[go: up one dir, main page]

US20190092754A1 - 5-(n-benzyl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication - Google Patents

5-(n-benzyl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication Download PDF

Info

Publication number
US20190092754A1
US20190092754A1 US16/202,653 US201816202653A US2019092754A1 US 20190092754 A1 US20190092754 A1 US 20190092754A1 US 201816202653 A US201816202653 A US 201816202653A US 2019092754 A1 US2019092754 A1 US 2019092754A1
Authority
US
United States
Prior art keywords
dimethylpiperidin
tert
tetrahydroisoquinolin
butoxy
acetic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US16/202,653
Inventor
Kyle J. Eastman
John F. Kadow
Kyle E. Parcella
B. Narasimhulu Naidu
Tao Wang
Zhiwei Yin
Zhongxing Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ViiV Healthcare UK No 5 Ltd
Original Assignee
ViiV Healthcare UK No 5 Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=56851651&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20190092754(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by ViiV Healthcare UK No 5 Ltd filed Critical ViiV Healthcare UK No 5 Ltd
Priority to US16/202,653 priority Critical patent/US20190092754A1/en
Assigned to VIIV Healthcare UK (No.5) Limited reassignment VIIV Healthcare UK (No.5) Limited ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PARCELLA, KYLE E., EASTMAN, KYLE J., KADOW, JOHN F., NAIDU, B. NARASIMHULU, WANG, TAO, YIN, ZHIWEI, ZHANG, ZHONGXING
Publication of US20190092754A1 publication Critical patent/US20190092754A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the invention relates to compounds, compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection. More particularly, the invention provides novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection. The invention also relates to methods for making the compounds hereinafter described.
  • HIV human immunodeficiency virus
  • HIV Human immunodeficiency virus
  • AIDS acquired immune deficiency syndrome
  • agents are classified as either nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), or entry inhibitors (one, maraviroc, targets the host CCR5 protein, while the other, enfuvirtide, is a peptide that targets the gp41 region of the viral gp160 protein).
  • a pharmacokinetic enhancer with no antiviral activity i.e., cobicistat, available from Gilead Sciences, Inc. under the tradename TYBOSTTM (cobicistat) tablets, has recently been approved for use in combinations with certain antiretroviral agents (ARVs) that may benefit from boosting.
  • the invention encompasses compounds of Formula I, including pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions, and their use in inhibiting HIV and treating those infected with HIV or AIDS.
  • the present invention it is now possible to provide compounds that are novel and are useful in the treatment of HIV. Additionally, the compounds may provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
  • the invention also provides pharmaceutical compositions comprising the compounds of the invention, including pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, and/or diluent.
  • the invention provides methods of treating HIV infection comprising administering a therapeutically effective amount of the compounds of the invention to a patient.
  • the invention provides methods for inhibiting HIV integrase.
  • the present invention is directed to these, as well as other important ends, hereinafter described.
  • Alkyl means a straight or branched saturated hydrocarbon comprised of 1 to 10 carbons, and preferably 1 to 6 carbons.
  • Alkenyl means a straight or branched alkyl group comprised of 2 to 10 carbons with at least one double bond and optionally substituted with 0-3 halo or alkoxy group.
  • Alkynyl means a straight or branched alkyl group comprised of 2 to 10 carbons, preferably 2 to 6 carbons, containing at least one triple bond and optionally substituted with 0-3 halo or alkoxy group.
  • Aryl mean a carbocyclic group comprised of 1-3 rings that are fused and/or bonded and at least one or a combination of which is aromatic.
  • the non-aromatic carbocyclic portion, where present, will be comprised of C 3 to C 7 alkyl group.
  • aromatic groups include, but are not limited to indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl and cyclopropylphenyl.
  • the aryl group can be attached to the parent structure through any substitutable carbon atom in the group.
  • Aryloxy is an aryl group attached to the parent structure by oxygen.
  • Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons.
  • Halo includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl and haloalkoxy include all halogenated isomers from monohalo to perhalo.
  • Heteroaryl is a subset of heterocyclic group as defined below and is comprised of 1-3 rings where at least one or a combination of which is aromatic and that the aromatic group contains at least one atom chosen from a group of oxygen, nitrogen or sulfur.
  • Heterocyclyl or heterocyclic means a cyclic group of 1-3 rings comprised of carbon and at least one other atom selected independently from oxygen, nitrogen and sulfur.
  • the rings could be bridged, fused and/or bonded, through a direct or spiro attachment, with the option to have one or a combination thereof be aromatic.
  • Examples include, but are not limited to, azaindole, azaindoline, azetidine, benzimidazole, bezodioxolyl, benzoisothiazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxazole, carbazole, chroman, dihalobezodioxolyl, dihydrobenzofuran, dihydrobenzo[1,4]oxazine, 1,3-dihydrobenzo[c]thiophene 2,2-dioxide, 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 2,3-dihydro-H-pyrrolo[3,4-c]pyridine and its regioisomeric variants, 6,7-dihydro-5H-pyrrolo[2,3-b]pyr
  • azaindole refers to any of the following regioisomers: 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, and 1H-pyrrolo[3,2-b]pyridine.
  • regioisomer variants notation as in, for example, “5H-pyrrolo[2,3-b]pyrazine and its regioisomeric variants” would also encompass 7H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-c]pyridazine, 1H-pyrrolo[2,3-d]pyridazine, 5H-pyrrolo[3,2-c]pyridazine, and 5H-pyrrolo[3,2-d]pyrimidine.
