Compositions of MU opioid receptor modulators and methods of use thereof

Abstract

The present disclosure provides compounds that are mitragynine pseudoindoxyl (MP) analogs and have activity in modulating mu opioid receptors. Also provided are pharmaceutical compositions comprising the compounds and methods of treating pain or opioid use disorder by administering the compounds to a subject in need thereof.

Description

COMPOSITIONS OF MU OPIOID RECEPTOR MODULATORS AND METHODS OF USE THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Application No. 63 / 678,929, titledCompositions of Mu Opioid Modulators and Methods of Use Thereof, filed August 2, 2024, which is hereby incorporated by reference in its entirety. STATEMENT OF FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under DA036246, DA045884,DA057790 and DA059978 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF INVENTION

[0003] The present disclosure relates to analgesic compositions, and more particularly tomitragynine pseudoindoxyl (MP) analogs as mu opioid receptor modulators for treating pain and opioid use disorders. BACKGROUND

[0004] Analgesics targeting the μ-opioid receptor (MOR) are effective for treating acuteto severe pain. However, these compounds are associated with serious adverse effects such as life-threatening respiratory depression and addiction. Current opioid medications often lead to tolerance, requiring escalating doses to maintain analgesic efficacy. This can increase the risk of side effects and opioid use disorder.

[0005] Mitragynine, an indole alkaloid derived from the plant Mitragyna speciosa(kratom), has shown promise as an alternative to traditional opioids. Mitragynine pseudoindoxyl (MP), a minor metabolite of mitragynine (J Med Chem.2021 Nov 16;64(22):16553–16572), demonstrates improved pharmacological properties compared to morphine, including slower development of antinociceptive tolerance and reduced respiratory depression at equianalgesic doses (J Med Chem.2016 Sep 2;59(18):8381–8397).

[0006] However, the molecular determinants governing MP's unique pharmacologicalprofile are not fully understood. Additionally, MP itself still exhibits some undesirable effects associated with MOR activation. There remains a need for novel compounds that can provideeffective analgesia while minimizing the risks of tolerance, withdrawal, respiratory depression, addiction, and other opioid-related adverse effects.

[0007] Developing improved MOR modulators with tailored pharmacological profilescould potentially address the current challenges in pain management and opioid use disorders. Compounds that retain analgesic efficacy while reducing side effects associated with traditional opioids would represent a substantial advance in this field.

[0008] The rational design of new chemical entities based on the MP scaffold, withsystematic modifications to modulate receptor efficacy and Gα-subtype selectivity, can yield compounds with enhanced therapeutic potential. Such compounds could potentially contribute to addressing the ongoing opioid epidemic by providing safer alternatives for pain management and treatment of opioid use disorders. SUMMARY

[0009] This summary is provided to introduce a selection of concepts in a simplifiedform that are further described below in the detailed description. This summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.

[0010] One aspect of the disclosure is a compound having the structure of Formula (1) ora pharmaceutically acceptable salt thereof:wherein R1 is hydrogen, C1-C6 alkyl, C1-C6 alkynyl, hydroxyl, alkoxyl, substituted alkoxyl, cycloalkyl, halo, nitrogen-containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen-containing heterocyclyl, 6-membered and fused ring oxygen-containing heterocyclyl, substituted heterocyclyl, -(CH2)n-R5, wherein, n is an integer from 0 to 4, and R5is aryl, substituted aryl, or heteroaryl, or -alkynylene-R6, wherein R6is aryl or substituted aryl; R2 is hydrogen, hydroxyl, halo, cyano, -C(O)NH2, C1-C6 alkyl, aryl, substituted aryl, cycloalkyl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; R3 is hydrogen, halogen, cyano, C(O)NH2, cycloalkyl, aryl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; and R4is hydrogen, C1-C3alkyl, phenyl, or benzyl; wherein at least one of R1, R2, and R3 are other than hydrogen; and wherein when R1 is methoxy at least one of R2 and R3 is other than hydrogen and R2 is other than cloro.

[0011] Another aspect of the disclosure is a compound having the structure of Formula(1Z) or a pharmaceutically acceptable salt thereof:wherein R1is C1-C6alkyl, C1-C6alkynyl, hydroxyl, alkoxyl, deuterated alkoxyl, substituted alkoxyl, cycloalkyl, halo, nitrogen-containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen-containing heterocyclyl, 6-membered and fused ring oxygen-containing heterocyclyl, halo-substituted heterocyclyl, -(CH2)n-R5, wherein, n is an integer from 0 to 4, and R5 is aryl, substituted aryl, or heteroaryl, or -alkynylene-R6, wherein R6 is aryl or substituted aryl; R2is hydrogen, hydroxyl, halo, cyano, -C(O)NH2, C1-C6alkyl, aryl, substituted aryl, cycloalkyl, nitrogen-containing heterocyclyl, or non-aromatic oxygen- containing heterocyclyl; R3is hydrogen, deuterium, halogen, cyano, C(O)NH2, cycloalkyl, aryl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; and R4is hydrogen, C1-C3alkyl, phenyl, or benzyl.

[0012] Yet another aspect of the disclosure is a compound having the structure ofFormula (4):wherein X is -CH-, O, N; X1 is –CH2-, O, -NH-; X2 is -CH2-, -CH-, O, N, or -NH-; n is an integer of 0 to 4; m is an integer of 0 to 2; and Y is.

[0013] A further aspect of the disclosure is a pharmaceutical composition comprising atherapeutically effective amount of the compound of any one of Formula 1, 1Z, 2, 3, or 4 and a pharmaceutically acceptable carrier.

[0014] Yet another aspect of the disclosure is a method of treating pain in a subject inneed thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formula 1, 1Z, 2, 3, or 4.

[0015] An additional aspect of the disclosure is a method of treating opioid use disorderin a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of Formula 1, 1Z, 2, 3, or 4.

[0016] The foregoing general description of the illustrative embodiments and thefollowing detailed description thereof are merely exemplary aspects of the teachings of this disclosure and are not restrictive. BRIEF DESCRIPTION OF FIGURES

[0017] Non-limiting and non-exhaustive examples are described with reference to thefollowing figures.

[0018] FIG. 1 shows (a) Chemical structures of C-9 and C-10 MP analogs featuringsubstitutions such as F, Cl, CN, CONH2, furan-3’-yl, phenyl, and cyclopropyl. (b) BRET assays to determine efficacy at µOR Gi1 using C-9 and C-10 MP analogs at 1 µM. Data are expressed as mean ± SEM of N=3-4 experiments. (c) Schild plot analysis of for BP1-94 at µOR. Schild plot showing the DRC for DAMGO in the presence of increasing concentrations of either BP1-94 or naloxone with N=3 experiments performed with quadruplets. The pA2 value (95%CI), representing the antagonist potency, was calculated for BP1-94 and naloxone are 8.9 (10.08-8.41) and 8.0 (8.28-7.89) respectively. (d) [3H]-NLX competitive binding data for BP1-94 and MP. BP1-94 (IC50 (95%Cl) = 1.6 (0.7-1.4) nM has a similar binding affinity to its precursor MP (IC50 = 1.4 (1.3-3.7) nM. Data are expressed as DRC of N=2 experiments.(e) [35S]GTPγS coupling assays in agonist mode (left) and antagonist mode(graph). Dose response curves of DAMGO, naloxone, BP1-94, or vehicle are shown. For agonist mode: data are expressed as mean ± SEM of N=3 experiments, performed in duplicate and normalized to DAMGO (100%) and Vehicle (0%). For antagonist mode: data are expressed as mean ± SEM of subtypes (Gi1, Gi2, Gi3, GolA, GoB, Gz) efficacy modulation for BP1-94 using TRUPATH on µOR. Data are expressed as dose response curves of N=2 to N=4 experiments, performed in duplicate and normalized to 100 nM DAMGO with Vehicle (100%) and and 100 nM DAMGO with 10 µM naloxone (0%). (f) Gα-protein experiments, performed in quadruplets and normalized to DAMGO. BP1-94 is flat for all Gα-protein subtypes i.e. no measurable efficacy was observed at any subtype (g) cAMP data todetermine efficacy at µOR of 10 μM of ligands (all relative to DAMGO). Data are presentedas bar graph as mean ± SEM of N=3 experiments performed in quadruplets. (h) BRET assaysfor recruitment of Nb39 to MOR of 10 μM of ligands (all relative to DAMGO). Data arepresented as bar graph as mean ± SEM of N=3 experiments performed in quadrats . (i) The efficacy of μOR activation by BP1-94 studied by GTPase-glo assay at 10 µM. Data are presented as bar graph. Six replicates were included for all conditions, and all experiments were repeated at least twice, yielding consistent results.

[0019] FIG. 2 shows (a) Dose response curves of BP1-94 and MP using the BRET assayfor mµOR. All data are normalized to DAMGO. Data are presented as DRC of N=3 experiments performed in quadrats. For potency and efficacy see Supplementary Table S10. (b)-(c) DRC of BP1-94 and MP in the cAMP assay for both hµOR and mµOR. All data are normalized to DAMGO. Data are presented as DRC of N=3-4 experiments performed in quadruplets. (d) The efficacy of μOR activation by BP1-94 was studied by GTPase-glo assay at 10 µM. Data are presented as bar graph. Six replicates were included for all conditions, and all experiments were repeated twice, yielding consistent results. (e) BRET assays were conducted to determine efficacy at µOR Gi1 using various reported ligands at 1 µM. Values are normalized to DAMGO. Data are presented as bar graph as mean ± SEM of N=3 experiments.

[0020] FIG. 3 shows (a) Cryo-EM structure of human μOR in the active state bound toBP1-94 stabilized by Gi heterotrimer and scFv16 The overall model is colored by chain with μOR and BP1-94 shown as pink helices and green sticks, respectively. The residues in μOR coordinated with BP1-94 are represented as sticks, and salt bridge formed between D3.32and tertiary amine in BP1-94 is shown as black dash lines. The YYH pocket, constituted by residues Y1.39, Y2.64, H7.36, accommodates the extended cyclopropyl group in BP1-94 and isshown as gray sphere. (b) Cryo-EM structure of mouse ^OR in the inactive state bound to BP1-94 stabilized by Nb6M. μOR is shown as cyan helices while BP1-94 is highlighted as purple stick in the inactive state. The surrounding residues interacting with ^OR are shown as sticks in which H bonds are labeled as yellow dash lines and YYH pocket is shown as gray sphere. (c) The active μOR–BP1-94 complex aligned with active μOR bound to MP, with TM1 and TM2 highlighted. BP1-94 in the active μOR is shown as green sticks. Key residues involved in μOR activation (Y1.39, Y2.64, H7.36, Q2.60, W6.48and Y7.43) are shown as sticks, colored according to their respective models. Conformational shifts between the two models are indicated by arrows. A notable outward movement is observed for the ‘YYH’ pocket residues and the polar residue Q2.60. (d) Alignment of active μOR–BP1-94 with active μOR bound to DAMGO, showing a consistent outward movement of the ‘YYH’ residues and Q2.60. (e) Alignment of inactive μOR–BP1-94 with the active μOR–BP1-94 complex, highlighting the conformational differences for W6.48and Y7.43and Y1.39, Y2.64, H7.36, Q2.60. In the inactive μOR, Y1.39, Y2.64, H7.36and Q2.60form tight contacts with BP1-94 (purple sticks). (f) Alignment of inactive μOR–BP1-94 with inactive μOR bound to naloxone and NAM 368, comparing the conformational change for W6.48and Y7.43and Y1.39, Y2.64, H7.36, Q2.60. BP1-94 and NAM 368 in the inactive μOR are shown as purple and gray sticks, respectively. The ‘YYH’ residues in the naloxone / 368-bound structure exhibit a pronounced outward shift. The color scheme for ligands and models is displayed in the center of the figure. (g) BRET assay data to determine efficacy at µOR Gi1 using C-10 MP analogs at 1 µM. Values are normalized to DAMGO. Data are presented as bar graph as mean ± SEM of N=3 experiments. (h) Overlapping of compounds 16 (pink) , 21 (brown) and BP1-94 (green) in the active state structure of BP1-94. (i) Overlay showing a representative frame from the MP active (light purple) and BP1-94 inactive (dark green) simulations. (j) Graph showing the mean ligand RMSD values from the 5 replicates for each simulation condition, individual replicates are shown, error bars show ± SEM. (k) Image shows the position of residues Y1.39, Y2.64and H7.36from a representative frame for the MP active state (light purple) and BP1-94 inactive state (dark green) simulations, residues and TMs are labelled, arrows indicate the largest movements between the two simulations; the movement of TM1 and residue H7.36. (l) Plot showing the frequency of distance between Y1.39(OH atom) and H7.36(NE2 atom) for the MP active and BP1-94 inactive simulations, arrows indicate the distance observed in the cryo-EM structures of MP active (light purple), BP1-94 active (light green), BP1-94 inactive (dark green) and ALV (orange).

[0021] FIG. 4 shows (a) Antinociception time course. C57BL / 6J mice were administeredBP1-94 (s.c.) and antinociception was measured using the 55 °C tail withdrawal assay. Data are shown as mean % antinociception (MPE) ± SEM at doses of 1, 3, 10, 30 and 100 mg / kg, s.c. (n = 8 each group) with repeated measures over time. BP1-94 showed antinociception with a ceiling effect. (b) ) Unbound brain concentrations of BP1-94 (30 mg / kg, s.c.) and MP(3 mg / kg, s.c.) in brain. Concentration of drugs were determined using LC-MS / MS. (c) BP1-94 antinociception in KO mice. Antinociception effect of BP1-94 (100 mg / kg, sc,) was evaluated in groups of (n = 8-9) in WT, µOR KO, norBNI pretreated, and NTI pretreated mice. Data are shown as mean % antinociception (MPE) ± SEM. (d) Unbound concentration of BP1-94 (at doses 30mg / kg and 100mg / kg, s.c.) and MP (with dose 3 mg / kg, s.c.) in brain and plasma. Concentration of drugs were determined using LC-MS / MS. (e) Unbound concentration of BP1-94 (at doses 30mg / kg and 100mg / kg, s.c.) and MP (at dose 3 mg / kg, s.c.) in brain. Total brain uptake calculated from the pk analysis. Concentration of drugs were determined using LC-MS / MS. (f) Time-dependent analgesia in a CIPN model of BP1- 94 (30 mg / kg, s.c.). Male & Female CD-1 mice were used (n=10 / group total). (g) Time- dependent analgesia of BP1-94 in an inflammatory pain model (CFA model) when the drug was subcutaneously administered at a dose of 30 mg / kg, s.c. Male and female CD-1 mice were used (n=10 / group total). Thresholds measured using von Frey filaments. Baseline taken on day 0, followed by injection of 20 µL of CFA into the right hind paw. Second baseline taken on day 1, followed by injection of 30 mg / kg, BP1-94 or vehicle s.c. and von Frey time course. The AUC showed a significant antinociception effect with *P=0.0354. (h) Dose- and time-dependent analgesic effect of BP1-94 in a CCI model of neuropathic pain. Data are % of Baseline withdrawal threshold (±SEM) at doses of 10, 30 and 100 mg / kg,s.c. (n = 8 each group) compared with gabapentin (50 mg / kg, i.p.) and saline. (i) Antinociceptive time course of morphine amd MP: Groups of C57BL / 6J mice were subcutaneously administered morphine at doses of 0.3, 1, 3 and 10 mg / kg (n = 8 each group for morphine) and 0.3, 0.6, 1 and 3 mg / kg (n = 8 each group for MP) with repeated measures over time and antinociception measured using the 55°C tail withdrawal assay. Data are shown as mean % antinociception (MPE) ± SEM. ED50calculation of BP1-94, morphine and MP from the antinociceptive time course and drug dose. BP1-94, morphine and MP have the ED50 values(95% CI) 2.6 (0.18- 36.9) mg / kg, 1.9 (0.42-8.13) mg / kg and 0.17(0.014-2.09) mg / k, s.c. respectively.

[0022] FIG. 5 shows (a)-(b) Respiratory depression and Locomotor effects. C57BL / 6Jmice were administered either saline, vehicle, morphine (30 mg / kg, sc), fentanyl (1mg / kg,i.p) BP1-94 (100 mg / kg, sc), BP1-94(100mg / kg, s.c.) + fentanyl (1mg / kg, i.p) and breath rate (a) and ambulation (b) were measured in a time dependent way. Data are presented as percentage of vehicle response ± SEM. (c) Infusions Earned Across Experimental Days. The number of infusions (Vehicle, Morphine, BP1-94 (0.3 mg / kg; red circles), and BP1-94 (1.0 mg / kg) earned during a 2-hour self-administration session across 14 days for four different treatment groups. On day 8, reinforcers were swapped. Rats failed to acquire self- administration for BP1-94 but rapidly acquired morphine self-administration. Further, rats previously self-administering morphine did not substitute BP1-94 for morphine; β indicate significant difference compared to the BP1-94. * indicate a significant difference from theVehicle group. Data shown as mean (± SEM). (d) BP1-94 (10 and 30 mg / kg), Morphine (10mg / kg) and U50,488h (30 mg / kg) treatment did not result in CPP or CPA changes when administered subcutaneously. (e) The physical dependence test using “flat dosing” chronic treatment. Saline, morphine (10 mg / kg; s.c.; n =10), BP1-94 (30 mg / kg, s.c.; n =10) toC57BL / 6J mice. Bars represents jumping frequency, stool consistency and teeth chattering frequency. (f) Amelioration of morphine withdrawal was examined using C57BL / 6J mice with BP1-94 (30 mg / kg, s.c.) or morphine (10 mg / kg, s.c.). The bar graphs show that BP1-94 significantly ameliorates morphine withdrawal symptoms, including jumping, stool consistency, and teeth chattering frequency.

[0023] FIG. 6 shows that chemical modifications to MP results in a low-efficacycandidate with efficacy lower than MP but higher than naloxone, BP1-94, which exhibits antinociceptive effects with reduced opioid adverse effects..

[0024] FIG. 7 (a)-(c) shows TRUPATH assay data highlighting the efficacy profiles ofthe SC111 and SC103 analogs, which demonstrate Gz selectivity. The data illustrate the structure-activity relationship contributing to this Gα-protein isoform selectivity and compared to morphine, SC111 shows a trend towards reduced tolerance to its antinociceptive effect. FIG.7(d) shows antinociceptive tolerance: C57Bl / 6J male mice (n=8) were used in the 55°C warm-water tail-withdrawal assay to measure tolerance effects. The mice were dosed twice daily, with an 8-hour interval between doses, at a dose of 2 Χ antinociceptive ED50 of either morphine (2.35 nmol and 22.5 nmol) or SC111 (51.1 nmol and 37.6 nmol) administered as i.c.v. Data are shown as mean percentage antinociception (MPE) ± SEM. This data represents that compared to morphine, SC111 shows a trend to have reduced tolerance in its antinociceptive effect.

[0025] FIG. 8 shows the (a) TRUPATH assay at MOR indicates that Z-MP shows higherefficacy for G-protein signaling than E-MP. Similar findings. (b) Z-MP showed more effectin antinociception in mice at 20 min with a dose 0.3 mg / kg than E-MP. DETAILED DESCRIPTION

[0026] The following description sets forth exemplary aspects of the present disclosure.It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure. Rather, the description also encompasses combinations and modifications to those exemplary aspects described herein.

[0027] The present disclosure relates to compositions and methods involving analogs ofmitragynine pseudoindoxyl (MP) as modulators of the mu opioid receptor. These compounds can be useful for treating pain and opioid use disorders.

[0028] MP analogs described herein can exhibit improved pharmacological propertiescompared to traditional opioid medications. In some cases, the disclosed compounds can provide effective analgesia while potentially reducing adverse effects commonly associated with opioid use. The MP-based scaffold allows for structural modifications that can tune the pharmacological profile of the resulting analogs owing to their Gi / o / z signaling profiles, efficacy and / or isoform Gα-selectivity.

[0029] The compounds of the present disclosure can interact with the mu opioid receptorin ways that differ from classical opioid agonists. This unique mechanism of action can contribute to a more favorable therapeutic profile in some instances. The MP analogs can offer new options for pain management and treatment of opioid dependence.

[0030] In some cases, the disclosed compounds can exhibit reduced tolerancedevelopment, decreased respiratory depression, and / or lower abuse potential compared to currently available opioid medications. The MP analogs can provide effective pain relief across various types of pain, including acute, chronic, cancer, and neuropathic pain in some instances.

[0031] The compositions described herein can be formulated into pharmaceuticalpreparations suitable for different routes of administration. Methods of synthesizing and using the disclosed compounds are also provided. The MP analogs can represent a new class of opioid receptor modulators with potential therapeutic applications.

[0032] Among the aspects of the disclosure is a compound having the structure ofFormula (1) or a pharmaceutically acceptable salt thereof:

[0033] wherein R1 is C1-C6 alkyl, C1-C6 alkynyl, hydroxyl, alkoxyl, substituted alkoxyl,cycloalkyl, halo, nitrogen-containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen-containing heterocyclyl, 6-membered and fused ring oxygen-containing heterocyclyl, -(CH2)n-R5, wherein, n is an integer from 0 to 4, and R5is aryl, substituted aryl, or heteroaryl, or -alkynylene-R6, wherein R6 is aryl or substituted aryl; R2 is hydrogen, hydroxyl, halo, cyano, -C(O)NH2, C1-C6alkyl, aryl, substituted aryl, cycloalkyl, nitrogen- containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; R3 is hydrogen, deuterium, halogen, cyano, C(O)NH2, cycloalkyl, aryl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; and R4 is hydrogen, C1-C3 alkyl, phenyl, or benzyl; wherein when R1is methoxy at least one of R2and R3is no hydrogen and R2is other than cloro.

[0034] The compound of Formula 1 can have R1 be methoxy, nitrogen-containingheterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen-containing heterocyclyl, halogen-substituted heterocyclyl, and -(CH2)n-R5, wherein, n is an integer from 0 to 4, and R5 is aryl, substituted aryl, or heteroaryl.

[0035] The compounds of Formula 1 can have R1 be methoxy.

[0036] The compounds of Formula 1 can have R1 be nitrogen-containing heterocyclyl, ornitrogen and oxygen-containing heterocyclyl.

[0037] Additionally, the compounds of Formula 1 can have R2 be hydrogen, deuterium,halo, cycloalkyl, or nitrogen-containing heterocyclyl.

[0038] The compounds of Formula 1 can have R2 be hydrogen.

[0039] The compounds of Formula 1 can have R2 be C3 to C7 cycloalkyl; morepreferably, R2is cyclopropyl.

[0040] Also, the compounds of Formula 1 can have R3 be hydrogen, halo, cycloalkyl, oraryl.

[0041] The compounds of Formula 1 can have R3 be hydrogen.

