obtained as a yellow solid. LCMS m/z 205.0 [M-H]- LCMS m/z 205.1 [M-H]- Step AD [3-(1-oxopropan-2-yl) phenyl] acetic acid
Figure imgf000147_0001
[0398] To a stirred solution of [3-(1-methoxyprop-1-en-2-yl) phenyl] acetic acid (130 mg, 0.63 mmol, 1 equiv.) in MeCN (1.5 mL, 0.42 M, 11.538 Vols) was added HCl (68.94 mg, 0.158 mL, 12 M, 1.891 mmol, 3 equiv.) at 0 oC. The reaction was stirred at 0 oC for 0.5 h under N2 atmosphere. TLC (Petroleum ether / Ethyl acetate = 1 / 1, Rf = 0.3) indicated reactant was consumed completely and one new spot formed. The reaction mixture was partitioned between EtOAc (2 mL × 3) and H2O (3 mL × 1). The organic phase was separated, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound [3- (1-oxopropan-2-yl) phenyl] acetic acid (100 mg, 0.52 mmol, yield 82.54%) was obtained as a yellow oil. EXAMPLE 20 Preparation of Compounds [5-(2-{[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl](phenyl)methyl]amino}ethyl)-2-methylphenyl]acetic acid (2016).
Figure imgf000147_0002
Step A.2-[5-[(E)-2-ethoxyvinyl]-2-methyl-phenyl]acetic acid
Figure imgf000148_0001
[0399] To a mixture of 2-(5-bromo-2-methyl-phenyl)acetic acid (1000 mg, 4.37 mmol) in 1,4-Dioxane (10 mL) and Water (2 mL) were added Pd(dppf)Cl2 (159.71 mg, 0.22 mmol), K2CO3 (1807.31 mg, 13.1 mmol) and 2-[(E)-2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1037.6 mg, 5.24 mmol). The reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 80 oC for 2 h under N2 atmosphere. TLC indicated reactant 1 was consumed completely and one new spot was formed. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue which was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~18% Ethyl acetate/Petroleum ethergradient @ 200 mL/min). Compound 2-[5-[(E)- 2-ethoxyvinyl]-2-methyl-phenyl]acetic acid (680 mg, 2.93 mmol, 67.18% yield) was obtained as a colorless oil. [0400] 1H NMR: (400 MHz, CDCl3) δ = 7.09 - 7.05 (m, 3H), 6.95 (d, J = 13.0 Hz, 1H), 5.80 (d, J = 12.9 Hz, 1H), 3.89 (q, J = 7.0 Hz, 2H), 3.64 (s, 2H), 2.28 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H). Step B.2-[2-methyl-5-(2-oxoethyl)phenyl]acetic acid
Figure imgf000148_0002
[0401] To a solution of 2-[5-[(E)-2-ethoxyvinyl]-2-methyl-phenyl]acetic acid (100 mg, 0.45 mmol) in MeCN (1 mL) was added HCl (0.08 mL, 1.0 mmol) at 0 oC. The mixture was stirred at 0 oC for 0.5 h. TLC indicated reactant 1 was consumed completely and one new spot formed. The residue was diluted with H2O (3 mL) and extracted with EtOAc (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue which was used to the next step directly. Compound 2-[2-methyl-5-(2- oxoethyl)phenyl]acetic acid (80 mg, 0.41 mmol, 91.67% yield) was obtained as a colorless oil. Step C. [5-(2-{[(S)-(7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl) (phenyl) methyl] amino}ethyl)-2-methylphenyl] acetic acid
Figure imgf000149_0001
[0402] To a solution of (1S)-1-(7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)- 1-phenylmethanamine (50 mg, 0.19 mmol, 1 equiv.) in MeOH (2 mL, 0.09 M, 40 Vols) was added AcOH (0.035 g, 0.58 mmol, 3 equiv.), NaBH3CN (0.12 g, 1.94 mmol, 10 equiv.) and [2-methyl-5-(2-oxoethyl) phenyl] acetic acid (0.075 g, 0.38 mmol, 2 equiv.). The mixture was stirred at 20 oC for 0.5 h. LC-MS showed Reactant 1 was consumed completely and desired mass was detected. After filtration, the mixture was purified by prep-HPLC (FA condition, column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 1.00%-30.00%,8.00min) to give desired compound [5-(2-{[(S)-(7-fluoro-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl) (phenyl) methyl] amino}ethyl)-2-methylphenyl] acetic acid (50 mg, 0.10 mmol, Yield 55.79%) as a white solid. LCMS m/z 434.3 [M+H]+
Step D. [5-(2-{[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)-2-methylphenyl]acetic acid and [5-(2-{[(S)-[(3R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}ethyl)-2- methylphenyl]acetic acid
Figure imgf000150_0001
[0403] The residue was purified by SFC separation (basic condition)(column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [A: CO2; B: MeOH(0.1%NH3H2O)]; B%: 40.00%-40.00%, 14.00min) to give desired compound [5-(2- {[(S)-[(3S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}ethyl)- 2-methylphenyl]acetic acid (14.6 mg, 0.033 mmol, Yield 28.774%) as a white solid, and compound [5-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)-2-methylphenyl]acetic acid (1.4 mg, 0.003 mmol, Yield 2.8%) as a white solid. [0404] 1H NMR: (400 MHz, DMSO-d6) δ = 8.20 (s, 1H), 7.45 (d, J = 2.5 Hz, 1H), 7.39 - 7.29 (m, 2H), 7.29 - 7.19 (m, 3 H), 7.01 (d, J = 7.7 Hz, 1H), 6.96 - 6.83 (m, 2H), 6.57 (dd, J = 11.1, 2.5 Hz, 1H), 6.24 (br s, 1H), 3.66 - 3.53 (m, 1H), 3.49 (s, 2H), 3.39 (s, 1H), 3.03 - 2.91 (m, 1H), 2.72 - 2.54 (m, 2H), 2.47 - 2.35 (m, 2H), 2.34 - 2.22 (m, 2H), 2.16 (s, 3 H), 2.09 - 1.93 (m, 1H). LCMS m/z 434.2 [M+H]+ (peak 1 in SFC) [0405] 1H NMR: (400 MHz, DMSO-d6) δ = 8.23 (s, 1H), 7.55 (d, J = 2.5 Hz, 1H), 7.36 - 7.27 (m, 4 H), 7.26 - 7.20 (m, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.96 - 6.85 (m, 2H), 6.54 (dd, J = 11.1, 2.5 Hz, 1H), 6.06 (br d, J = 1.6 Hz, 1H), 3.49 (s, 2H), 3.43 (d, J = 8.2 Hz, 1H), 3.07 (br dd, J = 16.8, 3.2 Hz, 1H), 2.77 (br d, J = 10.7 Hz, 1H), 2.69 - 2.60 (m, 4H), 2. 48 - 2.36 (m, 3H), 2.16 (s, 3H), 2.09 - 1.95 (m, 1H) LCMS m/z 434.2 [M+H]+ (peak 2 in SFC) EXAMPLE 21 Preparation of Compounds (2S)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}ethyl)phenyl]propanoic acid (2017A) and (2R)-2- [3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)phenyl]propanoic acid (2017B).
Figure imgf000151_0001
Step A.2-(3-bromophenyl)propanoic acid [0406] To a solution of M-bromophenylacetic acid (1 g, 4.65 mmol, 1 equiv.) in THF (10 mL, 0.46 M, 10 Vols) was added NaHMDS (0.54 g, 9.3 mL, 1 M, 9.3 mmol, 2 equiv.) for 0.5 under N2 atmosphere at 0 oC, then the reaction was added MeI (0.59 g, 0.25 mL, 2.28 g/mL, 4.65 mmol, 1 equiv.). The mixture was stirred at 25 oC for 1 h. TLC indicated reactant was consumed completely and one new spot formed. The reaction was quenched by addition aq. NH4Cl (30 mL) at 0 oC under N2 atmosphere. The resulting solution was extracted with ethyl acetate (2 ×30 mL) and the combined organic layers were concentrated under vacuum. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound 2-(3-bromophenyl)propanoic acid (730 mg, 2.86 mmol, yield 61.67%) was obtained as a white solid.1H NMR: (400 MHz, CDCl3) δ = 7.27 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.08 - 6.97 (m, 2H), 3.50 (q, J = 7.2 Hz, 1H), 1.33 - 1.27 (m, 3H) Step B.2-{3-[(1E)-2-ethoxyethenyl]phenyl}propanoic acid [0407] To a solution of 2-(3-bromophenyl)propanoic acid (300 mg, 1.31 mmol, 1 equiv.) and 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (389.09 mg, 1.96 mmol, 1.5 equiv.) in Dioxane (5 mL, 0.26 M, 16.66 Vols) and H2O (1 mL, 1.31 M, 3.33 Vols) were added K2CO3 (0.54 g, 3.92 mmol, 3 equiv.) and Pd(dppf)Cl2 (0.04 g, 0.06 mmol, 0.05 equiv.) with N2 for 3 times, and the reaction mixture was stirred at 80 °C for 12 h under N2 atmosphere. TLC indicated reactant was consumed completely and one new spot formed. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to get a residue, and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Column, Eluent of 0~3% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound 2-{3-[(1E)-2-ethoxyethenyl]phenyl}propanoic acid (200 mg, 0.72 mmol, yield 55.46%) was obtained as a yellow oil. LCMS m/z 219.1 [M- H]- . Step C.2-[3-(2-oxoethyl)phenyl]propanoic acid [0408] To a solution of 2-{3-[(1E)-2-ethoxyethenyl]phenyl}propanoic acid (150 mg, 0.68 mmol, 1 equiv.) in CH3CN (1 mL, 0.68 M, 6.66 Vols) was added HCl (0.04 g, 0.1 mL, 12 M, 1.2 mmol, 1.76 equiv.), and the reaction mixture was stirred at 0 °C for 0.5 h. TLC (Petroleum ether/Ethyl acetate = 1/1, Rf = 0.4) indicated reactant was consumed completely and one new spot formed. The mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with brine (10 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 2-[3-(2-oxoethyl)phenyl]propanoic acid (120 mg, 0.62 mmol, yield 91.67%) was obtained as a yellow oil. Step D.2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)phenyl]propanoic acid
Figure imgf000153_0001
[0409] To a solution of (1S)-1-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl]-1-phenylmethanamine (70 mg, 0.27 mmol, 1 equiv.) in CH3OH (2 mL, 0.13 M, 28.57 Vols) were added AcOH (0.04 g, 0.81 mmol, 3 equiv.), NaBH3CN (0.05 g, 0.81 mmol, 3 equiv.) and 2-[3-(2-oxoethyl)phenyl]propanoic acid (62.74 mg, 0.32 mmol, 1.2 equiv.), and the reaction mixture was stirred at 0 °C for 0.5 h under N2. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction did not work up, purified directly. The reaction mixture was concentrated under reduced pressure to get a residue, and the reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (FA condition; column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 1.00%-30.00%, 8.00min). Compound 2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}ethyl)phenyl]propanoic acid (30 mg, 0.06 mmol, yield 25.43%) was obtained as a yellow solid. LCMS m/z 434.2 [M+H]+ Step E (2S)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)phenyl]propanoic acid and (2R)-2-[3-(2-{[(S)-[(3R)-7- fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)phenyl]propanoic acid
Figure imgf000154_0001
[0410] The reaction mixture was purified by SFC (column: REGIS (s,s) WHELK- O1 (250mm*30mm,5um);mobile phase: [A: CO2;B: EtOH (0.1% NH3H2O)];B%: 30.00%- 30.00%, 13.00min). [0411] Compound (2S)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}ethyl)phenyl]propanoic acid (20.1 mg, 0.04 mmol, yield 67%) was obtained as a white solid. [0412] LCMS m/z 434.2 [M+H]+ [0413] (Peak 1 in SFC) [0414] 1H NMR: (400 MHz, DMSO-d6) δ = 7.55 (d, J = 2.6 Hz, 1H), 7.35 - 7.27 (m, 4H), 7.26 - 7.21 (m, 1H), 7.20 - 7.15 (m, 1H), 7.09 - 7.04 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H), 6.55 (dd, J = 2.6, 11.2 Hz, 1H), 6.07 (br s, 1H), 3.59 (q, J = 7.0 Hz, 1H), 3.40 (br d, J = 8.4 Hz, 1H), 3.08 (br dd, J = 3.8, 16.4 Hz, 1H), 2.79 - 2.73 (m, 1H), 2.70 - 2.52 (m, 5H), 2.47 - 2.39 (m, 1H), 2.08 - 1.96 (m, 1H), 1.31 (d, J = 7.0 Hz, 3H) [0415] Compound (2R)-2-[3-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}ethyl)phenyl]propanoic acid (9.2 mg, 0.021 mmol, yield 30.38%) was obtained as a white solid. [0416] LCMS m/z 434.2 [M+H]+ [0417] (Peak 2 in SFC) [0418] 1H NMR: (400 MHz, DMSO-d6) δ = 7.55 (d, J = 2.6 Hz, 1H), 7.35 - 7.27 (m, 4H), 7.27 - 7.21 (m, 1H), 7.20 - 7.15 (m, 1H), 7.09 - 7.03 (m, 2H), 6.99 (d, J = 7.6 Hz, 1H), 6.55 (dd, J = 2.6, 11.2 Hz, 1H), 6.07 (br s, 1H), 3.59 (q, J = 7.0 Hz, 1H), 3.43 (d, J = 8.4 Hz, 1H), 3.08 (br dd, J = 3.4, 16.4 Hz, 1H), 2.79 - 2.72 (m, 1H), 2.70 - 2.52 (m, 5H), 2.47 - 2.41 (m, 1H), 2.07 - 1.94 (m, 1H), 1.31 (d, J = 7.2 Hz, 3H) EXAMPLE 22 Preparation of Compound 2-{[4-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}ethyl)pyridin-2-yl]oxy}-2-methylpropanoic acid; trifluoroacetic acid (2018).
Figure imgf000155_0001
Step A. ethyl 2-[(4-bromopyridin-2-yl)oxy]-2-methylpropanoate
Figure imgf000155_0002
[0419] To a solution of 4-bromopyridin-2-ol (5 g, 28.73 mmol, 1 equiv.) in CH3CN (50 mL, 0.57 M, 10 Vols) was added Cs2CO3 (18.72 g, 57.47 mmol, 2 equiv.) and ethyl α- bromoisobutyrate (7.28 g, 37.35 mmol, 1.3 equiv.). The mixture was stirred at 50 oC for 12 h under N2 atmosphere. LC-MS showed bromide substrate was consumed and 30% desired mass was detected. The resultant mixture was filtered and the filter cake was washed with DCM (10 mL × 3). Then the combined filtrates were concentrated under reduced pressure to provide a residue. The residue was loaded to Biotage using a 20 g Agela flash silica gel column (eluted with 0% to 10% ethyl acetate in petroleum ether). The product fraction was combined and evaporated under reduced pressure to yield ethyl 2-[(4-bromopyridin-2-yl)oxy]-2- methylpropanoate (1.8 g, 5.43 mmol, Yield 18.91%) as a colorless oil. LCMS: m/z 287.9/289.9 [M+H]+ Step B. ethyl 2-({4-[(1E)-2-ethoxyethenyl]pyridin-2-yl}oxy)-2-methylpropanoate
Figure imgf000156_0001
[0420] A solution of ethyl 2-[(4-bromopyridin-2-yl)oxy]-2-methylpropanoate (1500 mg, 5.20 mmol, 1 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.54 g, 7.80 mmol, 1.5 equiv.), K2CO3 (2.15 g, 15.61 mmol, 3 equiv.) and Pd(dppf)Cl2 (380.91 mg, 0.52 mmol, 0.1 equiv.) in dioxane (15 mL, 0.34 M, 10 Vols) and H2O (3 mL, 1.73 M, 2 Vols) was stirred at 80 oC for 6 h under N2 atmosphere. LC-MS showed reactant 1 was consumed completely and desired mass was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with EtOAc (20 mL) and extracted with EtOAc (20 mL × 2). The combined organic layers were washed with H2O (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was loaded to Biotage using an Agela flash silica gel column (eluted with 0% to 5% ethyl acetate in petroleum ether). The product fraction was combined and evaporated under reduced pressure to yield ethyl 2-({4-[(1E)-2-ethoxyethenyl]pyridin-2- yl}oxy)-2-methylpropanoate (1.2 g, 3.76 mmol, Yield 72.28%) as a yellow oil. LCMS: m/z 280.0 [M+H]+ Step C.2-({4-[(1E)-2-ethoxyethenyl] pyridin-2-yl}oxy)-2-methylpropanoic acid
Figure imgf000156_0002
[0421] A solution of ethyl 2-({4-[(1E)-2-ethoxyethenyl]pyridin-2-yl}oxy)-2- methylpropanoate (600 mg, 2.14 mmol, 1 equiv) and LiOH (257.21 mg, 10.74 mmol, 5 equiv) in MeOH (6 mL, 0.35 M, 10 Vols) and H2O (3 mL, 0.71 M, 5 Vols) was stirred at 60 oC for 2 h. LC-MS showed reactant 1 was consumed completely and desired mass was detected. The product was purified by prep.-HPLC (neutral condition, column: WePure Biotech XP tC18 150*40*70um; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 1.00%-40.00%, 8.00min). Compound 2-({4-[(1E)-2-ethoxyethenyl]pyridin-2-yl}oxy)-2-methylpropanoic acid (300 mg, 1.13 mmol, Yield 52.80%) was obtained as a white solid. LCMS: m/z 252.0 [M+H]+ Step D.2-methyl-2-{[4-(2-oxoethyl)pyridin-2-yl]oxy}propanoic acid
Figure imgf000157_0001
[0422] To a solution of 2-({4-[(1E)-2-ethoxyethenyl]pyridin-2-yl}oxy)-2- methylpropanoicacid (90 mg, 0.35 mmol, 1 equiv.) in CH3CN (2 mL, 0.17 M, 22.22 Vols) was added HCl (0.2 mL, 12 M, 2.4 mmol, 6.70 equiv.) at 0 oC, the mixture was stirred at 25 oC for 1 h. LC-MS showed Reactant 1 was consumed completely and 53% peak with desired m/z was detected. The reaction mixture was concentrated under reduced pressure to remove solvent. Crude compound 2-methyl-2-{[4-(2-oxoethyl)pyridin-2-yl]oxy}propanoic acid (75 mg, 0.33 mmol, Yield 93.80%) was obtained as a yellow oil. LCMS: m/z 224.1 [M+H]+ Step E.2-{[4-(2-{[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)pyridin-2-yl]oxy}-2-methylpropanoic acid; trifluoroacetic acid
Figure imgf000157_0002
[0 3] o a so ut on o ( S)- -[(3 )-7- uoro- , ,3, -tetra y ro- ,5-nap t yr n- 3-yl]-1-phenylmethanamine hydrochloride (40 mg, 0.13 mmol, 1 equiv.) in MeOH (1 mL, 0.13 M, 25 Vols) were added TEA (13.77 mg, 0.13 mmol, 1 equiv.), AcOH (8.17 mg, 0.13 mmol, 1 equiv.), 2-methyl-2-{[4-(2-oxoethyl)pyridin-2-yl]oxy}propanoic acid (60.79 mg, 0.27 mmol, 2 equiv.) and NaBH3CN (25.66 mg, 0.40 mmol, 3 equiv.). The mixture was stirred at 0 oC for 0.5 h. LC-MS showed Reactant 1 was consumed completely and 54% peak with desired m/z was detected. The reaction was purified directly. The residue was purified by prep-HPLC (TFA condition, column: Phenomenex Luna C18 75*30mm*3um; mobile phase: [A: H2O (0.1% TFA); B: ACN]; B%: 10.00%-40.00%, 8.00min) to give desired compound 2-{[4-(2- {[(S)-[(3R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)pyridin-2-yl]oxy}-2-methylpropanoic acid; trifluoroacetic acid (30 mg, 0.05 mmol, Yield 38.08%) as a white solid. [0424] 1H NMR: (400 MHz, DMSO-d6) δ = 12.69 - 12.17 (m, 1H), 9.53 – 8.96 (m, 2H), 7.94 (d, J = 5.4 Hz, 1H), 7.70 (br d, J = 2.4 Hz, 1H), 7.54 - 7.47 (m, 5H), 6.70 - 6.55 (m, 3H), 4.30 (br s, 1H), 3.23 (br d, J = 16.4 Hz, 1H), 3.03 – 2.94 (m, 2H), 2.87 - 2.77 (m, 4H), 2.69 - 2.58 (m, 2H), 1.54 (s, 6H). QC-LCMS, HNMR, SFC: LCMS: m/z 465.2 [M+H]+ EXAMPLE 23 Preparation of Compound [(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]({2-[3-(1H-1,2,3,4-tetrazol-5-ylmethyl)phenyl]ethyl})amine (2019).