  • 6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine and its regioisomeric variants would encompass 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine and 6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine. It is also understood that the lack of “regioisomeric variants” notation does not in any way restrict the claim scope to the noted example only.
  • Terms with a hydrocarbon moiety include straight and branched isomers for the hydrocarbon portion with the indicated number of carbon atoms.
  • Bonding and positional bonding relationships are those that are stable as understood by practitioners of organic chemistry.
  • Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art.
  • a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • “Combination,” “coadministration,” “concurrent” and similar terms referring to the administration of a compound of Formula I with at least one anti-HIV agent mean that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (“HAART”) as understood by practitioners in the field of AIDS and HIV infection.
  • HAART highly active antiretroviral therapy
  • “Therapeutically effective” means the amount of agent required to provide a benefit to a patient as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.
  • Patient means a person infected with the HIV virus.
  • Treatment “Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” and related terms are used as understood by practitioners in the field of AIDS and HIV infection.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • the invention includes all stereoisomeric forms of the compounds including enantiomers and diastereromers. Methods of making and separating stereoisomers are known in the art.
  • the invention includes all tautomeric forms of the compounds.
  • the invention includes atropisomers and rotational isomers.
  • the invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
  • R 1 is selected from hydrogen, alkyl, or cycloalkyl
  • R 2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R 6 substituent and also with 0-3 halo or alkyl substituents
  • R 3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy
  • R 4 is selected from alkyl or haloalkyl
  • R 5 is alkyl
  • R 6 is selected from Ar 1 , (Ar 1 )alkyl, (chromanyl)alkyl, cyanocycloalkyl or (dihydrobenzodioxinyl)alkyl
  • R 2 is tetrahydroisoquinolinyl substituted with 1 R 6 substituent.
  • R 3 is piperidinyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.
  • R 6 is (Ar 1 )alkyl.
  • R 6 is Ar 1 , (chromanyl)alkyl, (dihydrobenzodioxinyl)alkyl, or cyanocycloalkyl.
  • Ar 1 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxy)alkoxy, (alkoxy)alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanocycloalkyl.
  • R 1 is selected from hydrogen, alkyl, or cycloalkyl
  • R 2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R 6 substituent and also with 0-3 halo or alkyl substituents
  • R 3 is piperidinyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy
  • R 4 is selected from alkyl or haloalkyl
  • R 5 is alkyl
  • R 6 is selected from Ar 1 , (Ar 1 )alkyl, (chromanyl)alkyl, cyanocycloalkyl or (dihydrobenzodioxinyl)alkyl
  • Ar 1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloal
  • R 1 is selected from hydrogen, alkyl, or cycloalkyl
  • R 2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R 6 substituent and also with 0-3 halo or alkyl substituents
  • R 3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy
  • R 4 is selected from alkyl or haloalkyl
  • R 5 is alkyl
  • R 6 is (Ar 1 )alkyl
  • Ar 1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl
  • R 1 is selected from hydrogen, alkyl, or cycloalkyl
  • R 2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R 6 substituent and also with 0-3 halo or alkyl substituents
  • R 3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy
  • R 4 is selected from alkyl or haloalkyl
  • R 5 is alkyl
  • R 6 is selected from Ar 1 , (chromanyl)alkyl, (dihydrobenzodioxinyl)alkyl, or cyanocycloalkyl
  • Ar 1 is phenyl substituted
  • R 1 is selected from hydrogen, alkyl, or cycloalkyl
  • R 2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R 6 substituent and also with 0-3 halo or alkyl substituents
  • R 3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy
  • R 4 is selected from alkyl or haloalkyl
  • R 5 is alkyl
  • R 6 is selected from Ar 1 , (Ar 1 )alkyl, (chromanyl)alkyl, cyanocycloalkyl or (dihydrobenzodioxinyl)alkyl
  • variable substituent including R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Ar 1 can be used independently with the scope of any other instance of a variable substituent.
  • the invention includes combinations of the different aspects.
  • composition useful for treating HIV infection comprising a therapeutic amount of a compound of Formula I and a pharmaceutically acceptable carrier.
  • the composition further comprises a therapeutically effective amount at least one other agent used for treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier.
  • the other agent is dolutegravir.
  • a method for treating HIV infection comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
  • the method further comprises administering a therapeutically effective amount of at least one other agent used for treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors.
  • the other agent is dolutegravir.
  • the other agent is administered to the patient prior to, simultaneously with, or subsequently to the compound of Formula I.
  • Preferred compounds in accordance with the present invention include the following:
  • compositions may typically be administered as pharmaceutical compositions. These compositions are comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and may contain conventional excipients and/or diluents. A therapeutically effective amount is that which is needed to provide a meaningful patient benefit.
  • Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles.
  • Compositions encompass all common solid and liquid forms, including capsules, tablets, lozenges, and powders, as well as liquid suspensions, syrups, elixirs, and solutions. Compositions are made using available formulation techniques, and excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) which are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa. (1985).
  • compositions which are normally formulated in dosage units and compositions providing from about 1 to 1000 milligram (“mg”) of the active ingredient per dose are typical. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is about 0.25-1000 mg/unit.
  • Liquid compositions are usually in dosage unit ranges.
  • the liquid composition will be in a unit dosage range of about 1-100 milligram per milliliter (“mg/mL”). Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL.