[0042] The compounds of Formula 1 can have R3 be halo.

[0043] The compounds of Formula 1 can have R3 be cyclopropyl.

[0044] Yet further, the compounds of Formula 1 can have R4 be hydrogen.

[0045] Another aspect of the disclosure is a compound having the structure of Formula(1Z) or a pharmaceutically acceptable salt thereof:

[0046] wherein R1 is C1-C6 alkyl, C1-C6 alkynyl, hydroxyl, alkoxyl, cycloalkyl, halo,nitrogen-containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen- containing heterocyclyl, 6-membered and fused ring oxygen-containing heterocyclyl, - (CH2)n-R5, wherein, n is an integer from 0 to 4, and R5 is aryl, substituted aryl, or heteroaryl, or -alkynylene-R6, wherein R6 is aryl or substituted aryl; R2 is hydrogen, hydroxyl, halo, cyano, -C(O)NH2, C1-C6alkyl, aryl, substituted aryl, cycloalkyl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; R3 is hydrogen, halogen, cyano, C(O)NH2, cycloalkyl, aryl, nitrogen-containing heterocyclyl, or non-aromatic oxygen- containing heterocyclyl; and R4 is hydrogen, C1-C3 alkyl, phenyl, or benzyl.

[0047] The compounds of Formula 1Z can have the following structures:.

[0048] Another aspect of the disclosure is that the compounds of Formula 1 can thestructure of Formula (2) or a pharmaceutically acceptable salt thereof:

[0049] wherein R2 is hydrogen, hydroxyl, fluoro, bromo, -C(O)NH2, C1-C6 alkyl, aryl,substituted aryl, cycloalkyl, nitrogen-containing heterocyclyl, or non-aromatic oxygen- containing heterocyclyl; R3is hydrogen, halogen, cyano, C(O)NH2, cycloalkyl, aryl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; and R11 is hydrogen or methyl; wherein at least one of R2and R3is other than hydrogen.

[0050] The compounds of Formula 2 can have R2 be fluoro bromo, C1 to C3 alkyl, or C3to C6cycloalkyl.

[0051] The compounds of Formula 2 can have R2 be C3 to C6 cycloalkyl or preferably,R2is cyclopropyl.

[0052] Additionally, the compounds of Formula 2 can have R3 be hydrogen, halogen, orcycloalkyl.

[0053] The compounds of Formula 2 can have R3 be hydrogen.

[0054] The compounds of Formula 2 can have R3 be fluoro, chloro, or bromo.

[0055] The compounds of Formula 2 can have R3 be C3 to C6 cycloalkyl; preferably, R3is cyclopropyl.

[0056] Additionally, the compounds of Formula 2 can have R11 is methyl.

[0057] The compounds of Formula 2 can have the structure of:.

[0058] Preferably, the compounds of Formula 2 can have the structure of:.

[0059] Additionally, the compounds of Formula 1 can have the structure of Formula (3):

[0060] wherein R1 is -C(O)NH2, halo, -OR12, wherein R12 is alkylene-aryl, alkylene-substituted aryl, alkylene-nitrogen-containing heterocyclyl, a C10 to C12 fused ring; nitrogen- containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen-containing heterocyclyl, C1 to C6 alkyl, C3 to C7 cycloalkyl, or -(CH2)n-R5, wherein, n is an integer from 0 to 4, and R5is aryl, substituted aryl, or heteroaryl, or -alkynylene-R6, wherein R6is aryl or substituted aryl.

[0061] The compounds of Formula 3 can have R1 be -OR12, wherein R12 is –(CH2)2-phenyl, -(CH2)3-phenyl, –(CH2)2-halo-substituted phenyl, –(CH2)2-C1-C3-alkyl-substituted phenyl, –(CH2)2-C1-C3-alkoxyl-substituted phenyl, –(CH2)2-nitrogen-containing heteroaryl.

[0062] The compounds of Formula 3 can have R1 be -OR12, wherein R12 is –(CH2)2-phenyl, -(CH2)3-phenyl, or –(CH2)2-tolyl.

[0063] The compounds of Formula 3 can have R1 be –(CH2)3-phenyl, -(CH2)4-phenyl, –(CH2)3-halo-substituted phenyl, –(CH2)3-C1-C3-alkyl-substituted phenyl, or –(CH2)3-C1-C3- alkoxyl-substituted phenyl, or–(CC-(CH2)2-phenyl.

[0064] The compounds of Formula 3 can have R1 be biphenyl, sulfur-containingheteroaryl, substituted sulfur-containing heteroaryl, nitrogen-containing heteroaryl, substituted nitrogen-containing heteroaryl, nitrogen- and oxygen-containing heteroaryl, substituted nitrogen- and oxygen-containing heteroaryl, or substituted nitrogen- and sulfur- containing heteroaryl.

[0065] The compounds of Formula 3 can have R1 be chloro or fluoro.

[0066] The compounds of Formula 3 can have R1 be C1 to C3 alkyl or C3 to C7cycloalkyl; preferably, R1 is cyclopropyl.

[0067] The compounds of Formula 3 can have R1 is nitrogen-containing heterocyclyl, ornitrogen and oxygen-containing heterocyclyl.

[0068] The compounds of Formula 3 can have the following structure:.

[0069] Preferably, the compound of Formula 3 has the following structure:.

[0070] The compound of claim 1, having the structure of Formula (4):wherein X is -CH-, O, N; X1 is –CH2-, O, -NH-; X2 is -CH2-, -CH-, O, N, or -NH-; n is an integer of 0 to 4; m is an integer of 0 to 2; and Y is.

[0071] When X2 is -CH2- or -CH-, the particular group depends on whether the ring isaromatic or saturated since the number of hydrogens will be determined by the number of bonds already attached to the carbon atom. Similarly, when X2is N or -NH-, the particular group depends on whether the ring is aromatic or saturated since the number of hydrogens will be determined by the number of bonds already attached to the nitrogen atom.

[0072] Another aspect of the disclosure is a pharmaceutical composition comprising atherapeutically effective amount of the compound of any one of Formula 1, 1Z, 2, 3, or 4 and a pharmaceutically acceptable carrier.

[0073] The pharmaceutical compositions can have the pharmaceutically acceptablecarrier be selected from the group consisting of a liquid, solid, semi-solid, and gel.

[0074] The pharmaceutical compositions can have the pharmaceutically acceptablecarrier be suitable for oral, parenteral, topical, or transdermal administration.

[0075] The pharmaceutical compositions can have the composition be formulated forcontrolled release.

[0076] The pharmaceutical compositions can have the controlled release formulationprovide sustained release of the compound over a period of at least 12 hours.

[0077] Additionally, an aspect of the disclosure is a method of treating pain in a subjectin need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, 1Z, 2, 3, or 4.

[0078] The method for treating pain, wherein the pain is selected from the groupconsisting of acute pain, chronic pain, neuropathic pain, and cancer-related pain.

[0079] The method for treating pain, wherein the pain is neuropathic pain.

[0080] The method for treating pain, wherein the compound is administered orally,parenterally, topically, or transdermally; preferably, the compound is administered orally.

[0081] Yet another aspect of the disclosure is a method of treating opioid use disorder ina subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula 1, 1Z, 2, 3, or 4.

[0082] The method of treating pain or opioid use disorder, wherein the therapeuticallyeffective amount of the compound is between about 1 mg / kg and about 100 mg / kg of body weight of the subject.

[0083] For example, Z-MP can have a Z configuration of the β-methoxyacrylate group.The Z configuration can refer to the stereochemistry of the double bond in this functional group.

[0084] SC111 can exhibit selectivity for certain G protein subtypes, such as Gz. Thisselectivity can be influenced by the specific substituents present on the MP-based scaffold. This is an important finding as Gαz KO mice showed little or no change in the supraspinal analgesia of a single dose of morphine, yet there was a marked increase in analgesic tolerance, and a decrease in lethality where the LD50 (dose at which 50% of animals die) was 700 mg / kg for wildtype and greater than 800 mg / kg for homozygous Gαz knockout mice.(Neuropharmacology 2004 May;46(6):836-46). Gz KO mice also show a markeddecrease in analgesic tolerance (Brain Res. 870, 10–19 (2000)).

[0085] The structural variations in these analogs can allow for tuning of pharmacologicalproperties. For instance, modifications at the R1, R2, and R3 positions can affect factors such as receptor binding affinity, efficacy, or metabolic stability.

[0086] The synthesis of mitragynine pseudoindoxyl (MP) analogs can involve chemicaltransformations of kratom extract. In some cases, the synthesis process can include multiple steps to modify the base MP scaffold and introduce various substituents.

[0087] One general method for synthesizing MP analogs can involve the following steps:Extraction of mitragynine from kratom leaves using organic solvents; Oxidation of mitragynine to form 7-hydroxymitragynine; Rearrangement of 7-hydroxymitragynine to form mitragynine pseudoindoxyl; and Further modifications to introduce substituents at specific positions.

[0088] The oxidation step can be carried out using oxidizing agents such as potassiumperoxymonosulfate in aetone-water. In some cases, the rearrangement step can involve microwave mediate heating with protic solvent like trifluoro ethanol .

[0089] Specific analogs with substituents at positions 9, 10, and 12 of the MP scaffoldcan be synthesized through transition metal-catalyzed cross-coupling, substitution reactions, Heck reaction followed by reduction. For example, to introduce substituents at position 9: demethylation followed by triflate formation and finally a cross-coupling reaction can be performed using an appropriate boronic acid; alkylation of the 9-OH or indoline NH can utilize alkyl halides and a base like sodium hydride, potassium carbonate, or cesium carbonate; demethylation can be achieved using aluminum chloride.;

[0090] For modifications at position 10: bromination followed by palladium catalysedSuzuki cross coupling with aryl or alkenyl boronic acid was perform;

[0091] To functionalize position 12: electrophilic bromination reaction followed bypalladium-catalyzed cross-coupling reactions can introduce cyclopropyl, aryl or heteroaryl groups.

[0092] In some cases, the final compounds can be converted to pharmaceuticallyacceptable salts through treatment with appropriate acids or bases.

[0093] These methods can be adapted and optimized for the synthesis of various MPanalogs with different substituents and structural features.

[0094] The compounds described herein can exhibit pharmacological properties thatdistinguish them from classical opioid agonists. In some cases, these compounds candemonstrate unique binding characteristics and functional selectivity at the mu opioid receptor.

[0095] Binding affinity studies can be conducted using radioligand competition assays.For example, the compound BP1-94 can exhibit a Ki value of approximately 0.8 nM at the human mu opioid receptor in such assays. This high affinity binding can contribute to the potent activity observed with some MP analogs.

[0096] Functional assays measuring G protein activation can be used to assess theefficacy of these compounds. In some instances, compounds like BP1-94 shows antagonist effect similar to naloxone in GTPγS assays however in an amplified cyclic adenosine monophosphate (cAMP) assay it has an efficacy of 30% with an EC50 value 12 nM.

[0097] The MP analogs can demonstrate selectivity for specific G protein subtypes. Forexample, some compounds can preferentially activate Gi / o / z proteins over β-arrestin recruitment pathways. This G protein bias can be quantified using bioluminescence resonance energy transfer (BRET) assays comparing G protein activation to β-arrestin recruitment.

[0098] In vitro studies examining the effects on cellular cAMP levels can provide furtherinsights into the functional activity of these compounds. For instance, BP1-94 can inhibit forskolin-stimulated cAMP accumulation in cells expressing the mu opioid receptor, with an EC50value of approximately 12 nM.

[0099] The binding mode of MP analogs to the mu opioid receptor can be investigatedusing cryo-electron microscopy (cryo-EM) structural analysis. Such studies can reveal specific interactions between the compounds and key residues in the receptor binding pocket, potentially explaining observed differences in efficacy and selectivity.

[0100] In vivo assays can be employed to evaluate the analgesic effects of thesecompounds. For example, the tail-flick test in rodents can be used to assess antinociceptive activity. In some cases, BP1-94 can produce dose-dependent analgesia with an ED50 value of approximately 2.6 mg / kg when administered subcutaneously.

[0101] The potential for respiratory depression, a common side effect of opioids, can beevaluated using the CLAMS assay in rodents. Some MP analogs can exhibit reduced respiratory depressant effects compared to classical opioids at equianalgesic doses.

[0102] Compounds described herein can be formulated as pharmaceutically acceptablesalts to enhance properties such as solubility or stability. For example, hydrochloride or fumarate salts of the MP analogs can be prepared and characterized.

[0103] In some instances, the efficacy of these compounds can be enhanced through theuse of positive allosteric modulators (PAMs) of the mu opioid receptor. Co-administration of a PAM with an MP analog can result in a leftward shift of the dose-response curve in functional assays and / or boosting efficacy.

[0104] Efficacy studies in terms of antinociception effects in mice were carried out usingZ-MP and E-MP using the warm water tail withdrawal assay.

[0105] Pharmacokinetic studies can be conducted to assess the absorption, distribution,metabolism, and excretion (ADME) properties of these compounds. For example, plasma concentrations of BP1-94 can be measured over time in brain and plasma to quantify unbound concentration following subcutaneous administration to determine bioavailability and half-life.

[0106] The potential for developing tolerance to the analgesic effects of thesecompounds can be evaluated through repeated dosing studies in animal models. Some MP analogs can demonstrate a reduced propensity for tolerance development compared to classical opioids.

[0107] In vitro metabolism studies using human liver microsomes or hepatocytes can beperformed to identify major metabolic pathways and potential drug-drug interactions. Such studies can inform the design of analogs with improved metabolic stability or reduced potential for interactions.

[0108] The abuse potential of these compounds can be assessed using self-administrationstudies in rodents. Some MP analogs can exhibit reduced reinforcing effects compared to classical opioids, potentially indicating a lower abuse liability.

[0109] Molecular dynamics simulations can be employed to study the interactionsbetween MP analogs and the mu opioid receptor over time. These computational approaches can provide insights into the structural basis for the observed pharmacological properties of these compounds.

[0110] In some cases, the pharmacological properties of MP analogs can be compared tothose of mitragynine and 7-hydroxymitragynine, the primary alkaloids found in kratom. Such comparisons can highlight the unique features of the synthetic analogs and their potential advantages as therapeutic agents.

[0111] The effects of these compounds on signal transduction pathways downstream ofthe mu opioid receptor can be investigated using phosphoproteomic approaches. Thesestudies can reveal differential activation of signaling cascades compared to classical opioids, potentially explaining observed differences in physiological effects.

[0112] Structure-activity relationship (SAR) studies can be conducted to correlatespecific structural features of the MP analogs with their pharmacological properties. Such analyses can guide the design of next-generation compounds with optimized profiles for therapeutic applications in pain management or treatment of opioid use disorders.

[0113] The compounds described herein can have potential therapeutic applications inpain management and treatment of opioid use disorders. In some cases, these compounds can provide effective analgesia while potentially reducing adverse effects commonly associated with opioid use.

[0114] For pain management, the MP analogs can be effective in treating various typesof pain, including acute pain, chronic pain, neuropathic pain, and cancer-related pain. In some instances, these compounds can be particularly useful for managing neuropathic pain, which can be challenging to treat with conventional analgesics.

[0115] Preclinical studies have demonstrated the analgesic efficacy of certain MPanalogs in animal models of pain. For example, the compound BP1-94 can produce dose- dependent analgesia in rodent models of acute and chronic pain.

[0116] The potential for reduced side effects can make these compounds attractiveoptions for pain management. In some instances, MP analogs can exhibit reduced respiratory depression compared to classical opioids at equianalgesic doses owing to their extremely low efficacy compared to MP and other opioid modulators discovered to date. This improved safety profile can allow for more effective pain relief with potentially fewer risks.

[0117] For the treatment of opioid use disorders, MP analogs can offer new therapeuticapproaches. These compounds can interact with the mu opioid receptor in ways that differ from classical opioid agonists, potentially leading to reduced abuse liability and dependence.

[0118] Preclinical studies have investigated the potential of MP analogs in models ofopioid dependence and withdrawal. For example, the compound BP1-94 can attenuate withdrawal symptoms in morphine-dependent animals when administered during opioid withdrawal. In some cases, BP1-94 can also reduce self-administration of opioids in animal models, suggesting a potential role in reducing drug-seeking behavior.

[0119] The compound BP1-94 can demonstrate promise in both pain management andtreatment of opioid use disorders. In some instances, BP1-94 can provide effective analgesia in models of neuropathic pain while exhibiting a reduced propensity for tolerancedevelopment compared to classical opioids. Additionally, BP1-94 can show potential in reducing opioid cravings and withdrawal symptoms in preclinical models of opioid dependence.

[0120] Administration of these compounds for therapeutic purposes can involve variousroutes, including oral, parenteral, topical, or transdermal delivery. The choice of administration route can depend on factors such as the specific indication, desired onset of action, and patient preferences.

[0121] Dosing of MP analogs for pain management or treatment of opioid use disorderscan vary depending on the specific compound and individual patient factors. In some cases, therapeutically effective amounts can range from about 1 mg / kg to about 100 mg / kg of body weight. More specifically, doses between about 5 mg / kg and about 50 mg / kg of body weight can be effective for certain indications.

[0122] The potential for combination therapy can also be explored. In some instances,MP analogs can be administered in conjunction with other therapeutic agents to enhance efficacy or address multiple aspects of pain or opioid use disorders. For example, co- administration with anti-inflammatory agents or antiemetics can provide complementary benefits in certain pain management scenarios.

[0123] Long-term studies can be necessary to fully evaluate the therapeutic potential andsafety profile of these compounds in clinical settings. Factors such as the development of tolerance, potential for dependence, and effects on cognitive function can need to be carefully assessed over extended periods of use.

[0124] In summary, MP analogs can offer promising new approaches for painmanagement and treatment of opioid use disorders. The unique pharmacological properties of these compounds can provide opportunities for improved therapeutic outcomes with potentially reduced risks compared to currently available options. However, further research and clinical evaluation can be necessary to fully establish the efficacy and safety of these compounds in human patients.

[0125] The compounds described herein can be formulated into various pharmaceuticalcompositions for administration to subjects. These compositions can include one or more of the disclosed compounds along with pharmaceutically acceptable carriers.

[0126] In some cases, the pharmaceutically acceptable carrier can be selected fromliquids, solids, semi-solids, and gels. The choice of carrier can depend on factors such as the desired route of administration and the physicochemical properties of the specific compound.

[0127] For oral administration, the compounds can be formulated into solid dosage formssuch as tablets, capsules, or powders. In some instances, these oral formulations can contain excipients such as binders, disintegrants, lubricants, and diluents. For example, a tablet formulation of BP1-94 can include microcrystalline cellulose as a binder, croscarmellose sodium as a disintegrant, and magnesium stearate as a lubricant.

[0128] Liquid formulations can also be prepared for oral administration. These caninclude solutions, suspensions, or emulsions of the active compound. In some cases, aqueous or non-aqueous vehicles can be used along with solubilizing agents, preservatives, and flavoring agents.

[0129] For parenteral administration, the compounds can be formulated into sterileinjectable solutions or suspensions. These formulations can use water, saline, or other suitable vehicles. In some instances, solubilizing agents such as propylene glycol or polyethylene glycol can be included to enhance solubility.

[0130] Topical formulations can be prepared for administration through the skin. Thesecan include creams, ointments, gels, or transdermal patches. For example, a transdermal patch containing SC111 and / or BP1-94 can be formulated using a polymer matrix and suitable penetration enhancers.

[0131] The pharmaceutical compositions can be formulated for controlled release insome cases. These formulations can provide sustained release of the compound over a period of at least 12 hours. Controlled release can be achieved through various mechanisms such as polymer matrices, coated pellets, or osmotic systems.

[0132] The therapeutically effective amount of the compound in these formulations canvary depending on factors such as the specific compound, indication, and individual patient characteristics. In some cases, the amount can range from about 1 mg to about 100 mg per dose. More specifically, doses between about 5 mg and about 50 mg can be effective for certain indications.

[0133] When considering dosing based on body weight, therapeutically effectiveamounts can range from about 1 mg / kg to about 100 mg / kg of body weight of the subject. The specific dosage can be adjusted based on factors such as the severity of the condition and the patient's response to treatment.

[0134] In some instances, the pharmaceutical compositions can include additionaltherapeutic agents along with the compounds described herein. For pain management, theseadditional agents can include analgesics or anti-inflammatory agents. Antiemetic agents can also be included to manage potential side effects.

[0135] For the treatment of opioid use disorders, the compositions can be formulated toinclude additional therapeutic agents such as naltrexone, buprenorphine, or methadone. These combinations can be designed to address multiple aspects of opioid dependence and withdrawal.

[0136] The choice of administration route can depend on factors such as the specificindication and desired onset of action. Oral administration can be preferred for chronic conditions due to convenience and patient compliance. Parenteral administration can be used for acute conditions requiring rapid onset of action. Topical or transdermal delivery can be suitable for localized effects or when steady blood levels are desired.

[0137] Dosing regimens can be tailored based on the pharmacological properties of thespecific compound. For example, compounds with longer half-lives can allow for once-daily dosing, while those with shorter half-lives can require multiple daily doses to maintain therapeutic effects.

[0138] In developing these formulations, considerations can include stability,bioavailability, and potential drug-drug interactions. Stability studies can be conducted to determine appropriate storage conditions and shelf life for the pharmaceutical compositions.

[0139] Bioavailability studies can inform the design of formulations to enhanceabsorption and distribution of the active compound. In some cases, techniques such as particle size reduction or use of solubility enhancers can be employed to improve bioavailability.

[0140] The potential for drug-drug interactions can be evaluated when formulatingcombinations with additional therapeutic agents. Compatibility studies and in vitro metabolism assays can be used to assess potential interactions and inform appropriate dosing strategies.

[0141] In summary, the compounds described herein can be formulated into variouspharmaceutical compositions suitable for different routes of administration. These formulations can be designed to provide appropriate dosing, controlled release, and combinations with other therapeutic agents as needed for specific indications such as pain management or treatment of opioid use disorders.

[0142] The MP-based scaffold can serve as the foundational structure upon which novelmu opioid receptor modulators are built. This scaffold can provide a template that allows forstrategic modifications to tune the pharmacological properties of the resulting compounds. The core structure of the MP scaffold can contribute to the high binding affinity observed for the mu opioid receptor, while also potentially influencing the compounds' functional selectivity due extremely low efficacy compared to MP alone or other mu opioid agonists and / or distinct Gz selectively of some other analogs.

[0143] Synthesis methods can play a crucial role in realizing the potential of the MP-based scaffold. These methods can allow for the introduction of specific substituents at key positions on the scaffold. The ability to selectively modify these positions can enable fine- tuning of the compounds' pharmacological profiles.