Figure imgf000158_0001
Step A.5-[(3-bromophenyl) methyl]-1H-1,2,3,4-tetrazole
Figure imgf000158_0002
[0425] To a stirred solution of 2-(3-bromophenyl)acetonitrile (5 g, 25.50 mmol, 1 equiv.) and Et3N.HCl (10.53 g, 76.51 mmol, 3 equiv.) in Tol. (70 mL, 0.36 M, 14 Vols) was added NaN3 (4.41 g, 67.83 mmol, 2.66 equiv.) at 20 oC under N2. The reaction was stirred at 100 oC for 12 h under N2 atmosphere. LC-MS showed the reactant was consumed completely and desired mass was formed. The mixture was adjusted to pH = 9 with aq. NaOH at 20 oC. The mixture was diluted with H2O (500 mL) and extracted with EtOAc (100 mL × 2). The organic phase was separated, washed with brine (50 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was filtered and the filter cake was washed with 80 mL of CH2Cl2, dried in vacuum to give a product. Compound 5-[(3- bromophenyl)methyl]-1H-1,2,3,4-tetrazole (1.9 g, 7.70 mmol, yield 30.22%) was obtained as a pale yellow solid. 1H NMR: (400 MHz, DMSO-d6) δ = 7.53 (s, 1H), 7.51 - 7.45 (m, 1H), 7.35 - 7.23 (m, 2H), 4.31 (s, 2H). LCMS m/z 236.9/238.9 [M-H]- Step B.5-({3-[(1E)-2-ethoxyethenyl] phenyl} methyl)-1H-1,2,3,4-tetrazole [0426] A solution of 5-[(3-bromophenyl)methyl]-1H-1,2,3,4-tetrazole (600 mg, 2.5 mmol, 1 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (745.62 mg, 3.76 mmol, 1.5 equiv.), K2CO3 (1.04 g, 7.52 mmol, 3 equiv.) and Pd(dppf)Cl2 (0.18 g, 0.24 mmol, 0.1 equiv.) in dioxane (8 mL, 0.31 M, 13.33 Vols) and H2O (2 mL, 1.25 M, 3.33 Vols) was degassed and purged with N2 for 3 times. The reaction was stirred at 80 oC for 12 h under N2 atmosphere. Two batches were carried out in parallel (300 mg × 2). LC-MS showed the reactant was remained and desired mass was formed. The mixture was adjusted to pH = 5 with 1 M HCl aqueous solution. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (12 mL × 3). The organic phase was separated, washed with brine (10 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 20 g SepaFlash@ Silica Flash Column, Eluent of 0~70% Ethyl acetate/CH2Cl2 @ 100 mL/min). Compound 5-({3-[(1E)-2-ethoxyethenyl]phenyl}methyl)-1H-1,2,3,4-tetrazole (230 mg, 0.89 mmol, yield 71.63%) was obtained as a yellow oil. LCMS m/z 231.0 [M+H]+ Step C.2-[3-(1H-1,2,3,4-tetrazol-5-ylmethyl) phenyl] acetaldehyde
Figure imgf000160_0001
[0427] To a stirred solution of 5-({3-[(1E)-2-ethoxyethenyl] phenyl} methyl)-1H- 1,2,3,4-tetrazole (100 mg, 0.43 mmol, 1 equiv.) in CH3CN (1 mL, 0.43 M, 10 Vols), was added HCl (0.03 mL, 12 M, 0.43 mmol, 1 equiv.) at 0 oC. The reaction was stirred at 0 oC for 0.5 h under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate = 0/1, Rf = 0.5) indicated reactant was remained and one new spot formed. The mixture was diluted with H2O (2 mL) and extracted with EtOAc (1 mL × 2). The organic phase was separated, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 2-[3-(1H- 1,2,3,4-tetrazol-5-ylmethyl)phenyl]acetaldehyde (70 mg, 0.34 mmol, yield 79.71%) was obtained as a yellow oil. Step D. [(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]({2-[3-(1H- 1,2,3,4-tetrazol-5-ylmethyl)phenyl]ethyl})amine
Figure imgf000160_0002
[0428] To a solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (40 mg, 0.16 mmol, 1 equiv.) in MeOH (1 mL, 0.16 M, 25 Vols) was added TEA (16.91 mg, 0.16 mmol, 1 equiv.) to adjusted pH = 7, then was added AcOH (20.07 mg, 0.33 mmol, 2 equiv.) to adjusted pH = 5. Then 2-[3-(1H-1,2,3,4-tetrazol-5- ylmethyl) phenyl]acetaldehyde (60 mg, 0.29 mmol, 1.77 equiv.) and NaBH3CN (21.00 mg, 0.33 mmol, 2 equiv.) were added into the reaction. The mixture was stirred at 20 oC for 0.5 h. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was concentrated under reduced pressure to get a residue, and the residue was filtered and the filtrate was purified by Prep.-HPLC (TFA condition, column: Phenomenex Luna C1875*30mm*3um; mobile phase: [A: H2O (0.1%TFA); B: ACN]; B%: 5.00%-30.00%, 8.00min). Compound [(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]({2- [3-(1H-1,2,3,4-tetrazol-5-ylmethyl)phenyl]ethyl})amine (18.8 mg, 0.04 mmol, yield 26.29%) was obtained as a yellow solid. (TFA salt) LCMS m/z 426.2 [M+H]+ [0429] 1H NMR: (400 MHz, DMSO-d6) δ = 9.82 - 9.30 (m, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.53 - 7.40 (m, 6H), 7.34 (br d, J = 8.4 Hz, 1H), 7.26 - 7.21 (m, 1H), 7.12 (br d, J = 7.6 Hz, 1H), 7.01 - 6.97 (m, 2H), 4.41 (br d, J = 7.0 Hz, 1H), 4.22 (s, 2H), 3.40 - 3.36 (m, 1H), 3.12 (br d, J = 9.0 Hz, 1H), 3.04 - 2.90 (m, 3H), 2.87 - 2.68 (m, 4H). EXAMPLE 24 Preparation of Compound [(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]({2-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]ethyl})amine (2020).
Figure imgf000161_0001
Step A 5-{3-[(1E)-2-ethoxyethenyl]phenyl}-1H-1,2,3,4-tetrazole
Figure imgf000161_0002
[0430] To a solution of 5-(3-bromophenyl)-1H-1,2,3,4-tetrazole (2 g, 8.89 mmol, 1 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.64 g, 13.33 mmol, 1.5 equiv.) in dioxane (20 mL, 0.44 M, 10 Vols) and H2O (4 mL, 2.22 M, 2 Vols) was added K2CO3 (3684.80 mg, 26.66 mmol, 3 equiv.) and Pd(dppf)Cl2 (650.26 mg, 0.89 mmol, 0.1 equiv.) with N2 for 3 times. The reaction was stirred at 90 oC for 8 h under N2 atmosphere. TLC indicated reactant 1 was consumed completely and one new spot formed. The reaction mixture was extracted with EtOAc (30 mL × 3) and H2O (30 mL). The organic phase was separated, washed with brine (20 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue and the residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~17% Ethyl acetate/Petroleum ether gradient @ 80 mL/min). Compound 5-{3-[(1E)-2- ethoxyethenyl]phenyl}-1H-1,2,3,4-tetrazole (1.3 g, 6.01 mmol, Yield 67.65%) was obtained as a yellow solid. LCMS m/z 217.1 [M+H]+ Step B 2-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]acetaldehyde
Figure imgf000162_0001
[0431] To a solution of 5-{3-[(1E)-2-ethoxyethenyl]phenyl}-1H-1,2,3,4-tetrazole (100 mg, 0.46 mmol, 1 equiv.) in CH3CN (2 mL, 0.23 M, 20 Vols) was added HCl (0.051 g, 0.12 mL, 12 M, 1.39 mmol, 3 equiv.). The mixture was stirred at 0 oC for 0.5 h under N2 atmosphere. TLC indicated reactant was remained and one new spot formed. The reaction mixture was extracted with EtOAc (2 mL × 3) and H2O (2 mL). The organic phase was separated, washed with brine (2 mL × 2), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 2-[3-(1H-1,2,3,4-tetrazol-5- yl)phenyl]acetaldehyde (80 mg, 0.43 mmol, Yield 91.93%) was obtained as a yellow solid. Step C [(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]({2-[3-(1H- 1,2,3,4-tetrazol-5-yl)phenyl]ethyl})amine
Figure imgf000162_0002
[0432] To a stirred solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (30 mg, 0.125 mmol, 1 equiv.) in CH3OH (1 mL, 0.13 M, 33.33 Vols) was added 2-[3-(1H-1,2,3,4-tetrazol-5-yl)phenyl]acetaldehyde (35.39 mg, 0.19 mmol, 1.5 equiv.) and CH3COOH (8 mg, 0.05 mL, 0.13 mmol, 1 equiv.). Then NaBH3CN (16 mg, 0.25 mmol, 2 equiv.) was added to the mixture. The reaction was stirred at 0 oC over 0.5 h. The reaction was monitored by LCMS. LCMS showed reactant 1 was consumed completely and 33% peak with desired mass was detected. The residue was dissolved in CH3OH (2 mL), and the resulting solution was purified by prep-HPLC (FA condition) (column: Phenomenex luna C18 100*40 mm*5 um; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 1.00%- 50.00%, 8.00 min; flow rate: 50.00 ml/min). The HPLC fractions were combined, lyophilized to give [(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]({2-[3-(1H-1,2,3,4- tetrazol-5-yl)phenyl]ethyl})amine (7.8 mg, 0.019 mmol, Yield 14.99%) as a white solid. [0433] 1H NMR: (400 MHz, DMSO-d6) δ = 7.90 - 7.78 (m, 2H), 7.76 - 7.68 (m, 1H), 7.50 - 7.38 (m, 6H), 7.27 (br d, J = 7.4 Hz, 1H), 6.95 (br dd, J = 4.8, 7.8 Hz, 1H), 6.86 - 6.78 (m, 1H), 5.94 - 5.81 (m, 1H), 4.17 - 4.03 (m, 1H), 3.30 - 3.14 (m, 2H), 3.10 - 2.97 (m, 2H), 2.94 - 2.71 (m, 7H), 2.68 - 2.57 (m, 2H) LCMS m/z 412.2 [M+H]+ EXAMPLE 25 Preparation of Compound 5-{[3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl]amino}ethyl)phenyl]methyl}-1,3-thiazolidine-2,4-dione (2021).
Figure imgf000163_0001
Step A 5-[(3-bromophenyl) methyl]-1,3-thiazolidine-2,4-dione
Figure imgf000164_0001
[0434] To a solution of 2,4-thiazolidinedione (2.5 g, 21.34 mmol, 1 equiv.) in THF (40 mL, 0.53 M, 16 Vols) was cooled to -78 oC and degassed and purged with N2 for 3 times. Then n-BuLi (2.73 g, 17.07 mL, 2.5 M, 42.69 mmol, 2 equiv.) was added dropwise into the mixture over 20 mins under N2, then warmed to 0 oC for 20 mins under N2 atmosphere. The reaction was cooled to -78 °C, and 1-bromo-3-(bromomethyl) benzene (5.33 g, 21.34 mmol, 1 equiv.) in THF (20 mL, 1.06 M, 8 Vols) was added dropwise to the mixture at -78 oC. The solution was stirred for 20 mins at the same temperature, then the reaction was warmed to 20 oC and stirred at this temperature for 11 h under N2. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was quenched by addition NH4Cl (50 mL) at 0 °C. The residue was diluted with H2O (80 mL) and extracted with EtOAc (40 mL × 3). The organic phase was separated, washed with brine (40 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash@ Silica Flash Column, Eluent of 0~35% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound 5-[(3-bromophenyl) methyl]-1, 3-thiazolidine-2, 4-dione (2.5 g, 7.86 mmol, yield 36.83%) was obtained as a white solid. LCMS m/z 283.8/285.8 [M-H]- [0435] 1H NMR: (400 MHz, CDCl3) δ = 9.22 (br s, 1H), 7.51 - 7.36 (m, 2H), 7.24 - 7.12 (m, 2H), 4.51 (dd, J = 4.0, 9.8 Hz, 1H), 3.52 (d, J = 4.0 Hz, 1H), 3.12 (dd, J = 9.6, 14.2 Hz, 1H).
Step B 5-({3-[(1E)-2-ethoxyethenyl] phenyl} methyl)-1, 3-thiazolidine-2, 4-dione
Figure imgf000165_0001
[0436] A stirred solution of 5-[(3-bromophenyl)methyl]-1,3-thiazolidine-2,4-dione (1 g, 3.49 mmol, 1 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.38 g, 6.99 mmol, 2 equiv.), K2CO3 (1.44 g, 10.48 mmol, 3 equiv.) and Pd(dppf)Cl2 (127.85 mg, 0.17 mmol, 0.05 equiv.) in dioxane (20 mL, 0.17 M, 20 Vols) and H2O (5 mL, 0.69 M, 5 Vols) was degassed and purged with N2 for 3 times. The reaction was stirred at 90 oC for 10 h under N2 atmosphere. LC-MS showed the reactant was consumed completely and desired mass was formed. The residue was diluted with H2O (40 mL) and extracted with EtOAc (15 mL × 3). The organic phase was separated, washed with brine (20 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 40 g SepaFlash@ Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound 5-({3-[(1E)-2- ethoxyethenyl] phenyl} methyl)-1, 3-thiazolidine-2, 4-dione (400 mg, 1.29 mmol, yield 37.14%) was obtained as a yellow oil. LCMS m/z 276.1 [M-H]- Step C 2-{3-[(2, 4-dioxo-1, 3-thiazolidin-5-yl) methyl] phenyl} acetaldehyde
Figure imgf000165_0002
[0437] To a stirred solution of 5-({3-[(1E)-2-ethoxyethenyl] phenyl}methyl)-1,3- thiazolidine-2,4-dione (100 mg, 0.36 mmol, 1 equiv.) in CH3CN (2 mL, 0.18 M, 20 Vols) was added HCl (65.73 mg, 0.15 mL, 12 M, 1.80 mmol, 5 equiv.) at 0 oC. The reaction was stirred at 0 oC for 0.5 h under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate = 3/1, Rf = 0.4) indicated reactant was consumed completely and one new spot formed. The residue was diluted with H2O (2 mL × 1) and extracted with EtOAc (2 mL × 2). The organic phase was separated, dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 2-{3-[(2, 4-dioxo-1, 3-thiazolidin-5-yl) methyl] phenyl} acetaldehyde (70 mg, 0.28 mmol, yield 77.87%) was obtained as a yellow oil. Step D 5-{[3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)phenyl]methyl}-1,3-thiazolidine-2,4-dione
Figure imgf000166_0001
[0438] To a solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (40 mg, 0.16 mmol, 1 equiv.) in MeOH (1.5 mL, 0.11 M, 37.5 Vols) was added AcOH (10.03 mg, 0.16 mmol, 1 equiv.) to adjusted pH = 5, was added 2-{3- [(2, 4-dioxo-1, 3-thiazolidin-5-yl)methyl]phenyl}acetaldehyde (70 mg, 0.28 mmol, 1.68 equiv.), then NaBH3CN (0.02 g, 0.33 mmol, 2 equiv.) was added. The mixture was stirred at 20 oC for 0.5 h. LC-MS showed the reactant was remained and desired mass was formed. The reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (column: WePure Biotech XP tC18150*40*7um; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 20.00%-50.00%, 8.00min). Compound 5-{[3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl]amino}ethyl)phenyl]methyl}-1,3-thiazolidine-2,4-dione (13.3 mg, 0.02 mmol, yield 16.50%) was obtained as a white solid. [0439] 1H NMR: (400 MHz, DMSO-d6) δ = 7.63 (dd, J = 1.4, 4.6 Hz, 1H), 7.37 - 7.28 (m, 4H), 7.25 (dt, J = 2.6, 6.2 Hz, 1H), 7.21 - 7.13 (m, 1H), 7.06 - 6.98 (m, 3H), 6.84 (dd, J = 4.6, 8.2 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.73 - 5.62 (m, 1H), 4.90 - 4.79 (m, 1H), 3.49 - 3.34 (m, 2H), 3.11 - 2.97 (m, 2H), 2.79 - 2.54 (m, 6H), 2.09 - 2.01 (m, 1H). LCMS m/z 473.1 [M+H]+ EXAMPLE 26 Preparation of Compound 3-[3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl]amino}ethyl)phenyl]propanoic acid; formic acid (2022).
Figure imgf000167_0001
Step A.3-{3-[(1E)-2-ethoxyethenyl]phenyl}propanoic acid
Figure imgf000167_0002
[0440] To a solution of 3-(3-bromophenyl)propanoic acid (1 g, 4.36 mmol, 1 equiv.) in dioxane (10 mL, 0.43 M, 10 Vols) and H2O (2 mL, 2.18 M, 2 Vols) were added K2CO3 (1.81 g, 13.09 mmol, 3 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (1.03 g, 5.23 mmol, 1.2 equiv.) and Pd(dppf)Cl2 (159.55 mg, 0.21 mmol, 0.05 equiv.) purged with N2 for 3 times. The reaction was stirred at 100 oC for 12 h under N2 atmosphere. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was diluted between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~10% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound 3-{3-[(1E)-2- ethoxyethenyl]phenyl}propanoic acid (830 mg, 3.58 mmol, yield 82.00%) was obtained as a yellow oil. LCMS m/z 221.2 [M+H]+ [0441] 1H NMR: (400 MHz, CDCl3) δ = 12.01 - 10.60 (m, 1H), 7.23 - 7.17 (m, 1H), 7.11 - 7.06 (m, 2H), 7.01 - 6.96 (m, 2H), 5.83 (d, J = 13.0 Hz, 1H), 3.91 (q, J = 7.0 Hz, 2H), 2.97 - 2.91 (m, 2H), 2.72 - 2.67 (m, 2H), 1.39 - 1.33 (m, 3H) Step B.3-[3-(2-oxoethyl)phenyl]propanoic acid
Figure imgf000168_0001
[0442] To a solution of (3-{3-[(1E)-2-ethoxyethenyl]phenyl}propanoic acid (300 mg, 1.36 mmol, 1 equiv.) in CH3CN (2 mL, 0.68 M, 6.66 Vols) was added HCl (0.1 mL, 12 M, 1.2 mmol, 0.88 equiv.). The mixture was stirred at 0 oC for 0.5 h. TLC (Petroleum ether/Ethyl acetate = 1/1, Rf = 0.4) indicated reactant was consumed completely and one new spot formed. The reaction mixture was diluted between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 3-[3-(2- oxoethyl)phenyl]propanoic acid (260 mg, 1.35 mmol, yield 99.31%) was obtained as a yellow solid. Step C.3-[3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)phenyl]propanoic acid; formic acid
Figure imgf000168_0002
[0443] To a solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (50 mg, 0.20 mmol, 1 equiv.) in MeOH (1 mL, 0.20 M, 20 Vols) were added AcOH (37.63 mg, 0.62 mmol, 3 equiv.), NaBH3CN (39.38 mg, 0.62 mmol, 3 equiv.), 3-[3-(2-oxoethyl)phenyl]propanoic acid (48.19 mg, 0.25 mmol, 1.2 equiv.). The mixture was stirred at 0 oC for 0.5 h. LC-MS showed amine substrate was remained and desired mass was formed. The reaction did not work up, purified directly. The reaction mixture was concentrated under reduced pressure to get a residue, and the reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (FA condition; column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [A: H2O (0.2% FA); B: ACN]; B%: 1.00%-30.00%, 8.00min). Compound 3-[3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)phenyl]propanoic acid; formic acid (9.1 mg, 0.02 mmol, yield 9.38%) was obtained as a white solid. LCMS m/z 416.3 [M+H]+ [0444] 1H NMR: (400 MHz, DMSO-d6) δ = 8.18 (s, 1H), 7.62 (dd, J = 1.0, 4.6 Hz, 1H), 7.36 - 7.21 (m, 5H), 7.16 - 7.10 (m, 1H), 7.04 - 6.98 (m, 2H), 6.94 (br d, J = 7.6 Hz, 1H), 6.85 (dd, J = 4.6, 8.0 Hz, 1H), 6.71 (dd, J = 1.2, 7.9 Hz, 1H), 5.69 (br s, 1H), 3.42 (br s, 1H), 3.08 (br d, J = 13.6 Hz, 1H), 2.79 - 2.71 (m, 3H), 2.70 - 2.55 (m, 6H), 2.46 - 2.39 (m, 2H), 2.07 - 1.99 (m, 1H) EXAMPLE 27 Preparation of Compound 3-[4-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl]amino}ethyl)phenyl]propanoic acid (2023). Step A 3-{4-[(1E)-2-ethoxyethenyl] phenyl} propanoic acid
Figure imgf000169_0001
[0445] To a solution of 3-(4-bromophenyl)propanoic acid (1 g, 4.36 mmol, 1 equiv.) in dioxane (20 mL, 0.22 M, 20 Vols) and H2O (2 mL, 2.18 M, 2 Vols) was added Pd(dppf)Cl2 (0.32 g, 0.44 mmol, 0.1 equiv.) K2CO3 (1.81 g, 13.10 mmol, 3 equiv.) and 2- [(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.04 g, 5.24 mmol, 1.2 equiv.). The mixture was stirred at 80 °C for 12 h under N2. LC-MS showed the reactant was consumed completely and desired mass was detected. The reaction was successful. The mixture acidified pH to 5 with aqueous solution of hydrochloric acid (1mol/L). The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The organic phase was separated, washed with brine (50 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 40 g SepaFlash@ Silica Flash Column, Eluent of 5~10% Ethyl acetate/Petroleum ether gradient @ 80 mL/min). Compound 3-{4-[(1E)-2- ethoxyethenyl] phenyl} propanoic acid (750 mg, 3.06 mmol, yield 70.20%) was obtained as white solid. LCMS m/z 219.1 [M-H]- Step B 3-[4-(2-oxoethyl) phenyl] propanoic acid
Figure imgf000170_0001
[0446] To a solution of 3-{4-[(1E)-2-ethoxyethenyl]phenyl}propanoic acid (150 mg, 0.68 mmol, 1 equiv.) in CH3CN (4 mL, 0.17 M, 26.67 Vols) at 0 °C was added HCl (0.2 mL, 0.68 mmol, 1 equiv.). The mixture was stirred at 0 °C for 0.5 h. TLC (Petroleum ether/Ethyl acetate = 2/1, Rf = 0.5) indicated reactant was consumed completely and one new spot formed. The reaction was successful. The reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (10 mL × 3). The organic phase was separated, washed with brine (10 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. Compound 3-[4-(2-oxoethyl) phenyl] propanoic acid (130 mg, 0.61 mmol, yield 89.38%) was obtained as yellow oil.