  • mg/mL milligram per milliliter
  • other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is about 1-100 mg/mL.
  • the invention encompasses all conventional modes of administration; oral and parenteral methods are preferred.
  • the dosing regimen will be similar to other antiretroviral agents used clinically.
  • the daily dose will be about 1-100 milligram per kilogram (“mg/kg”) body weight daily.
  • mg/kg milligram per kilogram
  • more compound is required orally and less parenterally.
  • the specific dosing regimen will be determined by a physician using sound medical judgment.
  • the compounds of this invention desirably have activity against HIV. Accordingly, another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, excipient and/or diluent.
  • the invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating AIDS and HIV infection.
  • the compound can also be used in combination therapy wherein the compound and one or more of the other agents are physically together in a fixed-dose combination (FDC).
  • FDC fixed-dose combination
  • Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, HIV capsid inhibitors, anti-infectives, and immunomodulators, such as, for example, PD-1 inhibitors, PD-L1 inhibitors, antibodies, and the like.
  • the compound of Formula I will generally be given in a daily dose of about 1-100 mg/kg body weight daily in conjunction with other agents.
  • the other agents generally will be given in the amounts used therapeutically.
  • the specific dosing regimen will be determined by a physician using sound medical judgment.
  • nucleoside HIV reverse transcriptase inhibitors examples include abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine.
  • non-nucleoside HIV reverse transcriptase inhibitors examples include delavirdine, efavirenz, etrivirine, nevirapine, and rilpivirine.
  • HIV protease inhibitors examples include amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and, tipranavir.
  • HIV fusion inhibitor An example of an HIV fusion inhibitor is enfuvirtide or T-1249.
  • An example of an HIV entry inhibitor is maraviroc.
  • HIV integrase inhibitors examples include dolutegravir, elvitegravir, or raltegravir.
  • An example of an HIV attachment inhibitor is fostemsavir.
  • An example of an HIV maturation inhibitor is BMS-955176, having the following structure:
  • contemplated herein are combinations of the compounds of Formula I, together with one or more agents useful in the treatment of AIDS.
  • the compounds of the invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines, such as those in the following non-limiting table:
  • ANTIVIRALS Drug Name Manufacturer Indication ANTIVIRALS
  • AIDS, ARC non-nucleoside reverse transcriptase inhibitor
  • COMPLERA Gilead HIV infection, AIDS, ARC; combination with emtricitabine, rilpivirine, and tenofovir disoproxil fumarate 097 Hoechst/Bayer HIV infection, AIDS, ARC (non-nucleoside reverse transcriptase (RT) inhibitor) Amprenavir Glaxo Wellcome HIV infection, 141 W94 AIDS, ARC GW 141 (protease inhibitor) Abacavir (1592U89) Glaxo Wellcome HIV infection, GW 1592 AIDS, ARC (RT inhibitor) Acemannan Carrington Labs ARC (Irving, TX) Acyclovir Burroughs Wellcome HIV infection, AIDS, ARC AD-439 Tanox Biosystems HIV infection, AIDS, ARC AD-519 Tanox Biosystems HIV infection,
  • AIDS, ARC, HIV Ind. Ltd. (Osaka, positive Japan) asymptomatic ddC Hoffman-La Roche HIV infection, AIDS, Dideoxycytidine ARC ddI Bristol-Myers Squibb HIV infection, AIDS, Dideoxyinosine ARC; combination with AZT/d4T DMP-450 AVID HIV infection, (Camden, NJ) AIDS, ARC (protease inhibitor) Efavirenz Bristol Myers Squibb HIV infection, (DMP 266, SUSTIVA ®) AIDS, ARC (-)6-Chloro-4-(S)- (non-nucleoside RT cyclopropylethynyl- inhibitor) 4(S)-trifluoro- methyl-1,4-dihydro- 2H-3,1-benzoxazin- 2-one, STOCRINE EL10 Elan Corp, PLC HIV infection (Gainesville, GA) Etravirine Tibotec/J & J HIV infection
  • HIV infection HIV infection, AIDS, ARC Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Interferon alfa-n3 Interferon Sciences ARC, AIDS Indinavir Merck HIV infection, AIDS, ARC, asymptomatic HIV positive, also in combination with AZT/ddI/ddC ISIS 2922 ISIS Pharmaceuticals CMV retinitis KNI-272 Nat'l Cancer Institute HIV-assoc.
  • Lamivudine 3TC Glaxo Wellcome HIV infection, AIDS, ARC (reverse transcriptase inhibitor); also with AZT Lobucavir Bristol-Myers Squibb CMV infection Nelfinavir Agouron HIV infection, Pharmaceuticals AIDS, ARC (protease inhibitor) Nevirapine Boeheringer HIV infection, Ingleheim AIDS, ARC (RT inhibitor) Novapren Novaferon Labs, Inc. HIV inhibitor (Akron, OH) Peptide T Peninsula Labs AIDS Octapeptide (Belmont, CA) Sequence Trisodium Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc.