[0144] The pharmacological properties of the synthesized compounds can arise from theinterplay between their structural features and interactions with the mu opioid receptor. In some cases, the specific substituents introduced during synthesis can influence factors such as binding affinity, efficacy, and G protein subtype selectivity. For instance, compounds exhibiting preferential activation of Gz over other Gi / o / z subtypes can result from particular structural modifications made possible by the synthesis methods.

[0145] The formulation of these compounds into pharmaceutical compositions canfurther enhance their therapeutic potential. Careful selection of excipients and delivery systems can optimize the bioavailability and pharmacokinetics of the active compounds. In some cases, controlled release formulations can provide sustained therapeutic effects while potentially reducing the frequency of dosing.

[0146] The interaction between the MP-based scaffold and formulation strategies can beparticularly important for achieving desired therapeutic outcomes. For example, the structural features of certain analogs can influence their solubility or stability, which in turn can inform the choice of formulation approach. Conversely, specific formulation techniques can be employed to overcome potential limitations in the physicochemical properties of some compounds.

[0147] The synthesis methods and formulation strategies can work in concert to addresschallenges in developing effective therapeutics. For instance, if initial pharmacological studies reveal promising activity but poor oral bioavailability for a particular analog, modifications to the synthesis or formulation can be explored to improve its drug-like properties.

[0148] The pharmacological properties of the synthesized compounds can guideformulation decisions and dosing strategies. Analogs exhibiting high potency can allow forlower doses in pharmaceutical compositions, potentially reducing the risk of side effects. Similarly, compounds with longer half-lives can be suitable for once-daily dosing formulations.

[0149] In some cases, the unique pharmacological profiles of certain MP analogs canopen up new possibilities for combination therapies. The formulation of these compounds with other therapeutic agents can be explored to address multiple aspects of pain or opioid use disorders simultaneously.

[0150] The iterative process of synthesis, pharmacological evaluation, and formulationdevelopment can drive the optimization of these compounds for therapeutic applications. Insights gained from in vitro and in vivo studies can inform subsequent rounds of analog design and synthesis, leading to compounds with improved efficacy and safety profiles.

[0151] The interaction between structural features and pharmacological properties canalso influence the potential for reducing adverse effects commonly associated with opioid use. For example, analogs demonstrating reduced respiratory depression in preclinical studies can be prioritized for further development and formulation.

[0152] In summary, the MP-based scaffold, synthesis methods, pharmacologicalproperties, and formulations can work together as interconnected elements in the development of novel mu opioid receptor modulators. This integrated approach can allow for the creation of compounds with optimized therapeutic profiles for pain management and treatment of opioid use disorders.

[0153] Disclosed herein are novel analogs of a mitragynine pseudoindoxyl (MP)-basedscaffold to target the μ-opioid receptor (MOR)( J Med Chem. 2016 Sep 2;59(18):8381–8397),having efficient analgesic effect in thermal, neuropathic, and cancer pain models with reduced life-threatening side effects. This can lead to an improvement in current opioid epidemic in the USA and elsewhere.

[0154] Mitragynine pseudoindoxyl (MP), a minor metabolite of kratom derived indolealkaloid mitragynine (J. Med. Chem.2021, 64, 22, 16553–16572) shows improved pharmacological properties with slower antinociceptive tolerance and reduced respiratory depression at equianalgesic doses when compared with morphine. In this patent, we map out the molecular determinants by diversifying different positions at the aromatic ring of MP and develop SAR with analogs having different efficacy and potency at MOR.

[0155] The present disclosure identifies an extremely low efficacy candidate havingefficacy in between agonist and antagonist with potent analgesic effect in different painmodels with reduced opioid-related side effects. Some candidate analogs show unique Gz isoform selectivity. Most mu opioid modulators signal through Gi / o / z subtypes and show no isoform selectivity.

[0156] This rational design, overall low receptor efficacy, and G-protein isoformselectivity can contribute significantly to the future treatment of opioid use disorders as well as for treating pain. MODULATION AGENTS

[0157] As described herein, gene and / or associated protein expression has beenimplicated in various diseases, disorders, and conditions. As such, modulation of gene and protein expression can be used for treatment of such conditions. A modulation agent can modulate response, such as by inducing or inhibiting gene and / or protein expression signaling. Modulation can comprise modulating protein expression on cells, modulating the quantity of gene / protein expressing cells, or modulating the quality of gene / protein expressing cells.

[0158] Modulation agents can be any composition or method that modulates expressionon cells. For example, a modulation agent can be an activator, an inhibitor, an agonist, or an antagonist. As another example, the modulation can be the result of gene editing.

[0159] A modulation agent can be an antibody (e.g., a monoclonal antibody). Amodulating agent can be an agent that induces or inhibits progenitor cell differentiation into gene / protein expressing cells. SIGNAL REDUCTION, ELIMINATION, OR INHIBITION BY SMALL MOLECULE INHIBITORS, shRNA, siRNA, OR ASOs

[0160] As described herein, a modulation agent can be used for use in various therapies,such as to reduce / eliminate or enhance / increase expression signals. For example, a modulation agent can be a small molecule inhibitor, a short hairpin RNA (shRNA), or a short interfering RNA (siRNA). As another example, RNA (e.g., long noncoding RNA (lncRNA))can be targeted with antisense oligonucleotides (ASOs) as a therapeutic. Processes formaking ASOs targeted to RNAs are well known; see e.g., Zhou et al.2016 Methods Mol Biol.1402:199-213. Except as otherwise noted herein, therefore, the process of the present disclosure can be carried out in accordance with such processes. INHIBITING AGENT

[0161] Inhibition of agents as described herein can be determined by standardpharmaceutical procedures in assays or cell cultures for determining the IC50. The halfmaximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. The IC50 is a quantitative measure that indicates how much of a particular inhibitory substance (e.g., pharmaceutical agent or drug) is needed to inhibit, in vitro, a given biological process or biological component by 50%. The biological component could be an enzyme, cell, cell receptor, or microorganism, for example. IC50values are typically expressed as molar concentration. IC50is generally used as a measure of antagonist drug potency in pharmacological research. IC50 is comparable to other measures of potency, such as EC50for excitatory drugs. EC50represents the dose or plasma concentration required for obtaining 50% of a maximum effect in vivo. IC50 can be determined with functional assays or with competition binding assays. CHEMICAL AGENT

[0162] Examples of μ-opioid receptor (MOR)-targeting agents are described herein.Agents can include one or more compounds according to the MP-based scaffold disclosed herein, including but not limited to analogs of the MP-based scaffold described herein, or pharmaceutically acceptable salts thereof.

[0163] The formulas, analogs, and R groups can be optionally substituted orfunctionalized with one or more groups independently selected from the group consisting of hydroxyl; C1-10alkyl hydroxyl; amine; C1-10carboxylic acid; C1-10carboxyl; straight chain or branched C1-10alkyl, optionally containing unsaturation; a C2-10cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; straight chain or branched C1-10alkyl amine; heterocyclyl; heterocyclic amine; and aryl comprising a phenyl; heteroaryl containing from 1 to 4 N, O, or S atoms; unsubstituted phenyl ring; substituted phenyl ring; unsubstituted heterocyclyl; and substituted heterocyclyl, wherein the unsubstituted phenyl ring or substituted phenyl ring can be optionally substituted with one or more groups independently selected from the group consisting of hydroxyl; C1-10alkyl hydroxyl; amine; C1-10carboxyl; C1-10carboxylic acid; C1-10carboxyl; straight chain or branched C1-10alkyl, optionally containing unsaturation; straight chain or branched C1-10alkyl amine, optionally containing unsaturation; a C2-10cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; straight chain or branched C1-10alkyl amine; heterocyclyl; heterocyclic amine; aryl comprising a phenyl; and heteroaryl containing from 1 to 4 N, O, or S atoms; andthe unsubstituted heterocyclyl or substituted heterocyclyl can be optionally substituted with one or more groups independently selected from the group consisting of hydroxyl; C1-10alkyl hydroxyl; amine; C1-10carboxylic acid; C1-10carboxyl; straight chain or branched C1-10alkyl, optionally containing unsaturation; straight chain or branched C1-10alkyl amine, optionally containing unsaturation; a C2-10cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; heterocyclyl; straight chain or branched C1-10alkyl amine; heterocyclic amine; and aryl comprising a phenyl; and heteroaryl containing from 1 to 4 N, O, or S atoms. Any of the above can be further optionally substituted.

[0164] The term "imine" or "imino", as used herein, unless otherwise indicated, caninclude a functional group or chemical compound containing a carbon-nitrogen double bond. The expression "imino compound", as used herein, unless otherwise indicated, refers to a compound that includes an "imine" or an "imino" group as defined herein. The "imine" or "imino" group can be optionally substituted.

[0165] The term "hydroxyl", as used herein, unless otherwise indicated, can include -OH. The "hydroxyl" can be optionally substituted.

[0166] The terms "halogen" and "halo", as used herein, unless otherwise indicated,include a chlorine, chloro, Cl; fluorine, fluoro, F; bromine, bromo, Br; or iodine, iodo, or I.

[0167] The term "acetamide", as used herein, is an organic compound with the formulaCH₃CONH₂. The "acetamide" can be optionally substituted.

[0168] The term "aryl", as used herein, unless otherwise indicated, include a carbocyclicaromatic group. Examples of aryl groups include, but are not limited to, phenyl, benzyl, naphthyl, or anthracenyl. The "aryl" can be optionally substituted.

[0169] The terms "amine" and "amino", as used herein, unless otherwise indicated,include a functional group that contains a nitrogen atom with a lone pair of electrons and wherein one or more hydrogen atoms have been replaced by a substituent such as, but not limited to, an alkyl group or an aryl group. The "amine" or "amino" group can be optionally substituted.

[0170] The term "alkyl", as used herein, unless otherwise indicated, can include saturatedmonovalent hydrocarbon radicals having straight or branched moieties, such as but not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl groups, etc. Representative straight-chain lower alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, - n-butyl, -n-pentyl, -n-hexyl, -n-heptyl and -n-octyl; while branched lower alkyl groupsinclude, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2- methylbutyl, 2-methylpentyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, 3,3-dimethylpentyl, 2,3,4-trimethylpentyl, 3- methylhexyl, 2,2-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 3,5-dimethylhexyl, 2,4-dimethylpentyl, 2-methylheptyl, 3-methylheptyl, unsaturated C1-10alkyls include, but are not limited to, -vinyl, -allyl, -1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl, - 3-methyl-1-butenyl, -2-methyl-2-butenyl, -2,3-dimethyl-2-butenyl, 1-hexyl, 2-hexyl, 3-hexyl, -acetylenyl, -propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2-pentynyl, or -3-methyl-1 butynyl. An alkyl can be saturated, partially saturated, or unsaturated. The "alkyl" can be optionally substituted.

[0171] The term "carboxyl", as used herein, unless otherwise indicated, can include afunctional group consisting of a carbon atom double bonded to an oxygen atom and single bonded to a hydroxyl group (-COOH). The "carboxyl" can be optionally substituted.

[0172] The term "carbonyl", as used herein, unless otherwise indicated, can include afunctional group consisting of a carbon atom double-bonded to an oxygen atom (C=O). The "carbonyl" can be optionally substituted.

[0173] The term "alkenyl", as used herein, unless otherwise indicated, can include alkylmoieties having at least one carbon-carbon double bond wherein alkyl is as defined above and including E and Z isomers of said alkenyl moiety. An alkenyl can be partially saturated or unsaturated. The "alkenyl" can be optionally substituted.

[0174] The term "alkynyl", as used herein, unless otherwise indicated, can include alkylmoieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. An alkynyl can be partially saturated or unsaturated. The "alkynyl" can be optionally substituted.

[0175] The term "acyl", as used herein, unless otherwise indicated, can include afunctional group derived from an aliphatic carboxylic acid, by removal of the hydroxyl (– OH) group. The "acyl" can be optionally substituted.

[0176] The term "alkoxyl", as used herein, unless otherwise indicated, can include O-alkyl groups wherein alkyl is as defined above and O represents oxygen. Representative alkoxyl groups include, but are not limited to, -O-methyl, -O-ethyl, -O-n-propyl, -O-n-butyl, - O-n-pentyl, -O-n-hexyl, -O-n-heptyl, -O-n-octyl, -O-isopropyl, -O-sec-butyl, -O-isobutyl, -O- tert-butyl, -O-isopentyl, -O-2-methylbutyl, -O-2-methylpentyl, -O-3-methylpentyl, -O-2,2- dimethylbutyl, -O-2,3-dimethylbutyl, -O-2,2-dimethylpentyl, -O-2,3-dimethylpentyl, -O-3,3- dimethylpentyl, -O-2,3,4-trimethylpentyl, -O-3-methylhexyl, -O-2,2-dimethylhexyl, -O-2,4-dimethylhexyl, -O-2,5-dimethylhexyl, -O-3,5-dimethylhexyl, -O-2,4dimethylpentyl, -O-2- methylheptyl, -O-3-methylheptyl, -O-vinyl, -O-allyl, -O-1-butenyl, -O-2-butenyl, -O- isobutylenyl, -O-1-pentenyl, -O-2-pentenyl, -O-3-methyl-1-butenyl, -O-2-methyl-2-butenyl, - O-2,3-dimethyl-2-butenyl, -O-1-hexyl, -O-2-hexyl, -O-3-hexyl, -O-acetylenyl, -O-propynyl, - O-1-butynyl, -O-2-butynyl, -O-1-pentynyl, -O-2-pentynyl and -O-3-methyl-1-butynyl, -O- cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O-cyclohexyl, -O-cycloheptyl, -O-cyclooctyl, - O-cyclononyl and -O-cyclodecyl, -O-CH2-cyclopropyl, -O-CH2-cyclobutyl, -O-CH2- cyclopentyl, -O-CH2-cyclohexyl, -O-CH2-cycloheptyl, -O-CH2-cyclooctyl, -O- CH2- cyclononyl, -O-CH2-cyclodecyl, -O-(CH2)2-cyclopropyl, -O-(CH2)2-cyclobutyl, -O-(CH2)2- cyclopentyl, -O-(CH2)2-cyclohexyl, -O-(CH2)2-cycloheptyl, -O-(CH2)2-cyclooctyl, -O- (CH2)2-cyclononyl, or -O-(CH2)2-cyclodecyl. An alkoxyl can be saturated, partially saturated, or unsaturated. The "alkoxyl" can be optionally substituted.

[0177] The term "cycloalkyl", as used herein, unless otherwise indicated, can include anaromatic, a non-aromatic, saturated, partially saturated, or unsaturated, monocyclic or fused, spiro or unfused bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 1 to 10 carbon atoms (e.g., 1 or 2 carbon atoms if there are other heteroatoms in the ring), preferably 3 to 8 ring carbon atoms. Examples of cycloalkyls include, but are not limited to, C3-10cycloalkyl groups include, but are not limited to, -cyclopropyl, -cyclobutyl, - cyclopentyl, -cyclopentadienyl, -cyclohexyl, -cyclohexenyl, -1,3-cyclohexadienyl, -1,4- cyclohexadienyl, -cycloheptyl, -1,3-cycloheptadienyl, -1,3,5-cycloheptatrienyl, -cyclooctyl, and -cyclooctadienyl. The term "cycloalkyl" also can include -lower alkyl-cycloalkyl, wherein lower alkyl and cycloalkyl are as defined herein. Examples of -lower alkyl- cycloalkyl groups include, but are not limited to, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2- cyclopentyl, -CH2-cyclopentadienyl, -CH2-cyclohexyl, -CH2-cycloheptyl, or -CH2- cyclooctyl. The "cycloalkyl" can be optionally substituted. A "cycloheteroalkyl", as used herein, unless otherwise indicated, can include any of the above with a carbon substituted with a heteroatom (e.g., O, S, N).

[0178] The term "heterocyclic" or "heteroaryl", as used herein, unless otherwiseindicated, can include an aromatic or non-aromatic cycloalkyl in which one to four of the ring carbon atoms are independently replaced with a heteroatom from the group consisting of O, S, and N. Representative examples of a heterocycle include, but are not limited to,benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, coumarinyl, isoquinolinyl, pyrrolyl, pyrrolidinyl, thiophenyl, furanyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, quinolinyl, pyrimidinyl, pyridinyl, pyridonyl, pyrazinyl, pyridazinyl, isothiazolyl, isoxazolyl, (1,4)- dioxane, (1,3)-dioxolane, 4,5-dihydro-1H-imidazolyl, or tetrazolyl. Heterocycles can be substituted or unsubstituted. Heterocycles can also be bonded at any ring atom (i.e., at any carbon atom or heteroatom of the heterocyclic ring). A heterocyclic can be saturated, partially saturated, or unsaturated. The "heterocyclic" can be optionally substituted.

[0179] The term "indole", as used herein, is an aromatic heterocyclic organic compoundwith formula C₈H₇N. It has a bicyclic structure, consisting of a six-membered benzene ring fused to a five-membered nitrogen-containing pyrrole ring. The "indole" can be optionally substituted.

[0180] The term "cyano", as used herein, unless otherwise indicated, can include a -CNgroup. The "cyano" can be optionally substituted.

[0181] The term "alcohol", as used herein, unless otherwise indicated, can include acompound in which the hydroxyl functional group (-OH) is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms. The "alcohol" can be optionally substituted.

[0182] The term "solvate" is intended to mean a solvate form of a specified compoundthat retains the effectiveness of such compound. Examples of solvates include compounds of the invention in combination with, for example, water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, or ethanolamine.

[0183] The term "mmol", as used herein, is intended to mean millimole. The term"equiv", as used herein, is intended to mean equivalent. The term "mL", as used herein, is intended to mean milliliter. The term "g", as used herein, is intended to mean gram. The term "kg", as used herein, is intended to mean kilogram. The term "µg", as used herein, is intended to mean micrograms. The term "h", as used herein, is intended to mean hour. The term "min", as used herein, is intended to mean minute. The term "M", as used herein, is intended to mean molar. The term "µL", as used herein, is intended to mean microliter. The term "µM", as used herein, is intended to mean micromolar. The term "nM", as used herein, is intended to mean nanomolar. The term "N", as used herein, is intended to mean normal. The term "amu", as used herein, is intended to mean atomic mass unit. The term "°C", as used herein, is intended to mean degree Celsius. The term "wt / wt", as used herein, is intended to mean weight / weight. The term "v / v", as used herein, is intended to mean volume / volume. The term "MS", as usedherein, is intended to mean mass spectroscopy. The term "HPLC", as used herein, is intended to mean high performance liquid chromatograph. The term "RT", as used herein, is intended to mean room temperature. The term "e.g.", as used herein, is intended to mean example. The term "N / A", as used herein, is intended to mean not tested.

[0184] As used herein, the expression "pharmaceutically acceptable salt" refers topharmaceutically acceptable organic or inorganic salts of a compound of the invention. Preferred salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt can involve the inclusion of another molecule such as an acetate ion, a succinate ion, or another counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt can have more than one charged atom in its structure. In instances where multiple charged atoms are part of the pharmaceutically acceptable salt, the pharmaceutically acceptable salt can have multiple counterions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterion. As used herein, the expression "pharmaceutically acceptable solvate" refers to an association of one or more solvent molecules and a compound of the invention. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. As used herein, the expression "pharmaceutically acceptable hydrate" refers to a compound of the invention, or a salt thereof, that further can include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. FORMULATION

[0185] The agents and compositions described herein can be formulated by anyconventional manner using one or more pharmaceutically acceptable carriers or excipients as described in, for example, Remington's Pharmaceutical Sciences (A.R. Gennaro, Ed.), 21st edition, ISBN: 0781746736 (2005), incorporated herein by reference in its entirety. Such formulations will contain a therapeutically effective amount of a biologically active agentdescribed herein, which can be in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the subject.

[0186] The term "formulation" refers to preparing a drug in a form suitable foradministration to a subject, such as a human. Thus, a "formulation" can include pharmaceutically acceptable excipients, including diluents or carriers.

[0187] The term "pharmaceutically acceptable" as used herein can describe substances orcomponents that do not cause unacceptable losses of pharmacological activity or unacceptable adverse side effects. Examples of pharmaceutically acceptable ingredients can be those having monographs in United States Pharmacopeia (USP 29) and National Formulary (NF 24), United States Pharmacopeial Convention, Inc, Rockville, Maryland, 2005 ("USP / NF"), or a more recent edition, and the components listed in the continuously updated Inactive Ingredient Search online database of the FDA. Other useful components that are not described in the USP / NF, etc., can also be used.

[0188] The term "pharmaceutically acceptable excipient," as used herein, can includeany and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic, or absorption delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art (see generally Remington's Pharmaceutical Sciences (A.R. Gennaro, Ed.), 21st edition, ISBN: 0781746736 (2005)). Except insofar as any conventional media or agent is incompatible with an active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0189] A "stable" formulation or composition can refer to a composition havingsufficient stability to allow storage at a convenient temperature, such as between about 0 ºC and about 60 ºC, for a commercially reasonable period of time, such as at least about one day, at least about one week, at least about one month, at least about three months, at least about six months, at least about one year, or at least about two years.

[0190] The formulation should suit the mode of administration. The agents of use withthe current disclosure can be formulated by known methods for administration to a subject using several routes which include, but are not limited to, parenteral, pulmonary, oral, topical, intradermal, intratumoral, intranasal, inhalation (e.g., in an aerosol), implanted, intramuscular, intraperitoneal, intravenous, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, intrathecal, ophthalmic, transdermal, buccal, and rectal. The individual agents can also be administered in combination with one or more additionalagents or together with other biologically active or biologically inert agents. Such biologically active or inert agents can be in fluid or mechanical communication with the agent(s) or attached to the agent(s) by ionic, covalent, Van der Waals, hydrophobic, hydrophilic, or other physical forces.

[0191] Controlled-release (or sustained-release) preparations can be formulated to extendthe activity of the agent(s) and reduce dosage frequency. Controlled-release preparations can also be used to affect the time of onset of action or other characteristics, such as blood levels of the agent, and consequently, affect the occurrence of side effects. Controlled-release preparations can be designed to initially release an amount of an agent(s) that produces the desired therapeutic effect, and gradually and continually release other amounts of the agent to maintain the level of therapeutic effect over an extended period of time. In order to maintain a near-constant level of an agent in the body, the agent can be released from the dosage form at a rate that will replace the amount of agent being metabolized or excreted from the body. The controlled-release of an agent can be stimulated by various inducers, e.g., change in pH, change in temperature, enzymes, water, or other physiological conditions or molecules.

[0192] Agents or compositions described herein can also be used in combination withother therapeutic modalities, as described further below. Thus, in addition to the therapies described herein, one can also provide to the subject other therapies known to be efficacious for treatment of the disease, disorder, or condition. THERAPEUTIC METHODS

[0193] Also provided is a process of treating, preventing, or reversing pain symptomsand / or opioid use disorder in a subject in need thereof via administration of a therapeutically effective amount of a MOR-targeting agent, so as to provide safer analgesics with decreased adverse effects.