Step C 3-[4-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)phenyl]propanoic acid
Figure imgf000171_0001
[0447] To a solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (50 mg, 0.21 mmol, 1 equiv.) in MeOH (1 mL, 0.21 M, 20 Vols) was added AcOH (0.63 mmol, 3 equiv.), 3-[4-(2-oxoethyl) phenyl] propanoic acid (0.04 g, 0.21 mmol, 1 equiv.) and NaBH3CN (0.04 g, 0.63 mmol, 3 equiv.). The mixture was stirred at 25 °C for 1 h. LC-MS showed the reactant was consumed completely and desired mass was detected. The reaction was successful. The reaction mixture was concentrated under reduced pressure to get a residue, and the reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (column: Phenomenex Luna C18100*30mm*3um; mobile phase: [water (FA)- ACN]; B%: 1% - 25%, 8 min). Compound 3-[4-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl]amino}ethyl)phenyl]propanoic acid (23.7 mg, 0.06 mmol, yield 27.30%) was obtained as white solid. LCMS m/z 416.3 [M+H]+ . 1H NMR: (400 MHz, DMSO-d6) δ = 8.19 (s, 1H), 7.63 (dd, J = 1.4, 4.6 Hz, 1H), 7.36 - 7.27 (m, 4H), 7.26 - 7.21 (m, 1H), 7.11 - 7.05 (m, 2H), 7.04 - 6.99 (m, 2H), 6.84 (dd, J = 4.6, 8.2 Hz, 1H), 6.70 (dd, J = 1.4, 8.0 Hz, 1H), 5.68 (br s, 1H), 3.42 (d, J = 8.4 Hz, 1H), 3.03 (br dd, J = 3.4, 16.8 Hz, 1H), 2.79 - 2.69 (m, 3H), 2.69 - 2.53 (m, 4H), 2.49 - 2.44 (m, 3H), 2.43 - 2.37 (m, 1H), 2.07 - 1.97 (m, 1H).
EXAMPLE 28 Preparation of Compound 3-[4-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl]amino}ethyl)pyridin-2-yl]propanoic acid hydrochloride (2024)
Figure imgf000172_0001
Step A ethyl 3-(4-bromopyridin-2-yl) prop-2-enoate
Figure imgf000172_0002
[0448] To a solution of triethyl phosphonoacetate (5.42 g, 24.19 mmol, 1.5 equiv.) in THF (60 mL, 0.27 M, 20 Vols) was added t-BuOK (2.72 g, 24.19 mL, 1 M, 24.19 mmol, 1.5 equiv.) at 0 oC for 1 h, and then to the above mixture was added 4-bromopyridine-2- carbaldehyde (3 g, 16.13 mmol, 1 equiv.) in THF (5 mL, 3.23 M, 1.67 Vols). The mixture was stirred at 0 oC for 0.5 h. TLC indicated reactant 1 was consumed completely and one new spot formed. The reaction mixture was extracted with H2O (100 mL) and EtOAc (30 × 3 mL). The organic phase was separated, washed with brine (100 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound ethyl 3-(4-bromopyridin-2- yl) prop-2-enoate (3.5 g, 12.98 mmol, Yield 80.5%) was obtained as a white solid. [0449] 1H NMR: (400 MHz, DMSO-d6) δ = 8.51 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 0.86 Hz, 1H), 7.69 (dd, J = 5.2, 1.34 Hz, 1H), 7.63 (d, J = 15.8 Hz, 1H), 6.93 (d, J = 15.6 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H). Step B ethyl 3-(4-bromopyridin-2-yl) propanoate
Figure imgf000173_0001
[0450] To a solution of ethyl 3-(4-bromopyridin-2-yl) prop-2-enoate (2 g, 7.81 mmol, 1 equiv.) in CH3OH (20 mL, 0.39 M, 10 Vols) was added NaBH4 (443.15 mg, 11.71 mmol, 1.5 equiv.) at 0 oC under N2 and then to the above solution was added CoCl2 (101.39 mg, 0.78 mmol, 0.1 equiv.). The mixture was stirred at 25 °C for 2 h under N2. TLC indicated reactant 1 was consumed completely and one new spot formed. The reaction mixture was extracted with H2O (40 mL) and EtOAc (10 × 3 mL). The organic phase was separated, washed with brine (10 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate/Petroleum ether gradient @ 150mL/min). Compound ethyl 3-(4-bromopyridin-2-yl) propanoate (1.4 g, 5.15 mmol, Yield 65.98%) was obtained as a colorless liquid. [0451] 1H NMR: (400 MHz, DMSO-d6) δ = 8.35 (br d, J = 5.2 Hz, 1H), 7.60 (s, 1H), 7.48 (br d, J = 4.8 Hz, 1H), 4.03 (q, J = 7.0 Hz, 2H), 3.07 - 2.89 (m, 2H), 2.73 (br t, J = 7.2 Hz, 2H), 1.14 (br t, J = 7.0 Hz, 3H). LCMS m/z 257.9/260.1 [M+H]+ Step C ethyl 3-{4-[(1Z)-2-ethoxyethenyl]pyridin-2-yl}propanoate(Crude)
Figure imgf000173_0002
[0452] To a solution of ethyl 3-(4-bromopyridin-2-yl)propanoate (600 mg, 2.33 mmol, 1 equiv.) in dioxane (4 mL, 0.58 M, 6.67 Vols) and H2O (0.5 mL, 4.65 M, 0.83 Vols) were added 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (552.51 mg, 2.79 mmol, 1.2 equiv.), K2CO3 (0.96 g, 6.97 mmol, 3 equiv.) and Pd(dppf)Cl2 (170.09 mg, 0.23 mmol, 0.1 equiv.). The mixture was stirred at 80 °C for 2 h. LC-MS showed Reactant 1 was consumed completely and desired mass was detected. The reaction was concentrated to dryness to afford ethyl 3-{4-[(1Z)-2-ethoxyethenyl]pyridin-2-yl}propanoate (550 mg, 2.206 mmol) as crude product. This reaction requires further purification. LCMS m/z 250.1 [M+H]+ Step CA ethyl 3-{4-[(1Z)-2-ethoxyethenyl]pyridin-2-yl}propanoate [0453] The crude product ethyl 3-{4-[(1Z)-2-ethoxyethenyl]pyridin-2- yl}propanoate (550 mg, 2.21 mmol) was extracted with H2O (10 mL) and EtOAc (3 × 3 mL). The organic phase was separated, washed with brine (10 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~25% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). Compound ethyl 3-{4-[(1Z)-2- ethoxyethenyl]pyridin-2-yl}propanoate (500 mg, 1.97 mmol, Yield 89.09%) was obtained as a white solid. LCMS m/z 250.0 [M+H]+ Step D.3-{4-[(1E)-2-ethoxyethenyl]pyridin-2-yl}propanoic acid
Figure imgf000174_0001
[0454] To a solution of ethyl 3-{4-[(1E)-2-ethoxyethenyl]pyridin-2-yl}propanoate (250 mg, 1.00 mmol, 1 equiv.) in MeOH (2 mL, 0.50 M, 8 Vols) and H2O (1 mL, 1.00 M, 4 Vols) was added NaOH (200.50 mg, 5.01 mmol, 5 equiv.). The mixture was stirred at 40 oC for 12 h. TLC indicated reactant 1 was consumed completely and one new spot formed. The reaction mixture was adjusted pH to 5 by aq. HCl (1 M) .The reaction mixture was extracted with H2O (10 mL) and EtOAc (10 × 3 mL). The organic phase was separated, washed with brine (10 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was dissolved in CH3OH (5 mL), and the resulting solution was purified by prep-HPLC (TFA condition, column: 3_Phenomenex Luna C1875*30 mm*3 um; mobile phase: [A: H2O (0.1% TFA); B: ACN]; B%: 1.00%-30.00%, 8.00 min). Compound 3-{4-[(1E)- 2-ethoxyethenyl]pyridin-2-yl}propanoic acid (150 mg, 0.63 mmol, Yield 62.88%) was obtained as a yellow oil. LCMS m/z 222.2 [M+H]+ Step E.3-[4-(2-oxoethyl)pyridin-2-yl]propanoic acid [0455] To a solution of 3-{4-[(1E)-2-ethoxyethenyl]pyridin-2-yl}propanoic acid (40 mg, 0.181 mmol, 1 equiv.) in CH3CN (0.5 mL, 0.36 M, 12.5 Vols) was added HCl (0.01 mL, 12 M, 0.12 mmol, 0.66 equiv.) dropwise at 0 oC. The reaction was stirred at 0 oC for 2 h. TLC showed Reactant was consumed completely and one new spot formed. The reaction mixture was concentrated to afford 3-[4-(2-oxoethyl)pyridin-2-yl]propanoic acid (32 mg, 0.17 mmol) as yellow oil. Step F.3-[4-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)pyridin-2-yl]propanoic acid hydrochloride
Figure imgf000175_0001
[0456] To a solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (15 mg, 0.063 mmol, 1 equiv.) and AcOH (0.05 mL, 0.063 mmol, 1 equiv.) in CH3OH (1 mL, 0.063 M, 66.67 Vols) was added 3-[4-(2-oxoethyl)pyridin- 2-yl]propanoic acid (18.16 mg, 0.094 mmol, 1.5 equiv.), NaBH3CN (11.82 mg, 0.19 mmol, 3 equiv.) dropwise at 0 oC. The reaction was stirred at 0 oC for 1 h. LCMS showed Reactant 1 was resumed and 35% peak with desired mass was detected. The residue was dissolved in CH3OH (2 mL), and the resulting solution was purified by prep-HPLC (HCl condition, column: Phenomenex Gemini-NX 80*40 mm*3 um; mobile phase: [A: H2O (0.04%HCl); B: ACN]; B%: 1.00%-10.00%, 15.00 min). Compound 3-[4-(2-{[(S)-phenyl((3R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl]amino}ethyl)pyridin-2-yl]propanoic acid hydrochloride (10 mg, 0.022 mmol, Yield 35.73%) was obtained as a yellow oil. [0457] 1H NMR: (400 MHz, DMSO-d6) δ = 10.89 - 10.42 (m, 2H), 8.78 - 8.55 (m, 1H), 7.88 (br d, J = 5.4 Hz, 1H), 7.81 (s, 1H), 7.74 - 7.64 (m, 3H), 7.54 - 7.39 (m, 6H), 7.32 - 7.23 (m, 1H), 4.44 (br s, 1H), 3.47 (br s, 4H), 3.36 (br d, J = 10.8 Hz, 5H), 3.24 - 3.12 (m, 4H), 3.11 - 3.01 (m, 2H), 2.92 (br s, 2H), 2.85 - 2.69 (m, 4H) [0458] 1H NMR (400 MHz, DMSO-d6+D2O) δ = 8.56 (d, J = 6.0 Hz, 1H), 7.85 (d, J = 4.8 Hz, 1H), 7.70 (s, 1H), 7.61 (br d, J = 5.8 Hz, 1H), 7.55 - 7.40 (m, 8H), 4.39 (br d, J = 7.4 Hz, 1H), 3.48 - 3.40 (m, 1H), 3.33 - 3.25 (m, 1H), 3.20 - 3.03 (m, 6H), 2.97 - 2.88 (m, 1H), 2.81 - 2.72 (m, 4H) EXAMPLE 29 Preparation of Compound 3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)benzoic acid; formic acid (2025) Step A.3-[(1E)-2-ethoxyethenyl]benzoic acid
[0459] To a solution of 3-bromobenzoic acid (1 g, 4.97 mmol, 1 equiv.) in dioxane (10 mL, 0.49 M, 10 Vols) and H2O (2 mL, 2.48 M, 2 Vols) were added K2CO3 (2.06 g, 14.92 mmol, 3 equiv.), 2-[(1E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.18 g, 5.97 mmol, 1.2 equiv.) and Pd(dppf)Cl2 (0.18 g, 0.24 mmol, 0.05 equiv.) with N2 for 3 times. The reaction was stirred at 100 oC for 12 h under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate = 3/1, Rf = 0.5) indicated reactant was consumed completely and one new spot formed. The reaction mixture was diluted between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~5% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). Compound 3-[(1E)-2-ethoxyethenyl]benzoic acid (780 mg, 3.65 mmol, yield 73.41%) was obtained as a yellow solid. [0460] 1H NMR: (400 MHz, CDCl3) δ = 13.25 - 10.96 (m, 1H), 7.98 (s, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.41 - 7.34 (m, 1H), 7.09 (d, J = 13.0 Hz, 1H), 5.89 (d, J = 13.0 Hz, 1H), 3.94 (q, J = 7.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H) Step B.3-(2-oxoethyl)benzoic acid [0461] To a solution of (3-[(1E)-2-ethoxyethenyl]benzoic acid (200 mg, 1.04 mmol, 1 equiv.) was added in CH3CN (2 mL, 0.52 M, 10 Vols) was added HCl (0.1 mL, 12 M, 1.2 mmol, 1.15 equiv.). The mixture was stirred at 0 oC for 0.5 h. TLC (Petroleum ether/Ethyl acetate = 1/1, Rf = 0.4) indicated reactant was consumed completely and one new spot formed. The reaction mixture was diluted between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 3-(2-oxoethyl)benzoic acid (180 mg, 0.98 mmol, yield 94.84%) was obtained as a yellow oil. Step C.3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)benzoic acid; formic acid
Figure imgf000178_0001
[0462] To a solution of (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (25 mg, 0.10 mmol, 1 equiv.) in MeOH (1 mL, 0.10 M, 40 Vols) was added AcOH (18.81 mg, 0.31 mmol, 3 equiv.), NaBH3CN (19.69 mg, 0.31 mmol, 3 equiv.) and 3-(2-oxoethyl)benzoic acid (20.57 mg, 0.12 mmol, 1.2 equiv.). The mixture was stirred at 0 oC for 0.5 h. LC-MS showed the reactant was consumed completely and desired mass was formed. The reaction mixture was diluted between EtOAc (10 mL × 3) and H2O (10 mL). The organic phase was separated, washed with brine (10 mL × 1), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The reaction was filtered and the filtrate was purified by Prep.-HPLC (FA condition; column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [A: H2O(0.2% FA); B: ACN]; B%: 1.00%-30.00%, 8.00min). Compound 3-(2-{[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]amino}ethyl)benzoic acid; formic acid (6.1 mg, 0.01 mmol, yield 13.47%) was obtained as a white solid. LCMS m/z 388.2 [M+H]+ [0463] 1H NMR: (400 MHz, DMSO-d6) δ = 8.14 (s, 1H), 7.75 - 7.70 (m, 2H), 7.63 (dd, J = 1.2, 4.6 Hz, 1H), 7.38 - 7.30 (m, 6H), 7.27 - 7.21 (m, 1H), 6.83 (dd, J = 4.8, 8.0 Hz, 1H), 6.69 (dd, J = 1.4, 8.0 Hz, 1H), 5.67 (br s, 1H), 3.49 (br s, 1H), 3.05 (br d, J = 14.2 Hz, 1H), 2.81 - 2.59 (m, 7H), 2.09 - 2.00 (m, 1H) EXAMPLE 30 Preparation of Compounds {3-[(2S)-1-{[(S)-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (2026A), and {3- [(2R)-1-{[(S)-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (2026B).
Figure imgf000179_0001
Step A.1-bromo-3-(1-methoxyprop-1-en-2-yl)benzene
Figure imgf000179_0002
[0464] To a solution of (methoxymethyl)triphenylphosphanium chloride (5.16 g, 15.07 mmol, 1.5 equiv.) in THF (30 mL, 0.33 M, 15 Vols) was added t-BuOK (15.07 mL, 1 M, 15.07 mmol, 1.5 equiv.), the mixture was stirred at 0 oC for 1 h, and then the reaction mixture was added M-bromoacetophenone (2 g, 10.04 mmol, 1 equiv.), stirred at 25 °C for 11 h under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate = 5/1) showed reactant 1 (Rf = 0.7) was consumed completely and one new spot (Rf = 0.8) formed. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~0% Ethyl acetate/Petroleum ether gradient @ 100 mL/min). TLC (Petroleum ether/Ethyl acetate = 5/1, Rf = 0.8). Compound 1-bromo-3-(1-methoxyprop-1-en-2-yl)benzene (500 mg, 2.20 mmol, yield 21.91%) was obtained as a yellow oil. [0465] 1H NMR: (400 MHz, CDCl3) δ = 7.53 (br dd, J = 1.0, 7.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.25 - 7.19 (m, 1H), 7.19 - 7.12 (m, 1H), 6.45 - 6.14 (m, 1H), 3.75 - 3.69 (m, 3H), 2.00 - 1.85 (m, 3H) Step B.4-[3-(1-methoxyprop-1-en-2-yl)phenyl]-1,2-oxazole
Figure imgf000180_0001
[0466] To a solution of 1-bromo-3-(1-methoxyprop-1-en-2-yl)benzene (500 mg, 2.20 mmol, 1 equiv.) in THF (5 mL, 0.44 M, 10 Vols) and H2O (1 mL, 2.20 M, 2 Vols) were added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (0.51 g, 2.64 mmol, 1.2 equiv.), K3PO4 (1.40 g, 6.60 mmol, 3 equiv.) and Catacxium A-Pd-G2 (0.14 g, 0.22 mmol, 0.1 equiv.), and the reaction mixture was stirred at 80 °C for 2 h under N2 atmosphere. TLC (Petroleum ether/Ethyl acetate = 3/1) showed reactant 1 (Rf = 0.8) was consumed completely and one new spot (Rf = 0.7) formed. The residue was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~3% Ethyl acetate/Petroleum ether gradient @ 100mL/min). TLC (Petroleum ether/Ethyl acetate = 3/1, Rf = 0.7). Compound 4-[3-(1-methoxyprop-1-en-2-yl)phenyl]-1,2-oxazole (500 mg, 2.09 mmol, yield 94.95%) was obtained as a brown oil. [0467] 1H NMR: (400 MHz, CDCl3) δ = 8.68 (d, J = 5.6 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 7.78 - 7.52 (m, 1H), 7.41 - 7.27 (m, 3H), 6.51 - 6.15 (m, 1H), 3.74 (d, J = 18.8 Hz, 3H), 2.04 - 1.94 (m, 3H) Step C. [3-(1-methoxyprop-1-en-2-yl)phenyl]acetic acid
Figure imgf000180_0002
[0468] To a solution of 4-[3-(1-methoxyprop-1-en-2-yl)phenyl]-1,2-oxazole (450 mg, 2.09 mmol, 1 equiv.) in CH3OH (8 mL, 0.26 M, 17.77 Vols) and H2O (4 mL, 0.52 M, 8.88 Vols) was added NaOH (0.83 g, 20.90 mmol, 10 equiv.), and the reaction mixture was stirred at 100 °C for 12 h. LCMS showed reactant 1 was consumed completely and 96% peak with desired was detected. The reaction mixture was adjusted to pH = 4 by 1M HCl. The aqueous phase was extracted with Ethyl acetate (5 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated give a residue. Compound [3-(1- methoxyprop-1-en-2-yl)phenyl]acetic acid (400 mg, 1.86 mmol, yield 89.06%) was obtained as a yellow oil. LCMS m/z 205.1 [M-H]- Step D. [3-(1-oxopropan-2-yl)phenyl]acetic acid
Figure imgf000181_0001
[0469] To a solution of [3-(1-methoxyprop-1-en-2-yl)phenyl]acetic acid (300 mg, 1.45 mmol, 1 equiv.) in CH3CN (3 mL, 0.48 M, 10 Vols) was added HCl (0.3 mL, 12 M, 3.6 mmol, 2.47 equiv.), and the reaction mixture was stirred at 0 °C for 0.5 h. TLC showed reactant 1 was consumed completely and one new spot formed. The residue was diluted with H2O (3 mL) and extracted with ethyl acetate (3 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. Compound [3-(1- oxopropan-2-yl)phenyl]acetic acid (270 mg, 1.40 mmol) was obtained as a yellow oil. Step E: [3-(1-{[(S)-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl)phenyl]acetic acid
Figure imgf000181_0002
[0470] To a solution of (1S)-1-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl]-1-phenylmethanamine (60 mg, 0.18 mmol, 1 equiv.) in CH3OH (1 mL, 0.18 M, 16.66 Vols) were added CH3COOH (33.96 mg, 0.56 mmol, 3 equiv.), NaBH3CN (35.54 mg, 0.56 mmol, 3 equiv.) and [3-(1-oxopropan-2-yl)phenyl]acetic acid (0.04 g, 0.22 mmol, 1.2 equiv.), and the reaction mixture was stirred at 0 °C for 0.5 h. LCMS showed reactant 1 was consumed completely and 56.74 % peak with desired mass was detected. The reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (neutral condition, column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 25.00%-55.00%, 8.00min; flow rate: 25.00 ml/min). Compound [3-(1-{[(S)-[(3R)-7- bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}propan-2- yl)phenyl]acetic acid (5.4 mg, 0.01 mmol, yield 5.66%) was obtained as a white solid (delivered) and Compound [3-(1-{[(S)-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl)phenyl]acetic acid (40 mg, 0.079 mmol, Yield 41.941%) was obtained as a white solid (used for SFC separation). LCMS m/z 494.1/496.1 [M+H]+ [0471] 1H NMR: (400 MHz, DMSO-d6) δ = 7.66 (d, J = 2.0 Hz, 1H), 7.35 - 7.27 (m, 3H), 7.24 - 7.15 (m, 3H), 7.07 - 7.03 (m, 1H), 7.02 - 6.97 (m, 2H), 6.89 (d, J = 2.0 Hz, 1H), 6.02 (br s, 1H), 3.50 (d, J = 3.8 Hz, 2H), 3.37 (br s, 1H), 3.04 - 2.97 (m, 1H), 2.74 (br dd, J = 5.4, 12.2 Hz, 2H), 2.62 (br d, J = 10.4 Hz, 2H), 2.44 - 2.40 (m, 1H), 2.36 (br d, J = 7.2 Hz, 1H), 2.05 - 1.93 (m, 1H), 1.15 (dd, J = 3.8, 7.0 Hz, 3H) Step F: {3-[(2S)-1-{[(S)-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid {3-[(2R)-1-{[(S)-[(3R)-7-bromo- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid
Figure imgf000182_0001
[0472] The material (40 mg) was purified by SFC separation (column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [A: CO2; B: CH3OH (0.1% NH3H2O)]; B%: 40.00%-40.00%, 11.00min; flow rate: 70.00g/min). [0473] Compound {3-[(2S)-1-{[(S)-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (18.1 mg, 0.03 mmol, yield 45.06%) was obtained as a white solid. LCMS m/z 494.1/496.1 [M+H]+ (Peak 1 in SFC) [0474] 1H NMR: (400 MHz, DMSO-d6) δ = 7.66 (d, J = 2.0 Hz, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.15 (m, 4H), 7.05 (d, J = 7.6 Hz, 1H), 7.02 - 6.96 (m, 2H), 6.89 (d, J = 2.0 Hz, 1H), 6.02 (br s, 1H), 3.51 (s, 2H), 3.00 (br dd, J = 3.2, 16.7 Hz, 1H), 2.78 - 2.70 (m, 2H), 2.68 - 2.57 (m, 3H), 2.43 (dd, J = 7.2, 11.6 Hz, 1H), 2.36 - 2.26 (m, 1H), 2.03 - 1.92 (m, 1H), 1.14 (d, J = 7.0 Hz, 3H) [0475] Compound {3-[(2R)-1-{[(S)-[(3R)-7-bromo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (9 mg, 0.01 mmol, Yield 21.51%) was obtained as a white solid. LCMS m/z 494.1/496.1 [M+H]+ (Peak 2 in SFC). [0476] 1H NMR: (400 MHz, DMSO-d6) δ = 7.66 (d, J = 1.4 Hz, 1H), 7.35 - 7.28 (m, 4H), 7.26 - 7.21 (m, 1H), 7.20 - 7.14 (m, 1H), 7.05 - 6.96 (m, 3H), 6.89 (d, J = 1.6 Hz, 1H), 6.02 (br s, 1H), 3.49 (s, 2H), 3.01 (br dd, J = 4.0, 16.8 Hz, 1H), 2.81 - 2.71 (m, 2H), 2.63 - 2.56 (m, 2H), 2.35 (d, J = 7.2 Hz, 2H), 2.06 - 1.96 (m, 1H), 1.15 (d, J = 7.0 Hz, 3H) EXAMPLE 31 Preparation of Compound {3-[(2S)-1-{[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid (2027).