  • HIV infection other CMV infections PNU-140690 Pharmacia Upjohn HIV infection, AIDS, ARC (protease inhibitor) Probucol Vyrex HIV infection, AIDS RBC-CD4 Sheffield Med. HIV infection, Tech (Houston, TX) AIDS, ARC Ritonavir Abbott HIV infection, AIDS, ARC (protease inhibitor) Saquinavir Hoffmann- HIV infection, LaRoche AIDS, ARC (protease inhibitor) Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS, Didehydrodeoxy- ARC Thymidine Tipranavir Boehringer Ingelheim HIV infection, AIDS, ARC (protease inhibitor) Valaciclovir Glaxo Wellcome Genital HSV & CMV Infections Virazole Viratek/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC VX-478 Vertex HIV infection, AIDS, ARC Zalcitabine Hoffmann-LaRoche HIV
  • AIDS ARC (Irving, TX) CL246, 738 Wyeth AIDS, Kaposi's Lederle Labs sarcoma FP-21399 Fuki ImmunoPharm Blocks HIV fusion with CD4 + cells
  • Gamma Interferon Genentech ARC in combination w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS Macrophage Colony Sandoz Stimulating Factor Granulocyte Hoechst-Roussel AIDS Macrophage Colony Immunex Stimulating Factor Granulocyte Schering-Plough AIDS, Macrophage Colony combination Stimulating Factor w/AZT HIV Core Particle Rorer Seropositive HIV Immunostimulant IL-2 Cetus AIDS, in combination Interleukin-2 w/AZT IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in Interleukin-2 Immunex combination w/AZT IL-2 Chiron AIDS, increase in Interleukin-2 CD4 cell counts
  • Kaposi's sarcoma Muramyl-Tripeptide Granulocyte Amgen AIDS, in combination Colony Stimulating w/AZT Factor Remune Immune Response Immunotherapeutic Corp.
  • rCD4 Genentech AIDS ARC Recombinant Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a AIDS, ARC, in combination w/AZT SK&F106528 Smith Kline HIV infection Soluble T4 Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF w/gamma Interferon ANTI-INFECTIVES Clindamycin with Pharmacia Upjohn PCP Primaquine Fluconazole Pfizer Cryptococcal meningitis, candidiasis Pastille Squib
  • the compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section.
  • the structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification.
  • the variables in the schemes are meant only to illustrate how to make some of the compounds of this invention.
  • the disclosure is not limited to the foregoing illustrative examples and the examples should be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced.
  • Mobile phase A 9:1 H 2 O/acetonitrile with 10 mM NH 4 OAc and mobile phase B:A:9:1 acetonitrile/H 2 O with 10 mM NH 4 OAc; or mobile phase A: 9:1 H 2 O/acetonitrile with 0.1% TFA and mobile phase B:A:9:1 acetonitrile/H 2 O with 0.1% TFA; or mobile phase A: water/MeOH (9:1) with 20 mM NH 4 OAc and mobile phase B: 95:5 MeOH/H 2 O with 20 mM NH 4 OAc or mobile phase A: water/MeOH (9:1) with 0.1% TFA and mobile phase B: 95:5 MeOH/H 2 O with 0.1% TFA or mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate.
  • Bromine (72.8 mL, 1.4 mol) was added via addition funnel over 60 min to a mechanically stirred cold (ice-water bath) solution of 2,6-dimethylpyridin-4-ol (87 g, 706 mmol) and 4-methylmorpholine (156 mL, 1.4 mol) in dichloromethane (1 L) and methanol (100 mL) and then stirred for 2 h at rt. Additional bromine ( ⁇ 15 mL) was added based on monitoring by LCMS. The product was filtered, washed with ether, and dried under vacuum to give 3,5-dibromo-2,6-dimethylpyridin-4-ol 176.8 g (88%).
  • Triethylamine 28.8 mL, 206 mmol was added to a nitrogen purged solution of 3,5-dibromo-2,6-dimethylpyridin-4-ol (58 g, 206 mmol) and phosphorous oxychloride (57.7 mL, 619 mmol) in chloroform (450 mL) and stirred for 1 h at rt, then 3 h at 80° C. The reaction was removed from heating and immediately concentrated under house vacuum; then under high vacuum.
  • the homogeneous brown reaction mixture was rapidly transferred via cannula to a solution of ethyl 2-chloro-2-oxoacetate (6.14 ml, 54.9 mmol, degassed for 5 min by bubbling N2 through the solution) in THF (50 mL) maintained at ⁇ 30° C.
  • the resulting reaction mixture was stirred (1.5 h) while warming to 0° C.
  • taken up in to Et 2 O (200 mL) washed with 1:1 sat Na 2 CO 3 /1M NH 4 Cl (3 ⁇ 50 mL), dried (MgSO 4 ), filtered and concentrated to give brown viscous oil.
  • the propan-2-ol (38.2 mL, 499 mmol) was added drop wise over 15 min to a cold (0° C.), nitrogen purged solution of oxalyl dichloride (101 g, 799 mmol) and the reaction was stirred at room temperature for 2.5 h. Then a reflux condenser was fitted and a slight vacuum was applied for about 1 h until HCl gas was removed (the HCl was trapped in by a sat'd solution of NaHCO 3 ). The reflux condenser was removed and the flask was fitted with a short path distillation head.
  • reaction mixture was transferred via cannula into a 1 L RB-flask containing isopropyl 2-chloro-2-oxoacetate (26.6 g, 176 mmol) in THF (160 mL) maintained at ⁇ 60° C., and the reaction stirred an additional 2.5 h while being allowed to warm to ⁇ 10° C.
  • the reaction was quenched upon diluted with a mixture of 10% NH 4 Cl solution (80 mL) in ether (320 mL).
  • the organic layer was washed with 160 mL of sat'd NaHCO 3 /10% NH 4 Cl solution (1:1), brine, and dried (Na 2 SO 4 ).