[0194] Methods described herein are generally performed on a subject in need thereof. Asubject in need of the therapeutic methods described herein can be a subject having, diagnosed with, suspected of having, or at risk for developing pain symptoms and / or opioid use disorder. A determination of the need for treatment will typically be assessed by a history, physical exam, or diagnostic tests consistent with the disease or condition at issue. Diagnosis of the various conditions treatable by the methods described herein is within the skill of the art. The subject can be an animal subject, including a mammal, such as horses, cows, dogs, cats, sheep, pigs, mice, rats, monkeys, hamsters, guinea pigs, and humans or chickens. For example, the subject can be a human subject.

[0195] Generally, a safe and effective amount of a MOR-targeting agent is, for example,an amount that would cause the desired therapeutic effect in a subject while minimizing undesired side effects. In various embodiments, an effective amount of a MOR-targeting agent described herein can substantially inhibit, slow the progress of, or limit the development of pain symptoms and / or opioid use disorder.

[0196] According to the methods described herein, administration can be parenteral,pulmonary, oral, topical, intradermal, intramuscular, intraperitoneal, intravenous, intratumoral, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, ophthalmic, buccal, or rectal administration.

[0197] When used in the treatments described herein, a therapeutically effective amountof a MOR-targeting agent can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt form and with or without a pharmaceutically acceptable excipient. For example, the compounds of the present disclosure can be administered, at a reasonable benefit / risk ratio applicable to any medical treatment, in a sufficient amount to reduce, eliminate, or manage pain symptoms.

[0198] The amount of a composition described herein that can be combined with apharmaceutically acceptable carrier to produce a single dosage form will vary depending upon the subject or host treated and the particular mode of administration. It will be appreciated by those skilled in the art that the unit content of agent contained in an individual dose of each dosage form need not in itself constitute a therapeutically effective amount, as the necessary therapeutically effective amount could be reached by administration of a number of individual doses.

[0199] Toxicity and therapeutic efficacy of compositions described herein can bedetermined by standard pharmaceutical procedures in cell cultures or experimental animals for determining the LD50(the dose lethal to 50% of the population) and the ED50, (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index that can be expressed as the ratio LD50 / ED50, where larger therapeutic indices are generally understood in the art to be optimal.

[0200] The specific therapeutically effective dose level for any particular subject willdepend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration; the route of administration; the rate of excretion of the compositionemployed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts (see e.g., Koda- Kimble et al. (2004) Applied Therapeutics: The Clinical Use of Drugs, Lippincott Williams & Wilkins, ISBN 0781748453; Winter (2003) Basic Clinical Pharmacokinetics, 4thed., Lippincott Williams & Wilkins, ISBN 0781741475; Sharqel (2004) Applied Biopharmaceutics & Pharmacokinetics, McGraw-Hill / Appleton & Lange, ISBN 0071375503). For example, it is well within the skill of the art to start doses of the composition at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by an attending physician within the scope of sound medical judgment.

[0201] Again, each of the states, diseases, disorders, and conditions, described herein, aswell as others, can benefit from compositions and methods described herein. Generally, treating a state, disease, disorder, or condition includes reversing or delaying the appearance of clinical symptoms in a mammal that can be afflicted with or predisposed to the state, disease, disorder, or condition but does not yet experience or display clinical or subclinical symptoms thereof. Treating can also include inhibiting the state, disease, disorder, or condition, e.g., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof. Furthermore, treating can include relieving the disease, e.g., causing regression of the state, disease, disorder, or condition or at least one of its clinical or subclinical symptoms. A benefit to a subject to be treated can be either statistically significant or at least perceptible to the subject or a physician.

[0202] Administration of a MOR-targeting agent can occur as a single event or over atime course of treatment. For example, a MOR-targeting agent can be administered daily, weekly, bi-weekly, or monthly. For treatment of acute conditions, the time course of treatment will usually be at least several days. Certain conditions could extend treatment from several days to several weeks. For example, treatment could extend over one week, two weeks, or three weeks. For more chronic conditions, treatment could extend from several weeks to several months or even a year or more.

[0203] Treatment in accord with the methods described herein can be performed prior toor before, concurrent with, or after conventional treatment modalities for pain symptoms and / or opioid use disorder.

[0204] A MOR-targeting agent can be administered simultaneously or sequentially withanother agent, such as an antibiotic, an anti-inflammatory, or another agent. For example, a MOR-targeting agent can be administered simultaneously with another agent, such as an antibiotic or an anti-inflammatory. Simultaneous administration can occur through administration of separate compositions, each containing one or more of a MOR-targeting agent, an antibiotic, an anti-inflammatory, or another agent. Simultaneous administration can occur through administration of one composition containing two or more of a MOR-targeting agent, an antibiotic, an anti-inflammatory, or another agent. A MOR-targeting agent can be administered sequentially with an antibiotic, an anti-inflammatory, or another agent. For example, a MOR-targeting agent can be administered before or after administration of an antibiotic, an anti-inflammatory, or another agent.

[0205] Active compounds are administered at a therapeutically effective dosagesufficient to treat a condition associated with a condition in a patient. For example, the efficacy of a compound can be evaluated in an animal model system that can be predictive of efficacy in treating the disease in a human or another animal, such as the model systems shown in the examples and drawings.

[0206] An effective dose range of a therapeutic can be extrapolated from effective dosesdetermined in animal studies for a variety of different animals. In general, a human equivalent dose (HED) in mg / kg can be calculated in accordance with the following formula (see e.g., Reagan-Shaw et al., FASEB J., 22(3):659-661, 2008, which is incorporated herein by reference):

[0207] HED (mg / kg) = Animal dose (mg / kg) × (Animal Km / Human Km)

[0208] Use of the Km factors in conversion results in more accurate HED values, whichare based on body surface area (BSA) rather than only on body mass. Kmvalues for humans and various animals are well known. For example, the Kmfor an average 60 kg human (with a BSA of 1.6 m2) is 37, whereas a 20 kg child (BSA 0.8 m2) would have a Kmof 25. Kmfor some relevant animal models are also well known, including: mice Km of 3 (given a weight of 0.02 kg and BSA of 0.007); hamster Kmof 5 (given a weight of 0.08 kg and BSA of 0.02);rat Kmof 6 (given a weight of 0.15 kg and BSA of 0.025) and monkey Kmof 12 (given a weight of 3 kg and BSA of 0.24).

[0209] Precise amounts of the therapeutic composition depend on the judgment of thepractitioner and are peculiar to each individual. Nonetheless, a calculated HED dose provides a general guide. Other factors affecting the dose include the physical and clinical state of the patient, the route of administration, the intended goal of treatment, and the potency, stability, and toxicity of the particular therapeutic formulation.

[0210] The actual dosage amount of a compound of the present disclosure orcomposition comprising a compound of the present disclosure administered to a subject can be determined by physical and physiological factors such as type of animal treated, age, sex, body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the subject and on the route of administration. These factors can be determined by a skilled artisan. The practitioner responsible for administration will typically determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject. The dosage can be adjusted by the individual physician in the event of any complication.

[0211] In some embodiments, the MOR-targeting agent can be administered in anamount from about 1 mg / kg to about 100 mg / kg, or about 1 mg / kg to about 50 mg / kg, or about 1 mg / kg to about 25 mg / kg, or about 1 mg / kg to about 15 mg / kg, or about 1 mg / kg to about 10 mg / kg, or about 1 mg / kg to about 5 mg / kg, or about 3 mg / kg. In some embodiments, a MOR-targeting agent such as a compound according to the MP-based scaffold described herein, such as an analog described herein, can be administered in a range of about 1 mg / kg to about 200 mg / kg, or about 50 mg / kg to about 200 mg / kg, or about 50 mg / kg to about 100 mg / kg, or about 75 mg / kg to about 100 mg / kg, or about 100 mg / kg.

[0212] The effective amount can be less than 1 mg / kg / day, less than 500 mg / kg / day, lessthan 250 mg / kg / day, less than 100 mg / kg / day, less than 50 mg / kg / day, less than 25 mg / kg / day or less than 10 mg / kg / day. It can alternatively be in the range of 1 mg / kg / day to 200 mg / kg / day.

[0213] In other non-limiting examples, a dose can also comprise from about 1 micro-gram / kg / body weight, about 5 microgram / kg / body weight, about 10 microgram / kg / body weight, about 50 microgram / kg / body weight, about 100 microgram / kg / body weight, about 200 microgram / kg / body weight, about 350 microgram / kg / body weight, about 500 microgram / kg / body weight, about 1 milligram / kg / body weight, about 5 milligram / kg / bodyweight, about 10 milligram / kg / body weight, about 50 milligram / kg / body weight, about 100 milligram / kg / body weight, about 200 milligram / kg / body weight, about 350 milligram / kg / body weight, about 500 milligram / kg / body weight, to about 1000 mg / kg / body weight or more per administration, and any range derivable therein. In non-limiting examples of a derivable range from the numbers listed herein, a range of about 5 mg / kg / body weight to about 100 mg / kg / body weight, about 5 microgram / kg / body weight to about 500 milligram / kg / body weight, etc., can be administered, based on the numbers described above. ADMINISTRATION

[0214] Agents and compositions described herein can be administered according tomethods described herein in a variety of means known to the art. The agents and composition can be used therapeutically either as exogenous materials or as endogenous materials. Exogenous agents are those produced or manufactured outside of the body and administered to the body. Endogenous agents are those produced or manufactured inside the body by some type of device (biologic or other) for delivery within or to other organs in the body.

[0215] As discussed above, administration can be parenteral, pulmonary, oral, topical,intradermal, intratumoral, intranasal, inhalation (e.g., in an aerosol), implanted, intramuscular, intraperitoneal, intravenous, intrathecal, intracranial, intracerebroventricular, subcutaneous, intranasal, epidural, intrathecal, ophthalmic, transdermal, buccal, and rectal.

[0216] Agents and compositions described herein can be administered in a variety ofmethods well known in the arts. Administration can include, for example, methods involving oral ingestion, direct injection (e.g., systemic or stereotactic), implantation of cells engineered to secrete the factor of interest, drug-releasing biomaterials, polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, implantable matrix devices, mini-osmotic pumps, implantable pumps, injectable gels and hydrogels, liposomes, micelles (e.g., up to 30 µm), nanospheres (e.g., less than 1 µm), microspheres (e.g., 1-100 µm), reservoir devices, a combination of any of the above, or other suitable delivery vehicles to provide the desired release profile in varying proportions. Other methods of controlled-release delivery of agents or compositions will be known to the skilled artisan and are within the scope of the present disclosure.

[0217] Delivery systems can include, for example, an infusion pump which can be usedto administer the agent or composition in a manner similar to that used for delivering insulin or chemotherapy to specific organs or tumors. Typically, using such a system, an agent or composition can be administered in combination with a biodegradable, biocompatiblepolymeric implant that releases the agent over a controlled period of time at a selected site. Examples of polymeric materials include polyanhydrides, polyorthoesters, polyglycolic acid, polylactic acid, polyethylene vinyl acetate, and copolymers and combinations thereof. In addition, a controlled release system can be placed in proximity of a therapeutic target, thus requiring only a fraction of a systemic dosage.

[0218] Agents can be encapsulated and administered in a variety of carrier deliverysystems. Examples of carrier delivery systems include microspheres, hydrogels, polymeric implants, smart polymeric carriers, and liposomes (see generally, Uchegbu and Schatzlein, eds. (2006) Polymers in Drug Delivery, CRC, ISBN-10: 0849325331). Carrier-based systems for molecular or biomolecular agent delivery can: provide for intracellular delivery; tailor biomolecule / agent release rates; increase the proportion of biomolecule that reaches its site of action; improve the transport of the drug to its site of action; allow colocalized deposition with other agents or excipients; improve the stability of the agent in vivo; prolong the residence time of the agent at its site of action by reducing clearance; decrease the nonspecific delivery of the agent to nontarget tissues; decrease irritation caused by the agent; decrease toxicity due to high initial doses of the agent; alter the immunogenicity of the agent; decrease dosage frequency; improve taste of the product; or improve shelf life of the product. SCREENING

[0219] Also provided are screening methods.

[0220] The subject methods find use in the screening of a variety of different candidatemolecules (e.g., potentially therapeutic candidate molecules). Candidate substances for screening according to the methods described herein include, but are not limited to, fractions of tissues or cells, nucleic acids, polypeptides, siRNAs, antisense molecules, aptamers, ribozymes, triple helix compounds, antibodies, and small (e.g., less than about 2000 MW, or less than about 1000 MW, or less than about 800 MW) organic molecules or inorganic molecules including but not limited to salts or metals.

[0221] Candidate molecules encompass numerous chemical classes, for example, organicmolecules, such as small organic compounds having a molecular weight of more than 50 and less than about 2,500 Daltons. Candidate molecules can comprise functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl, or carboxyl group, and usually at least two of the functional chemical groups. The candidate molecules can comprise cyclical carbonor heterocyclic structures and / or aromatic or polyaromatic structures substituted with one or more of the above functional groups.

[0222] A candidate molecule can be a compound in a library database of compounds.One of skill in the art will be generally familiar with, for example, numerous databases for commercially available compounds for screening (see e.g., ZINC database, UCSF, with 2.7 million compounds over 12 distinct subsets of molecules; Irwin and Shoichet (2005) J Chem Inf Model 45, 177-182). One of skill in the art will also be familiar with a variety of search engines to identify commercial sources or desirable compounds and classes of compounds for further testing (see e.g., ZINC database; eMolecules.com; and electronic libraries of commercial compounds provided by vendors, for example, ChemBridge, Princeton BioMolecular, Ambinter SARL, Enamine, ASDI, Life Chemicals, etc.).

[0223] Candidate molecules for screening according to the methods described hereininclude both lead-like compounds and drug-like compounds. A lead-like compound is generally understood to have a relatively smaller scaffold-like structure (e.g., molecular weight of about 150 to about 350 kD) with relatively fewer features (e.g., less than about 3 hydrogen donors and / or less than about 6 hydrogen acceptors; hydrophobicity character xlogP of about -2 to about 4). In contrast, a drug-like compound is generally understood to have a relatively larger scaffold (e.g., molecular weight of about 150 to about 500 kD) with relatively more numerous features (e.g., less than about 10 hydrogen acceptors and / or less than about 8 rotatable bonds; hydrophobicity character xlogP of less than about 5) (see e.g., Lipinski (2000) J. Pharm. Tox. Methods 44, 235-249). Initial screening can be performed with lead-like compounds.

[0224] When designing a lead from spatial orientation data, it can be useful tounderstand that certain molecular structures are characterized as being "drug-like". Such characterization can be based on a set of empirically recognized qualities derived by comparing similarities across the breadth of known drugs within the pharmacopoeia. While it is not required for drugs to meet all, or even any, of these characterizations, it is far more likely for a drug candidate to meet with clinical success if it is drug-like.

[0225] Several of these "drug-like" characteristics have been summarized into the fourrules of Lipinski (generally known as the "rules of fives" because of the prevalence of the number 5 among them). While these rules generally relate to oral absorption and are used to predict the bioavailability of a compound during lead optimization, they can serve aseffective guidelines for constructing a lead molecule during rational drug design efforts such as can be accomplished by using the methods of the present disclosure.

[0226] The four "rules of five" state that a candidate drug-like compound should have atleast three of the following characteristics: (i) a weight less than 500 Daltons; (ii) a log of P less than 5; (iii) no more than 5 hydrogen bond donors (expressed as the sum of OH and NH groups); and (iv) no more than 10 hydrogen bond acceptors (the sum of N and O atoms). Also, drug-like molecules typically have a span (breadth) of between about 8Å to about 15Å. KITS

[0227] Also provided are kits. Such kits can include an agent or composition describedherein and, in certain embodiments, instructions for administration. Such kits can facilitate performance of the methods described herein. When supplied as a kit, the different components of the composition can be packaged in separate containers and admixed immediately before use. Components include, but are not limited to analogs and precursors described herein. Such packaging of the components separately can, if desired, be presented in a pack or dispenser device which can contain one or more unit dosage forms containing the composition. The pack can, for example, comprise metal or plastic foil such as a blister pack. Such packaging of the components separately can also, in certain instances, permit long-term storage without losing activity of the components.

[0228] Kits can also include reagents in separate containers such as, for example, sterilewater or saline to be added to a lyophilized active component packaged separately. For example, sealed glass ampules can contain a lyophilized component and in a separate ampule, sterile water, sterile saline each of which has been packaged under a neutral non-reacting gas, such as nitrogen. Ampules can consist of any suitable material, such as glass, organic polymers, such as polycarbonate, polystyrene, ceramic, metal, or any other material typically employed to hold reagents. Other examples of suitable containers include bottles that can be fabricated from similar substances as ampules and envelopes that can consist of foil-lined interiors, such as aluminum or an alloy. Other containers include test tubes, vials, flasks, bottles, syringes, and the like. Containers can have a sterile access port, such as a bottle having a stopper that can be pierced by a hypodermic injection needle. Other containers can have two compartments that are separated by a readily removable membrane that upon removal permits the components to mix. Removable membranes can be glass, plastic, rubber, and the like.

[0229] In certain embodiments, kits can be supplied with instructional materials.Instructions can be printed on paper or another substrate, and / or can be supplied as an electronic-readable medium or video. Detailed instructions can not be physically associated with the kit; instead, a user can be directed to an Internet web site specified by the manufacturer or distributor of the kit.

[0230] A control sample or a reference sample as described herein can be a sample froma healthy subject or sample, a wild-type subject or sample, or from populations thereof. A reference value can be used in place of a control or reference sample, which was previously obtained from a healthy subject or a group of healthy subjects or a wild-type subject or sample. A control sample or a reference sample can also be a sample with a known amount of a detectable compound or a spiked sample.

[0231] Compositions and methods described herein utilizing molecular biology protocolscan be according to a variety of standard techniques known to the art (see e.g., Sambrook and Russel (2006) Condensed Protocols from Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, ISBN-10: 0879697717; Ausubel et al. (2002) Short Protocols in Molecular Biology, 5th ed., Current Protocols, ISBN-10: 0471250929; Sambrook and Russel (2001) Molecular Cloning: A Laboratory Manual, 3d ed., Cold Spring Harbor Laboratory Press, ISBN-10: 0879695773; Elhai, J. and Wolk, C. P.1988. Methods in Enzymology 167, 747-754; Studier (2005) Protein Expr Purif.41(1), 207–234; Gellissen, ed. (2005) Production of Recombinant Proteins: Novel Microbial and Eukaryotic Expression Systems, Wiley-VCH, ISBN-10: 3527310363; Baneyx (2004) Protein Expression Technologies, Taylor & Francis, ISBN-10: 0954523253).

[0232] Definitions and methods described herein are provided to better define the presentdisclosure and to guide those of ordinary skill in the art in the practice of the present disclosure. Unless otherwise noted, terms are to be understood according to conventional usage by those of ordinary skill in the relevant art.

[0233] In some embodiments, numbers expressing quantities of ingredients, propertiessuch as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments of the present disclosure are to be understood as being modified in some instances by the term "about." In some embodiments, the term "about" is used to indicate that a value includes the standard deviation of the mean for the device or method being employed to determine the value. In some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon thedesired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the present disclosure are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the present disclosure can contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. The recitation of discrete values is understood to include ranges between each value.

[0234] In some embodiments, the terms "a" and "an" and "the" and similar referencesused in the context of describing a particular embodiment (especially in the context of certain of the following claims) can be construed to cover both the singular and the plural, unless specifically noted otherwise. In some embodiments, the term "or" as used herein, including the claims, is used to mean "and / or" unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive.

[0235] The terms "comprise," "have" and "include" are open-ended linking verbs. Anyforms or tenses of one or more of these verbs, such as "comprises," "comprising," "has," "having," "includes" and "including," are also open-ended. For example, any method that "comprises," "has" or "includes" one or more steps is not limited to possessing only those one or more steps and can also cover other unlisted steps. Similarly, any composition or device that "comprises," "has" or "includes" one or more features is not limited to possessing only those one or more features and can cover other unlisted features.

[0236] All methods described herein can be performed in any suitable order unlessotherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided with respect to certain embodiments herein is intended merely to better illuminate the present disclosure and does not pose a limitation on the scope of the present disclosure otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the present disclosure.

[0237] Groupings of alternative elements or embodiments of the present disclosuredisclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0238] All publications, patents, patent applications, and other references cited in thisapplication are incorporated herein by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other reference was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Citation of a reference herein shall not be construed as an admission that such is prior art to the present disclosure.

[0239] Having described the present disclosure in detail, it will be apparent thatmodifications, variations, and equivalent embodiments are possible without departing the scope of the present disclosure defined in the appended claims. Furthermore, it should be appreciated that all examples in the present disclosure are provided as non-limiting examples.

[0240] A number of implementations have been described. Nevertheless, it will beunderstood that various modifications can be made without departing from the spirit and scope of the disclosure. Accordingly, other implementations are within the scope of the following claims. EXAMPLES

[0241] The following non-limiting examples are provided to further illustrate the presentdisclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples that follow represent approaches the inventors have found function well in the practice of the present disclosure and thus can be considered to constitute examples of modes for its practice. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific cases that are disclosed and still obtain a like or similar result without departing from the spirit and scope of the present disclosure. Example 1: Preparation of 7-OH MitragynineRed Indonesian kratom powderExample 2: Synthesis of C10 and C12 MP analogsOM

[0242] Reagents and condition: (a) tetrafluoroethylene (TFE), 95 °C, 1 hour, microwave,90%. (b) 2,6-dichloro-1-fluoropyridinium tetrafluoroborate, nitromethane, dry dichloromethane (DCM), 0 °C, 24 hours, 45-55%; (c) N-chlorosuccinimide (NCS) or N- bromosuccinimide (NBS), dry acetonitrile (CAN), 0 °C to room temperature (rt), 12 hours. 32-47% (d) Zn(CN)2, Pd(PPh3)4, N,N-dimethylformamide (DMF), 80 °C, 2 hours, 30%; (e) Pd(OAc)2, 1,1-bis(diphenylphophino)ferrocene (dppf), imidazole, Co2(CO)8, NH4Cl, N,N-diisopropylehtylamine (DIPEA), dry 1,4-dioxane, 90 °C, 24 hours, 32%; (f) Boronicacid / boronic acid pinacol ester, Pd(PPh3)4, K2CO3, MeOH:Toluene (1:2), 80 °C, 2-16 hours32%-57%; (g) vinyl boronic acid or prop-1-en-2-yl, cyclohex-1-en-1-yl and 3,6-Dihydro-2H-pyran-4-boronic acid pinacol ester, (PPh3)4, K2CO3, dry toluene : MeOH (2:1), 80 °C, 12-16 hours. (h) 10% Pd / C, H2, dry MeOH, rt, 4-8 hours; 32-65% yield after 2 steps.