Figure imgf000183_0001
Step A. (2S)-N-[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]-2-[3-(1,2-oxazol-4-yl)phenyl]propanamide
Figure imgf000184_0001
[0477] To a solution of (2S)-2-[3-(1,2-oxazol-4-yl)phenyl]propanoic acid (63.54 mg, 0.29 mmol, 1 equiv.) and (1S)-1-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]-1-phenylmethanamine (70 mg, 0.28 mmol, 1 equiv.) in CH2Cl2 (3 mL, 0.097 M, 47.22 Vols) at 0 °C were added TEA (147.99 mg, 0.20 mL, 0.73 g/mL, 1.46 mmol, 5 equiv.) and T4P (316.12 mg, 0.27 mL, 1.18 g/mL, 0.44 mmol, 1.5 equiv.). The mixture was stirred at 25 °C for 2 h under N2. LCMS showed the reactant was consumed completely and desired mass was detected. The reaction mixture was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 40 mL/min). Compound (2S)-N-[(S)-[(3R)- 7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]-2-[3-(1,2-oxazol-4- yl)phenyl]propanamide (95 mg, 0.18 mmol, Yield 64.58%) was obtained as a white solid. LCMS m/z 453.2 [M+H]+ Step B. [(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl][(2S)- 2-[3-(1,2-oxazol-4-yl)phenyl]propyl]amine
Figure imgf000184_0002
[0478] To a solution of (2S)-N-[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]-2-[3-(1,2-oxazol-4-yl)phenyl]propanamide (95 mg, 0.18 mmol, 1.018 equiv.) in diglyme (1 mL, 0.18 M, 10.53 Vols) at 0 °C were added BF3.Et2O (0.30 g, 0.26 mL, 1.15 g/mL, 2.10 mmol, 12 equiv.) and NaBH4 (30 mg, 0.79 mmol, 4.52 equiv.). The mixture was stirred at 40 °C for 4 h under N2. LCMS showed the reactant was consumed completely and desired mass was detected. The reaction was successful. The reaction mixture was quenched by addition MeOH (5 mL) at 0 °C. the mixture was stirred at 70 oC for 1 h. The reaction mixture was concentrated under reduced pressure to get a residue. and the residue was purified by flash silica gel chromatography.(ISCO@; 20 g SepaFlash@ Silica Flash Column, Eluent of 60~70% THF/DCM @ 80 mL/min). Compound [(S)-[(3R)-7-methyl-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl][(2S)-2-[3-(1,2-oxazol-4- yl)phenyl]propyl]amine (80 mg, 0.109 mmol, Yield 61.34%) was obtained as yellow soild. LCMS m/z 439.2 [M+H]+ Step C. {3-[(2S)-1-{[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}propan-2-yl]phenyl}acetic acid
Figure imgf000185_0001
[0479] A solution of [(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl][(2S)-2-[3-(1,2-oxazol-4-yl)phenyl]propyl]amine (70 mg, 0.096 mmol, 1 equiv.) and LiOH (22.94 mg, 0.96 mmol, 10 equiv.) in EtOH (1.5 mL, 0.064 M, 21.43 Vols) and H2O (0.5 mL, 0.19 M, 7.14 Vols) at 20 °C was degassed under vacuum and purged with N2 several times, then the reaction mixture was stirred at 80 °C for 12 h under N2 atmosphere. LCMS showed Reactant 1 was consumed completely and desired mass was detected. The reaction did not work up, purified directly. The residue was purified by prep-HPLC (neutral condition)(column: Waters Xbridge BEH C18100 x 30mm x 10um;mobile phase: [A: H2O (10 mM NH4HCO3); B: ACN]; B%: 15.00%-45.00%, 8.00 min) to give {3-[(2S)-1-{[(S)-[(3R)- 7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl](phenyl)methyl]amino}propan-2- yl]phenyl}acetic acid (4 mg, 0.009 mmol, Yield 9.70%) as a white solid. [0480] 1H NMR (400 MHz, DMSO-d6) δ = 7.50 - 7.45 (m, 1H), 7.35 - 7.29 (m, 2H), 7.27 - 7.17 (m, 4H), 7.09 - 7.04 (m, 2H), 7.03 - 6.97 (m, 1H), 6.57 - 6.52 (m, 1H), 5.64 - 5.58 (m, 1H), 3.49 (s, 2H), 3.38 - 3.37 (m, 1H), 3.07 - 2.97 (m, 2H), 2.82 - 2.73 (m, 1H), 2.71 - 2.65 (m, 1H), 2.62 - 2.55 (m, 2H), 2.48 - 2.41 (m, 2H), 2.35 - 2.30 (m, 1H), 2.10 (s, 3H), 1.95 (tt, J = 4.4, 9.0 Hz, 1H), 1.18 - 1.12 (m, 3H) [0481] 1H NMR (400 MHz, DMSO-d6 + D2O) δ = 7.51 - 7.45 (m, 1H), 7.35 - 7.28 (m, 2H), 7.25 - 7.16 (m, 4H), 7.07 - 6.95 (m, 3H), 6.63 - 6.52 (m, 1H), 3.52 - 3.44 (m, 2H), 3.38 - 3.31 (m, 1H), 3.02 - 2.93 (m, 1H), 2.80 - 2.71 (m, 1H), 2.69 - 2.62 (m, 1H), 2.60 - 2.54 (m, 2H), 2.46 - 2.37 (m, 1H), 2.35 - 2.28 (m, 1H), 2.09 (s, 3H), 2.00 - 1.88 (m, 1H), 1.17 - 1.05 (m, 3H) LCMS m/z 430.2 [M+H]+ EXAMPLE 32 Preparation of Compound [4-methyl-3-(2-{[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]amino}ethyl)phenyl]acetic acid; formic acid (2028).
Figure imgf000186_0001
Step AA 4-bromo-2-(2-methoxyethenyl)-1-methylbenzene
Figure imgf000186_0002
[0482] To a solution of (methoxymethyl)triphenylphosphanium chloride (5.16 g, 15.07 mmol, 1.5 equiv.) and t-BuOK (1.69 g, 15.07 mL, 1 M, 15.07 mmol, 1.5 equiv.) in THF (30 mL, 0.33 M, 15 Vols), the reaction mixture was stirred at 0 °C for 0.5 h under N2, 5-bromo- 2-methylbenzaldehyde (2 g, 10.04 mmol, 1 equiv.) were added to the mixture, and the reaction mixture was stirred at 20 °C for 11.5 h under N2. TLC showed Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~2% Ethyl acetate/Petroleum ethergradient @ 100 mL/min). [0483] Compound 4-bromo-2-(2-methoxyethenyl)-1-methylbenzene (1.9 g, 8.11 mmol, Yield 80.76%) was obtained as a white solid. [0484] 1H NMR: (400 MHz, DMSO-d6) δ = 8.01 - 7.90 (m, 1H), 7.61 - 7.49 (m, 1H), 7.24 - 7.13 (m, 2H), 7.12 - 7.03 (m, 1H), 6.45 - 6.39 (m, 1H), 5.90 - 5.77 (m, 1H), 5.24 (d, J = 7.1 Hz, 1H), 3.80 - 3.73 (m, 1H), 3.70 - 3.61 (m, 2H), 2.25 - 2.16 (m, 3H). LCMS m/z 227.1 [M+H]+ Step AB 4-[3-(2-methoxyethenyl)-4-methylphenyl]-1,2-oxazole
Figure imgf000187_0001
[0485] To a solution of 4-bromo-2-(2-methoxyethenyl)-1-methylbenzene (1.8 g, 7.92 mmol, 1 equiv.) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-oxazole (1.7 g, 8.71 mmol, 1.1 equiv.) in THF (20 mL, 0.396 M, 11.11 Vols) H2O (5 mL, 1.58 M, 2.77 Vols) were added K3PO4 (5.04 g, 23.77 mmol, 3 equiv.) and Catacxium A-Pd-G2 (0.26 g, 0.39 mmol, 0.05 equiv.), and the reaction mixture was stirred at 80 °C for 2 h under N2. TLC showed Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 80 mL/min). [0486] Compound 4-[3-(2-methoxyethenyl)-4-methylphenyl]-1,2-oxazole (1.3 g, 5.73 mmol, Yield 72.38%) was obtained as a white solid. LCMS m/z 216.1 [M+H]+ Step AC [3-(2-methoxyethenyl)-4-methylphenyl]acetic acid
Figure imgf000188_0001
[0487] To a solution of 4-[3-(2-methoxyethenyl)-4-methylphenyl]-1,2-oxazole (400 mg, 1.85 mmol, 1 equiv.) in MeOH (2 mL, 0.92 M, 5 Vols) H2O (0.5 mL, 3.71 M, 1.25 Vols) were added NaOH (0.22 g, 5.575 mmol, 3 equiv.), and the reaction mixture was stirred at 100 °C for 12 h under N2. LCMS showed Reactant 1 was consumed completely and desired mass was detected. The reaction mixture was adjusted to pH= 5 by HCl (1 M, in H2O). The aqueous phase was extracted with ethyl acetate (5 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated give a residue. Compound [3-(2- methoxyethenyl)-4-methylphenyl]acetic acid (300 mg, 1.29 mmol, Yield 69.66%) was obtained as a white solid. [0488] LCMS m/z 205.0 [M-H]- Step AD. [4-methyl-3-(2-oxoethyl)phenyl]acetic acid
Figure imgf000188_0002
[0489] To a solution of [3-(2-methoxyethenyl)-4-methylphenyl]acetic acid (300 mg, 1.29 mmol, 1 equiv.) in MeCN (2 mL, 0.64 M, 6.66 Vols) were added MeCN (2 mL, 0.64 M, 6.66 Vols), and the reaction mixture was stirred at 0 °C for 0.5 h under N2. TLC indicated Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated to give a residue. Compound [4-methyl-3-(2-oxoethyl)phenyl]acetic acid (220 mg, 1.145 mmol, Yield 88.41%) was obtained as a white solid. [0490] Note: The residue was used to the next step directly. Step A. benzyl N-(5-bromo-2-methylpyridin-3-yl)
Figure imgf000189_0001
[0491] To a stirred solution of 5-bromo-2-methylpyridin-3-amine (40 g, 213.85 mmol, 1 equiv.) and pyridine (84.58 g, 86.48 mL, 0.97 g/mL, 1069.29 mmol, 5 equiv.) in DCM (900 mL, 0.23 M, 22.5 Vols) was added benzyl chloroformate (43.77 g, 36.18 mL, 1.21 g/mL, 256.63 mmol, 1.2 equiv.) at 0 oC. The reaction was stirred at 25 oC for 24 h under N2 atmosphere. LCMS showed the reactant was remained and desired mass was formed. The reaction mixture was concentrated under reduced pressure to get a residue. The reaction mixture was partitioned between EtOAc (1 L×3) and sat. aq. NaHCO3 (1.5 L). The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 150 mL/min). Compound benzyl N-(5-bromo-2-methylpyridin-3-yl)carbamate (52 g, 155.43 mmol, Yield 72.679%) was obtained as a brown solid. [0492] 1H NMR: (400 MHz, DMSO-d6) δ = 9.43 - 9.34 (m, 1H), 8.37 - 8.29 (m, 1H), 8.16 - 8.05 (m, 1H), 7.53 - 7.29 (m, 5H), 5.26 - 5.14 (m, 2H), 2.41 - 2.36 (m, 3H), 2.46 - 2.33 (m, 3H) LCMS m/z 320.9/322.9 [M+H]+ Step B.3-{[(benzyloxy)carbonyl]amino}-5-bromo-2-methylpyridin-1-ium-1-olate (flow chemistry) [0493] Solution 1: benzyl N-(5-bromo-2-methyl-3-pyridyl)carbamate,1 eq, 52 g } in {DCE, 520 mL } [0494] Solution 2: {m-CPBA, 2.5 eq, 91.34 g } in {DCE, 520 mL } [0495] The solution 1 was pumped by Pump 1 {S1, P1, 21.42 mL/min } to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 10.68 mL, 70 °C FLR1, PFA, Coils reactor, 6.350 (1/4’’) mm, 119.52 mL, 70 °C}. [0496] The solution 2 was pumped by Pump 2 {S2, P2, 21.98 mL/min to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 10.68 mL, 70 °C FLR1, PFA, Coils reactor, 6.35 (1/4’’) mm, 119.52 mL, 70 °C}. [0497] The residence time of flow reactor 1 was {FLR1,3 min }. [0498] The mixture was collected with a bottle (contained 1 L aq.Na2SO3). [0499] The Pump 1 and Pump 2 was started at the same time. [0500] The reaction mixture was collected after running 3 mins. [0501] Take a sample for analysis after 3 mins. LCMS showed desired mass was detected and the starting material was consumed. [0502] The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (300 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. Compound 3-{[(benzyloxy)carbonyl]amino}-5-bromo-2-methylpyridin-1-ium-1-olate (42 g, 112.10 mmol, Yield 69.24%) was obtained as a white solid. LCMS m/z 336.8/338.8 [M+H]+ Step C. benzyl N-[5-bromo-2-(hydroxymethyl)pyridin-3-yl]carbamate
Figure imgf000190_0001
[0503] To a solution of 3-{[(benzyloxy)carbonyl]amino}-5-bromo-2- methylpyridin-1-ium-1-olate (20 g, 59.31 mmol, 1 equiv.) in CHCl3 (400 mL, 0.15 M, 20 Vols) were added TFAA (302.2 g, 200 mL, 1.51 g/mL, 1438.83 mmol, 24.25 equiv.) at 0°C, and the reaction mixture was stirred at 70 °C for 12 h under N2. LC-MS showed Reactant 1 was consumed completely and one main peak with desired mass was detected. The reaction was combined with another batch for work up and purification. The reaction mixture was adjueted to pH=7 by sat. aq. NaHCO3 solution. The aqueous phase was extracted with EtOAc (600 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~30% Ethyl acetate/Petroleum ether gradient @ 120 mL/min). Compound benzyl N-[5-bromo-2-(hydroxymethyl)pyridin-3-yl]carbamate (35 g, 101.72 mmol) was obtained as a white solid. LCMS m/z 338.9/336.9 [M+H]+ Step D. benzyl N-[5-bromo-2-(bromomethyl)pyridin-3-yl]carbamate
Figure imgf000191_0001
[0504] Solution 1: { benzyl N-[5-bromo-2-(hydroxymethyl)-3- pyridyl]carbamate,1 eq, 38 g } in { DCE, 300 mL } [0505] Solution 2: { PBr3,3 eq, 84.295 g } in { DCE, 300 mL } [0506] The solution 1 was pumped by Pump 1 {S1, P1, 18.024 mL/min } to flow reactor 1 {FLR1, PFA, Coils reactor, 3.175(1/8’’) mm, 63.046 mL, 50 °C FLR1, PFA, Dynamic mixer, 1 mL, 50 °C}. [0507] The solution 2 was pumped by Pump 2 { S2, P2, 13.999 mL/min to flow reactor 1 { FLR1,PFA,Coils reactor, 3.175(1/8’’) mm, 63.046 mL, 50 °C FLR1, PFA, Dynamic mixer, 1 mL,50 °C}. [0508] The residence time of flow reactor 1 was { FLR1,2 min }. [0509] The mixture was collected with a bottle [0510] The Pump 1 and Pump 2 was started at the same time. [0511] The reaction mixture was collected after running 2 mins. [0512] Take a sample for analysis after 2 mins, [0513] TLC showed Reactant 1 was consumed completely and one new spot formed. [0514] The reaction mixture was quenched by saturated NaHCO3 solution (300 mL) and extracted with EtOAc (200 mL × 3). The combined organic phase was washed with brine (200 mL × 1), dried over anhydrous Na2SO4, filtered and concentrated give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 120 mL/min). TLC Plate 1 (Petroleum ether/Ethyl acetate = 5/1, Rf = 0.5). Compound benzyl N-[5-bromo-2- (bromomethyl)pyridin-3-yl]carbamate (28 g, 64.38 mmol, Yield 62.02%) was obtained as a white solid. [0515] LCMS m/z 398.9/400.9 [M+H]+ Step E. methyl (3S)-2-[(3-{[(benzyloxy)carbonyl]amino}-5-bromopyridin-2-yl)methyl]-3- [(tert-butoxycarbonyl)amino]-3-phenylpropanoate
Figure imgf000192_0001
[0516] Two reactions were carried out in parallel. [0517] To a solution of methyl (3S)-3-[(tert-butoxycarbonyl)amino]-3- phenylpropanoate (3.49 g, 12.49 mmol, 1 equiv.) in DCM (100 mL, 0.12 M, 28.64 Vols) was cooled to -70 oC, then dropwise added LiHMDS (31.24 mL, 1 M, 31.24 mmol, 2.5 equiv.) under N2, the mixture was stirred at -70 oC for 0.5 h, then benzyl N-[5-bromo-2- (bromomethyl)pyridin-3-yl]carbamate (5 g, 12.49 mmol, 1 equiv.) in DCM (30 mL, 0.41 M, 8.59 Vols) was dropwise added to the mixture, the mixture was stirred at -70 oC for 1.5 h. LC- MS showed Reactant 1 was consumed completely and desired mass was detected. The reaction mixture was quenched by saturated NH4Cl solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4, filtered and concentrated give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 220 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 150 mL/min). [0518] Compound methyl (3S)-2-[(3-{[(benzyloxy)carbonyl]amino}-5- bromopyridin-2-yl)methyl]-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate (6.2 g, 8.59 mmol) was obtained as a white solid. LCMS m/z 598.2/600.0 [M+H]+ Step F. methyl (3S)-2-[(3-amino-5-methylpyridin-2-yl)methyl]-3-[(tert- butoxycarbonyl)amino]-3-phenylpropanoate
Figure imgf000193_0001
[0519] To a solution of methyl (3S)-2-[(3-{[(benzyloxy)carbonyl]amino}-5- bromopyridin-2-yl)methyl]-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate (3 g, 5.01 mmol, 1 equiv.) and trimethyl-1,3,5,2,4,6-trioxatriborinane (3146.14 mg, 6.29 mL, 50 w/v %, 25.06 mmol, 5 equiv.) in Tol (50 mL, 0.1 M, 16.66 Vols) and H2O (10 mL, 0.50 M, 3.33 Vols) were added Na2CO3 (1593.82 mg, 15.03 mmol, 3 equiv.) and Ruphos Pd G3 (419.74 mg, 0.50 mmol, 0.1 equiv.) , and the reaction mixture was stirred at 80 °C for 2 h under N2. LC-MS showed Reactant 1 was consumed completely and desired mass was detected. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (60 mL) and extracted with EtOAc (60 mL × 3). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate/Petroleum ethergradient @ 80 mL/min). [0520] Compound methyl (3S)-2-[(3-{[(benzyloxy)carbonyl]amino}-5- methylpyridin-2-yl)methyl]-3-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate (2.1 g, 3.46 mmol, Yield 69.08%) was obtained as yellow oil. [0521] Compound methyl (3S)-2-[(3-amino-5-methylpyridin-2-yl)methyl]-3- [(tert-butoxycarbonyl)amino]-3-phenylpropanoate (1 g, 1.97 mmol, Yield 39.45%) was obtained as a yellow oil. LCMS m/z 400.2 [M+H]+
Step G. tert-butyl N-[(S)-(7-methyl-2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3- yl)(phenyl)methyl]carbamate [0522] A solution of methyl (3S)-2-[(3-amino-5-methylpyridin-2-yl)methyl]-3- [(tert-butoxycarbonyl)amino]-3-phenylpropanoate (1 g, 1.978 mmol, 1 equiv.) in AcOH (10 mL, 0.19 M, 10 Vols), the reaction mixture was stirred at 70 °C for 0.5 h. LC-MS showed Reactant 1 was consumed completely and desired mass was detected. The reaction mixture was concentrated to give a residue. The reaction mixture was adjueted to pH=7 by saturated NaHCO3 solution. The aqueous phase was extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated give a residue. Compound tert-butyl N-[(S)-(7-methyl-2-oxo-3,4-dihydro-1H-1,5-naphthyridin-3- yl)(phenyl)methyl]carbamate (700 mg, 1.505 mmol, Yield 76.10%) was obtained as a white solid. LCMS m/z 368.2 [M+H]+ Step H. tert-butyl N-[(S)-[(3S)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]carbamate tert-butyl N-[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]carbamate (Flow chemistry)