  • reaction mixture became a clear solution at this point.
  • the tube was sealed and stirred at rt for 16 h. LCMs at this point showed incomplete reaction. So, the reaction mixture was cooled down to ⁇ 30° C. and bubbled isobutene ( ⁇ 15 min). After 24 h, reaction mixture was neutralized with sat. Na 2 CO 3 (20 mL), organic layer separated and aqueous layer was extracted with CH 2 Cl 2 (25 mL).
  • 6-Bromo-2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline (1.00 g, 2.85 mmol)
  • 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.09 g, 4.28 mmol)
  • Pd(dppf)Cl 2 0.209 g, 0.285 mmol
  • potassium acetate (0.840 g, 8.55 mmol
  • This compound is prepared using 6-bromo-2-(2-fluoro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline by following the procedure described above for 2-(2-chloro-6-methylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline.
  • LCMS (M+H) 382.2.
  • Step 1 To a mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (500 mg), (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid (365 mg) and Cs 2 CO 3 (715 mg) in 1,4-dioxane (25 mL) and water (5 mL) was added Pd(PPh 3 ) 4 (127 mg). The mixture was flushed with nitrogen and then heated at 85° C. for 3 hours.
  • Step 2 To a solution of (S)-tert-butyl 6-(5-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg) in CH 2 Cl 2 (20 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 3 hours.
  • Step 3 To a solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate (10 mg) in MeOH (1 mL) and THF (1 mL) was added sodium hydroxide (0.158 mL, 1N). The reaction was stirred at 80° C. for 2 hours. The mixture was acidified by 1N HCl to pH ⁇ 4. All the solvents were removed under vacuum to give a residue was purified by preparative HPLC system. LCMS: MS (M+H) + calcd. 480.3; observ. 480.3.
  • Step 1 To a mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (1.1 g), (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid (0.649 g) and Cs 2 CO 3 (1.527 g) in 1,4-dioxane (40 mL) and water (8 mL) was added Pd(PPh 3 ) 4 (0.271 g). The mixture was flushed with nitrogen and then heated at 85° C. for 5 hours.
  • Step 2 To a solution of (S)-tert-butyl 6-(5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (420 mg) in CH 2 Cl 2 (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 4 hours.
  • Step 1 Na 2 CO 3 or K 2 C 03 or Cs 2 CO 3 or NaH (1-20 eq.) was added into a solution of (S)-ethyl of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate (1 eq.) and an electrophile (1-20 eq.) in acetonitrile or THF or DMF or dioxane. The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). After removal of solvents under vacuum, the residue was used as was or purified by the preparative HPLC system.
  • Step 2 To a solution of the product from the step 1 (1 eq.) in MeOH or EtOH and THF (volume ratio 20:1 to 1:20) was added NaOH or KOH (1 to 100 eq.). The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). The mixture was acidified by 1N HCl to pH ⁇ 4. Removal of the solvents under vacuum gave a residue which was purified by the preparative HPLC system.
  • Step 1 A solution of (S)-Ethyl or (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate (1 eq.) and an aldehyde (1-10 eq.) in DMF was stirred at room temperature for 2-24 hours, before NaCNBH 3 (1-20 eq.) and AcOH (1-200 eq.) were added. The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). After the reaction was quenched with water, it was extracted with EtOAc. The combined organic layer was washed with water, brine, dried over MgSO 4 and concentrated under vacuum. The residue was used as was or purified by the preparative HPLC system.
  • Step 2 To a solution of the product from the step 1 (1 eq.) in MeOH or EtOH and THF (volume ratio 20:1 to 1:20) was added NaOH or KOH (1 to 100 eq.). The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). The mixture was acidified by 1N HCl to pH ⁇ 4. Removal of the solvents under vacuum gave a residue which was purified by the preparative HPLC system.
  • Step 1 To a mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (1 equiv), 2-(arylalkyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (1 to 5 equiv.) and cesium carbonate (2 to 10 equiv.) in 1,4-dioxane/water was added Pd(Ph 3 P) 4 (0.1 to 1 equiv.).
  • Step 2 To a solution of the product from the step 1 (1 eq.) in MeOH or EtOH and THF (volume ratio 20:1 to 1:20) was added NaOH or KOH (1 to 100 eq.). The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). The mixture was acidified by 1N HCl to pH ⁇ 4. Removal of the solvents under vacuum gave a residue which was purified by the preparative HPLC system.
  • LCMS (M + H) 602.5 52 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6- dimethyl-5-(2-(2-methyl-5-(trifluoromethyl)benzyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
  • Method A: LCMS (M + H) 652.5 53 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-dichlorobenzyl)-1,2,3,4- tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6- dimethylpyridin-3-yl)acetic acid
  • Method A: LCMS (M + H) 638.4 54 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl
  • 1,4-Dioxane (1 ml) and Water (0.2 ml) were added under N 2 .
  • the reaction was heated at 80° C. for 1 h.
  • the reaction was concentrated, adsorbed onto celite and was purified on silica gel (Biotage, EtOAc/hexanes gradient, 0-100% over 10 CVs)
  • the isolated residue was subjected to hydrolysis conditions by treating with 0.1 mL of 5N NaOH, in 1.5 mL of EtOH, and was stirred at 80 C overnight.
  • the reaction mixture containing the product was submitted to the Single Compound Purification team for purification and analysis.