[0243] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-5-fluoro-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.16 (dd, J = 12.2, 8.8 Hz, 1H), 6.38 (dd, J = 8.8, 2.7 Hz, 1H), 4.96 (s, 1H), 4.13 (dd, J = 3.0, 1.0 Hz, 3H), 3.67 (s, 3H), 3.63 (s, 3H), 3.13 (d, J = 10.7 Hz, 2H), 2.81 – 2.75 (m, 1H), 2.36- 2.28 (m, 2H), 2.20 – 2.11 (m, 2H), 1.95 – 1.85 (m, 1H), 1.68-1.48 (m, 2H), 1.50 (d, J = 12.1 Hz, 1H), 1.22 – 1.16 (m, 1H), 1.10 – 1.05 (m, 1H), 0.84 (t, J = 7.5 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.7 (J = 4.0 Hz), 168.8, 160.3, 158.0, 146.1 (J = 235 Hz), 144.6 (J = 10.0 Hz), 126.4 (J = 23.0 Hz), 112.9, 111.4, 104.3 (J = 8.0 Hz), 76.1, 73.6, 61.7, 61.5, 54.7, 53.1, 51.2, 39.9, 38.3, 35.1, 23.7, 19.2, 12.8. HRMS calculated for C23H29FN2O5H+= 433.2133; found = 433.2132.

[0244] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-bromo-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.6 Hz, 1H), 7.28 (s, 1H), 6.45 (d, J = 8.6 Hz, 1H), 5.30 (s, 1H), 4.02 (s, 3H), 3.67 (s, 3H), 3.61 (s, 3H), 3.16 – 3.09 (m, 2H), 2.76 (dt, J = 12.3, 3.7 Hz, 1H), 2.32 – 2.24 (m, 2H), 2.21 – 2.08 (m, 3H), 1.93 – 1.84 (m, 1H), 1.65 – 1.54 (m, 1H), 1.52 – 1.46 (m, 1H), 1.20 – 1.12 (m, 1H), 1.04 (dd, J = 10.6, 3.5 Hz, 1H), 0.82 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 198.4, 168.8, 161.4, 160.3, 154.9, 141.0, 113.7, 111.3, 107.5, 102.9, 75.7, 73.6, 62.1, 61.5, 54.7, 53.1, 51.2, 39.9, 38.3, 35.1, 23.7, 19.2, 12.8. HRMS calculated for C23H29BrN2O5H+= 493.1260; found = 493.1261.BP1-84

[0245] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-cyano-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.5 Hz, 1H), 7.29 (s, 1H), 6.46 (d, J = 8.6 Hz, 1H), 5.88 (s, 1H), 4.26 (s, 3H), 3.68 (s, 3H), 3.62 (s, 3H), 3.17 – 3.09 (m, 2H), 2.77 (dd, J = 8.4, 4.0 Hz, 1H), 2.39 – 2.28 (m, 2H), 2.25 – 2.18 (m, 2H), 2.15 – 2.09 (m, 1H), 1.96 – 1.86 (m, 1H), 1.57 (d, J = 6.1 Hz, 1H), 1.50 (d, J = 12.1 Hz, 1H), 1.20 – 1.13 (m, 1H), 1.10 – 1.04 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 197.4, 168.7, 163.7, 162.0, 160.3, 141.5, 117.6, 111.2, 110.5, 105.5, 91.3, 75.6, 73.4, 62.5, 61.5, 54.6, 53.0, 51.2, 39.9, 38.2, 35.0, 23.7, 19.2, 12.8. HRMS calculated for C24H29N3O5Na+= 462.1999; found = 462.1998.BP1-90

[0246] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-carbamoyl-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 1H), 7.69 (s, 1H), 7.30 (s, 1H), 6.61 (d, J = 8.7 Hz, 1H), 5.63 (s, 2H), 4.13 (s, 3H), 3.67 (s, 3H), 3.63 (s, 3H), 3.18-3.13 (m, 2H), 2.79 (dd, J = 9.5, 3.7 Hz, 1H), 2.36-2.32 (m, 2H), 2.25-2.20 (m, 2H), 2.18 – 2.12 (m, 1H), 1.95- 1.92 (m, 1H), 1.71-1.58 (m, 1H), 1.52 (d, J = 13.1 Hz, 1H), 1.21 (d, J = 10.1Hz, 1H), 1.07 (d, J = 9.8 Hz, 1H), 0.85 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 198.36, 168.77, 166.69, 164.39, 160.38, 160.35, 158.18, 141.46, 113.34, 111.24, 106.66, 76.03, 73.52, 62.88, 61.56, 54.65, 53.10, 51.23, 39.91, 38.41, 34.85, 23.69, 19.17, 12.81. HRMS calculated for C24H31N3O6H+= 458.2286; found = 458.2285.

[0247] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-methoxy-3-oxo-5-(pyrimidin-5-yl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 8.84 (s, 2H), 7.39 (d, J = 8.4 Hz, 1H), 7.30 (s, 1H), 6.65 (d, J = 8.4 Hz, 1H), 5.44 (s, 1H), 3.96 (s, 3H), 3.69 (s, 3H), 3.62 (s, 3H), 3.17 – 3.12 (m, 2H), 2.83-2.78 (m, 1H), 2.37 – 2.31 (m, 2H), 2.27-2.22 (m, 2H), 2.15 (dd, J = 11.3, 3.1 Hz, 1H), 1.97 – 1.91 (m, 1H), 1.66-1.61 (m, 1H), 1.51 (d, J = 12.0 Hz, 1H), 1.24- 1.18 (m, 1H), 1.15 – 1.09 (m, 1H), 0.85 (t, J = 7.2 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 198.9, 168.8, 162.6, 160.3, 156.5, 156.4, 138.9, 132.0, 131.7, 128.5, 115.7, 112.6, 111.5, 106.8, 75.7, 73.5, 62.4, 61.5, 54.8, 53.2, 51.2, 40.0, 38.2, 35.4, 23.8, 19.3, 12.8. HRMS calculated for C27H32N4O5H+= 493.2445; found = 493.2446.

[0248] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-methoxy-3-oxo-5-phenyl-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.48 – 7.43 (m, 3H), 7.38 (t, J = 7.6 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 8.4 Hz, 1H), 5.21 (s, 1H), 3.83 (s, 3H), 3.69 (s, 3H), 3.63 (s, 3H), 3.19 – 3.11 (m, 2H), 2.84 – 2.78 (m, 1H), 2.36 – 2.30 (m, 2H), 2.30 – 2.20 (m, 2H), 2.15 (dd, J = 11.2, 3.2 Hz, 1H), 1.97 – 1.89 (m, 1H), 1.65 (d, J = 6.1 Hz, 1H), 1.51 (d, J = 11.9 Hz, 1H), 1.25 – 1.12 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.5, 168.9, 161.7, 160.3, 155.6, 140.3, 137.8, 129.2, 128.1, 126.5, 123.5, 113.1, 111.6, 106.4, 75.6, 73.4, 61.9, 61.5, 54.8, 53.2, 51.2, 40.1, 38.3, 35.4, 23.8, 19.3, 12.9. HRMS calculated for C29H34N2O5H+= 491.2468; found = 491.2469.ClAP-104

[0249] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-(4-chlorophenyl)-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1NMR (400 MHz, CDCl3) δ 7.44 – 7.30 (m, 6H), 6.60 (d, J = 8.5 Hz, 1H), 5.28 (s, 1H), 3.83 (s, 3H), 3.70 (s, 3H), 3.63 (s, 3H), 3.18 – 3.11 (m, 2H), 2.83 - 2.78 (m, 1H), 2.36 – 2.22 (m, 4H), 2.17 - 2.13 (m, 1H), 1.95 -1.91 (m, 1H), 1.67 -1.61 (m, 1H), 1.53 -1.50 (m, 1H), 1.25 – 1.18 (m, 1H), 1.16 – 1.11 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 168.8, 161.8, 160.3, 155.6, 139.9, 136.2, 132.3, 130.5, 128.2, 122.2, 113.0, 111.5, 106.5, 75.6, 73.5, 61.9, 61.5, 54.8, 53.3, 51.2, 40.1, 38.3, 35.4, 23.8, 19.3, 12.9. HRMS calculated for C29H33ClN2O5H+= 525.2156; found = 525.2159.AP-105

[0250] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-5-(4-fluorophenyl)-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.44 – 7.36 (m, 3H), 7.30 (s, 1H), 7.06 (t, J = 8.7 Hz, 2H), 6.60 (d, J = 8.4 Hz, 1H), 5.23 (s, 1H), 3.82 (s, 3H), 3.70 (s, 3H), 3.63 (s, 3H), 3.19 – 3.11 (m, 2H), 2.81 (dt, J = 12.4, 3.6 Hz, 1H), 2.39 – 2.21 (m, 4H), 2.15 (dd, J = 11.3, 3.2 Hz, 1H), 1.98 – 1.89 (m, 1H), 1.67-1.60 (m, 1H), 1.51 (d, J = 11.4 Hz, 1H), 1.25-1.18 (m, 1H), 1.17 – 1.10 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 168.8, 161.7 (J = 244 Hz), 161.7, 160.3, 155.5, 140.0, 133.7(J = 3 Hz), 130.7 (J = 8 Hz), 122.5, 115.0 (J = 21 Hz), 113.0, 111.6, 106.5, 75.6, 73.5, 61.8, 61.5, 54.8, 53.2, 51.2, 40.1, 38.3, 35.4, 23.8, 19.3, 12.9. HRMS calculated for C29H33FN2O5H+= 509.2452; found = 509.2455.BP1-107

[0251] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-methoxy-5-methyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.20 (d, J = 8.2 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 5.06 (s, 1H), 3.98 (s, 3H), 3.67 (s, 3H), 3.62 (s, 3H), 3.14 (d, J = 10.3 Hz, 2H), 2.82 – 2.75 (m, 1H), 2.35 – 2.28 (m, 2H), 2.27 – 2.15 (m, 3H), 2.13 (s, 3H), 1.94 – 1.87 (m, 1H), 1.64 (td, J = 12.8, 9.2 Hz, 1H), 1.50 (d, J = 11.8 Hz, 1H), 1.23 – 1.14 (m, 1H), 1.07 (d, J = 10.8 Hz, 1H), 0.85 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.5, 168.8, 161.1, 160.3, 156.2, 140.3, 118.7, 113.1, 111.5, 105.9, 75.3, 73.6, 61.4, 61.4, 54.8, 53.3, 51.2, 40.0, 38.4, 35.2, 23.7, 19.2, 14.7, 12.9. HRMS calculated for C24H32N2O5H+= 429.2384; found = 429.2384.

[0252] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-cyclopropyl-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.47 (d, J = 8.4 Hz, 1H), 4.99 (s, 1H), 4.02 (s, 3H), 3.67 (s, 3H), 3.63 (s, 3H), 3.12 (t, J = 8.7 Hz, 2H), 2.84 – 2.74 (m, 1H), 2.33 – 2.21 (m, 3H), 2.16 – 2.04 (m, 2H), 1.92 – 1.86 (m, 1H), 1.68-1.60 (m, 2H), 1.52 – 1.47 (m, 1H), 1.29-1.24 (m, 1H), 1.10 – 1.04 (m, 1H), 0.88 – 0.82 (m, 5H), 0.57 – 0.49 (m, 2H).13C NMR (100 MHz, CDCl3) δ 199.5, 173.8, 168.8, 160.6, 160.2, 135.2, 124.3, 113.2, 111.6, 106.2, 75.5, 73.5, 61.8, 61.4, 54.8, 53.2, 51.2, 40.1, 38.4, 35.3, 23.8, 19.3, 12.9, 8.8, 7.2, 6.9. HRMS calculated for C26H34N2O5H+= 455.2540; found = 455.2541.AP-70

[0253] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5,6'-diethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.49 (d, J = 8.2 Hz, 1H), 5.00 (s, 1H), 3.99 (s, 3H), 3.67 (s, 3H), 3.63 (s, 3H), 3.17 – 3.09 (m, 2H), 2.83 – 2.74 (m, 1H), 2.60-2.47 (m, 3H), 2.36 – 2.26 (m, 2H), 2.23 – 2.12 (m, 2H), 1.95 – 1.83 (m, 1H), 1.70 (d, J = 15.8 Hz, 2H), 1.50 (d, J = 12.0 Hz, 1H), 1.13 (t, J = 8 Hz, 3H), 1.08 (d, J = 11.6 Hz, 1H), 0.84 (t, J = 8 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.6, 168.9, 161.1, 160.2, 155.9, 139.1, 125.2, 113.1, 111.6, 106.2, 75.3, 73.5, 61.9, 61.4, 54.8, 53.3, 51.2, 40.1, 38.4, 35.4, 23.8, 22.1, 19.3, 15.6, 12.9. HRMS calculated for C25H34N2O5H+= 443.2541; found = 443.2540.AP-72

[0254] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-5-isopropyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 7.6 Hz, 2H), 6.52 (d, J = 8.4 Hz, 1H), 5.00 (s, 1H), 3.98 (s, 3H), 3.67 (s, 3H), 3.63 (s, 3H), 3.27 (q, J = 6.9 Hz, 1H), 3.17 – 3.07 (m, 2H), 2.82 – 2.74 (m, 1H), 2.35 – 2.09 (m, 5H), 1.94 – 1.86 (m, 1H), 1.64 (dt, J = 13.2, 6.0 Hz, 1H), 1.50 (d, J = 11.6 Hz, 1H), 1.25 – 1.20 (m, 1H), 1.16 (t, J = 7.1 Hz, 6H), 1.12 – 1.06 (m, 1H), 0.85 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.7, 168.9, 160.9, 160.2, 155.3, 136.1, 129.6, 113.0, 111.6, 106.5, 75.3, 73.4, 62.1, 61.4, 54.8, 53.3, 51.2, 40.1, 38.4, 35.5, 29.7, 25.7, 23.4, 19.3, 12.9. HRMS calculated for C26H36N2O5H+= 457.2697; found = 457.2696.

[0255] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-cyclohexyl-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1HNMR (400 MHz, CDCl3) δ 7.28 (d, J = 7.6 Hz, 2H), 6.51 (d, J = 8.4 Hz, 1H), 4.99 (s, 1H), 3.99 – 3.94 (m, 3H), 3.67 (s, 3H), 3.63 (s, 3H), 3.17 – 3.09 (m, 2H), 2.92 – 2.85 (m, 1H), 2.79 (dt, J = 12.1, 3.4 Hz, 1H), 2.35 – 2.26 (m, 2H), 2.22 – 2.11 (m, 2H), 1.93 – 1.86 (m, 1H), 1.84 – 1.76 (m, 3H), 1.72 (dd, J = 8.2, 3.4 Hz, 3H), 1.63 (dt, J = 13.2, 6.0 Hz, 1H), 1.50 (d, J = 11.5 Hz, 1H), 1.38 (d, J = 6.1 Hz, 2H), 1.33 – 1.28 (m, 1H), 1.27 – 1.13 (m, 3H), 1.11 – 1.05 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.7, 168.9, 160.8, 160.2, 155.3, 136.7, 129.0, 113.0, 111.6, 106.4, 75.3, 73.4, 62.2, 61.4, 54.8, 53.3, 51.2, 40.1, 38.4, 35.9, 35.6, 34.2, 33.9, 27.0, 23.9, 19.3, 12.9. HRMS calculated for C29H40N2O5H+= 497.3009; found = 497.3009.BP1-99

[0256] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-methoxy-3-oxo-5-(tetrahydro-2H-pyran-4-yl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3- methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.29 (m, 2H), 6.53 (d, J = 8.4 Hz, 1H), 5.08 (s, 1H), 4.07 – 4.03 (m, 2H), 3.99 (s, 3H), 3.68 (s, 3H), 3.63 (s, 3H), 3.58 – 3.51 (m, 2H), 3.18 – 3.09 (m, 3H), 2.83 – 2.74 (m, 1H), 2.34 – 2.27 (m, 2H), 2.22 (d, J = 8.8 Hz, 1H), 2.13 (dd, J = 11.2, 2.8 Hz, 1H), 1.92 – 1.86 (m, 1H), 1.78 – 1.68 (m, 4H), 1.64 – 1.60 (m, 2H), 1.53 – 1.47 (m, 1H), 1.19 (dd, J = 11.8, 7.1 Hz, 1H), 1.11 – 1.05 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.6, 168.9, 161.0, 160.2, 155.6, 136.5, 126.6, 112.9, 111.6, 106.4, 75.4, 73.5, 68.6, 62.3, 61.4, 54.8, 53.3, 51.2, 40.1, 38.4, 35.5, 33.6, 33.8, 23.9, 19.3, 12.9. HRMS calculated for C28H38N2O6H+= 499.2803; found = 499.2804.

[0257] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-7-fluoro-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (399 MHz, CDCl3) δ 7.29 (s, 1H), 7.08 (dd, J = 10.1, 8.7 Hz, 1H), 6.01 (dd, J = 8.7, 2.5Hz, 1H), 5.22 (s, 1H), 3.87 (s, 3H), 3.67 (s, 3H), 3.63 (s, 3H), 3.17 – 3.10 (m, 2H), 2.80 – 2.72 (m, 1H), 2.37 – 2.30 (m, 2H), 2.26 – 2.19 (m, 2H), 2.14 (dd, J = 11.4, 3.2 Hz, 1H), 1.97 – 1.91 (m, 1H), 1.65 – 1.59 (m, 1H), 1.54 – 1.48 (m, 1H), 1.21-1.15 (m, 1H), 1.13 – 1.08 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 198.9(J = 3 Hz), 168.9, 160.4 (J = 20 Hz), 154.3 (J = 2 Hz), 149.5 (J = 15 Hz),143.4 (J = 235 Hz), 122.5 (J = 18 Hz), 111.7 (J = 4 Hz), 111.4, 97.7 (J = 4 Hz), 76.0, 73.2, 61.4, 55.9, 54.6, 53.1, 51.2, 40.0, 38.4, 35.0, 23.6, 19.2, 12.9. HRMS calculated for C23H29FN2O5H+= 433.2133; found = 433.2132.BP1-75P

[0258] Methyl (E)-2-((2S,6'S,7'S,8a'S)-7-chloro-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.34 – 7.26 (m, 2H), 6.10 (d, J = 8.8 Hz, 1H), 5.38 (s, 1H), 3.87 (s, 3H), 3.64 (s, 3H), 3.61 (s, 3H), 3.17 – 3.08 (m, 2H), 2.81 – 2.68 (m, 1H), 2.37 – 2.29 (m, 2H), 2.22 – 2.08 (m, 3H), 2.02 – 1.90 (m, 1H), 1.64-1.57 (m, 1H), 1.53 – 1.45 (m, 1H), 1.21 – 1.14 (m, 1H), 1.06-1.03 (m, 1H), 0.84 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.0, 168.9, 160.4, 157.7, 157.1, 136.8, 111.3, 110.8, 107.9, 99.9, 75.9, 73.3, 61.3, 55.9, 54.5, 53.1, 51.2, 39.9, 38.3, 34.5, 23.6, 19.1, 12.8. HRMS calculated for C23H29ClN2O5H+= 449.1838; found = 449.1835.

[0259] Methyl (E)-2-((2S,6'S,7'S,8a'S)-7-bromo-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 8.5 Hz, 1H), 7.25 (s, 1H), 6.04 (d, J = 8.6 Hz, 1H), 5.56 (s, 1H), 3.83 (s, 3H), 3.62 (s, 3H), 3.58 (s, 3H), 3.14 – 3.06 (m, 2H), 2.73 – 2.68 (m, 1H), 2.35 – 2.25 (m, 2H), 2.21 – 2.12 (m, 2H), 2.09 (dd, J = 11.3, 3.1 Hz, 1H), 1.97 – 1.88 (m, 1H), 1.59 (m, 1H), 1.51 – 1.43 (m, 1H), 1.16 (m, 1H), 1.04 – 0.97 (m, 1H), 0.81 (t, J =7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.2, 168.9, 160.4, 159.0, 157.7, 139.9, 111.2, 110.7, 100.6, 95.4, 75.7, 73.5, 61.3, 55.9, 54.6, 53.2, 51.2, 39.8, 38.3, 34.3, 23.6, 19.0, 12.8. HRMS calculated for C23H29BrN2O5H+= 493.1260; found = 493.1261.BP1-85

[0260] Methyl (E)-2-((2S,6'S,7'S,8a'S)-7-cyano-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.6 Hz, 1H), 7.31 (s, 1H), 6.24 (d, J = 8.7 Hz, 1H), 5.79 (s, 1H), 3.96 (s, 3H), 3.69 (s, 3H), 3.64 (s, 3H), 3.17- 3.11 (m, 2H), 2.80 – 2.73 (m, 1H), 2.39 – 2.27 (m, 2H), 2.26 – 2.19 (m, 2H), 2.18 – 2.10 (m, 1H), 1.97 – 1.89 (m, 1H), 1.63- 1.58 (m, 1H), 1.52- 1.51 (m, 1H), 1.19 (m, 1H), 1.11-1.08 (m, 1H), 0.85 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 197.6, 168.9, 162.1, 162.0, 160.4, 141.7, 116.2, 111.2, 109.5, 100.9, 85.9, 76.0, 72.9, 61.4, 56.4, 54.5, 52.9, 51.2, 39.8, 38.5, 34.7, 23.7, 19.1, 12.8. HRMS calculated for C24H29N3O5Na+= 462.1999; found = 462.1996.