Figure imgf000194_0001
[0523] Solution 1: tert-butyl N-[(S)-(7-methyl-2-oxo-3,4-dihydro-1H-1,5- naphthyridin-3-yl)-phenyl-methyl]carbamate, 1 eq, 0.7 g in DCM, 5 mL./THF,3.5 mL, add TMSCl, 4.8 eq, 0.785 g, 25 °C [0524] Solution 2: .LAH, 6 eq, 0.343 g in THF, 3.5 mL [0525] The volume of flow reactor 1 FLR1, PFA, Coils reactor, 3.175(1/8’’) mm,64.115 mL, 10 °C. The residence time of flow reactor 1 was {FLR1,10 min}. [0526] The flow rate of Pump1 was adjusted to {S1, P1, 4.467 mL/min}for solution 1. [0527] The flow rate of Pump2 was adjusted to {S2, P2, 1.945 mL/min}for solution 2. [0528] The mixture was collected with a bottle (contained 5 V 10% NaOH aq.), 0 °C. [0529] The Pump1 and Pump2 was started at the same time. The reaction mixture was collected after running 10 mins. LCMS showed Reactant 1 was consumed completely and desired mass was detected. The reaction mixture was filtered. The filtrate was concentrated to give a residue. The residue was purified by prep-HPLC (FA condition)(column: Phenomenex luna C18100 x 40mm x 5 um;mobile phase: [A: H2O(0.2% FA); B: ACN]; B%: 10.00%- 30.00%,8.00min) to give tert-butyl N-[(S)-[(3S)-7-methyl-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]carbamate (260 mg, 0.706 mmol, Yield 46.921%) as a white solid and tert-butyl N-[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]carbamate (240 mg, 0.625 mmol, Yield 41.507%) as a white solid. [0530] 1H NMR: (400 MHz, CDCl3) δ = 7.74 - 7.63 (m, 1H), 7.27 (s, 6H), 6.67 - 6.58 (m, 1H), 5.10 (br d, J = 8.9 Hz, 1H), 4.64 - 4.51 (m, 1H), 3.14 (dd, J = 9.2, 11.3 Hz, 1H), 2.70 - 2.47 (m, 3H), 2.34 (br s, 1H), 2.18 (s, 3H), 1.40 (br s, 9H). LCMS m/z 354.1 [M+H]+ (isomer A: peak 1 in SFC) [0531] 1H NMR: (400 MHz, CDCl3) δ = 7.66 (s, 1H), 7.27 (s, 6H), 6.56 - 6.50 (m, 1H), 5.08 - 4.88 (m, 1H), 4.65 - 4.41 (m, 1H), 3.10 - 2.89 (m, 2H), 2.87 - 2.63 (m, 2H), 2.33 - 2.23 (m, 2H), 2.13 (s, 3H), 1.44 - 1.19 (m, 10H). LCMS m/z 354.2 [M+H]+ (isomer B: peak 2 in SFC) Step I. (1S)-1-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-1- phenylmethanamine
Figure imgf000196_0001
[0532] A solution of tert-butyl N-[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl](phenyl)methyl]carbamate (240 mg, 0.62 mmol, 1 equiv.) in HCl/EtOAc (2 mL, 4 M, 8 mmol, 12.80 equiv.) was stirred at 25 °C for 0.5 h under N2. TLC showed Reactant 1 was consumed completely and one new spot formed. The reaction mixture was concentrated to give Compound (1S)-1-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]-1- phenylmethanamine (170 mg, 0.59 mmol, Yield 95.60%) as a white solid. LCMS m/z 254.1 [M+H]+ Step J. [4-methyl-3-(2-{[(S)-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)phenyl]acetic acid; formic acid
Figure imgf000196_0002
[0533] To a solution of (1S)-1-[(3R)-7-methyl-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]-1-phenylmethanamine (40 mg, 0.15 mmol, 1 equiv.) and TEA (0.048 g, 0.066 mL, 0.72 g/mL, 0.47 mmol, 3 equiv.) in MeOH (2 mL, 0.079 M, 50 Vols) were added AcOH (0.028 g, 0.01 mL, 0.47 mmol, 3 equiv.) the reaction was adjust pH to 5~6 , [4-methyl- 3-(2-oxoethyl)phenyl]acetic acid (0.046 g, 0.23 mmol, 1.5 equiv.) and NaBH3CN (0.03 g, 0.47 mmol, 3 equiv.) was added to the mixture. The reaction mixture was stirred at 25 °C for 0.5 h under N2. LC-MS showed Reactant 1 was consumed completely and desired mass was detected. The reaction did not work up, purified directly. The residue was purified by prep- HPLC (FA condition: column: Phenomenex Luna C18100*30mm*5um; mobile phase: [A: H2O(0.2% FA); B: ACN]; B%: 1.00%-30.00%, 8.00 min) to give [4-methyl-3-(2-{[(S)-[(3R)- 7-methyl-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl](phenyl)methyl]amino}ethyl)phenyl]acetic acid; formic acid (5.9 mg, 0.012 mmol, Yield 7.57%) as a white solid. [0534] 1H NMR: (400 MHz, DMSO-d6) δ = 8.16 - 8.12 (m, 1H), 7.52 - 7.47 (m, 1H), 7.37 - 7.30 (m, 4H), 7.28 - 7.21 (m, 1H), 7.04 - 6.97 (m, 2H), 6.97 - 6.89 (m, 1H), 6.59 - 6.53 (m, 1H), 5.70 - 5.62 (m, 1H), 3.47 - 3.40 (m, 4H), 3.16 - 3.05 (m, 2H), 2.77 - 2.56 (m, 5H), 2.48 - 2.32 (m, 2H), 2.11 (d, J = 5.1 Hz, 6H), 2.06 - 1.99 (m, 1H). [0535] 1H NMR: (400 MHz, DMSO-d6 + D2O) δ = 8.33 - 8.27 (m, 1H), 7.51 (d, J = 1.1 Hz, 1H), 7.42 - 7.30 (m, 5H), 7.03 - 6.88 (m, 3H), 6.68 (d, J = 0.9 Hz, 1H), 3.85 - 3.73 (m, 1H), 3.37 - 3.32 (m, 2H), 3.16 - 3.05 (m, 1H), 2.81 - 2.54 (m, 6H), 2.48 - 2.41 (m, 1H), 2.31 - 2.22 (m, 1H), 2.10 (s, 3H), 2.02 (s, 3H). [0536] Note: Chirality on six-member ring is assigned arbitrarily. LCMS m/z 430.2 [M+H]+ EXAMPLE 33 Preparation of Compound [(2S)-2-[3-(1,2-oxazol-4-yl)phenyl]propyl][(S)-phenyl((3R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]amine (2029).
Figure imgf000197_0001
Step A. (2S)-2-[3-(1,2-oxazol-4-yl)phenyl]-N-[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl]propanamide
Figure imgf000198_0001
[0537] To a solution of (2S)-2-[3-(1,2-oxazol-4-yl)phenyl]propanoic acid (65.35 mg, 0.30 mmol, 0.9 equiv.) and (1S)-1-phenyl-1-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methanamine (80 mg, 0.33 mmol, 1 equiv.) in DCM (2 mL, 0.15 M, 30.60 Vols) at 0 °C was added DIPEA (129.61 mg, 0.18 mL, 0.74 g/mL, 1.00 mmol, 3 equiv.) and T4P(50% T4P in EtOAc) (289.03 mg, 0.40 mmol, 1.2 equiv.). The mixture was stirred at 25 °C for 1 h under N2. LC-MS showed reactant 1 was consumed completely and 84% peak with desired mass (RT = 1.119 min) was detected. The reaction mixture was adjusted pH to 10 with Na2CO3 (5 mL) at 0 °C, and then extracted with CH2Cl2 (5 mL × 3). The combined organic layers were washed with brine (5 mL × 1), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO; 4 g SepaFlash Silica Flash Column, Eluent of 3~5% MeOH/CH2Cl2 @ 50 mL/min). (CH2Cl2/MeOH = 10/1, Rf = 0.5). Compound (2S)-2-[3-(1,2-oxazol-4-yl)phenyl]-N-[(S)- phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]propanamide (134 mg, 0.28 mmol, yield 91.41%) was obtained as a yellow soild. LCMS m/z 439.2 [M+H]+ 30 mg (2S)- 2-[3-(1,2-oxazol-4-yl)phenyl]-N-[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl]propanamide was purified by Prep.-HPLC (neutral condition, column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [A: H2O(10mM NH4HCO3); B: ACN]; B%: 35.00%-65.00%, 8.00min;flow rate: 25.00ml/min) Compound (2S)-2-[3-(1,2-oxazol-4- yl)phenyl]-N-[(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]propanamide (26.6 mg, 0.06 mmol, Yield 19.84%) was obtained as a white solid. LCMS m/z 439.2 [M+H]+ [0538] 1H NMR: (400 MHz, DMSO-d6) δ = 9.32 (s, 1H), 9.01 (s, 1H), 8.61 (d, J = 9.0 Hz, 1H), 7.73 - 7.64 (m, 1H), 7.54 - 7.44 (m, 2H), 7.31 - 7.22 (m, 5H), 7.22 - 7.15 (m, 2H), 7.00 - 6.89 (m, 1H), 6.82 (br d, J = 8.0 Hz, 1H), 5.89 (br s, 1H), 4.71 (t, J = 9.2 Hz, 1H), 3.78 (d, J = 7.0 Hz, 1H), 2.98 (br dd, J = 3.8, 16.8 Hz, 1H), 2.86 - 2.69 (m, 3H), 2.30 - 2.18 (m, 1H), 1.43 (d, J = 7.0 Hz, 3H) [0539] Compound (2S)-2-[3-(1,2-oxazol-4-yl)phenyl]-N-[(S)-phenyl((3R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]propanamide (104 mg, 0.21 mmol, yield 70.95%) was used for next step. Step B. [(2S)-2-[3-(1,2-oxazol-4-yl)phenyl]propyl][(S)-phenyl((3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl]amine
Figure imgf000199_0001
[0540] To a solution of (2S)-2-[3-(1,2-oxazol-4-yl)phenyl]-N-[(S)-phenyl((3R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]propanamide (50 mg, 0.11 mmol, 1 equiv.) in Diglyme (2 mL, 0.06 M, 40 Vols) were added BF3.OEt2 (194.19 mg, 0.17 mL, 1.15 g/mL, 1.37 mmol, 12 equiv.) and NaBH4 (30 mg, 0.79 mmol, 6.95 equiv.) at 0 oC, the mixture was stirred at 40 oC for 12 h under N2. LC-MS showed reactant 1 was consumed completely and 40% peak with desired mass (RT = 1.316 min) and 40% boron complex (RT=1.464 min) was detected. The reaction mixture was quenched by addition MeOH 5 mL at 0 °C. The mixture was stirred at 70 °C for 1 h. The reaction mixture was filtered and the filtrate was purified by Prep.-HPLC (neutral condition, column: Waters Xbridge BEH C18100*30mm*10um; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 40.00%-70.00%, 8.00 min; flow rate:25.00ml/min). [0541] Compound [(2S)-2-[3-(1,2-oxazol-4-yl)phenyl]propyl][(S)-phenyl((3R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl]amine (18.2 mg, 0.04 mmol, yield 36.92%) was obtained as a yellow solid. LCMS m/z 425.2 [M+H]+ [0542] 1H NMR: (400 MHz, DMSO-d6) δ = 9.42 (s, 1H), 9.14 (s, 1H), 7.62 (dd, J = 1.4, 4.6 Hz, 1H), 7.55 - 7.44 (m, 2H), 7.38 - 7.16 (m, 6H), 7.09 (d, J = 7.6 Hz, 1H), 6.83 (dd, J = 4.8, 8.0 Hz, 1H), 6.68 (dd, J = 1.4, 8.0 Hz, 1H), 5.64 (br d, J = 1.8 Hz, 1H), 3.42 - 3.38 (m, 1H), 3.30 - 3.24 (m, 1H), 3.09 - 2.96 (m, 1H), 2.86 - 2.77 (m, 1H), 2.74 - 2.58 (m, 3H), 2.45 - 2.35 (m, 1H), 2.07 - 1.91 (m, 2H), 1.19 (d, J = 7.0 Hz, 3H) EXAMPLE 34 Preparation of Compound 2-[4-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl]methyl]amino]ethyl]phenyl]acetic acid (2030).
Figure imgf000200_0001
Step A.2-[4-[(E)-2-ethoxyvinyl] phenyl] acetic acid
Figure imgf000200_0002
[0543] To a solution of 2-(4-bromophenyl)acetic acid (1000 mg, 4.65 mmol) in 1,4-Dioxane (25 mL) and Water (5 mL) were added Cs2CO3 (3030.18 mg, 9.3 mmol), 2-[(E)- 2-ethoxyvinyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1013.15 mg, 5.12 mmol) and Pd(dppf)Cl2 (337.44 mg, 0.47 mmol). The mixture was purged with N2 and stirred at 90 oC for 2.5 h. LCMS showed the starting material was consumed completely and the main peak with desired mass was detected. The reaction mixture was quenched by addition H2O (20 ml) at 0 °C, and then extracted with EtOAc (30 ml × 3), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product. The crude product was purified by flash column (ISCO 10 g silica, 0-100 % ethyl acetate in petroleum ether, gradient over 20 min). Based on TLC (Petroleum ether: ethyl acetate =1:1, Rf = 0.5). The compound 2-[4-[(E)-2-ethoxyvinyl] phenyl] acetic acid (1.2 g, 5.82 mmol, 92.31% yield) was obtained as a yellow solid. LCMS m/z 224.1 [M+H+18] + [0544] 1H NMR: (400 MHz, DMSO-d6) δ = 7.26 - 7.11 (m, 5H), 5.82 (d, J = 13.2 Hz, 1H), 3.96 (s, 2H), 3.50 (s, 2H), 1.26 (t, J = 7.0 Hz, 3H) Step B.2-[4-(2-oxoethyl) phenyl] acetic acid
Figure imgf000201_0001
[0545] To a stirred solution of 2-[4-(2-methoxyvinyl) phenyl] acetic acid (100 mg, 0.52 mmol) in MeCN (2 mL) was added HCl (0.1 mL, 1.2 mmol). Then the reaction was stirred at 20 °C for 30 min under N2. TLC (Petroleum ether: Ethyl acetate = 1: 1, Rf = 0.5, KMnO4) showed the starting material was consumed completely and a new spot formed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 × 3 mL). The combined organic layers were dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure. The compound 2-[4-(2-oxoethyl) phenyl] acetic acid (80 mg, 0.45 mmol, 86.29 % yield) was obtained as a pale yellow oil. [0546] 1H NMR: (400 MHz, DMSO-d6) δ = 9.70 (s, 1H), 7.25 - 7.25 (m, 2H), 7.24 - 7.18 (m, 2H), 3.76 (s, 2H), 3.57 (s, 2H) Step C.2-[4-[2-[[(S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl]methyl]amino]ethyl]phenyl]acetic acid
Figure imgf000201_0002
[0547] To a stirred solution of (S)-phenyl-[(3R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl]methanamine (40 mg, 0.17 mmol) in THF (1 mL) were added TEA (0.05 mL, 0.33 mmol， AcOH (0.04 mL, 0.67 mmol), 2-[4-(2-methoxyvinyl)phenyl]acetic acid (48.19 mg, 0.25 mmol) and NaBH3CN (15.75 mg, 0.25 mmol). The reaction mixture was degassed with N2 for three times. Then the reaction was stirred at 20 °C for 1 h under N2. LCMS showed starting material was consumed completely and and 20 % peak with desired mass was detected. The mixture was diluted with water (5 mL) and extracted with EtOAc (5 × 3 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by Prep-HPLC (XP t C18100 * 25 mm*7 um; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 1.00%-30.00 %, 8.00 min). The compound was lyophilized to give 2-[4-[2-[[(S)-phenyl-[(3R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl]methyl]amino]ethyl]phenyl]acetic acid (3.8 mg, 0.01 mmol, 5.66% yield) as a white solid. LCMS m/z 402.2 [M+H]+ [0548] 1H NMR: (400 MHz, DMSO-d6) δ = 7.64 (br d, J = 4.2 Hz, 1H), 7.38 - 7.29 (m, 4H), 7.28 - 7.19 (m, 1H), 7.07 (br d, J = 6.8 Hz, 2H), 6.96 (br d, J = 7.0 Hz, 2H), 6.84 (dd, J = 4.6, 7.8 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 5.67 (br s, 1H), 3.47 (br d, J = 8.2 Hz, 3H), 3.06 (br dd, J = 3.0, 16.6 Hz, 1H), 2.79 - 2.56 (m, 5H), 2.48 - 2.34 (m, 2H), 2.10 - 2.00 (m, 1H) EXAMPLE 35 Preparation of Compounds According to Scheme A. [0549] Additional compounds were prepared according to Procedure A. Their preparation is summarized in Table 1, below.
Table 1: Compounds prepared according to similar procedures as described previously.
Figure imgf000204_0001
Figure imgf000205_0001
EXAMPLE B p300 TR-FRET Competition Assay [0550] Exemplary compounds of the disclosure were tested for their potency of binding to p300 protein on a competition TR-FRET assay. The competition TR-FRET assay was run in dose-response format on a 384-well microplate. All reagents were diluted in reaction buffer (50 mM HEPES, pH = 7.5; 200 mM NaCl; 0.1% BSA; 1 mM TCEP, 0.01% Triton X- 100). Test compounds dissolved in DMSO were deposited on a plate using Echo 650 acoustic liquid handler (Beckman Coulter). The final DMSO concentration in the assay was 2%. Biotinylated p300 protein (a construct covering amino acids 1287-1652, with the following mutations: (i) 1523-1554 deletion, (ii) K1637R, and (iii) M1652G; with N-terminal methionine residue and a C-terminal peptide of the following sequence: CMLVELHTQSQDRFGGSG{Lys(biotin)} was preincubated with ten 3.16-fold serial dilutions of a test compound starting at 30 µM, 10 µM, 1 µM, or 100 nM, in duplicates, for 30 min at room temperature. Next, donor fluorophore Eu-W1024 chelate-labeled streptavidin (PerkinElmer) and 1-(6-((2-(4-(6-(2-((4-cyanophenethyl)amino)-2-phenylacetamido)pyridin- 3-yl)-1H-pyrazol-1-yl)ethyl)amino)-6-oxohexyl)-2-((1E,3E,5E)-5-(3,3-dimethyl-5-sulfonato- 1-(3-sulfonatopropyl)indolin-2-ylidene)penta-1,3-dien-1-yl)-3-methyl-3-(4-sulfonatobutyl)- 3H-indol-1-ium-5-sulfonate (the acceptor fluorophore-labeled p300 ligand) were added at final assay concentrations of 1 nM and 40 nM, respectively. The final p300 protein concentration in the assay was 2 nM. The mixture was allowed to equilibrate for 30 min at room temperature. The TR-FRET signal was measured using EnVision 2105 multimode plate reader (PerkinElmer) equipped with 337 nm TRF light unit, TRF laser LANCE D407/D630 dual mirror, and two emission filters: APC 665 (665 nm) filter and LANCE laser attenuated Europium (615 nm) filter. The signal was calculated as a ratio of fluorescent intensities at 665 nm and 615 nm. The signal was normalized to no-protein control (100% response) and vehicle control (0% response) and fitted using the four-parameter logistic regression model. The IC50 value (defined as a concentration, at which the assay response equaled 50%) was used as a measure of binding affinity of a test compound. [0551] Results from the TR-FRET Competition Assay of Example B are provided in Table 2 for compounds described in the synthetic Examples above.