  • the crude material was purified via preparative LC/MS to give desired product (7.6 mg).
  • 1,4-Dioxane (1.8 ml) and Water (0.4 ml) was added under N 2 .
  • the reaction was stirred at 80° C. for 1 hr.
  • the reaction was concentrated, adsorbed onto celite and was purified on silica gel (Biotage, EtOAc/hexanes gradient 0-100% over 10 CVs).
  • the isolated material was taken up in 1.5 mL of EtOH and treated with 5N aq NaOH (0.20 ml, 1.1 mmol).
  • the reaction was stirred overnight at 80 C.
  • the reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H 2 O/CH 3 CN gradient.
  • a recombinant NL-RLuc proviral clone was constructed in which a section of the nef gene from NL4-3 was replaced with the Renilla Luciferase gene. This virus is fully infectious and can undergo multiple cycles of replication in cell culture.
  • the luciferous reporter provides a simple and easy method for quantitating the extent of virus growth and consequently, the antiviral activity of test compounds.
  • the plasmid pNLRLuc contains the proviral NL-Rluc DNA cloned into pUC18 at the PvuII site.
  • the NL-RLuc virus was prepared by transfection of 293T cells with the plasmid pNLRLuc.
  • Transfections were performed using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad, Calif.) according to the manufacturer and the virus generated was titered in MT-2 cells.
  • the titrated virus was used to infect MT-2 cells in the presence of compound, and after 5 days of incubation, cells were processed and quantitated for virus growth by the amount of expressed luciferase.
  • Assay media was RPMI 1640 supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 units/ml penicillin G/100 units/ml streptomycin, 10 mM HEPES buffer pH 7.55 and 2 mM L-glutamine. The results from at least 2 experiments were used to calculate the EC 50 values.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • AIDS & HIV (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Disclosed are compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions comprising the compounds, methods for making the compounds and their use in inhibiting HIV integrase and treating those infected with HIV or AIDS.
Figure US20190092754A1-20190328-C00001

Description

    CROSS REFERENCE TO RELATED INVENTION
  • This application claims the benefit of U.S. provisional application Ser. No. 62/203,791 filed Aug. 11, 2015.
    • FIELD OF THE INVENTION
  • The invention relates to compounds, compositions, and methods for the treatment of human immunodeficiency virus (HIV) infection. More particularly, the invention provides novel inhibitors of HIV, pharmaceutical compositions containing such compounds, and methods for using these compounds in the treatment of HIV infection. The invention also relates to methods for making the compounds hereinafter described.
    • BACKGROUND OF THE INVENTION
  • Human immunodeficiency virus (HIV) has been identified as the etiological agent responsible for acquired immune deficiency syndrome (AIDS), a fatal disease characterized by destruction of the immune system and the inability to fight off life threatening opportunistic infections. Recent statistics indicate that an estimated 35.3 million people worldwide are infected with the virus (UNAIDS: Report on the Global HIV/AIDS Epidemic, 2013). In addition to the large number of individuals already infected, the virus continues to spread. Estimates from 2013 point to close to 3.4 million new infections in that year alone. In the same year there were approximately 1.6 million deaths associated with HIV and AIDS.
  • Current therapy for HIV-infected individuals consists of a combination of approved anti-retroviral agents. Over two dozen drugs are currently approved for HIV infection, either as single agents or as fixed dose combinations or single tablet regimens, the latter two containing 2-4 approved agents. These agents belong to a number of different classes, targeting either a viral enzyme or the function of a viral protein during the virus replication cycle. Thus, agents are classified as either nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleotide reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase inhibitors (INIs), or entry inhibitors (one, maraviroc, targets the host CCR5 protein, while the other, enfuvirtide, is a peptide that targets the gp41 region of the viral gp160 protein). In addition, a pharmacokinetic enhancer with no antiviral activity, i.e., cobicistat, available from Gilead Sciences, Inc. under the tradename TYBOST™ (cobicistat) tablets, has recently been approved for use in combinations with certain antiretroviral agents (ARVs) that may benefit from boosting.
  • In the US, where combination therapy is widely available, the number of HIV-related deaths has dramatically declined (Palella, F. J.; Delany, K. M.; Moorman, A. C.; Loveless, M. O.; Further, J.; Satten, G. A.; Aschman, D. J.; Holmberg, S. D. N. Engl. J. Med. 1998, 338, 853-860).
  • Unfortunately, not all patients are responsive and a large number fail this therapy. In fact, initial studies suggest that approximately 30-50% of patients ultimately fail at least one drug in the suppressive combination. Treatment failure in most cases is caused by the emergence of viral resistance. Viral resistance in turn is caused by the replication rate of HIV-1 during the course of infection combined with the relatively high viral mutation rate associated with the viral polymerase and the lack of adherence of HIV-infected individuals in taking their prescribed medications. Clearly, there is a need for new antiviral agents, preferably with activity against viruses already resistant to currently approved drugs. Other important factors include improved safety and a more convenient dosing regimen than many of the currently approved drugs.
  • Compounds which inhibit HIV replication have been disclosed. See, for example, the following patent applications: WO2007131350, WO2009062285, WO2009062288, WO2009062289, WO2009062308, WO2010130034, WO2010130842, WO2011015641, WO2011076765, WO2012033735, WO2013123148, WO2013134113, WO2014164467, WO2014159959, and WO2015126726.