[0261] Methyl (E)-2-((2S,6'S,7'S,8a'S)-7-carbamoyl-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.77 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.27 (s, 1H), 6.09 (d, J = 8.7 Hz, 1H), 5.64 (s, 2H), 3.94 (s, 3H), 3.63 (s, 3H), 3.61 (s, 3H), 3.16 – 3.10 (m, 2H), 2.77- 2.72(m, 1H), 2.35-2.26(m, 3H), 2.22-2.19 (m, 1H), 2.14 – 2.09 (m, 1H), 2.01 – 1.94 (m, 1H), 1.72-1.66 (m, 2H), 1.49-1.47 (m, 1H), 1.18 – 1.12 (m, 1H), 0.85 (d, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 169.1, 168.7, 161.9, 161.6, 160.2, 136.7, 111.6, 109.5, 106.0, 98.2, 75.6, 73.4, 61.2, 56.1, 54.5, 53.2, 51.2, 40.1, 38.5, 34.7, 23.8, 19.1, 12.9. HRMS calculated for C24H31N3O6H+= 458.2286; found = 458.2284.OMeBP1-95

[0262] Methyl (E)-2-((2S,6'S,7'S,8a'S)-7-cyclopropyl-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.15 (d, J = 8.2 Hz, 1H), 6.06 (d, J = 8.2 Hz, 1H), 5.40 (s, 1H), 3.86 (s, 3H), 3.63 (s, 3H), 3.62 (s, 3H), 3.17-3.14 (m, 2H), 2.78-2.73 (m, 1H), 2.41-2.33 (m, 2H), 2.25 – 2.09 (m, 3H), 2.03 – 1.94 (m, 1H), 1.67 – 1.63 (m, 1H), 1.52-1.49 (m, 1H), 1.28 - 1.17 (m, 1H), 1.09- 1.05 (m, 1H), 0.93 – 0.84 (m, 6H), 0.70 – 0.63 (m, 1H), 0.51- 0.46 (m, 1H).13C NMR (100 MHz, CDCl3) δ 199.7, 168.9, 162.0, 160.2, 156.8, 137.0, 117.4, 111.5, 109.1, 98.3, 75.4, 73.5, 61.4, 55.6, 54.7, 53.3, 51.2, 40.0, 38.5, 34.5, 23.7, 19.1, 12.9, 9.4, 4.5, 4.5. HRMS calculated for C26H34N2O5H+= 455.2540; found = 455.2542.

[0263] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-methoxy-3-oxo-7-(tetrahydro-2H-pyran-4-yl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3- methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.20 (d, J = 8.3 Hz, 1H), 6.16 (d, J = 8.2 Hz, 1H), 5.08 (s, 1H), 4.17 – 4.06 (m, 2H), 3.88 (s, 3H), 3.67-3.56 (m, 8H), 3.17- 3.13 (m, 2H), 2.80 – 2.67 (m, 2H), 2.37 (d, J = 7.6 Hz, 2H), 2.26-2.22 (m, 1H), 2.20 – 2.07 (m, 2H), 1.98 – 1.84 (m, 3H), 1.79 – 1.69 (m, 2H), 1.62 – 1.47 (m, 2H), 1.19 (dd, J = 13.0,6.8 Hz, 1H), 1.11 (dd, J = 12.7, 3.4 Hz, 1H), 0.86 (t, J = 7.1 Hz, 3H).13C NMR (100 MHz,CDCl3) δ 199.8, 168.8, 160.2, 159.6, 156.8, 134.5, 120.0, 111.5, 109.7, 99.2, 75.0, 73.7, 68.4, 68.3, 61.4, 55.6, 54.8, 53.3, 51.2, 40.0, 38.4, 35.1, 34.8, 32.9, 31.3, 23.8, 19.2, 13.0. HRMS calculated for C28H38N2O6H+= 499.2803; found = 499.2801.BP1-97

[0264] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-methoxy-3-oxo-7-(pyrimidin-5-yl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.92 (s, 2H), 7.33 (dd, J = 8.4, 1.4 Hz, 1H), 7.31 – 7.25 (m, 1H), 6.33 (d, J = 8.3 Hz, 1H), 5.37 (s, 1H), 3.96 (s, 3H), 3.68 (s, 3H), 3.63 (s, 3H), 3.15 – 3.04 (m, 2H), 2.85 – 2.73 (m, 1H), 2.39 – 2.29 (m, 2H), 2.24 (d, J = 4.8 Hz, 1H), 2.13 (d, J = 11.3 Hz, 1H), 1.94 – 1.82 (m, 2H), 1.58 – 1.46 (m, 2H), 1.26 – 1.15 (m, 2H), 0.82 (t, J = 6.8 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.3, 168.8, 160.4, 159.3, 158.8, 157.4, 155.8, 155.7, 138.4, 131.7, 111.4, 110.0, 109.8, 100.5, 75.4, 73.4, 61.5, 56.0, 54.5, 53.2, 51.3, 39.8, 38.3, 34.8, 24.2, 19.1, 12.8. HRMS calculated for C27H32N4O5H+= 493.2445; found = 493.2446.SC-117

[0265] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-methoxy-3-oxo-7-phenyl-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 16.2, 7.5 Hz, 4H), 7.42 – 7.28 (m, 3H), 7.26 (d, J = 2.7 Hz, 1H), 6.24 (d, J = 8.2 Hz, 1H), 5.45 (s, 1H), 3.94 (s, 3H), 3.63 (s, 6H), 3.13 – 3.01 (m, 2H), 2.80 (d, J = 12.5 Hz, 1H), 2.36 – 2.24 (m, 3H), 2.14 (d, J = 11.4 Hz, 1H), 1.86 (t, J = 8.5 Hz, 1H), 1.61 (s, 1H), 1.52 (s, 1H), 1.27 – 1.18 (m, 2H), 0.84 (t, J = 7.5 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 168.96, 160.35, 159.01, 138.07, 137.52, 129.18, 127.82, 127.22, 117.46, 111.50, 99.33, 75.18, 73.36, 61.43, 54.46, 53.15, 51.25, 39.93, 34.57, 24.03, 19.00, 12.89. HRMS calculated for C29H34N2O5H+= 491.2468; found = 491.2469. Example 3: BP1-94 analogs synthesis

[0266] Reagents and condition: (a) tert-butyldimethylsilyl chloride (TBDMS-Cl),Imidazole, dry DCM, 0 °C -rt, 5 hours, 72%; NBS, ACN, rt, 16 hours. (b) Cyclopropylboronic acid, K2CO3 Pd(OAc)2, tricyclohexylphosphine (PCy3), Toluene : water (10:1), 100°C, 16 hours, 46%. (c) tetra-n-butylammonium fluoride (TBAF), dry tetrahydrofuran (THF), 1 hour, rt, 43%.(d) NCS, dry ACN, 0 °C-rt, 12 hours.40%. (e) 2,6- dichloro-1-fluoropyridinium tetrafluoroborate, nitromethane, dry DCM, 0 °C, 24 hours, 51%; (f) tetradeuteroacetic acid (D4-AcOH), 80 °C, 48 hours, 32%; (g) MeI, NaH, THF, 60 °C, 4 hours; 57%.AP-101

[0267] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-cyclopropyl-6'-ethyl-4-hydroxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 11.85 (s, 1H), 7.63 (s, 1H), 7.40 (d, J = 0.7 Hz, 1H), 7.13 (dd, J =8.1, 0.9 Hz, 1H), 6.07 (d, J = 8.1 Hz, 1H), 4.12 (t, J = 10.1 Hz, 1H), 3.88 (d, J = 12.2 Hz, 1H), 3.75 (d, J = 0.8 Hz, 3H), 3.66 (d, J = 0.8 Hz, 3H), 3.03 (dt, J = 12.8, 3.4 Hz, 2H), 2.86 (q, J = 13.2 Hz, 3H), 2.58 (ddd, J = 12.7, 9.7, 2.3 Hz, 1H), 2.40 (dt, J = 14.3, 9.3 Hz, 1H), 1.91 (d, J = 11.8 Hz, 1H), 1.78 – 1.63 (m, 2H), 1.49 – 1.20 (m, 3H), 1.04 – 0.84 (m, 5H), 0.52 (dq, J = 9.6, 5.0 Hz, 1H), 0.43 (dtd, J = 8.9, 5.2, 3.6 Hz, 1H).13C NMR (100 MHz, CDCl3) δ 200.3, 168.1, 161.5, 160.4, 154.9, 139.7, 117.2, 108.5, 105.9, 102.9, 74.4, 71.5, 62.0, 53.9, 53.0, 51.6, 38.5, 38.1, 33.2, 22.6, 17.9, 11.9, 9.1, 5.2, 4.9. HRMS calculated for C25H32N2O5H+= 441.2384; found = 441.2383.AP-147

[0268] Methyl (E)-2-((2S,6'S,7'S,8a'S)-7-chloro-5-cyclopropyl-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (500 MHz, CDCl3) δ 11.61 (s, 1H), 7.78 (s, 1H), 7.41 (s, 1H), 7.19 (s, 1H), 4.15 – 4.07 (m, 1H), 4.02 (s, 3H), 3.89 (d, J = 12.3 Hz, 1H), 3.77 (s, 3H), 3.68 (s, 3H), 3.12 – 2.81 (m, 5H), 2.64 – 2.55 (m, 1H), 2.43 – 2.36 (m, 1H), 1.92 (d, J = 12.0 Hz, 1H), 1.73 – 1.66 (m, 1H), 1.39 (d, J = 14.0 Hz, 2H), 1.10 – 1.06 (m, 1H), 1.04 – 0.98 (m, 1H), 0.94 (t, J = 7.2 Hz, 3H), 0.64 – 0.57 (m, 1H), 0.53 – 0.46 (m, 1H).13C NMR (151 MHz, CDCl3) δ 196.6, 168.1, 161.6, 161.4, 151.9, 137.6, 122.6, 114.3, 110.4, 108.5, 75.0, 72.1, 62.0, 61.9, 53.9, 53.1, 51.6, 38.5, 38.0, 33.7, 22.5, 17.9, 12.0, 9.5, 5.4. HRMS calculated for C26H33ClN2O5H+= 489.2156; found = 489.2151.BP-109

[0269] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-cyclopropyl-6'-ethyl-7-fluoro-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (500 MHz, CDCl3) δ 7.31 (s, 1H), 7.00 (d, J = 12.7 Hz, 1H), 5.28 (s, 1H), 4.10 (s, 3H), 3.67 (s, 3H), 3.65 (s, 3H), 3.20 – 3.15 (m, 2H), 2.81 – 2.76 (m, 1H), 2.36 (t, J = 9.1 Hz, 2H), 2.25 – 2.11 (m, 3H), 2.05 – 1.96 (m, 1H), 1.74 – 1.60 (m, 2H), 1.55 – 1.50 (m, 1H), 1.25– 1.18 (m, 1H), 1.04 (d, J = 12.7 Hz, 1H), 0.97 – 0.994 (m, 2H), 0.88 (t, J = 7.3 Hz, 3H), 0.73 – 0.67 (m, 1H), 0.56 – 0.52 (m, 1H).13C NMR (151 MHz, CDCl3) δ 199.7, 168.8, 160.3, 158.1, 145.9(J = 234.5 Hz), 142.6 (J = 10.8 Hz), 124.6 (J = 19.8Hz), 119.1, 112.4, 111.4, 76.1, 73.9, 61.7, 61.5, 54.6, 53.2, 51.3, 39.9, 38.4, 34.4, 29.7, 23.6, 19.1, 12.8, 9.5, 5.0. HRMS calculated for C26H33FN2O5H+= 473.2452; found = 473.2447.AP-152

[0270] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-cyclopropyl-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl-7-d)-3-methoxyacrylate:1H NMR (500 MHz, CDCl3) δ 7.33 (s, 1H), 6.03 (d, J = 8.3 Hz, 1H), 3.87 (s, 5H), 3.70 (s, 3H), 3.65 (s, 3H), 3.63 – 3.47 (m, 3H), 3.46 – 3.38 (m, 1H), 2.88 (dtt, J = 18.1, 8.4, 4.5 Hz, 1H), 2.67 – 2.48 (m, 2H), 2.47 – 2.40 (m, 1H), 2.25 – 2.10 (m, 1H), 1.78 – 1.67 (m, 3H), 1.18 (dt, J = 14.3, 7.4 Hz, 1H), 0.90 – 0.83 (m, 4H), 0.60 (dt, J = 9.7, 5.0 Hz, 1H), 0.53 – 0.46 (m, 1H). HRMS calculated for C26H33DN2O5H+= 456.2609; found = 456.2604.AP2-3

[0271] Methyl (E)-2-((2S,6'S,7'S,8a'S)-5-cyclopropyl-6'-ethyl-4-methoxy-1-methyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.29 (s, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.30 (d, J = 8.5 Hz, 1H), 4.02 (s, 3H), 3.70 (s, 3H), 3.63 (s, 3H), 3.17 – 3.11 (m, 5H), 2.79 – 2.75 (m, 1H), 2.36 – 2.00 (m, 6H), 1.96 -1.88 (m, 1H), 1.71 – 1.59 (m, 1H), 1.48 (d, J = 11.2 Hz, 1H), 1.24 – 1.16 (m, 1H), 1.10 – 0.99 (m, 1H), 0.87 – 0.82 (m, 5H), 0.57 – 0.48 (m, 2H).13C NMR (100 MHz, CDCl3) δ 199.5, 168.9, 160.6, 160.2, 157.2, 135.6, 122.2, 111.7, 111.2, 102.3, 78.2, 74.5, 61.7, 61.4, 55.0, 53.8, 51.2, 40.3, 38.6, 31.9, 29.8, 24.1, 19.5, 12.9, 8.8, 7.1, 6.8. HRMS calculated for C27H36N2O5H+= 469.2697; found = 469.2699.Example 4: SC103 / SC111 analogs synthesis

[0272] Reagents and condition: (a) Allylarene, K2CO3, Pd(dppf)Cl2, dry 1,4-dioxane:water (10:1), 100 °C, 18 hours; (b) 10% Pd / C, H2, dry MeOH, rt, 4-8 hours, 40-55% yield after two steps; (c) Ar(CH2)nX, Cs2CO3, DMF, 80 °C, 12 hours; 45-70% yield. PSC-121

[0273] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-(benzyloxy)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.5 Hz, 2H), 7.30 – 7.25 (m, 3H), 6.40 (d, J = 8.1 Hz, 1H), 6.16 (d, J = 8.1 Hz, 1H), 5.19 (s, 3H), 3.66 (s, 3H), 3.62 (s, 3H), 3.20 – 3.09 (m, 2H), 2.83 – 2.74 (m, 1H), 2.39 – 2.28 (m, 2H), 2.25 – 2.13 (m, 2H), 1.93 – 1.88 (m, 1H), 1.62 (dt, J = 14.0, 6.8 Hz, 1H), 1.50 (d, J = 11.5 Hz, 1H), 1.28 – 1.09 (m, 3H), 0.85 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 168.8, 162.1, 160.2, 157.5, 138.5, 136.7, 128.5, 127.6, 126.6, 111.6, 110.1, 103.9, 100.6, 75.1, 73.4, 69.8, 61.4, 54.9, 53.3, 51.2, 40.1, 38.4, 35.2, 23.8, 19.3, 12.9. HRMS calculated for C29H34N2O5H+= 491.2546; found = 491.2541.SC-103

[0274] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-3-oxo-4-phenethoxy-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (500 MHz, CDCl3) δ 7.40 – 7.23 (m, 7H), 6.40 (dd, J = 8.2, 0.5 Hz, 1H), 6.12 (dd, J = 8.1, 0.6 Hz, 1H), 5.15 (s, 1H), 4.23 (t, J = 7.4 Hz, 2H), 3.69 (s, 3H), 3.65 (s, 3H), 3.24 – 3.19 (m, 2H), 3.18 – 3.12 (m, 2H), 2.81 (dt, J = 12.9, 3.7 Hz, 1H), 2.41 – 2.32 (m, 2H), 2.29 – 2.15 (m, 3H), 1.97 – 1.87 (m, 1H), 1.72 – 1.62 (m, 1H), 1.56 – 1.50 (m, 1H), 1.26 – 1.18 (m, 1H), 1.19 – 1.13 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 168.9, 162.1, 160.2, 157.8, 138.5, 137.9, 129.3, 128.5, 126.5, 111.6, 109.8, 103.6, 99.9, 75.1, 73.3, 69.2, 61.4, 54.8, 53.3, 51.1, 40.1, 38.4, 35.6, 35.1, 23.8, 19.3, 12.9. HRMS calculated for C30H36N2O5H+= 505.2695; found = 505.2692.SC-123

[0275] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-3-oxo-4-(3-phenylpropoxy)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.29 – 7.18 (m, 6H), 7.16 (d, J = 7.0 Hz, 1H), 6.35 (d, J = 8.1 Hz, 1H), 6.05 (d, J = 8.0 Hz, 1H), 5.10 (s, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.65 (s, 3H), 3.60 (s, 3H), 3.11 (d, J = 10.5 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.79 – 2.70 (m, 1H), 2.37 – 2.25 (m, 2H), 2.22 – 2.09 (m, 4H), 1.95 – 1.74 (m, 2H), 1.62 (tt, J = 14.0, 7.0 Hz, 1H), 1.47 (d, J = 11.6 Hz, 1H), 1.22 – 1.09 (m, 2H), 0.83 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 168.8, 162.1, 160.2, 158.0, 141.5, 138.6, 128.6, 128.3, 125.8, 111.6, 109.8, 103.5, 99.9, 74.9, 73.4, 67.2, 61.4, 54.9, 53.3, 51.2, 40.1, 38.4, 35.1, 31.9, 30.5, 23.8, 19.3, 12.9. HRMS calculated for C31H38N2O5Na+= 541.2678; found = 541.2673.AP-61

[0276] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(4-methylphenethoxy)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.33 – 7.20 (m, 4H), 7.13 (d, J = 7.6 Hz, 2H), 6.37 (d, J = 8.0 Hz, 1H), 6.08 (d, J = 8.1 Hz, 1H), 5.21 (s, 1H), 4.17 (t, J = 7.3 Hz, 2H), 3.66 (s, 3H), 3.63 (s, 3H), 3.15 (t, J = 7.1 Hz, 4H), 2.82 – 2.75 (m, 1H), 2.40 – 2.11 (m, 8H), 1.90 (p, J = 11.6 Hz, 1H), 1.70 – 1.58 (m, 1H), 1.51 (d, J = 11.5 Hz, 1H), 1.20 (d, J = 38.8 Hz, 6H), 0.86 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.3, 168.8, 162.1, 160.2, 157.8, 138.6, 136.0, 134.8, 129.2, 129.2, 111.5, 109.7, 103.6, 99.8, 74.9, 73.4, 69.4, 61.4, 54.8, 53.3, 51.2, 40.0, 38.4, 35.1, 33.5, 31.9, 29.7, 23.8, 22.7, 21.1, 19.3, 14.1, 12.9. HRMS calculated for C31H38N2O5H+= 519.2859; found = 519.2855.AP-63

[0277] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(4-methoxyphenethoxy)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.26 (q, J = 8.1 Hz, 4H), 6.85 (d, J = 8.2 Hz, 2H), 6.36 (d, J = 8.2 Hz, 1H), 6.08 (d, J = 8.1 Hz, 1H), 5.18 (s, 1H), 4.15 (t, J = 7.2 Hz, 2H), 3.77 (s, 3H), 3.65 (s, 3H), 3.62 (s, 3H), 3.13 (dt, J = 14.1, 4.7 Hz, 4H), 2.83 – 2.72 (m, 1H), 2.38 – 2.27 (m, 2H), 2.26 – 2.12 (m, 3H), 1.94 – 1.83 (m, 1H), 1.64 (td, J = 13.1, 12.4, 6.7 Hz, 1H), 1.50 (d, J = 11.5 Hz, 1H), 1.27 – 1.18 (m, 1H), 1.13 (d, J = 11.8 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 168.8, 162.1, 160.2, 158.3, 157.8, 138.6, 130.3, 130.1, 113.9, 111.6, 109.8, 103.6, 99.8, 75.0, 73.4, 69.4, 61.4, 55.2, 54.9, 53.3, 51.1, 40.1, 38.4,35.1, 34.7, 23.8, 19.3, 12.9. HRMS calculated for C31H38N2O6H+= 535.2808; found = 535.2803.AP-64

[0278] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-(2-(1H-imidazol-1-yl)ethoxy)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.69 (s, 1H), 7.40 (s, 1H), 7.31 – 7.23 (m, 2H), 7.05 (s, 1H), 6.42 (d, J = 8.1 Hz, 1H), 5.99 (d, J = 8.0 Hz, 1H), 5.34 (s, 1H), 4.39 (t, J = 5.0 Hz, 2H), 4.21 (t, J = 5.0 Hz, 2H), 3.67 (s, 3H), 3.62 (s, 3H), 3.18 (d, J = 11.6 Hz, 2H), 2.87 – 2.73 (m, 1H), 2.38 – 2.27 (m, 3H), 2.18 (d, J = 14.7 Hz, 2H), 2.00 – 1.88 (m, 1H), 1.66 (dq, J = 19.2, 8.4 Hz, 1H), 1.57 – 1.46 (m, 1H), 1.18 (dt, J = 27.4, 9.6 Hz, 2H), 0.85 (d, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.1, 174.3, 168.8, 162.0, 160.3, 156.7, 138.7, 137.7, 129.5, 120.6, 111.3, 109.5, 104.6, 99.5, 73.4, 67.7, 61.5, 54.8, 53.2, 51.2, 46.3, 39.9, 38.3, 35.1, 23.6, 19.2, 12.8. HRMS calculated for C27H34N4O5H+= 495.2607; found = 495.2602.AP-65

[0279] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(4-fluorophenethoxy)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J = 8.5, 5.7 Hz, 2H), 7.30 – 7.24 (m, 2H), 6.99 (dd, J = 9.7, 7.7 Hz, 2H), 6.38 (d, J = 8.1 Hz, 1H), 6.07 (d, J = 8.1 Hz, 1H), 5.21 (s, 1H), 4.17 (t, J = 6.9 Hz, 2H), 3.67 (d, J = 1.9 Hz, 3H), 3.62 (d, J = 1.9 Hz, 3H), 3.15 (q, J = 7.0 Hz, 4H), 2.80 (d, J = 11.7 Hz, 1H), 2.35 (d, J = 8.4 Hz, 2H), 2.22 (d, J = 31.5 Hz, 3H), 1.95 – 1.85 (m, 1H), 1.66 (dd, J = 17.7, 11.1 Hz, 1H), 1.57 – 1.46 (m, 1H), 1.16 (t, J = 10.2 Hz, 2H), 0.85 (d, J =7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.2, 168.8, 161.7 (J= 243 Hz), 162.1, 160.3, 157.7, 138.6, 133.8 (J = 3 Hz), 130.9 (J = 7 Hz), 115.3 (J = 21 Hz), 103.8, 99.7, 73.5, 69.1, 61.5, 54.8, 53.3, 51.2, 40.0, 38.4, 34.8, 33.4, 31.9, 29.7, 23.7, 22.7, 19.2, 17.8, 14.1, 12.9. HRMS calculated for C30H35FN2O5H+= 523.2608; found = 523.2603.AP-62