Table 2: TR-FRET competition assay IC50 data for representative compounds (Examples 1-35)*. * = AAAA is <100nM, AAA is 100-999nM, AA is 1,000-9,999nM, and A is >10,000nM.
Figure imgf000208_0001
Figure imgf000209_0001
Preparation of Compounds According to Scheme A. [0552] Additional compounds were prepared according to Procedure A. Their preparation is summarized in Table 3, below.
Table 3. TR-FRET competition assay IC50 data for representative compounds*. * = AAAA is <100 nM, AAA is 100-999.9 nM, AA is 1,000-10,000 nM, and A is >10,000 nM.
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
Figure imgf000238_0001
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Table 4A. TR-FRET competition assay IC50 data for representative compounds (R10 is H)*. * = AAAA is <100 nM, AAA is 100-999.9 nM, AA is 1,000-10, 000 nM, and A is >10,000 nM
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Table 4B. TR-FRET competition assay IC50 data for representative compounds (R10 is halogen)*. * = AAAA is <100 nM, AAA is 100-999.9 nM, AA is 1,000-10,000 nM, and A is >10,000 nM
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Table 4C. TR-FRET competition assay IC50 data for representative compounds (R10 is halogen)*. * = AAAA is <100nM, AAA is 100-999nM, AA is 1,000-9,999nM, and A is >10,000nM
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
AAAA is <100 nM, AAA is 100-999.9 nM, AA is 1,000-10,000 nM, and A is >10,000 nM Further Embodiments [0553] In some embodiments, the compound may be a compound, or pharmaceutically acceptable salt thereof, selected from: [0554] 2-(2-chloro-5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (3-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)ethyl)-4-methoxyphenyl)acetic acid; 2-(4-((S or R)-1-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((S or R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- (2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(pyridin-3-yl)methyl)amino)ethyl)-4- methylphenyl)acetic acid; 2-(3-((S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; 2-(3-(2-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-4- fluorophenyl)acetic acid; (R or S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-5-fluorophenyl)acetic acid; 2-(5-(2- (((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2- fluorophenyl)acetic acid; (R or S)-2-(4-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3- (2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4- fluorophenyl)acetic acid; 2-(2-methyl-5-(2-(((S)-((R and S)-2-oxo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; (R or S)-2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-chloro-5-(2-(((R)-((R)-8-cyano- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2- (2-(difluoromethyl)-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((S)-7-fluoro-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-methylphenyl)acetic acid; 2-(2-chloro-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-((S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 3-(3-((S)-1-(((R)-((R)- 8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)oxetane-3-carboxylic acid; (R and S)-2-(4-((R and S)-1-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-(2- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-5- fluorophenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-((R)- 5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; (S or R)-2-(3-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)-3- methoxypropanoic acid; 2-(2,4-dimethyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-4-methyl-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(5-((R or S)-1-(((S)-((R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methylphenyl)acetic acid; 2-(4-methyl-3-(2-(((S)-((S)-2-oxo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-methyl-3-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(5-(2-(((S)-((R)-7-fluoro-2- oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-2- methylphenyl)acetic acid; 2-(4-chloro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)-3- methoxypropanoic acid; (S or R)-2-(4-methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(2-fluorophenyl)methyl)amino)ethyl)phenyl)acetic acid; 2- (2-fluoro-5-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(3-((S or R)-1-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(2-fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2- methyl-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; 2-(5-(2- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)acetic acid; (S or R)-2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2- (3-((R and S)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)ethyl)phenyl)acetic acid; 2- (3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4- methylphenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(4-methyl-3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-3-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4- ((R or S)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)-3-methoxyphenyl)acetic acid; 2-(4-fluoro-3-((R or S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-chloro-3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2- (3-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(4-methoxy-3-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(4-fluoro-2-methyl-5-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-((R and S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 2-(2-chloro-5-((R or S)- 1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(5-((R and S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; 2-(3-((S)-1-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-5-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 3-(3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid; 2-(4-chloro-3-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; 5-(3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)thiazolidine-2,4-dione; (R or S)-2-(3-((R or S)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(3-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((S or R)-1-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(4-methyl-3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4- methoxyphenyl)acetic acid; 2-(3-((R and S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)- 2,4-difluorophenyl)acetic acid; 2-(2-methyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-methylthiophen-3-yl)acetic acid; 2-(2-methoxy-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(2,4-difluoro-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-methyl-3-((R and S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-chloro-5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(2,4-difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-5-fluorophenyl)propanoic acid; 2- (2,4-difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R o rS)-2-(2-fluoro-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((S)-((R)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)propanoic acid; 2-(5-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)acetic acid; 2-(3- fluoro-5-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-methyl-2-(4-methyl-3-(2-(((S)- ((S)-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((S)-((S)-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- fluorophenyl)acetic acid; 2-(2-chloro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-((R and S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(3- fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S)-2-(3-((2H-tetrazol-5- yl)methyl)phenyl)-N-((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)propan-1-amine; 2-(2-fluoro-4-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-((R and S)- 1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(5-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)propan-2-yl)-2-fluorophenyl)acetic acid; 2-(4-methoxy-3-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3-fluorophenyl)acetic acid; 2-(3-((S or R)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(2-fluoro-5-((S or R)-1-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)-2- methylpropanoic acid; 2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)-2-(trifluoromethyl)phenyl)acetic acid; (R)-3-((R)-((3-((1H-tetrazol-5- yl)methyl)phenethyl)amino)(phenyl)methyl)-1,2,3,4-tetrahydroquinoxaline-5-carbonitrile; 2- (5-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; (R or S)-2-(3-(2-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4- fluorophenyl)propanoic acid; 2-(3-(2-(((S)-((R or S)-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2- chloro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(4-((R and S)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan- 2-yl)-3-methoxyphenyl)acetic acid; (R or S)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-5-fluorophenyl)propanoic acid; (R and S)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)propanoic acid; 2-(4-(2-(((S)-((R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)acetic acid; (R and S)-2-(2-chloro-5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(pyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)- 8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- fluorophenyl)propanoic acid; 2-(2-methoxy-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)- 2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)- 5-fluorophenyl)propanoic acid; 2-(3-(2-(((S)-((R and S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(2,4-difluoro- 5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(3- (2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(3- fluorophenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-((R and S)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3- yl)acetic acid; 2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)propanoic acid; (R and S)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(4-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)ethyl)phenyl)acetic acid; 2- (3-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)-4-fluorophenyl)acetic acid; 2-(2-fluoro-5-((R and S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)-2-methylpropanoic acid; (R and S)-(3-chloro-4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-chloro-5- ((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(5-((S or R)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3- yl)acetic acid; 2-(3-((R or S)-1-(((R)-(2-fluorophenyl)((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(2,4-dimethyl- 5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-chloro-4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-3- methylphenyl)acetic acid; (S or R)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; (R or S)-2-(5-(2-(((R)- ((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2,4- dimethylphenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)propanoic acid; 2-(2-methyl-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2-(3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4-fluorophenyl)propanoic acid; 2-(3-chloro-4-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(5-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)propanoic acid; (S or R)-2-(3-chloro-4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-((R or S)- 1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)- 2,4-difluorophenyl)acetic acid; 2-(3-((S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetamide; 2-(4-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-3-fluorophenyl)acetic acid; 2-(4-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)propanoic acid; 2-(4- (2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)acetic acid; 2-(2-methoxy-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-((R and S)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2- fluorophenyl)acetic acid; (S or R)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)propanoic acid; (R and S)-2-(4-methoxy- 3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4-methoxyphenyl)propanoic acid; 2- (4-(difluoromethyl)-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(2,4-difluoro-5-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(4-fluoro-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)- 2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)propanoic acid; 2-(5-((S or R)-1-(((R)-((R)- 8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(4-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(3-((1H-tetrazol-5- yl)methyl)phenyl)-N-((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)ethan- 1-amine; 2-(2-fluoro-5-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4-methylphenyl)acetic acid; (R or S)-2- (4-methoxy-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-4- methoxyphenyl)propanoic acid; (R)-3-((R)-((4-((1H-tetrazol-5- yl)methyl)phenethyl)amino)(phenyl)methyl)-1,2,3,4-tetrahydroquinoxaline-5-carbonitrile; (S or R)-2-(2-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)- 8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2- yl)thiophen-3-yl)acetic acid; 2-(3-chloro-4-((R and S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-methyl- 2-(4-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-2-yl)acetic acid; 2-(4- fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-2-yl)acetic acid; (R or S)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(2- fluorophenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(2-methyl-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-methyl-2-(3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-(2-(((S)-((R and S)-7-fluoro-2-oxo- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(2-fluoro-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R)-3-((S)-((2-(6-methylpyridin-3- yl)ethyl)amino)(phenyl)methyl)-1,2,3,4-tetrahydroquinoline-5-carbonitrile; 2-(5-(2-(((S)- ((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-2- methylphenyl)acetic acid; 2-(2,4-dimethyl-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4-(2- (((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3- methoxyphenyl)propanoic acid; (S or R)-2-(4-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2- (4-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(2-fluorophenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5- ((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)furan-2-yl)acetic acid; (R and S)-2-(3-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(2- fluorophenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-fluoro- 5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(5-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-dimethylphenyl)acetic acid; 2-(2-chloro-4-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(3-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(2-chloro-5-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)acetic acid; 2-(4- (2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(2- fluorophenyl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(4-methyl-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-methyl-3-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- ((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; 2-(4-methyl-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(4-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R or S)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetamide; 2-(3-((S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetamide; 2-methyl-2-(4-methyl-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-5-((S or R)-1-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; (S or R)-2-(2- methoxy-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; (S or R)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)ethyl)phenyl)-3-methoxypropanoic acid; 2-(3-((S or R)-1-(((S)- ((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)- 4-methylphenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-3- fluorophenyl)propanoic acid; (R or S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin- 3-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; 2-(2-cyclopropyl-5-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)furan-2-yl)acetic acid; 2-(3-fluoro-5- ((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-fluoro-5-((R and S)-1-(((R)-((R)-7- fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methylphenyl)acetic acid; 2-(4-chloro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 1-(3-((R and S)-1-(((S)-((R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)cyclopropane-1-carboxylic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2,4-difluorophenyl)-2- methylpropanoic acid; (R or S)-2-(3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (S or R)-2-(4-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((S)-((R and S)-7-fluoro-2-oxo- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetamide; 2-(4-methoxy-3-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (R or S)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; (R or S)-2-(4-fluoro-3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; 2-(5- (2-(((1S)-(7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)thiophen-3-yl)-2- methylpropanoic acid; (S or R)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)-4-fluorophenyl)propanoic acid; 2-(2,4-difluoro-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-chloro-4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-fluoro-2-methyl-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(5-(2-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2- methylphenyl)acetic acid; 2-(5-((R and S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; 2-(3- ((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)-4-fluorophenyl)acetic acid; 2-(4-chloro-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; 2-(2-chloro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; 2-(4-chloro-3-((S or R)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)- 2-methylpropanoic acid; 2-(4-chloro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-methyl-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-3-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-ethyl-5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2- methyl-2-(5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)thiophen-3-yl)propanoic acid; 2-(4-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2,4-dimethylphenyl)propanoic acid; 2-(5-((S or R)-1-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2- fluorophenyl)acetic acid; 2-(2,4-dimethyl-5-(2-(((S)-phenyl((R)-5,6,7,8-tetrahydropyrido[3,2- c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; (R and S)-5-(3-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)benzyl)thiazolidine-2,4-dione; (R or S)-2-(2-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)propanoic acid; 2-(4-((R or S)-1-(((S)-((R)- 5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R)-3-((R)-((3-(1H-tetrazol-5-yl)phenethyl)amino)(phenyl)methyl)-1,2,3,4- tetrahydroquinoxaline-5-carbonitrile; 2-(3-chloro-5-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (R or S)-2-(4-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(2-methoxy-5-((S or R)-1- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(3-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(4-chloro-3-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-fluoro-3-((S or R)-1-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-(difluoromethoxy)-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-((R or S)-1- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-methyl-2-(3-(2-(((S)-((S)-2-oxo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R)-1-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; (R or S)-2-(2,4-difluoro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R or S)-2-(2,4-difluoro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-4- methoxyphenyl)propanoic acid; 2-(2-chloro-3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4- chloro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-chloro-3- ((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(5-((R and S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; 2- (2-fluoro-4-((R and S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R and S)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetamide; 2- (2-chloro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(2,4-difluoro-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(2- fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(4-(2-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)propanoic acid; (S or R)-2-(2-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R and S)- 1-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-chloro-3-((S or R)-1-(((R)- ((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4- methylphenyl)acetic acid; (R or S)-2-(3-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)-2- (trifluoromethoxy)phenyl)acetic acid; 2-(3-chloro-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2- (5-((R or S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; 2-(2-fluoro-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-5-methoxyphenyl)acetic acid; (R or S)-2-(2-chloro-5- (2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R and S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetamide; (R or S)-2- (5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- fluorophenyl)acetic acid; (S or R)-2-(3-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(2- chloro-4-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-methoxy-5-((S or R)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-chloro-5-((R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-7- fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2,4- dimethylphenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 3-(3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid; 2-(2,4-difluoro-5-((R or S)- 1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)-2-methylpropanoic acid; 2-(5-((R and S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; 2-(2- methyl-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-methyl-2-(3-methyl-5-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-methyl-5-((S or R)-1-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (2-fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-((S or R)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R and S)-2-(3-methoxy-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(2-fluoro-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(4-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4- fluorophenyl)acetic acid; 2-(3-((S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetonitrile; 2-(3-chloro-5-(2-(((R)-((R)-8- cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(2-methoxy-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 3-(4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S)-2-(3-(2H-tetrazol-5-yl)phenyl)-N-((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propan-1-amine; 2-(2,4- difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(3-(1H-tetrazol-5-yl)phenyl)-N- ((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)ethan-1-amine; 2-(3-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)-4- (trifluoromethyl)phenyl)acetic acid; 2-(2,4-difluoro-3-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methyl-5- (2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)thiophen-3-yl)acetic acid; 2-(4-methyl-3-((R or S)-1-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (5-((S)-1-(((S or R)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; 2-(3-fluoro-4-((R and S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-fluoro-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2- (2-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(3-(2-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-5- methylphenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; 2-(2- fluoro-5-((R and S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(4-fluoro-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; 2-(4-fluoro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(2,4-difluoro-5-((S or R)-1- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(4-cyclopropyl-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(6-(2-(((S)- ((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)pyridin-3- yl)acetic acid; 2-(2-methyl-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-4-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; 2-(4-chloro-3-((R and S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(4-((S or R)-1-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)ethyl)phenyl)-3-methoxypropanoic acid; 2-(3-chloro-4-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(2,4-difluoro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-chloro-4-((R or S)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (2-methoxy-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-ethyl-3-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(2-fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(2- methyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetamide; 2-(3-fluoro-5-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; 2-(3-fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-chloro-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (R or S)-2-(3-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S)-1-(((S)-((S)-7-fluoro-2-oxo- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-chloro-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R and S)-1-(((S)-phenyl((R)-5,6,7,8- tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- fluoro-5-((R and S)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-methyl-3-(2-(((S)-phenyl((R)- 5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; (S)-2- (3-(isoxazol-4-yl)phenyl)-N-((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)propan-1-amine; 2-(3-fluoro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-((S or R)-1-(((S)-((R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-3-methoxyphenyl)acetic acid; (S or R)-2-(4-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(4-((R or S)-1-(((S)-((R)- 5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(4-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-2-yl)acetic acid; (R and S)-2-(3-fluoro-4- (2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-chloro-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or S)-3- methoxy-2-(3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S)-2-(3-(isoxazol-4-yl)phenyl)-N-((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propan-1-amine; 2-(5-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)thiophen-2-yl)acetic acid; 2-(5-((R)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; (R and S)-2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(4-(difluoromethoxy)-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(2-methoxy-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2,4-difluoro-5-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-(2-(((S or R)-((S or R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(pyridin-3-yl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(5-(2-(((R)-((R)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)ethyl)-2,4- difluorophenyl)acetic acid; (S or R)-2-(4-fluoro-3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2- (3-((R and S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-fluorophenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1- (((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan- 2-yl)phenyl)acetic acid; 2-(2-chloro-4-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2- chloro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((S)-((S)-7-fluoro-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetamide; 2-(2-fluoro-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (R or S)-2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-5-fluorophenyl)acetic acid; 2-(2-fluoro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-methoxy-4-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-chloro-4-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; (S)-2-(3-bromophenyl)-N-((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propan-1-amine; 2-(4-fluoro- 3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-((R and S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)-1- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-5-((S)-1-(((S or R)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; (R or S)-2-(5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)propanoic acid; (S or R)-2-(3- methyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(4-fluoro-3-(2-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-5-methylphenyl)propanoic acid; 3-(3-((R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid; (S or R)-2-(3- fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-methyl-3-((S or R)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-((R and S)-1-(((R)-(3-fluorophenyl)((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-methyl- 2-(4-methyl-3-(2-(((R)-phenyl((R)-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-methyl-3-(2-(((R)-phenyl((R)-5,6,7,8- tetrahydropyrazino[2,3-c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)thiophen- 2-yl)acetic acid; 2-(3-((S or R)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-5-(2-(((R)- ((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(pyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)furan-2-yl)acetic acid; 2-(3-((R or S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-5-methylphenyl)acetic acid; 2-(3-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-chloro-3-((R or S)-1-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2- methylpropanoic acid; 2-(4-(2-(((R)-(3-fluorophenyl)((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((R or S)-1-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-5- methoxyphenyl)acetic acid; 2-(2-methyl-5-(2-(((S)-phenyl((R and S)-5,6,7,8- tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methoxy- 4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-methyl-2-(2-methyl-5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2- fluoro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(2,4-difluoro-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; (R or S)-2-(2,4-difluoro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3- ((R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan- 2-yl)phenyl)acetamide; 2-methyl-2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(3-ethyl-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)ethyl)amino)ethyl)-2,4-dimethylphenyl)acetic acid; 2-(5-((R or S)-1-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin- 3-yl)methyl)amino)ethyl)-4-(trifluoromethoxy)phenyl)acetic acid; 2-(4-chloro-3-((R or S)-1- (((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(5-(2-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)thiophen-2-yl)acetic acid; 2- (3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)acetic acid; 2-(5-((S or R)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; (R or S)-2-(2-fluoro-3-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(3-((R or S)-1-(((R)-((R)-7- fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(2-fluoro-5-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)- 2-methylpropanoic acid; (S or R)-2-(2-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; (S or R)-2-(2-fluoro-3- (2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-methyl-2-(2-methyl-3-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3- methoxy-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (5-((S or R)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; 2-(3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)-5- (trifluoromethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)furan-2-yl)acetic acid; (R or S)-2-(3- ((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan- 2-yl)phenyl)propanoic acid; 2-(5-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin- 2-yl)(phenyl)methyl)amino)ethyl)furan-3-yl)acetic acid; 2-(3-((R or S)-1-(((S)-((R)-7-fluoro- 2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-chloro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methyl-3-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2- fluoro-3-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)-1-(((S)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)- 1-(((S)-((S)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-chloro-5-((S or R)-1-(((R)- ((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)-5-(trifluoromethoxy)phenyl)acetic acid; 2-(2-chloro-5-((S or R)-1- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)-2-methylpropanoic acid; 2-(3-(2-(((S)-((S or R)-7-(1-methyl-1H-pyrazol-4-yl)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(3-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetamide; 2-(4- fluoro-3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)-1-(((R)-((R)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-5- fluorophenyl)acetic acid; 2-(3-chloro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- cyclopropyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(5-((S or R)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-fluorophenyl)acetic acid; 2-(2-fluoro-5-((R and S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-fluoro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)- 2-(3-(2-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((S)-((S)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4- methylphenyl)acetic acid; 2-(5-((R or S)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; 2-(5-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1- (((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phen+G466yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-fluoro- 5-((R or S)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R)-2-(3-(isoxazol-4-yl)phenyl)-N- ((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propenamide; (R)-2-(3- (isoxazol-4-yl)phenyl)-N-((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)propan-1-amine; 