  • What is now needed in the art are additional compounds which are novel and useful in the treatment of HIV. Additionally, these compounds may desirably provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanisms of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability. Also needed are new formulations and methods of treatment which utilize these compounds.
    • SUMMARY OF THE INVENTION
  • The invention encompasses compounds of Formula I, including pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions, and their use in inhibiting HIV and treating those infected with HIV or AIDS.
  • By virtue of the present invention, it is now possible to provide compounds that are novel and are useful in the treatment of HIV. Additionally, the compounds may provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
  • The invention also provides pharmaceutical compositions comprising the compounds of the invention, including pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient, and/or diluent.
  • In addition, the invention provides methods of treating HIV infection comprising administering a therapeutically effective amount of the compounds of the invention to a patient.
  • In addition, the invention provides methods for inhibiting HIV integrase.
  • Also provided in accordance with the invention are methods for making the compounds of the invention.
  • The present invention is directed to these, as well as other important ends, hereinafter described.
    • DESCRIPTION OF THE INVENTION
  • Unless specified otherwise, these terms have the following meanings.
  • “Alkyl” means a straight or branched saturated hydrocarbon comprised of 1 to 10 carbons, and preferably 1 to 6 carbons.
  • “Alkenyl” means a straight or branched alkyl group comprised of 2 to 10 carbons with at least one double bond and optionally substituted with 0-3 halo or alkoxy group.
  • “Alkynyl” means a straight or branched alkyl group comprised of 2 to 10 carbons, preferably 2 to 6 carbons, containing at least one triple bond and optionally substituted with 0-3 halo or alkoxy group.
  • “Aryl” mean a carbocyclic group comprised of 1-3 rings that are fused and/or bonded and at least one or a combination of which is aromatic. The non-aromatic carbocyclic portion, where present, will be comprised of C3 to C7 alkyl group. Examples of aromatic groups include, but are not limited to indanyl, indenyl, naphthyl, phenyl, tetrahydronaphthyl and cyclopropylphenyl. The aryl group can be attached to the parent structure through any substitutable carbon atom in the group.
  • “Arylalkyl” is a C1-C5 alkyl group attached to 1 to 2 aryl groups and linked to the parent structure through the alkyl moiety. Examples include, but are not limited to, —(CH2)nPh with n=1-5, —CH(CH3)Ph, —CH(Ph)2.
  • “Aryloxy” is an aryl group attached to the parent structure by oxygen.
  • “Cycloalkyl” means a monocyclic ring system composed of 3 to 7 carbons.
  • “Halo” includes fluoro, chloro, bromo, and iodo.
  • “Haloalkyl” and “haloalkoxy” include all halogenated isomers from monohalo to perhalo.
  • “Heteroaryl” is a subset of heterocyclic group as defined below and is comprised of 1-3 rings where at least one or a combination of which is aromatic and that the aromatic group contains at least one atom chosen from a group of oxygen, nitrogen or sulfur.
  • “Heterocyclyl or heterocyclic” means a cyclic group of 1-3 rings comprised of carbon and at least one other atom selected independently from oxygen, nitrogen and sulfur. The rings could be bridged, fused and/or bonded, through a direct or spiro attachment, with the option to have one or a combination thereof be aromatic. Examples include, but are not limited to, azaindole, azaindoline, azetidine, benzimidazole, bezodioxolyl, benzoisothiazole, benzothiazole, benzothiadiazole, benzothiophene, benzoxazole, carbazole, chroman, dihalobezodioxolyl, dihydrobenzofuran, dihydrobenzo[1,4]oxazine, 1,3-dihydrobenzo[c]thiophene 2,2-dioxide, 2,3-dihydrobenzo[d]isothiazole 1,1-dioxide, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 2,3-dihydro-H-pyrrolo[3,4-c]pyridine and its regioisomeric variants, 6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine and its regioisomeric variants, furanylphenyl, imidazole, imidazo[1,2-a]pyridine, indazole, indole, indoline, isoquinoline, isoquinolinone, isothiazolidine 1,1-dioxide, morpholine, 2-oxa-5-azabicyclo[2.2.1]heptane, oxadiazole-phenyl, oxazole, phenylaztidine, phenylindazole, phenylpiperidine, phenylpiperizine, phenyloxazole, phenylpyrrolidine, piperidine, pyridine, pyridinylphenyl, pyridinylpyrrolidine, pyrimidine, pyrimidinylphenyl, pyrrazole-phenyl, pyrrolidine, pyrrolidin-2-one, 1H-pyrazolo[4,3-c]pyridine and its regioisomeric variants, pyrrole, 5H-pyrrolo[2,3-b]pyrazine, 7H-pyrrolo[2,3-d]pyrimidine and its regioisomeric variants, quinazoline, quinoline, quinoxaline, tetrahydroisoquinoline, 1,2,3,4-tetrahydro-1,8-naphthyridine, tetrahydroquinoline, 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, 1,2,5-thiadiazolidine 1,1-dioxide, thiophene, thiophenylphenyl, triazole, or triazolone. Unless otherwise specifically set forth, the heterocyclic group can be attached to the parent structure through any suitable atom in the group that results in a stable compound.