[0280] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-((2,3-dihydro-1H-inden-2-yl)oxy)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.34 – 7.27 (m, 2H), 7.23 – 7.13 (m, 4H), 6.40 (d, J = 8.2 Hz, 1H), 6.17 (d, J = 8.1 Hz, 1H), 5.21 (m, 2H), 3.67 (s, 3H), 3.62 (s, 3H), 3.42 (t, J = 5.7 Hz, 2H), 3.32 (dd, J = 7.3, 4.6 Hz, 2H), 3.13 (d, J = 12.6 Hz, 2H), 2.76 (d, J = 11.0 Hz, 1H), 2.30 (d, J = 7.1 Hz, 2H), 2.22 – 2.10 (m, 3H), 1.87 (s, 1H), 1.64 (s, 1H), 1.49 (d, J = 10.2 Hz, 1H), 1.11 (s, 1H), 0.85 (s, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 168.8, 162.3, 160.2, 157.0, 140.4, 138.4, 126.7, 124.6, 111.7, 110.2, 103.7, 101.6, 78.8, 74.9, 73.4, 61.4, 54.9, 53.3, 51.1, 39.8, 38.3, 35.2, 29.7, 23.8, 19.3, 12.9. HRMS calculated for C31H36N2O5H+= 517.2702; found = 517.2698.SC-111

[0281] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-3-oxo-4-(3-phenylpropyl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.32 – 7.09 (m, 7H), 6.65 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 7.3 Hz, 1H), 5.08 (s, 1H), 3.64 (s, 3H), 3.61 (s, 3H), 3.13 (d, J = 10.8 Hz, 2H), 2.96 (t, J = 7.8 Hz, 2H), 2.78 (m, 1H), 2.68 (t, J = 7.9 Hz, 2H), 2.34 – 2.24 (m, 2H), 2.20 – 2.10 (m, 2H), 1.89 (m, 3H), 1.63 (dt, J = 12.8, 6.1 Hz, 1H), 1.49 (d, J = 11.6 Hz, 1H), 1.26 – 1.13 (m, 2H), 1.03 (d, J = 11.3 Hz, 1H), 0.84 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 168.8 , 161.5 ,160.2, 144.2, 136.5, 128.4, 128.2, 125.6, 118.5, 111.6, 109.1, 74.9, 73.4, 61.4, 54.8, 53.3, 51.1, 40.0, 38.4, 35.8, 35.1, 32.1, 31.8, 23.8, 19.2, 12.9. HRMS calculated for C31H38N2O4Na+= 525.2729; found = 525.2724.SC-124

[0282] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-3-oxo-4-(4-phenylbutyl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.28 – 7.22 (m, 4H), 7.20 – 7.08 (m, 3H), 6.65 (d, J = 8.1 Hz, 1H), 6.49 (d, J = 7.2 Hz, 1H), 5.14 (s, 1H), 3.65 (s, 3H), 3.62 (s, 3H), 3.15 (d, J = 10.9 Hz, 2H), 2.99 – 2.89 (m, 2H), 2.83 – 2.74 (m, 1H), 2.64 (t, J = 7.5 Hz, 2H), 2.36 – 2.09 (m, 4H), 2.03 (d, J = 4.8 Hz, 1H), 1.96 – 1.84 (m, 1H), 1.66 (m, 4H), 1.51 (d, J = 11.7 Hz, 1H), 1.29 – 1.13 (m, 3H), 0.85 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 202.5, 168.8, 161.5, 160.3, 144.5, 142.8, 136.5, 128.4, 128.1, 125.5, 118.6, 111.5, 109.0, 74.8, 73.4, 61.4, 54.8, 53.3, 51.2, 40.0, 38.4, 35.7, 35.2, 31.7, 31.4, 30.2, 29.7, 23.8, 19.2, 12.8. HRMS calculated C32H40N2O4H+= 517.3066; found = 517.3061.SC-125

[0283] Methyl (E)-2-((2S,6'S,7'S)-6'-ethyl-3-oxo-4-(4-phenylbut-1-yn-1-yl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate : 1HNMR (400 MHz, CDCl3) δ 7.32 – 7.26 (m, 6H), 7.22 – 7.18 (m, 1H), 6.74 (t, J = 8.2 Hz, 2H), 5.12 (s, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 3.14 (d, J = 10.5 Hz, 2H), 3.00 (t, J = 7.8 Hz, 2H), 2.77 (t, J = 7.7 Hz, 3H), 2.39- 2.31 (m, 2H), 2.26 – 2.12 (m, 3H), 1.94 – 1.86 (m, 1H), 1.64 –1.58 (m, 1H), 1.51 (d, J = 9.8 Hz, 1H), 1.23 – 1.16 (m, 1H), 1.10 (d, J = 12.6 Hz, 1H), 0.85 (t, J = 7.3 Hz, 3H). HRMS calculated for C32H36N2O4Na+= 535.2573; found = 535.2574.AP-108

[0284] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(3-(4-fluorophenyl)propyl)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 5.7 Hz, 2H), 7.24 – 7.16 (m, 1H), 7.15 – 7.11 (m, 1H), 6.97 – 6.86 (m, 2H), 6.66 (dd, J = 7.7, 5.2 Hz, 1H), 6.48 (d, J = 7.3 Hz, 1H), 5.32 (s, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 3.22 – 3.12 (m, 2H), 2.94 (t, J = 7.7 Hz, 2H), 2.80 (dd, J = 12.1, 3.8 Hz, 1H), 2.66 (t, J = 7.9 Hz, 2H), 2.31 (q, J = 9.3, 8.2 Hz, 3H), 2.23 – 2.11 (m, 2H), 1.94 – 1.87 (m, 2H), 1.64 (dd, J = 9.7, 4.1 Hz, 1H), 1.52 (d, J = 11.7 Hz, 1H), 1.16 (dd, J = 9.9, 7.0 Hz, 2H), 1.07 – 1.00 (m, 1H), 0.87 (d, J = 7.8 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 202.5, 168.8, 161.6, 160.3, 148.9, 144.0, 136.6, 130.6, 129.8, 129.7, 118.5, 114.9, 114.8, 111.5, 109.2, 74.7, 73.5, 61.4, 54.7, 53.3, 51.2, 40.0, 38.4, 35.1, 32.2, 31.7, 29.7, 23.7, 22.3, 19.2, 12.8. HRMS calculated for C31H37FN2O4H+= 521.2816; found = 521.2811.AP-85

[0285] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-3-oxo-4-(3-(p-tolyl)propyl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.28 (s, 2H), 7.08 (d, J = 2.6 Hz, 4H), 6.67 – 6.63 (m, 1H), 6.50 (d, J = 7.3 Hz, 1H), 5.12 (s, 1H), 3.65 (s, 3H), 3.62 (s, 3H), 3.14 (d, J = 9.3 Hz, 2H), 2.97 – 2.94 (m, 2H), 2.79 (dt, J = 12.2, 3.7 Hz, 2H), 2.64 (d, J = 7.9 Hz, 2H), 2.30 (s, 3H), 2.24 – 2.18 (m, 3H), 2.14 (dd, J = 11.4, 3.2 Hz, 2H), 1.91 – 1.87 (m, 2H), 1.63 (dd, J = 12.7, 6.7 Hz,1H), 1.50 (d, J = 11.6 Hz, 1H), 1.15 (d, J = 6.4 Hz, 1H), 1.06 – 1.00 (m, 1H), 0.85 (s, 3H).13C NMR (100 MHz, CDCl3) δ 202.5, 168.8, 161.5, 160.3, 144.3, 139.5, 136.5, 134.9, 128.9, 128.3, 118.5, 111.6, 109.0, 74.9, 73.5, 61.4, 54.8, 53.3, 51.2, 40.1, 38.4, 38.4, 35.4, 35.1, 32.2, 31.8, 23.8, 20.9, 19.3, 12.9. HRMS calculated for C32H40N2O4H+= 517.3066; found = 517.3062.AP-84

[0286] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(3-(4-methoxyphenyl)propyl)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.30 – 7.24 (m, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 7.3 Hz, 1H), 5.43 (s, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.62 (s, 3H), 3.21 (d, J = 10.3 Hz, 2H), 2.97 – 2.91 (m, 2H), 2.80 (dt, J = 7.4, 4.4 Hz, 1H), 2.64 (d, J = 7.8 Hz, 2H), 2.35 (dd, J = 19.7, 10.4 Hz, 3H), 2.26 – 2.18 (m, 2H), 1.97 – 1.88 (m, 2H), 1.86 (d, J = 5.9 Hz, 1H), 1.66 (dd, J = 12.8, 6.9 Hz, 1H), 1.54 (d, J = 11.6 Hz, 1H), 1.14 (dd, J = 6.9, 3.6 Hz, 1H), 1.09 – 1.03 (m, 1H), 0.85 (d, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 202.3, 168.8, 161.6, 160.4, 157.6, 149.5, 144.3, 136.7, 134.6, 130.2, 129.3, 118.5, 113.6, 113.3, 109.1, 73.7, 61.5, 55.2, 54.8, 53.3, 51.2, 39.9, 38.4, 34.9, 32.3, 31.7, 29.7, 23.7, 19.1, 12.8. HRMS calculated for C32H40N2O5H+= 533.3015; found = 517.3013.SC-126

[0287] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-([1,1'-biphenyl]-4-yl)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.65 – 7.59 (m, 6H), 7.47 – 7.41 (m, 3H), 7.38 – 7.27 (m, 2H), 6.84 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 7.2 Hz, 1H), 5.44 (s, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.18 (d, J = 11.1 Hz, 2H), 2.81 (dt, J = 12.9, 3.5 Hz, 1H), 2.30 (dq, J = 18.0, 11.2, 8.8 Hz, 4H), 2.16 (d, J = 11.1 Hz, 1H), 1.96 (p, J = 11.5 Hz, 1H), 1.68 (tt, J = 14.0, 7.0 Hz, 1H), 1.53 (d, J = 11.5 Hz, 1H), 1.28 – 1.22 (m, 1H), 1.16 (d, J = 12.6 Hz, 1H), 0.87 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 201.3, 168.8, 161.9, 160.3, 141.7, 141.0, 140.8, 136.6, 136.6, 129.7, 128.8, 128.7, 127.2, 127.2, 127.1, 126.4, 119.8, 116.4, 111.5, 110.6, 74.8, 73.7, 61.5, 54.8, 53.4, 51.2, 40.0, 38.4, 35.3, 23.8, 19.2, 12.9. HRMS calculated for C34H36N2O4Na+= 559.2573; found = 559.2567. Example 5: C9 MP Analogs SynthesisH9-SnBu3MP AP-102

[0288] Reagents and condition: (a) Oxone, Sat. NaHCO3, Acetone, 0 °C-rt, 1 h, 45%. (b)AlCl3, Ethanethiol, dry DCM, 0 °C-rt, 5 hours, 40%. (c) N-phenyl- bis(trifluoromethanesulfonimide), Et3N, dry DCM, rt, 15 hours, 68%. (d) Bis(pinacolato)diboron, KOAc, Pd(dppf)Cl2, DPPF, dry 1,4-dioxane, 100 °C, 18 hours; CuCl2, MeOH : Water (2:1.5), 80 °C, 12 hours, 40%. (e) Zn(CN)2, Pd(PPh3)4, DMF, 80 °C, 2 h; (f) Pd(OAc)2, dppf, imidazole, Co2(CO)8, NH4Cl, DIPEA, dry 1,4-dioxane, 90 °C, 24 hours, 32%; (g) Boronic acid / boronic acid pinacol ester, Pd(PPh3)4, K2CO3, MeOH:Toluene (1:2), 80 °C, 2-16 hours 32%-57%. (h) LiCl, Pd(PPh3)4, bis(tributyltin), dry 1,4-dioxane, 100 °C, 24 hours, 65%. (i) Silver trifluoromethanesulfonate, 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate)8, dry acetone, rt, 20 min., 25%.BP1-7

[0289] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-3-oxo-4-(pyrimidin-5-yl)-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.85 (s, 2H), 7.49 – 7.45 (m, 1H), 7.29 (s, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 7.3 Hz, 1H), 5.42 (s, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 3.14 (d, J = 9.7 Hz, 2H), 2.79 (dt, J = 12.8, 3.6 Hz, 1H), 2.32 – 2.27 (m, 2H), 2.21 (d, J = 11.4 Hz, 1H), 2.14 (d, J = 10.8 Hz, 1H), 1.96-1.91 (m, 1H), 1.74 – 1.56 (m, 2H), 1.26-1.18 (m, 2H), 1.09 (d, J = 12.8 Hz, 1H), 0.84 (d, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 201.2, 161.7, 160.2, 157.8, 156.5, 136.9, 134.1, 131.2, 119.4, 112.2, 111.5, 75.2, 73.5, 61.5, 54.8, 53.2, 51.1, 40.0, 38.2, 35.2, 23.8, 19.3, 12.8. HRMS calculated for C26H30N4O4H+= 463.2345; found = 463.2343.BP1-11

[0290] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(imidazo[1,2-a]pyridin-6-yl)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 8.42 – 8.37 (m, 1H), 7.66 – 7.58 (m, 3H), 7.44 (dd, J = 8.3, 7.3 Hz, 1H), 7.33 (dd, J = 9.4, 1.7 Hz, 1H), 7.30 (s, 1H), 6.87 (d, J = 8.2 Hz, 1H), 6.72 (d, J = 7.3 Hz, 1H), 5.40 (s, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.20 – 3.10 (m, 2H), 2.83 – 2.77 (m, 1H), 2.35 – 2.29 (m, 2H), 2.22 (d, J = 11.3 Hz, 1H), 2.14 (d, J = 11.3 Hz, 1H), 1.96 – 1.90 (m, 1H), 1.70-1.62 (m, 1H), 1.53-1.50 (m, 1H), 1.29 – 1.17 (m, 2H), 1.13-1.10 (m, 1H), 0.86 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 201.4, 168.8, 162.0, 160.3, 145.0, 137.6, 136.9, 133.9, 126.9, 125.7, 122.6, 119.6, 116.4, 112.7, 111.5, 111.2, 75.1, 73.7, 61.5, 61.5, 54.8, 53.3, 51.2, 40.0, 38.3, 35.3, 23.8, 19.3, 12.8. HRMS calculated for C29H32N4O4H+= 501.2502; found = 501.2498.

[0291] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-(3-chlorothiophen-2-yl)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate: 1HNMR (400 MHz, CDCl3) δ 7.41 (dd, J = 8.3, 7.3 Hz, 1H), 7.33 – 7.28 (m, 2H), 6.99 (d, J = 5.3 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.73 (dd, J = 7.4, 0.8 Hz, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 3.30 – 3.03 (m, 2H), 2.86 – 2.76 (m, 1H), 2.38 – 2.20 (m, 4H), 2.20 – 2.06 (m, 1H), 2.01 – 1.90 (m, 1H), 1.75 – 1.60 (m, 1H), 1.56 – 1.48 (m, 1H), 1.24 – 1.17 (m, 1H), 1.13 (d, J = 10.3 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 168.8, 161.2, 160.4, 136.3, 131.9, 130.3, 128.0, 124.7, 124.1, 121.1, 111.9, 111.4, 110.0, 73.5, 61.5, 54.7, 53.3, 51.2, 40.0, 38.3, 35.1, 29.7, 23.8, 19.2, 12.8. HRMS calculated for C26H29ClN2O4SH+= 501.1615; found = 501.1610.BP1-15

[0292] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-(benzo[d]oxazol-5-yl)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 8.13 (s, 1H), 7.88 (s, 1H), 7.63-7.60 (m, 1H), 7.55-7.50 (m, 1H), 7.47 (d, J = 7.7 Hz, 1H), 7.39 (s, 1H), 6.99 (d, J = 8.3 Hz, 1H), 6.71 (d, J = 7.0 Hz, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.50 – 3.42 (m, 1H), 3.08 – 2.95 (m, 2H), 2.91 – 2.80 (m, 2H), 2.54 – 2.44 (m, 1H), 2.40 – 2.31 (m, 2H), 1.86-1.82 (m, 1H), 1.70-1.65 (m, 3H), 1.46-1.42 (m, 1H), 1.19 (dt, J = 14.5, 7.1 Hz, 1H), 0.88 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 205.1, 181.8, 168.1, 161.5, 152.9, 141.7, 138.1, 137.9, 134.3, 127.2, 121.2, 120.2, 111.7, 110.1, 110.0, 75.9, 71.3, 61.7, 53.3, 51.5, 43.8, 38.6, 38.2, 34.2, 22.8, 17.9, 12.0.HRMS calculated for C29H31N3O5H+= 502.2342; found = 502.2337.BP1-19

[0293] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(3-fluoropyridin-4-yl)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 8.50 (s, 1H), 8.44 (d, J = 4.9 Hz, 1H), 7.47 (t, J = 8.0 Hz, 1H), 7.29-7.27 (m, 2H), 6.93 (d, J = 8.3 Hz, 1H), 6.67 (d, J = 7.2 Hz, 1H), 5.29 (s, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 3.15-3.12 (m, 2H), 2.81-2.77 (m, 1H), 2.32-2.23 (m, 2H), 2.20 – 2.08 (m, 2H), 1.93 (s, 1H), 1.70-1.63 (m, 1H), 1.51 (s, 1H), 1.25-1.21 (m, 2H), 1.09 (d, J = 12.5 Hz, 1H), 0.86 (t, J = 7.2 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 200.9, 168.8, 160.9, 160.2, 145.3, 138.2, 137.9, 136.6, 131.4, 125.1, 119.6, 117.3, 112.4, 111.6, 73.5, 61.5, 54.8, 53.3, 51.2, 40.1, 38.2, 35.1, 23.8, 19.3, 12.9. HRMS calculated for C27H30FN3O4H+= 480.2299; found = 480.2295.BP1-21

[0294] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(2-methylthiazol-5-yl)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (500 MHz, CDCl3) δ 8.18 (s, 1H), 7.38 (t, J = 7.8 Hz, 1H), 7.30 (s, 1H), 6.82 (dd, J = 11.0, 7.8 Hz, 2H), 5.29 (s, 1H), 3.69 (s, 3H), 3.63 (s, 3H), 3.18 – 3.13 (m, 2H), 2.83 – 2.78 (m, 1H), 2.74 (s, 3H), 2.34-2.33 (m, 2H), 2.26-2.22 (m, 2H), 2.16-2.13 (m, 1H), 1.98 – 1.91 (m, 1H), 1.70 – 1.61 (m, 1H), 1.53-1.52 (m, 1H), 1.24 – 1.18 (m, 1H), 1.14 – 1.07 (m, 1H), 0.87 (t, J = 7.5 Hz, 4H).13C NMR (100 MHz, CDCl3) δ 201.1, 168.8, 166.7, 161.9, 142.7, 136.7, 134.0, 130.9, 119.5, 115.9, 111.6, 111.1, 75.0, 73.5, 61.5, 61.4, 54.9, 53.3, 51.2, 51.1, 40.1, 38.3, 35.5, 23.8, 19.3, 12.9. HRMS calculated for C26H31N3O4SH+= 482.2114; found = 482.2108.BP1-23

[0295] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-(3,5-dimethylisoxazol-4-yl)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (500 MHz, CDCl3) δ 7.43 (dd, J = 8.3, 7.2 Hz, 1H), 7.31 (d, J = 1.2 Hz, 1H), 6.86 (dd, J = 8.0, 2.7 Hz, 1H), 6.51 (dd, J = 7.2, 4.3 Hz, 1H), 5.25 (s, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.16-3.14 (m, 2H), 2.82-2.79 (m, 1H), 2.33 (s, 1H), 2.31 (br.s, 3H), 2.28-2.26 (m, 2H), 2.22 – 2.19 (m, 1H), 2.17 (br.s, 3H), 2.12 (s, 1H), 1.92 (dt, J = 9.7, 5.9 Hz, 1H), 1.69 – 1.63 (m, 1H), 1.52 (d, J = 11.2 Hz, 1H), 1.21 (d, J = 11.0 Hz, 1H), 1.07 – 0.99 (m, 1H), 0.87 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.0, 168.1, 166.3, 162.8, 161.6, 138.1, 129.3, 120.6, 115.2, 113.2, 112.1, 108.4, 74.6, 71.2, 62.1, 54.0, 53.2, 51.5, 38.6, 38.1, 34.2, 22.8, 17.8, 11.9, 11.7, 10.7, 10.6. HRMS calculated for C27H33N3O5H+= 480.2498; found = 480.2497.

[0296] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(5-methylthiophen-2-yl)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 3.6 Hz, 1H), 7.33 (dd, J = 8.2, 7.5 Hz, 1H), 7.28 (s, 1H), 6.88 – 6.85 (m, 1H), 6.77 – 6.74 (m, 1H), 6.72 (dd, J = 8.3, 0.8 Hz, 1H), 5.22 (s, 1H), 3.67 (s, 3H), 3.62 (s, 3H), 3.16-3.13 (m, 2H), 2.80 – 2.75 (m, 1H), 2.50 (s, 3H), 2.46 (s, 1H), 2.35 – 2.28 (m, 2H), 2.23 – 2.21 (m, 1H), 2.15-2.11 (m, 1H), 1.95 – 1.90 (m, 1H), 1.66 – 1.61 (m, 1H), 1.52-1.49 (m, 1H), 1.21-1.18 (m, 1H), 1.14 – 1.08 (m, 1H), 0.86 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 201.0, 168.8, 162.2, 160.3, 141.2, 137.1, 136.6, 134.8, 129.5, 126.0, 122.8, 118.9, 111.6, 109.9, 74.9, 73.8, 61.5, 54.9, 53.4, 40.1, 38.4, 35.5, 29.7, 23.8, 19.3, 15.4, 12.9. HRMS calculated for C27H32N2O4SH+= 481.2161; found = 481.2156.BP1-27

[0297] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-(1H-indazol-6-yl)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.66-7.64 (m, 1H), 7.45- 7.42 (m, 1H), 7.32-7.30 (m, 2H), 6.86 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 5.30 (s, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.16-3.14 (m, 2H), 2.84-2.78 (m, 1H), 2.33-2.28 (m, 2H), 2.22-2.18 (m, 1H), 2.14-2.11 (m, 1H), 1.95-1.90 (m, 1H), 1.68-1.63 (m, 2H), 1.25 (s, 2H), 1.15-1.12 (m, 1H), 0.86 (t, J = 8.0 Hz, 3H).HRMS calculated for C29H32N4O4H+= 501.2502; found = 501.2497.