2-(3-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 2-(3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 2-(3-((R or S)-1-(((S)- ((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)-1- (((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-methylphenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1- (((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2,4-dimethyl-5- (2-(((S)-phenyl((S)-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(4-methyl-3- (2-(((S)-phenyl((S)-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((R)-7-fluoro-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(5-(2-(((S)-1-((S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)- 2,4-dimethylphenyl)acetic acid; (R and S)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(3-(2-(((S)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)ethyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid; 2-(5-(2-(((S)-1-((R or S)-5- cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(5-(2-(((S)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)- 2,4-dimethylphenyl)acetic acid; 2-(3-(2-(((S)-1-((S or R)-5-cyano-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid; 2-(5- (2-(((R)-1-((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2,4- dimethylphenyl)acetic acid; 2-(5-(2-(((S)-1-((S or R)-5-cyano-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2,2,2-trifluoroacetic acid--2-(5-(2-(((R)-1-((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-(2-(((R)-1-((R or S)-5-cyano-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid ; 2-(5-(2-(((R)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)- 2-methylphenyl)acetic acid; 2-(3-(2-(((R)-((R)-6,7-dihydro-5H-pyridazino[3,4-b][1,4]oxazin- 7-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid; 2-(3-(2-(((R)-1- ((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-4- methylphenyl)-2-methylpropanoic acid; (R or S)-2-(2-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3- methyl-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(3-((S or R)-1-(((R)-((R)-7- fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(2-methyl-3-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S)-2-(3- (isoxazol-4-yl)phenyl)-N-((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)propanamide; (S)-2-(3-bromophenyl)-N-((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propanamide; 2-(5-(2-(((R)-((S)-4-amino-3- chloro-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-7-yl)(phenyl)methyl)amino)ethyl)- 2-methylphenyl)acetic acid; 2-(3-((R and S)-1-(((R)-((R)-6,7-dihydro-5H-pyridazino[3,4- b][1,4]oxazin-7-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methanamine; (R)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methanamine; 2-(3-(2-(((R)-((R)-6,7-dihydro-5H- pyridazino[3,4-b][1,4]oxazin-7-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(3-((S)-1-(((R)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)-1-(((R)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-((R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)-1-(((R)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)- 1-(((R)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methanamine; 2-(5-(2-(((R)-((R)-6,7-dihydro-5H-pyridazino[3,4-b][1,4]oxazin-7- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-((R)-1-(((S)-phenyl((S)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (3-((S)-1-(((S)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)- 1-(((S)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-chloro-4-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methanamine; (S or R)-2-(3-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(3-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-fluorophenyl)acetic acid; 2-(5-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)thiophen- 3-yl)acetic acid; (S or R)-2-(3-(2-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(3-(2-(((R)-((R)-2,3- dihydro-1H-pyrido[2,3-b][1,4]thiazin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)ethyl)thiophen-2-yl)acetic acid; 2-(2- chloro-4-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2-(3-(2-(((S)-((S)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)- 2-(4-(2-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R or S)-1-(((S)-((S)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2-(4-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetamide; 2-(4-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)-1-(((R)-(2- fluorophenyl)((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)-2-methylpropanoic acid; 2-(2,4-difluoro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(3-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-((S)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(3-(2-(((R)-1-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)-1- phenylethyl)amino)ethyl)phenyl)acetic acid and 2-(3-(2-(((S)-1-((S)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)-1-phenylethyl)amino)ethyl)phenyl)acetic acid (1/1); (R or S)-2-(4- ((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R or S)-2-(2-fluoro-3-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(3-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-(1-((tert- butoxycarbonyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-3-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((R and S)-1-(((S)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)-1-(((R)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid. [0555] In some embodiments, the compound may be a compound, or pharmaceutically acceptable salt thereof, selected from: 2-(2-methyl-5-(2-(((S)-((R and S)-2- oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((S)-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-methyl-2-(3-(2-(((S)-((S)-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4- methyl-3-(2-(((S)-((S)-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-methyl-2-(4-methyl-3-(2-(((S)-((S)-2- oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((R)-1-((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)ethyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid; 2-(5-(2-(((R)-1-((R or S)-5- cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-(2-(((R)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)- 4-methylphenyl)-2-methylpropanoic acid ; 2,2,2-trifluoroacetic acid--2-(5-(2-(((R)-1-((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(5-(2-(((R)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)ethyl)amino)ethyl)-2,4-dimethylphenyl)acetic acid; 2-(5-(2-(((S)-1-((S or R)-5-cyano-2- oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(5-(2- (((R)-1-((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2,4- dimethylphenyl)acetic acid; 2-(3-(2-(((S)-1-((S or R)-5-cyano-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid; 2-(5- (2-(((S)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2,4- dimethylphenyl)acetic acid; 2-(5-(2-(((S)-1-((R or S)-5-cyano-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-(2-(((S)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-4-methylphenyl)-2- methylpropanoic acid; 2-(3-(2-(((S)-((S)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(5-(2-(((S)-1-((S)-5-cyano- 2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2,4-dimethylphenyl)acetic acid; 2- (3-(2-(((S)-((R and S)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(3-((S)-1-(((S)-((S)-7-fluoro- 2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(5-(2-(((1S)-(7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-((R)-1-(((S)-((S)-7-fluoro- 2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(5-(2-(((S)-((R)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-(2-(((S)-((R)-7-fluoro-2- oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; 2-(3-(2-(((S)-((S)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)(phenyl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(3-(2-(((S or R)-((S or R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(pyridin-3-yl)methyl)amino)ethyl)-4- methylphenyl)acetic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(pyridin-3-yl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((S or R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4- ((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-((S)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(4-(2- (((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R or S)-1-(((S)-((R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- ((S or R)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-((S or R)-1-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((S)-((S)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- ((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(3-(2-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2- (3-(2-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-4- fluorophenyl)acetic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; (R or S)-2-(4-(2-(((S)-((S)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(4-((R and S)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2- (4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3- fluorophenyl)acetic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)-5-fluorophenyl)acetic acid; 2-(5-(2-(((S)-((R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; (S or R)-2-(4-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R and S)-2-(3-((R and S)-1- (((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(4-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(4-(2- (((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2- fluorophenyl)acetic acid; (S or R)-2-(3-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R and S)-2-(4-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R or S)-2-(3-((R or S)-1-(((S)- ((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R and S)-2-(3-(2-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(3-((S or R)-1-(((S)-((S)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (S or R)-2-(3-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(4-(2-(((S)-((R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)acetic acid; 2-(4-((R and S)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 2-(4-(2-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)-1- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-methyl-2-(3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R and S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((S)- ((S or R)-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((R or S)-7-(1-methyl-1H- pyrazol-4-yl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-fluoro-3- (2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 3-(3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid; 3-(3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid; (S or R)-2-(3-((R or S)-1- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (S or R)-2-(3-((S or R)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(2-fluoro-4-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-fluoro-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-3-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- fluoro-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-3-((R or S)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- fluoro-4-((R and S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-fluoro-3-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(2-fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(3-fluoro-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2- fluoro-5-((R and S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(4-fluoro-3-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(2-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(3-fluoro-4-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3- fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(3-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(4- fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(2-fluoro-3-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(2-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-4-((R and S)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(2-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-methoxy-5-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methyl-5-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-methoxy-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-methyl-3-((R and S)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4- methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-chloro-4-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methyl-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-chloro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methyl-5-((R or S)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- chloro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-chloro-5-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methoxy-4-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-4-methyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-methyl-3-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4- methyl-3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2,4-dimethyl-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-fluoro- 2-methyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-methoxy-4-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4- methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-methoxy-5-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(4-methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-methoxy-5-((R or S)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2- methyl-5-(2-(((S)-phenyl((R and S)-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(difluoromethyl)-3-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2- (difluoromethyl)-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-methyl-3-(2-(((S)-phenyl((R)-5,6,7,8- tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-methyl-3- (2-(((S)-phenyl((S)-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)acetic acid; (R and S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; 2- (2,4-dimethyl-5-(2-(((S)-phenyl((R)-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-((S or R)-1-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 2- (3-(2-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(2,4-dimethyl-5-(2-(((S)- phenyl((S)-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)propanoic acid; 2-(4-((R or S)-1-(((S)- ((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; (S or R)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)propanoic acid; 2-(3-(2-(((S)-((R and S)-7- fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4- methylphenyl)acetic acid; 2-(5-(2-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((S)- ((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(5-(2-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((S)-7- fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4- methylphenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)- 1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan- 2-yl)-4-methylphenyl)acetic acid; 2-(6-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)pyridin-3-yl)acetic acid; 2-(2-fluoro-5-((S)-1-(((S or R)-((R)- 7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((1H-tetrazol- 5-yl)methyl)phenyl)-N-((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)ethan-1-amine; (R or S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; 2-(4-((R and S)-1-(((S)- ((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-3- methoxyphenyl)acetic acid; (S or R)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; 2-(2-fluoro-5-((R or S)-1- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R or S)-1- (((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-fluoro-5-((R or S)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-fluoro-3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; (R)-3-((S)-((2-(6-methylpyridin-3-yl)ethyl)amino)(phenyl)methyl)- 1,2,3,4-tetrahydroquinoline-5-carbonitrile; 2-(4-fluoro-3-((S or R)-1-(((S)-((R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2,4-difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-fluoro-5-((R or S)-1-(((S)-((R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1-(((S)- ((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phen+G466yl)methyl)amino)propan- 2-yl)phenyl)acetic acid; **correct name?; 2-(3-fluoro-5-((S or R)-1-(((S)-((R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1-(((S)- ((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-((S or R)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(1H-tetrazol- 5-yl)phenyl)-N-((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)ethan-1- amine; 2-(5-((S)-1-(((S or R)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; 2-(3-((R or S)-1-(((S)- ((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)- 4-methylphenyl)acetic acid; 2-(4-((S or R)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)-3-methoxyphenyl)acetic acid; 2-(5-((S or R)-1-(((S)- ((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)- 2-methylphenyl)acetic acid; 2-(3-((S or R)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4-methylphenyl)acetic acid; 2-(5-((R or S)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; 2-(4-((R or S)-1-(((S)- ((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-3- methoxyphenyl)acetic acid; 2-(5-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; (R and S)- 5-(3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)benzyl)thiazolidine-2,4-dione; 1-(3-((R and S)-1-(((S)-((R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)cyclopropane-1-carboxylic acid; 2-(3-((R and S)-1-(((S)-phenyl((R)-5,6,7,8- tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2-(2,4-difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-5-((R and S)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)-2- methylpropanoic acid; 5-(3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)thiazolidine-2,4-dione; 2-(2-fluoro-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(2-fluoro-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 3-(4-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2,4- difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (S or R)-2-(2,4-difluoro-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(2,4-difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-5-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)-2- methylpropanoic acid; 2-(3-((S or R)-1-(((S)-((R)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R or S)-1- (((S)-((R)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid [0556] While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art. The various aspects and embodiments disclosed herein are for purposes of illustration and are not intended to be limiting, with the true scope and spirit being indicated by the following claims.

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (IIIe-1): (IIIe-1), or a pharmaceutically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is aryl substituted with 1 to 3 substituents selected from -CH2C(O)H, alkyl, substituted alkyl, cyano, halogen, and R60, wherein the aryl is phenyl and the C1-C6 substituted alkyl is C1-C6 alkylene substituted with 1 to 3 R60, spiro-connected cycloalkyl or spiro- connected heterocycloalkyl; R60 is alkyl, cyano, -COOH, halogen, haloalkyl and alkoxy; and R10 is hydrogen, or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein R60 is -COOH, cyano, fluoro, methyl, methoxy or -CF3.
3. The compound of claim 2, wherein R6 is phenyl substituted with –(CH2)COOH, or phenyl substituted with C1-C6 alkylene substituted with -COOH or cyano and optionally substituted with a spiro-connected C3 to C6 cycloalkyl or a spiro-connected 3 to 6 member heterocycloalkyl. 4. The compound of claim 3, wherein R6 is phenyl further substituted with one or two methyl. 5. The compound of claim 2, wherein R6 is phenyl substituted with cyano or alkyl substituted with cyano. 6. The compound of claim 2, wherein R6 is ,
Figure imgf000340_0001
7. The compound of claim 6, wherein R6 is , or
Figure imgf000340_0002
8. The compound of claim 6, wherein R6 is
Figure imgf000341_0001
,
Figure imgf000341_0002
9. The compound of claim 6, wherein each R60 is independently methyl, fluoro or methoxy. 10. The compound of claim 6, wherein R6 is , or
Figure imgf000341_0003
11. The compound of claim 2, wherein R6 is selected from:
Figure imgf000341_0004
Figure imgf000342_0001
12. The compound of claim 2, wherein R6 is phenyl substituted with C1-C6 alkylene substituted with -COOH and substituted with a spiro-connected C3 to C6 cycloalkyl or a spiro- connected 3 to 6 member heterocycloalkyl. 13. The compound of claim 12, wherein R6 is , , or . 14. A compound of Formula (IIIe-1): or a pharmaceut
Figure imgf000343_0001
ically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is aryl substituted with 1 to 3 substituents selected from -CH2C(O)H, alkyl, substituted alkyl, cyano, halogen, and R60, wherein the aryl is phenyl and the C1-C6 substituted alkyl is C1-C6 alkylene substituted with 1 to 3 R60, spiro-connected cycloalkyl or spiro- connected heterocycloalkyl; R10 is pyrazolyl substituted with alkyl, or a pharmaceutically acceptable salt thereof. 15. The compound of claim 14, wherein R10 is methyl, fluoro or 16. The compound of claim 15, wherein R6 is phenyl substituted with –(C1-C6 alkyl)COOH, -CN or -CH2CN; and R60 is cyano, fluoro, methyl, methoxy or -CF3. 17. The compound of claim 16, wherein R6 is ,
Figure imgf000344_0001
18. The compound of claim 17, wherein R6 is , or
Figure imgf000345_0001
19. The compound of any one of claims 1-18, wherein the compound is a compound of Formula (VI-A), or a pharmaceutically acceptable salt thereof:
Figure imgf000345_0002
(IV-A). 20. The compound of claim 19, wherein the compound is a compound of Formula (VI-A-1), or a pharmaceutically acceptable salt thereof: (IV-A-1).
Figure imgf000345_0003
21. The compound of claim 19, wherein the compound is a compound of Formula (VI-A-2), or a pharmaceutically acceptable salt thereof:
Figure imgf000346_0001
22. The compound of claim 1, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof.
Figure imgf000346_0002
23. The compound of claim 1, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof.
Figure imgf000346_0003
24. The compound of claim 1, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof. 25. A compound of Formula (IIIe-1): R
Figure imgf000347_0001
or a pharmaceutically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is aryl substituted with 1 to 3 substituents selected from -CH2C(O)H, alkyl, substituted alkyl, cyano, halogen, and R60, wherein the aryl is phenyl and the C1-C6 substituted alkyl is C1-C6 alkylene substituted with 1 to 3 R60, spiro-connected cycloalkyl or spiro- connected heterocycloalkyl; R10 is fluoro, or a pharmaceutically acceptable salt thereof. 26. The compound of claim 25, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof.
27. The compound of claim 25, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof. 28. The compound of claim 25, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof. 29. The compound of claim 25, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof. 30. A compound of Formula (IIIe-1):
Figure imgf000348_0001
or a pharmaceutically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is optionally substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl; R10 is pyrazolyl substituted with methyl, or a pharmaceutically acceptable salt thereof. 31. The compound of claim 30, wherein R10 is . 32. The compound of claim 31, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof. 33. A compound of Formula (IIIe-1):
Figure imgf000349_0001
or a pharmaceutically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is optionally substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl; R10 is C1-C6 alkyl substituted with -COOH, or a pharmaceutically acceptable salt thereof. 34. A compound of Formula (IIIe-1): (IIIe-1), or a pharmaceutically acceptable salt thereof, wherein: R1a is hydrogen; R2b and R2c are each independently hydrogen; R3a and R3b are each independently hydrogen; R4a is phenyl; R4b is hydrogen; J is NH; R5 is -L-R6; L is -CH2CH2- or -CH2CH(CH3)-; R6 is optionally substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl; R10 is methyl, or a pharmaceutically acceptable salt thereof.
35. The compound of claim 34, wherein the compound is the compound , or a pharmaceutically acceptable salt thereof. 36. A compound, or pharmaceutically acceptable salt thereof, selected from the group consisting of: 2-(2-chloro-5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (3-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)ethyl)-4-methoxyphenyl)acetic acid; 2-(4-((S or R)-1-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((S or R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- (2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(pyridin-3-yl)methyl)amino)ethyl)-4- methylphenyl)acetic acid; 2-(3-((S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; 2-(3-(2-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-4- fluorophenyl)acetic acid; (R or S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-5-fluorophenyl)acetic acid; 2-(5-(2- (((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2- fluorophenyl)acetic acid; (R or S)-2-(4-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3- (2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4- fluorophenyl)acetic acid; 2-(2-methyl-5-(2-(((S)-((R and S)-2-oxo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; (R or S)-2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-chloro-5-(2-(((R)-((R)-8-cyano- 3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2- (2-(difluoromethyl)-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((S)-7-fluoro-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-methylphenyl)acetic acid; 2-(2-chloro-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-((S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 3-(3-((S)-1-(((R)-((R)- 8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)oxetane-3-carboxylic acid; (R and S)-2-(4-((R and S)-1-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-(2- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-5- fluorophenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-((R)- 5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; (S or R)-2-(3-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)-3- methoxypropanoic acid; 2-(2,4-dimethyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-4-methyl-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(5-((R or S)-1-(((S)-((R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methylphenyl)acetic acid; 2-(4-methyl-3-(2-(((S)-((S)-2-oxo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-methyl-3-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(5-(2-(((S)-((R)-7-fluoro-2- oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-2- methylphenyl)acetic acid; 2-(4-chloro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)-3- methoxypropanoic acid; (S or R)-2-(4-methyl-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(2-fluorophenyl)methyl)amino)ethyl)phenyl)acetic acid; 2- (2-fluoro-5-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(3-((S or R)-1-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(2-fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2- methyl-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; 2-(5-(2- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)acetic acid; (S or R)-2-(3-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2- (3-((R and S)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)ethyl)phenyl)acetic acid; 2- (3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4- methylphenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(4-methyl-3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-3-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4- ((R or S)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)-3-methoxyphenyl)acetic acid; 2-(4-fluoro-3-((R or S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-chloro-3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2- (3-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(4-methoxy-3-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(4-fluoro-2-methyl-5-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-((R and S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 2-(2-chloro-5-((R or S)- 1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(5-((R and S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; 2-(3-((S)-1-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-5-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 3-(3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid; 2-(4-chloro-3-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)acetic acid; 5-(3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)thiazolidine-2,4-dione; (R or S)-2-(3-((R or S)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(3-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((S or R)-1-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(4-methyl-3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4- methoxyphenyl)acetic acid; 2-(3-((R and S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)- 2,4-difluorophenyl)acetic acid; 2-(2-methyl-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-methylthiophen-3-yl)acetic acid; 2-(2-methoxy-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(2,4-difluoro-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-methyl-3-((R and S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-chloro-5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(2,4-difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-5-fluorophenyl)propanoic acid; 2- (2,4-difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R o rS)-2-(2-fluoro-5-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((S)-((R)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)propanoic acid; 2-(5-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)acetic acid; 2-(3- fluoro-5-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-methyl-2-(4-methyl-3-(2-(((S)- ((S)-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((S)-((S)-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- fluorophenyl)acetic acid; 2-(2-chloro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-((R and S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(3- fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S)-2-(3-((2H-tetrazol-5- yl)methyl)phenyl)-N-((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)propan-1-amine; 2-(2-fluoro-4-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-((R and S)- 1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(5-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)propan-2-yl)-2-fluorophenyl)acetic acid; 2-(4-methoxy-3-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3-fluorophenyl)acetic acid; 2-(3-((S or R)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(2-fluoro-5-((S or R)-1-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)-2- methylpropanoic acid; 2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)-2-(trifluoromethyl)phenyl)acetic acid; (R)-3-((R)-((3-((1H-tetrazol-5- yl)methyl)phenethyl)amino)(phenyl)methyl)-1,2,3,4-tetrahydroquinoxaline-5-carbonitrile; 2- (5-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; (R or S)-2-(3-(2-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4- fluorophenyl)propanoic acid; 2-(3-(2-(((S)-((R or S)-7-(1-methyl-1H-pyrazol-4-yl)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2- chloro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(4-((R and S)-1-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan- 2-yl)-3-methoxyphenyl)acetic acid; (R or S)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-5-fluorophenyl)propanoic acid; (R and S)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)propanoic acid; 2-(4-(2-(((S)-((R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)acetic acid; (R and S)-2-(2-chloro-5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(pyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)- 8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- fluorophenyl)propanoic acid; 2-(2-methoxy-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)- 2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)- 5-fluorophenyl)propanoic acid; 2-(3-(2-(((S)-((R and S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(2,4-difluoro- 5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(3- (2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(3- fluorophenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-((R and S)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3- yl)acetic acid; 2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)propanoic acid; (R and S)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(4-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)ethyl)phenyl)acetic acid; 2- (3-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)-4-fluorophenyl)acetic acid; 2-(2-fluoro-5-((R and S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)-2-methylpropanoic acid; (R and S)-(3-chloro-4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-chloro-5- ((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(5-((S or R)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3- yl)acetic acid; 2-(3-((R or S)-1-(((R)-(2-fluorophenyl)((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(2,4-dimethyl- 5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-chloro-4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-3- methylphenyl)acetic acid; (S or R)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; (R or S)-2-(5-(2-(((R)- ((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2,4- dimethylphenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)propanoic acid; 2-(2-methyl-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2-(3-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4-fluorophenyl)propanoic acid; 2-(3-chloro-4-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(5-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)propanoic acid; (S or R)-2-(3-chloro-4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-((R or S)- 1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)- 2,4-difluorophenyl)acetic acid; 2-(3-((S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetamide; 2-(4-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-3-fluorophenyl)acetic acid; 2-(4-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-fluorophenyl)propanoic acid; 2-(4- (2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)acetic acid; 2-(2-methoxy-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-((R and S)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2- fluorophenyl)acetic acid; (S or R)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)propanoic acid; (R and S)-2-(4-methoxy- 3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-4-methoxyphenyl)propanoic acid; 2- (4-(difluoromethyl)-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(2,4-difluoro-5-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(4-fluoro-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)- 2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)propanoic acid; 2-(5-((S or R)-1-(((R)-((R)- 8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(4-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(3-((1H-tetrazol-5- yl)methyl)phenyl)-N-((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)ethan- 1-amine; 2-(2-fluoro-5-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4-methylphenyl)acetic acid; (R or S)-2- (4-methoxy-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-4- methoxyphenyl)propanoic acid; (R)-3-((R)-((4-((1H-tetrazol-5- yl)methyl)phenethyl)amino)(phenyl)methyl)-1,2,3,4-tetrahydroquinoxaline-5-carbonitrile; (S or R)-2-(2-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)- 8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2- yl)thiophen-3-yl)acetic acid; 2-(3-chloro-4-((R and S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-methyl- 2-(4-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-2-yl)acetic acid; 2-(4- fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-2-yl)acetic acid; (R or S)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(2- fluorophenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(2-methyl-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-methyl-2-(3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-(2-(((S)-((R and S)-7-fluoro-2-oxo- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(2-fluoro-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R)-3-((S)-((2-(6-methylpyridin-3- yl)ethyl)amino)(phenyl)methyl)-1,2,3,4-tetrahydroquinoline-5-carbonitrile; 2-(5-(2-(((S)- ((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-2- methylphenyl)acetic acid; 2-(2,4-dimethyl-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4-(2- (((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3- methoxyphenyl)propanoic acid; (S or R)-2-(4-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2- (4-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(2-fluorophenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5- ((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)furan-2-yl)acetic acid; (R and S)-2-(3-(2-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(2- fluorophenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-fluoro- 5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(5-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-dimethylphenyl)acetic acid; 2-(2-chloro-4-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(3-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(2-chloro-5-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)acetic acid; 2-(4- (2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(2- fluorophenyl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(4-methyl-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-methyl-3-((S or R)-1-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- ((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; 2-(4-methyl-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(4-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R or S)-1-(((R)-((R)-8- cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetamide; 2-(3-((S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetamide; 2-methyl-2-(4-methyl-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-5-((S or R)-1-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; (S or R)-2-(2- methoxy-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; (S or R)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)ethyl)phenyl)-3-methoxypropanoic acid; 2-(3-((S or R)-1-(((S)- ((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)- 4-methylphenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-3- fluorophenyl)propanoic acid; (R or S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4-tetrahydroquinolin- 3-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; 2-(2-cyclopropyl-5-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)furan-2-yl)acetic acid; 2-(3-fluoro-5- ((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-fluoro-5-((R and S)-1-(((R)-((R)-7- fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methylphenyl)acetic acid; 2-(4-chloro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 1-(3-((R and S)-1-(((S)-((R)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)cyclopropane-1-carboxylic acid; 2-(5-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2,4-difluorophenyl)-2- methylpropanoic acid; (R or S)-2-(3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (S or R)-2-(4-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-(2-(((S)-((R and S)-7-fluoro-2-oxo- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)acetamide; 2-(4-methoxy-3-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (R or S)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; (R or S)-2-(4-fluoro-3-(2- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(4-(2-(((S)-((R)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-3-methoxyphenyl)propanoic acid; 2-(5- (2-(((1S)-(7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)thiophen-3-yl)-2- methylpropanoic acid; (S or R)-2-(3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)-4-fluorophenyl)propanoic acid; 2-(2,4-difluoro-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-chloro-4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-fluoro-2-methyl-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(5-(2-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2- methylphenyl)acetic acid; 2-(5-((R and S)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; 2-(3- ((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)-4-fluorophenyl)acetic acid; 2-(4-chloro-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; 2-(2-chloro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; 2-(4-chloro-3-((S or R)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)- 2-methylpropanoic acid; 2-(4-chloro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-methyl-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-3-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-ethyl-5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2- methyl-2-(5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)thiophen-3-yl)propanoic acid; 2-(4-(2-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2,4-dimethylphenyl)propanoic acid; 2-(5-((S or R)-1-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2- fluorophenyl)acetic acid; 2-(2,4-dimethyl-5-(2-(((S)-phenyl((R)-5,6,7,8-tetrahydropyrido[3,2- c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; (R and S)-5-(3-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)benzyl)thiazolidine-2,4-dione; (R or S)-2-(2-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)propanoic acid; 2-(4-((R or S)-1-(((S)-((R)- 5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R)-3-((R)-((3-(1H-tetrazol-5-yl)phenethyl)amino)(phenyl)methyl)-1,2,3,4- tetrahydroquinoxaline-5-carbonitrile; 2-(3-chloro-5-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (R or S)-2-(4-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(2-methoxy-5-((S or R)-1- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(3-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(4-chloro-3-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-fluoro-3-((S or R)-1-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-(difluoromethoxy)-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-((R or S)-1- (((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-methyl-2-(3-(2-(((S)-((S)-2-oxo-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R)-1-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(3-fluorophenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; (R or S)-2-(2,4-difluoro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R or S)-2-(2,4-difluoro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-4- methoxyphenyl)propanoic acid; 2-(2-chloro-3-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4- chloro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-chloro-3- ((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(5-((R and S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; 2- (2-fluoro-4-((R and S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R and S)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetamide; 2- (2-chloro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(2,4-difluoro-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(2- fluorophenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(4-(2-(((S)-((R)-5- cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)propanoic acid; (S or R)-2-(2-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R and S)- 1-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-chloro-3-((S or R)-1-(((R)- ((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4- methylphenyl)acetic acid; (R or S)-2-(3-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(5-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)-2- (trifluoromethoxy)phenyl)acetic acid; 2-(3-chloro-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2- (5-((R or S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; 2-(2-fluoro-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-5-methoxyphenyl)acetic acid; (R or S)-2-(2-chloro-5- (2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R and S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetamide; (R or S)-2- (5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- fluorophenyl)acetic acid; (S or R)-2-(3-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(2- chloro-4-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-methoxy-5-((S or R)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-chloro-5-((R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(5-(2-(((R)-((R)-7- fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2,4- dimethylphenyl)acetic acid; 2-(2-fluoro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 3-(3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid; 2-(2,4-difluoro-5-((R or S)- 1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)-2-methylpropanoic acid; 2-(5-((R and S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3- b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; 2-(2- methyl-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro- 1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-methyl-2-(3-methyl-5-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-methyl-5-((S or R)-1-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (2-fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(3-((S or R)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R and S)-2-(3-methoxy-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(2-fluoro-5-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(4-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4- fluorophenyl)acetic acid; 2-(3-((S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetonitrile; 2-(3-chloro-5-(2-(((R)-((R)-8- cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(2-methoxy-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 3-(4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S)-2-(3-(2H-tetrazol-5-yl)phenyl)-N-((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propan-1-amine; 2-(2,4- difluoro-5-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(3-(1H-tetrazol-5-yl)phenyl)-N- ((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)ethan-1-amine; 2-(3-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)-4- (trifluoromethyl)phenyl)acetic acid; 2-(2,4-difluoro-3-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methyl-5- (2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)thiophen-3-yl)acetic acid; 2-(4-methyl-3-((R or S)-1-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (5-((S)-1-(((S or R)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; 2-(3-fluoro-4-((R and S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-fluoro-5-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2- (2-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(3-(2-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-5- methylphenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; 2-(2- fluoro-5-((R and S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(4-fluoro-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; 2-(4-fluoro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(2,4-difluoro-5-((S or R)-1- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(4-cyclopropyl-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(6-(2-(((S)- ((R)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)pyridin-3- yl)acetic acid; 2-(2-methyl-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-4-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; 2-(4-chloro-3-((R and S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(4-((S or R)-1-(((R)- ((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)ethyl)phenyl)-3-methoxypropanoic acid; 2-(3-chloro-4-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(2,4-difluoro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-chloro-4-((R or S)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (2-methoxy-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-3-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-ethyl-3-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(2-fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(2- methyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-(2-(((R)-((R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)phenyl)acetamide; 2-(3-fluoro-5-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; 2-(3-fluoro-4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin- 3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-chloro-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (R or S)-2-(3-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S)-1-(((S)-((S)-7-fluoro-2-oxo- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-chloro-3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R and S)-1-(((S)-phenyl((R)-5,6,7,8- tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- fluoro-5-((R and S)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-methyl-3-(2-(((S)-phenyl((R)- 5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; (S)-2- (3-(isoxazol-4-yl)phenyl)-N-((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)propan-1-amine; 2-(3-fluoro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-((S or R)-1-(((S)-((R)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-3-methoxyphenyl)acetic acid; (S or R)-2-(4-fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(4-((R or S)-1-(((S)-((R)- 5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(4-((S or R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin- 2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-2-yl)acetic acid; (R and S)-2-(3-fluoro-4- (2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-chloro-5-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (S or S)-3- methoxy-2-(3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (S)-2-(3-(isoxazol-4-yl)phenyl)-N-((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propan-1-amine; 2-(5-((R or S)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2- yl)thiophen-2-yl)acetic acid; 2-(5-((R)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; (R and S)-2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(4-(difluoromethoxy)-3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; (R or S)-2-(2-methoxy-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2,4-difluoro-5-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-(2-(((S or R)-((S or R)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(pyridin-3-yl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(5-(2-(((R)-((R)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)ethyl)-2,4- difluorophenyl)acetic acid; (S or R)-2-(4-fluoro-3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2- (3-((R and S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-fluorophenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1- (((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan- 2-yl)phenyl)acetic acid; 2-(2-chloro-4-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2- chloro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((S)-((S)-7-fluoro-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(3-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetamide; 2-(2-fluoro-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; (R or S)-2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)-2,3-dihydro- 1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-5-fluorophenyl)acetic acid; 2-(2-fluoro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-methoxy-4-(2-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-chloro-4-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; (S)-2-(3-bromophenyl)-N-((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propan-1-amine; 2-(4-fluoro- 3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-((R and S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)-1- (((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-5-((S)-1-(((S or R)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; (R or S)-2-(5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2-methoxyphenyl)propanoic acid; (S or R)-2-(3- methyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(4-fluoro-3-(2-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-fluoro-5-((S or R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-5-methylphenyl)propanoic acid; 3-(3-((R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)oxetane-3-carboxylic acid; (S or R)-2-(3- fluoro-5-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2-methyl-3-((S or R)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-((R and S)-1-(((R)-(3-fluorophenyl)((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-methyl- 2-(4-methyl-3-(2-(((R)-phenyl((R)-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-methyl-3-(2-(((R)-phenyl((R)-5,6,7,8- tetrahydropyrazino[2,3-c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-(2- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)thiophen- 2-yl)acetic acid; 2-(3-((S or R)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(2-fluoro-5-(2-(((R)- ((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(pyridin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S or R)-2-(3-((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(5-((R or S)-1-(((R)-((R)-8-cyano- 1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan-2-yl)furan-2-yl)acetic acid; 2-(3-((R or S)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-5-methylphenyl)acetic acid; 2-(3-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(4-chloro-3-((R or S)-1-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2- methylpropanoic acid; 2-(4-(2-(((R)-(3-fluorophenyl)((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((R or S)-1-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-5- methoxyphenyl)acetic acid; 2-(2-methyl-5-(2-(((S)-phenyl((R and S)-5,6,7,8- tetrahydropyrido[3,2-c]pyridazin-7-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methoxy- 4-(2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-methyl-2-(2-methyl-5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(2- fluoro-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(2,4-difluoro-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)-2- methylpropanoic acid; (R or S)-2-(2,4-difluoro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3- ((R)-1-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)propan- 2-yl)phenyl)acetamide; 2-methyl-2-(5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)thiophen-3-yl)propanoic acid; 2-(3-ethyl-5-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(5-(2-(((R)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)ethyl)amino)ethyl)-2,4-dimethylphenyl)acetic acid; 2-(5-((R or S)-1-(((R)-((R)-7-fluoro- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2- methoxyphenyl)acetic acid; 2-(3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin- 3-yl)methyl)amino)ethyl)-4-(trifluoromethoxy)phenyl)acetic acid; 2-(4-chloro-3-((R or S)-1- (((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(5-(2-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)thiophen-2-yl)acetic acid; 2- (3-(2-(((R)-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)(phenyl)methyl)amino)ethyl)-2- methoxyphenyl)acetic acid; 2-(5-((S or R)-1-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)propan-2-yl)thiophen-3-yl)acetic acid; (R or S)-2-(2-fluoro-3-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (S or R)-2-(3-((R or S)-1-(((R)-((R)-7- fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(2-fluoro-5-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)- 2-methylpropanoic acid; (S or R)-2-(2-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-methoxyphenyl)acetic acid; (S or R)-2-(2-fluoro-3- (2-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-methyl-2-(2-methyl-3-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3- methoxy-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (5-((S or R)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2,4-difluorophenyl)acetic acid; 2-(3-(2-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)-5- (trifluoromethyl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)(phenyl)methyl)amino)ethyl)furan-2-yl)acetic acid; (R or S)-2-(3- ((R or S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan- 2-yl)phenyl)propanoic acid; 2-(5-(2-(((R)-((R)-8-cyano-3,4-dihydro-2H-benzo[b][1,4]oxazin- 2-yl)(phenyl)methyl)amino)ethyl)furan-3-yl)acetic acid; 2-(3-((R or S)-1-(((S)-((R)-7-fluoro- 2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-chloro-3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-methyl-3-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2- fluoro-3-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)-1-(((S)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)- 1-(((S)-((S)-7-fluoro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-chloro-5-((S or R)-1-(((R)- ((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)-5-(trifluoromethoxy)phenyl)acetic acid; 2-(2-chloro-5-((S or R)-1- (((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)-2-methylpropanoic acid; 2-(3-(2-(((S)-((S or R)-7-(1-methyl-1H-pyrazol-4-yl)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(3-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)acetamide; 2-(4- fluoro-3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)-1-(((R)-((R)-2,3- dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-5- fluorophenyl)acetic acid; 2-(3-chloro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3- cyclopropyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(2-fluoro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(5-((S or R)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-fluorophenyl)acetic acid; 2-(2-fluoro-5-((R and S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-fluoro-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)- 2-(3-(2-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((S)-((S)-7-fluoro- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-4- methylphenyl)acetic acid; 2-(5-((R or S)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; 2-(5-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methylphenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1- (((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-fluoro-5-((S or R)-1-(((S)-((R)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phen+G466yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-fluoro- 5-((R or S)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R)-2-(3-(isoxazol-4-yl)phenyl)-N- ((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propenamide; (R)-2-(3- (isoxazol-4-yl)phenyl)-N-((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)propan-1-amine; 2-(3-((S or R)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 2-(3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-2-methoxyphenyl)acetic acid; 2-(3-((R or S)-1-(((S)- ((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-5-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)-1- (((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(2-fluoro-3-((R or S)-1-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-methylphenyl)acetic acid; 2-(4-fluoro-3-((R or S)-1- (((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(4-fluoro-3-((S or R)-1-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2,4-dimethyl-5- (2-(((S)-phenyl((S)-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((S)-7-fluoro-1,2,3,4-tetrahydro-1,5- naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(4-methyl-3- (2-(((S)-phenyl((S)-5,6,7,8-tetrahydropyrido[3,2-c]pyridazin-7- yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-(2-(((S)-((R)-7-fluoro-2-oxo-1,2,3,4- tetrahydro-1,5-naphthyridin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)-2-methylpropanoic acid; 2-(5-(2-(((S)-1-((S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)- 2,4-dimethylphenyl)acetic acid; (R and S)-2-(3-(2-(((R)-((R)-7-fluoro-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)propanoic acid; 2-(3-(2-(((S)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)ethyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid; 2-(5-(2-(((S)-1-((R or S)-5- cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(5-(2-(((S)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)- 2,4-dimethylphenyl)acetic acid; 2-(3-(2-(((S)-1-((S or R)-5-cyano-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid; 2-(5- (2-(((R)-1-((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2,4- dimethylphenyl)acetic acid; 2-(5-(2-(((S)-1-((S or R)-5-cyano-2-oxo-1,2,3,4- tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2,2,2-trifluoroacetic acid--2-(5-(2-(((R)-1-((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3- yl)ethyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-(2-(((R)-1-((R or S)-5-cyano-2-oxo- 1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid ; 2-(5-(2-(((R)-1-((R or S)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)- 2-methylphenyl)acetic acid; 2-(3-(2-(((R)-((R)-6,7-dihydro-5H-pyridazino[3,4-b][1,4]oxazin- 7-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)-2-methylpropanoic acid; 2-(3-(2-(((R)-1- ((S or R)-5-cyano-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)ethyl)amino)ethyl)-4- methylphenyl)-2-methylpropanoic acid; (R or S)-2-(2-methyl-3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3- methyl-5-((R or S)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R or S)-2-(3-((S or R)-1-(((R)-((R)-7- fluoro-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(2-methyl-3-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S)-2-(3- (isoxazol-4-yl)phenyl)-N-((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)propanamide; (S)-2-(3-bromophenyl)-N-((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)propanamide; 2-(5-(2-(((R)-((S)-4-amino-3- chloro-6-oxo-5,6,7,8-tetrahydropyrazino[2,3-c]pyridazin-7-yl)(phenyl)methyl)amino)ethyl)- 2-methylphenyl)acetic acid; 2-(3-((R and S)-1-(((R)-((R)-6,7-dihydro-5H-pyridazino[3,4- b][1,4]oxazin-7-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (S)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methanamine; (R)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methanamine; 2-(3-(2-(((R)-((R)-6,7-dihydro-5H- pyridazino[3,4-b][1,4]oxazin-7-yl)(phenyl)methyl)amino)ethyl)-4-methylphenyl)acetic acid; 2-(3-((S)-1-(((R)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)-1-(((R)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-((R)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)-1-(((R)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((R)- 1-(((R)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)- 1-(((S)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; (S)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methanamine; 2-(5-(2-(((R)-((R)-6,7-dihydro-5H-pyridazino[3,4-b][1,4]oxazin-7- yl)(phenyl)methyl)amino)ethyl)-2-methylphenyl)acetic acid; 2-(3-((R)-1-(((S)-phenyl((S)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2- (3-((S)-1-(((S)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S)- 1-(((S)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-chloro-4-((R or S)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methanamine; (S or R)-2-(3-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; (R or S)-2-(3-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-((S or R)-1-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3- yl)(phenyl)methyl)amino)propan-2-yl)-4-fluorophenyl)acetic acid; 2-(5-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)thiophen- 3-yl)acetic acid; (S or R)-2-(3-(2-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R and S)-2-(3-(2-(((R)-((R)-2,3- dihydro-1H-pyrido[2,3-b][1,4]thiazin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(5-(2-(((R)-((R)-2,3-dihydro-1H- pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)amino)ethyl)thiophen-2-yl)acetic acid; 2-(2- chloro-4-((S or R)-1-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2-(3-(2-(((S)-((S)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)- 2-(4-(2-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)ethyl)phenyl)propanoic acid; 2-(4-((R or S)-1-(((S)-((S)-5-cyano- 1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; (R and S)-2-(4-((R or S)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-((R or S)-1-(((R)- phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetamide; 2-(4-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(3-((S or R)-1-(((R)-(2- fluorophenyl)((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)-2-methylpropanoic acid; 2-(2,4-difluoro-5-((S or R)-1-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)-2-methylpropanoic acid; 2-(3-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)acetic acid; 2-(4-(2-(((S)-((S)-5-cyano-1,2,3,4- tetrahydroquinolin-3-yl)(phenyl)methyl)amino)ethyl)phenyl)acetic acid; (S or R)-2-(4-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methyl)amino)propan-2- yl)phenyl)propanoic acid; 2-(3-(2-(((R)-1-((R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl)-1- phenylethyl)amino)ethyl)phenyl)acetic acid and 2-(3-(2-(((S)-1-((S)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl)-1-phenylethyl)amino)ethyl)phenyl)acetic acid (1/1); (R or S)-2-(4- ((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; (R or S)-2-(2-fluoro-3-(2-(((S)- phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid; (R or S)-2-(3-((S or R)-1-(((S)-((S)-5-cyano-1,2,3,4-tetrahydroquinolin-3- yl)(phenyl)methyl)amino)propan-2-yl)phenyl)propanoic acid; 2-(3-(1-((tert- butoxycarbonyl)amino)propan-2-yl)phenyl)acetic acid; 2-(2-fluoro-3-(2-(((S)-phenyl((R)- 1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)amino)ethyl)phenyl)acetic acid; 2-(3-((R and S)-1-(((S)-phenyl((S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2- yl)phenyl)acetic acid; 2-(3-((S)-1-(((S)-phenyl((R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3- yl)methyl)amino)propan-2-yl)phenyl)acetic acid; and 2-(3-((S)-1-(((R)-phenyl((S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)propan-2-yl)phenyl)acetic acid. 37. A pharmaceutical composition comprising the compound of any one of Claims 1 to 36 and a pharmaceutically acceptable excipient. 38. A method of treating a disease or disorder associated with p300 activity in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound of any one of Claims 1-36 or the pharmaceutical composition of claim 37.
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US3632581A (en) * 1968-10-08 1972-01-04 American Home Prod Schiff bases of quinoxaline-2-carboxal-dehydes and their reduction products
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WO2004106298A1 (en) * 2003-05-30 2004-12-09 Janssen Pharmaceutica N.V. Indole derivatives with an improved antipsychotic activity
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WO2013136288A1 (en) * 2012-03-16 2013-09-19 Lupin Limited Substituted 3,4-dihydro-2h-benzo[b] [1,4]oxazine compounds as calcium sensing receptor modulators
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Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BROWN, J. A. L.: "Patent spotlight: small-molecule lysine acetyltransferase inhibitors (KATi", PHARMACEUTICAL PATENT ANALYST, vol. 9, no. 1, 2020, pages 17 - 28, XP009562677, DOI: 10.4155/ppa-2019- 0025 *
FIORENTINO, F. ET AL.: "Lysine Acetyltransferase Inhibitors: Structure-Activity Relationships and Potential Therapeutic Implications", FUTURE MEDICINAL CHEMISTRY, vol. 10, no. 9, 2018, pages 1067 - 91, XP009562678, DOI: 10.4155/fmc-2017-0244 *

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