[0298] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-(benzo[b]thiophen-2-yl)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.84 – 7.79 (m, 2H), 7.40 (t, J = 7.9 Hz, 1H), 7.34 – 7.30 (m, 2H), 7.29 (s, 1H), 7.01 (d, J = 7.4 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 5.42 (s, 1H), 3.69 (s, 3H), 3.62 (s, 3H), 3.19-3.16 (m, 2H), 2.82-2.80 (m, 1H), 2.37-2.35 (m, 2H), 2.28 (s, 2H), 1.99-1.96 (m, 1H), 1.70-1.64 (m, 3H), 1.54 (s, 1H), 1.17-1.15 (m, 1H), 0.88 (d, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 224.0, 174.6, 174.6, 162.3, 160.4, 156.8, 140.5, 139.9, 139.3, 136.7, 134.5, 126.2, 124.3, 121.9, 120.0, 118.2, 115.8, 111.3, 77.3, 74.9, 74.0, 61.6, 54.8, 53.4, 51.1, 40.0, 38.4, 35.5, 29.7, 23.8, 19.2, 12.8. HRMS calculated for C30H32N2O4SH+= 517.2161; found = 517.2157.BP1-31

[0299] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-8a'-methyl-4-(1-methyl-1H-pyrazol-5-yl)-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3- methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 1.9 Hz, 1H), 7.42 (t, J = 8.3, 1H), 7.29 (s, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.64 (d, J = 7.3 Hz, 1H), 6.27 (d, J = 1.9 Hz, 1H), 5.34 (s, 1H), 3.69 (s, 3H), 3.68 (s, 3H), 3.62 (s, 3H), 3.15 – 3.10 (m, 2H), 2.77 (dt, J = 13.2, 3.6 Hz, 1H), 2.31-2.24 (m, 3H), 2.20-2.17 (m, 1H), 2.11 (dd, J = 11.0, 3.3 Hz, 1H), 1.92 – 1.86 (m, 1H), 1.69-1.61 (m, 1H), 1.50 (d, J = 11.5 Hz, 1H), 1.23 – 1.15 (m, 1H), 1.03 (dt, J = 12.6, 2.9 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 200.7, 168.8, 161.1, 160.3, 139.8, 138.1, 136.5, 128.9, 120.3, 117.9, 112.0, 111.6, 106.7, 75.2, 73.3, 61.5, 54.8, 53.2, 51.2, 40.1, 38.2, 36.9, 35.2, 23.9, 19.3, 12.8. HRMS calculated for C26H32N4O4H+= 465.2502; found = 465.2495.

[0300] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-(2-chloro-1-methyl-1H-imidazol-5-yl)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.42 (dd, J = 8.3, 7.2 Hz, 1H), 7.30 (s, 1H), 6.96 (s, 1H), 6.90 (d, J = 8.4 Hz, 1H), 6.66 – 6.60 (m, 1H), 5.40 (s, 1H), 3.70 (s, 3H), 3.63 (s, 3H), 3.37 (s, 3H), 3.19 – 3.09 (m, 2H), 2.82 – 2.74 (m, 1H), 2.35-2.26 (m, 2H), 2.24-2.12 (m, 2H), 1.94-1.84 (m, 1H), 1.69-1.63 (m, 1H), 1.51 (d, J = 11.4 Hz, 1H), 1.20 (t, J = 6.9 Hz, 2H), 1.02 (d, J = 12.5 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 200.8, 168.8, 161.4, 160.3, 136.9, 133.5, 132.1, 127.4, 127.2, 120.7, 117.7, 112.2, 111.4, 75.1, 73.5, 54.7, 53.3, 40.0, 38.2, 35.2, 31.8, 31.7, 29.7, 23.9, 19.2, 12.8. HRMS calculated for C26H31ClN4O4H+= 499.2112; found = 499.2107.BP1-35

[0301] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-(6-cyanopyridin-3-yl)-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:NMR (400 MHz, CDCl3) δ 8.77 (d, J = 4.0 Hz, 1H), 7.99 (dd, J = 8.0 Hz, 4.0 Hz, 1H), 7.67- 7.63 (m, 2H), 7.48-7.46 (m, 1H), 7.30 (s, 1H), 6.97 (d, J = 8.0 Hz, 1H), 6.66 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H), 3.62 (s, 3H), 3.34-3.29 (m, 2H), 2.85-2.82 (m, 1H), 2.44-2.40 (m, 2H), 2.34-2.24 (m, 3H), 1.60-1.56 (m, 1H), 1.43-1.39 (m, 1H), 1.27-1.23 (m, 2H), 1.13-1.11 (m, 1H), 0.86 (t, J = 8.0 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.9, 168.0, 161.5, 150.9, 138.3, 137.4, 136.1, 132.8, 132.0, 127.4, 119.8, 113.6, 113.0, 108.4, 76.7, 75.0, 71.4, 62.1, 54.0, 53.2, 51.6, 38.1, 34.0, 22.8, 17.8, 12.0.HRMS calculated for C28H30N4O4H+= 487.2345; found = 487.2341.

[0302] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4,6'-diethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (500 MHz, CDCl3) δ 7.33 – 7.29 (m, 2H), 6.69 (dd, J = 8.2, 0.8 Hz, 1H), 6.57 (dd, J = 7.3, 0.8 Hz, 1H), 5.07 (s, 1H), 3.69 (s, 3H), 3.65 (s, 3H), 3.20 – 3.13 (m, 2H), 3.05 – 2.92 (m, J = 7.2 Hz, 2H), 2.82 (dt, J = 12.1, 3.7 Hz, 1H), 2.38 – 2.14 (m, 5H), 1.97 – 1.89 (m, 1H), 1.66 (d, J = 14.9 Hz, 2H), 1.53 (d, J = 11.2 Hz, 1H), 1.22 (d, J = 7.5 Hz, 3H), 1.10 – 1.04 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 202.5, 168.8, 161.4, 160.2, 146.1, 136.6, 118.1, 117.6, 111.6, 108.9, 74.8, 73.3, 61.4, 54.8, 53.3, 51.1, 40.1, 38.4, 35.2, 25.0, 23.8, 19.2, 14.5, 12.7. HRMS calculated for C24H32N2O4H+= 413.2434; found = 413.2432.

[0303] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-carbamoyl-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 7.40 (d, J = 16.8 Hz, 2H), 7.29 (d, J = 7.3 Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 5.86 (d, J = 50.3 Hz, 2H), 3.72 (s, 3H), 3.71 (s, 3H), 3.16 (d, J = 11.4 Hz, 1H), 3.02 (d, J = 12.2 Hz, 3H), 2.97 – 2.82 (m, 2H), 2.59 – 2.40 (m, 3H), 1.89 – 1.69 (m, 3H), 1.62 (d, J = 11.1 Hz, 1H), 1.19 (d, J = 10.7 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 203.0, 173.7, 168.7, 166.1, 162.6, 160.3, 137.5, 131.9, 122.7, 115.6, 74.2, 61.5, 54.7, 53.1, 51.2, 39.9, 38.3, 35.3, 29.7, 23.6, 19.2, 12.8. HRMS calculated for C23H29N3O5H+= 428.2179; found = 428.2180.

[0304] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-cyclopropyl-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.28 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 6.11 (d, J = 7.6 Hz, 1H), 5.07 (s, 1H), 3.66 (s, 3H), 3.62 (s, 3H), 3.15 – 3.07 (m, 3H), 2.80 (dt, J = 10.0, 3.4 Hz, 1H), 2.33 (d, J = 7.4 Hz, 2H), 2.27 – 2.20 (m, 2H), 2.14 (dd, J = 11.4, 3.1 Hz, 1H), 1.94 – 1.85 (m, 1H), 1.80 (s, 1H), 1.71 – 1.60 (m, 1H), 1.54 – 1.47 (m, 1H), 1.20 (dt, J = 8.3, 5.4 Hz, 1H), 1.10 – 1.04 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H), 0.79 – 0.69 (m, 2H).13C NMR (100 MHz, CDCl3) δ 203.1, 168.9, 161.0, 160.2, 147.1, 136.7, 118.8, 111.6, 111.1, 107.7, 74.9, 73.4, 61.4, 54.9, 53.3, 51.2, 40.1, 38.4, 35.4, 23.8, 19.3, 12.9, 11.0, 10.6, 10.4. HRMS calculated for C25H32N2O4H+= 425.2435; found = 425.2434.SC112

[0305] Methyl (E)-2-((2S,6'S,7'S,8a'S)-4-chloro-6'-ethyl-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.30 – 7.23 (m, 2H), 6.72 (d, J = 8.2 Hz, 1H), 6.65 (d, J = 7.6 Hz, 1H), 5.35 (s, 1H), 3.66 (s, 3H), 3.61 (s, 3H), 3.13 (dd, J = 9.3, 4.6 Hz, 2H), 2.78 (dt, J = 12.7, 3.7 Hz, 1H), 2.37 – 2.27 (m, 2H), 2.26 – 2.10 (m, 3H), 1.93 – 1.87 (m, 1H), 1.66 – 1.55 (m, 1H), 1.50 (d, J = 11.6 Hz, 1H), 1.22 – 1.14 (m, 1H), 1.12 – 1.05 (m, 1H), 0.84 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.4, 168.7, 161.7, 160.2, 137.2, 132.0, 118.9, 117.0, 111.4, 109.7, 75.5, 73.4, 61.5, 54.7, 53.1, 51.2, 39.9, 38.2, 35.10, 23.7, 19.2, 12.8. HRMS calculated for C22H27ClN2O4H+= 419.1659; found = 419.1658.AP-102

[0306] Methyl (E)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-fluoro-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 10.71 (s, 1H), 7.92 (s, 1H), 7.40 (s, 2H), 6.72 (d, J = 8.0 Hz, 1H), 6.39 – 6.29 (m, 1H), 3.96 – 3.79 (m, 2H), 3.76 (s, 3H), 3.66 (s, 3H), 3.11- 3.16 (m, 1H), 3.08 – 2.90 (m, 3H), 2.77-2.87 (m, 1H), 2.60 - 2.55 (m, 1H), 2.44 – 2.31 (m, 1H), 1.94-1.85 (m, 1H), 1.65 – 1.41 (m, 2H), 1.39 – 1.21 (m, 2H), 0.92(t, J = 3.5 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 196.3, 168.1, 162.3 (J = 6 Hz), 161.6, 159.3 (J = 261 Hz), 140.3 (J = 10 Hz), 108.3, 108.1 (J = 4 Hz), 106.6 (J = 17 Hz), 104.1 (J = 18 Hz), 74.9, 71.6, 62.1, 54.3, 53.3, 51.6, 38.5, 38.1, 33.9,22.8, 17.8, 11.9. HRMS calculated for C22H27FN2O4H+ = 403.2028; found = 403.2027.Example 6: Z-MP and Z-BP1-94 Synthesis

[0307] Methyl (Z)-2-((2S,6'S,7'S,8a'S)-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.41 – 7.31 (m, 1H), 6.41 (d, J = 8.1 Hz, 1H), 6.18 (d, J = 8.1 Hz, 1H), 5.95 (s, 1H), 5.07 (s, 1H), 3.92 (s, 3H), 3.72 (d, J = 7.2 Hz, 6H), 3.17 – 3.06 (m, 2H), 2.74 – 2.65 (m, 1H), 2.43 – 2.30 (m, 3H), 2.19 – 2.10 (m, 1H), 1.90 – 1.81 (m, 1H), 1.57 (d, J = 10.9 Hz, 1H), 1.38 (q, J = 11.8 Hz, 2H), 1.27 – 1.18 (m, 1H), 1.10 (dd, J = 12.2, 3.4 Hz, 1H), 0.84 (t, J = 7.3 Hz, 3H).13C NMR (100 MHz, CDCl3) δ 199.1, 167.0, 161.7, 158.7, 155.3, 138.8, 111.1, 109.6, 103.7, 99.1, 74.8, 71.9, 61.8, 55.7, 54.5, 52.6, 51.3, 38.7, 38.3, 35.8, 23.7, 18.0, 12.7. HRMS calculated for C23H30N2O5Na+= 437.2052; found = 437.2047.Z-BP1-94

[0308] Methyl (Z)-2-((2S,6'S,7'S,8a'S)-5-cyclopropyl-6'-ethyl-4-methoxy-3-oxo-2',3',6',7',8',8a'-hexahydro-5'H-spiro[indoline-2,1'-indolizin]-7'-yl)-3-methoxyacrylate:1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 1.7 Hz, 1H), 6.96 (dd, J = 8.4, 1.7 Hz, 1H), 6.47 (dd,J = 8.4, 1.6 Hz, 1H), 5.96 (s, 1H), 4.91 (s, 1H), 4.04 (s, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.18 – 3.11 (m, 2H), 2.72 (d, J = 13.1 Hz, 1H), 2.39 – 2.28 (m, 3H), 2.17 – 2.06 (m, 2H), 1.89 – 1.83 (m, 1H), 1.56 (d, J = 11.1 Hz, 1H), 1.43 – 1.38 (m, 1H), 1.25 – 1.18 (m, 1H), 1.05 (d, J = 12.1 Hz, 1H), 0.90 – 0.81 (m, 5H), 0.60 – 0.50 (m, 2H).13C NMR (100 MHz, CDCl3) δ 199.2, 167.1, 160.3, 157.1, 155.4, 135.3, 124.6, 113.1, 111.0, 106.3, 75.1, 72.3, 61.9, 54.6, 52.8, 51.3, 38.8, 38.3, 36.2, 23.8, 18.1, 12.7, 8.8, 7.4, 7.0. HRMS calculated for C26H34N2O5H+= 455.2540; found = 455.2541. Example 6: EC50and Emaxusing BRET assay

[0309] The assays used to obtain the data in the various figures and the following tablesare generally described in the following references: Olsen, R. H. J. et al. TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat Chem Biol 16, 841–849 (2020); Chakraborty, S. et al. A Novel Mitragynine Analog with Low-Efficacy Mu Opioid Receptor Agonism Displays Antinociception with Attenuated Adverse Effects. J.Med. Chem.64, 13873–13892 (2021); and Faouzi, A. et al. Structure-based design of bitopicligands for the µ-opioid receptor. Nature 613, 767–774 (2023).

[0310] A number of implementations have been described. Nevertheless, it will beunderstood that various modifications may be made without departing from the spirit andscope of the disclosure. Accordingly, other implementations are within the scope of the following claims.

Claims

CLAIMS 1. A compound having the structure of Formula (1) or a pharmaceutically acceptable salt thereof:wherein R1 is C1-C6 alkyl, C1-C6 alkynyl, hydroxyl, alkoxyl, substituted alkoxyl, cycloalkyl, halo, nitrogen-containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen- containing heterocyclyl, 6-membered and fused ring oxygen-containing heterocyclyl, substituted heterocyclyl, -(CH2)n-R5, wherein, n is an integer from 0 to 4, and R5is aryl, substituted aryl, or heteroaryl, or -alkynylene-R6, wherein R6 is aryl or substituted aryl; R2is hydrogen, hydroxyl, halo, cyano, -C(O)NH2, C1-C6alkyl, aryl, substituted aryl, cycloalkyl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; R3 is hydrogen, halogen, cyano, C(O)NH2, cycloalkyl, aryl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; and R4is hydrogen, C1-C3alkyl, phenyl, or benzyl; wherein when R1 is methoxy at least one of R2 and R3 is no hydrogen and R2 is other than cloro.

2. The compound of claim 1, wherein R1is methoxy, nitrogen-containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen-containing heterocyclyl, and -(CH2)n-R5, wherein, n is an integer from 0 to 4, and R5is aryl, substituted aryl, or heteroaryl.

3. The compound of claim 1, wherein R1is methoxy.

4. The compound of claim 1, wherein R1 is nitrogen-containing heterocyclyl, or nitrogen and oxygen-containing heterocyclyl.

5. The compound of any one of claims 1 to 4, wherein R2 is hydrogen, halo, cycloalkyl, or nitrogen-containing heterocyclyl.

6. The compound of any one of claims 1 to 4, wherein R2 is hydrogen.

7. The compound of any one of claims 1 to 4, wherein R2 is C3 to C7 cycloalkyl.

8. The compound of any one of claims 1 to 4, wherein R2 is cyclopropyl.

9. The compound of any one of claims 1 to 8, wherein R3 is hydrogen, halo, cycloalkyl, or aryl.

10. The compound of any one of claims 1 to 8, wherein R3 is hydrogen.

11. The compound of any one of claims 1 to 8, wherein R3 is halo.

12. The compound of any one of claims 1 to 8, wherein R3 is cyclopropyl.

13. The compound of any one of claims 1 to 12, wherein R4 is hydrogen.

14. A compound having the structure of Formula (1Z) or a pharmaceutically acceptable salt thereof:wherein R1is C1-C6alkyl, C1-C6alkynyl, hydroxyl, alkoxyl, deuterated alkoxyl, substituted alkoxyl, cycloalkyl, halo, nitrogen-containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen-containing heterocyclyl, 6-membered and fused ring oxygen-containing heterocyclyl, halo-substituted heterocyclyl, -(CH2)n-R5, wherein, n is an integer from 0 to 4,and R5 is aryl, substituted aryl, or heteroaryl, or -alkynylene-R6, wherein R6 is aryl or substituted aryl; R2is hydrogen, hydroxyl, halo, cyano, -C(O)NH2, C1-C6alkyl, aryl, substituted aryl, cycloalkyl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; R3 is hydrogen, deuterium, halogen, cyano, C(O)NH2, cycloalkyl, aryl, nitrogen- containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; and R4 is hydrogen, C1-C3 alkyl, phenyl, or benzyl.

15. The compound of claim 14, wherein the compound has the following structure:.

16. The compound of claim 1, having the structure of Formula (2) or a pharmaceutically acceptable salt thereof:R2is hydrogen, hydroxyl, fluoro, bromo, -C(O)NH2, C1-C6alkyl, aryl, substituted aryl, cycloalkyl, nitrogen-containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; R3 is hydrogen, deuterium, halogen, cyano, C(O)NH2, cycloalkyl, aryl, nitrogen- containing heterocyclyl, or non-aromatic oxygen-containing heterocyclyl; and R11 is hydrogen or methyl; wherein at least one of R2 and R3 is other than hydrogen.

17. The compound of claim 16, wherein R2 is fluoro bromo, C1 to C3 alkyl, or C3 to C6 cycloalkyl.

18. The compound of claim 16, wherein R2 is C3 to C6 cycloalkyl.

19. The compound of claim 16, wherein R2 is cyclopropyl.

20. The compound of any one of claims 16 to 19, wherein R3 is hydrogen, halogen, or cycloalkyl.

21. The compound of any one of claims 16 to 19, wherein R3is hydrogen.

22. The compound of any one of claims 16 to 19, wherein R3 is fluoro, chloro, or bromo.

23. The compound of any one of claims 16 to 19, wherein R3 is C3 to C6 cycloalkyl.

24. The compound of any one of claims 16 to 19, wherein R3 is cyclopropyl.

25. The compound of any one of claims 16 to 24, wherein R11 is methyl.

26. The compound of claim 16, having the structure of:.

27. The compound of claim 16, having the structure of:.

28. The compound of claim 1, having the structure of Formula (3):wherein R1 is -C(O)NH2, halo, -OR12, wherein R12 is alkylene-aryl, alkylene- substituted aryl, alkylene-nitrogen-containing heterocyclyl, a C10to C12fused ring; nitrogen- containing heterocyclyl, sulfur-containing heterocyclyl, nitrogen and oxygen-containing heterocyclyl, C1to C6alkyl, C3to C7cycloalkyl, or -(CH2)n-R5, wherein, n is an integer from 0 to 4, and R5 is aryl, substituted aryl, or heteroaryl, or -alkynylene-R6, wherein R6 is aryl or substituted aryl.

29. The compound of claim 28, wherein R1 is -OR12, wherein R12 is –(CH2)2-phenyl, - (CH2)3-phenyl, –(CH2)2-halo-substituted phenyl, –(CH2)2-C1-C3-alkyl-substituted phenyl, – (CH2)2-C1-C3-alkoxyl-substituted phenyl, –(CH2)2-nitrogen-containing heteroaryl.

30. The compound of claim 28, wherein R1 is -OR12, wherein R12 is –(CH2)2-phenyl, - (CH2)3-phenyl, or –(CH2)2-tolyl.

31. The compound of claim 28, wherein R1is –(CH2)3-phenyl, -(CH2)4-phenyl, –(CH2)3- halo-substituted phenyl, –(CH2)3-C1-C3-alkyl-substituted phenyl, or –(CH2)3-C1-C3-alkoxyl- substituted phenyl, or–(CC-(CH2)2-phenyl.

32. The compound of claim 28, wherein R1 is biphenyl, sulfur-containing heteroaryl, substituted sulfur-containing heteroaryl, nitrogen-containing heteroaryl, substituted nitrogen- containing heteroaryl, nitrogen- and oxygen-containing heteroaryl, substituted nitrogen- and oxygen-containing heteroaryl, or substituted nitrogen- and sulfur-containing heteroaryl.

33. The compound of claim 28, wherein R1is chloro or fluoro.

34. The compound of claim 28, wherein R1is C1to C3alkyl or C3to C7cycloalkyl.

35. The compound of claim 28, wherein R1 is cyclopropyl.

36. The compound of claim 28, wherein R1 is nitrogen-containing heterocyclyl, or nitrogen and oxygen-containing heterocyclyl.

37. The compound of claim 27, wherein the compound has the following structure:N.

38. The compound of claim 28, wherein the compound has the following structure:.

39. A compound having the structure of Formula (4):wherein X is -CH-, O, N; X1is –CH2-, O, -NH-; X2 is -CH2-, -CH-, O, N, or -NH-; n is an integer of 0 to 4; m is an integer of 0 to 2; and Y is.

40. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 39 and a pharmaceutically acceptable carrier.

41. The pharmaceutical composition of claim 40, wherein the pharmaceutically acceptable carrier is selected from the group consisting of a liquid, solid, semi-solid, and gel.

42. The pharmaceutical composition of claim 40 or 41, wherein the pharmaceutically acceptable carrier is suitable for oral, parenteral, topical, or transdermal administration.

43. The pharmaceutical composition of any one of claims 40 to 42, wherein the composition is formulated for controlled release.

44. The pharmaceutical composition of claim 43, wherein the controlled release formulation provides sustained release of the compound over a period of at least 12 hours.

45. A method of treating pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 39.

46. The method of claim 45, wherein the pain is selected from the group consisting of acute pain, chronic pain, neuropathic pain, and cancer-related pain.

47. The method of claim 46, wherein the pain is neuropathic pain.

48. The method of any one of claims 45 to 47, wherein the compound is administered orally, parenterally, topically, or transdermally.

49. The method of claim 48, wherein the compound is administered orally.

50. A method of treating opioid use disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 39.

51. The method of any one of claims 45 to 50, wherein the therapeutically effective amount of the compound is between about 1 mg / kg and about 100 mg / kg of body weight of the subject.

52. A composition comprising one or more compounds of the MP-based scaffold formula (I):as described herein.

53. The composition of claim 52, comprising at least one of BP1-94, SC111, and Z-MP.

54. A method of treating pain symptoms in a subject in need thereof, the method comprising: administering to the subject a composition comprising one or more compounds of the MP-based scaffold formula (I):.

55. The method of claim 54, wherein the composition comprises at least one of BP1-94, SC111, and Z-MP.

56. A method of treating opioid use disorder in a subject in need thereof, the method comprising: administering to the subject a composition comprising one or more compounds of the MP-based scaffold formula (I):

57. The method of claim 56, wherein the composition comprises at least one of BP1-94, SC111, and Z-MP.

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