  • It is understood that a subset of the noted heterocyclic examples encompass regioisomers. For instance, “azaindole” refers to any of the following regioisomers: 1H-pyrrolo[2,3-b]pyridine, 1H-pyrrolo[2,3-c]pyridine, 1H-pyrrolo[3,2-c]pyridine, and 1H-pyrrolo[3,2-b]pyridine. In addition the “regioisomer variants” notation as in, for example, “5H-pyrrolo[2,3-b]pyrazine and its regioisomeric variants” would also encompass 7H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-c]pyridazine, 1H-pyrrolo[2,3-d]pyridazine, 5H-pyrrolo[3,2-c]pyridazine, and 5H-pyrrolo[3,2-d]pyrimidine. Similarly, 6,7-dihydro-5H-pyrrolo[2,3-b]pyrazine and its regioisomeric variants would encompass 6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine and 6,7-dihydro-5H-pyrrolo[2,3-c]pyridazine. It is also understood that the lack of “regioisomeric variants” notation does not in any way restrict the claim scope to the noted example only.
  • “Heterocyclylalkyl” is a heterocyclyl moiety attached to the parent structure through C1-C5 alkyl group. Examples include, but are not limited to, —(CH2)n—R or —CH(CH3)—(RZ) where n=1-5 and that RZ is chosen from benzimidazole, imidazole, indazole, isooxazole, phenyl-pyrazole, pyridine, quinoline, thiazole, triazole, triazolone, oxadiazole.
  • Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion with the indicated number of carbon atoms.
  • Bonding and positional bonding relationships are those that are stable as understood by practitioners of organic chemistry.
  • Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • Substituents which are illustrated by chemical drawing to bond at variable positions on a multiple ring system (for example a bicyclic ring system) are intended to bond to the ring where they are drawn to append. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • “Combination,” “coadministration,” “concurrent” and similar terms referring to the administration of a compound of Formula I with at least one anti-HIV agent mean that the components are part of a combination antiretroviral therapy or highly active antiretroviral therapy (“HAART”) as understood by practitioners in the field of AIDS and HIV infection.
  • “Therapeutically effective” means the amount of agent required to provide a benefit to a patient as understood by practitioners in the field of AIDS and HIV infection. In general, the goals of treatment are suppression of viral load, restoration and preservation of immunologic function, improved quality of life, and reduction of HIV-related morbidity and mortality.
  • “Patient” means a person infected with the HIV virus.
  • “Treatment,” “therapy,” “regimen,” “HIV infection,” “ARC,” “AIDS” and related terms are used as understood by practitioners in the field of AIDS and HIV infection.
  • Those terms not specifically set forth herein shall have the meaning which is commonly understood and accepted in the art.
  • The invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • Some of the compounds of the invention exist in stereoisomeric forms. The invention includes all stereoisomeric forms of the compounds including enantiomers and diastereromers. Methods of making and separating stereoisomers are known in the art. The invention includes all tautomeric forms of the compounds. The invention includes atropisomers and rotational isomers.
  • The invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13C and 14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
  • In an aspect of the invention, there is provided a compound of Formula I:
  • Figure US20190092754A1-20190328-C00002
  • wherein:
    R1 is selected from hydrogen, alkyl, or cycloalkyl;
    R2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R6 substituent and also with 0-3 halo or alkyl substituents;
    R3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
    R4 is selected from alkyl or haloalkyl;
    R5 is alkyl;
    R6 is selected from Ar1, (Ar1)alkyl, (chromanyl)alkyl, cyanocycloalkyl or (dihydrobenzodioxinyl)alkyl; and
    Ar1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxy)alkoxy, (alkoxy)alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanocycloalkyl;
    or a pharmaceutically acceptable salt thereof.
  • In an aspect of the invention, R2 is tetrahydroisoquinolinyl substituted with 1 R6 substituent.
  • In an aspect of the invention, R3 is piperidinyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy.
  • In an aspect of the invention, R6 is (Ar1)alkyl.
  • In an aspect of the invention, R6 is Ar1, (chromanyl)alkyl, (dihydrobenzodioxinyl)alkyl, or cyanocycloalkyl.
  • In an aspect of the invention, Ar1 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxy)alkoxy, (alkoxy)alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanocycloalkyl.
  • In an aspect of the invention, there is provided a compound of Formula I:
  • Figure US20190092754A1-20190328-C00003
  • wherein:
    R1 is selected from hydrogen, alkyl, or cycloalkyl;
    R2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R6 substituent and also with 0-3 halo or alkyl substituents;
    R3 is piperidinyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
    R4 is selected from alkyl or haloalkyl;
    R5 is alkyl;
    R6 is selected from Ar1, (Ar1)alkyl, (chromanyl)alkyl, cyanocycloalkyl or (dihydrobenzodioxinyl)alkyl; and
    Ar1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxy)alkoxy, (alkoxy)alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanocycloalkyl;
    or a pharmaceutically acceptable salt thereof.
  • In an aspect of the invention, there is provided a compound of Formula I:
  • Figure US20190092754A1-20190328-C00004
  • wherein:
    R1 is selected from hydrogen, alkyl, or cycloalkyl;
    R2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R6 substituent and also with 0-3 halo or alkyl substituents;
    R3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
    R4 is selected from alkyl or haloalkyl;
    R5 is alkyl;
    R6 is (Ar1)alkyl; and
    Ar1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxy)alkoxy, (alkoxy)alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanocycloalkyl;
    or a pharmaceutically acceptable salt thereof.
  • In an aspect of the invention, there is provided a compound of Formula I:
  • Figure US20190092754A1-20190328-C00005
  • wherein:
    R1 is selected from hydrogen, alkyl, or cycloalkyl;
    R2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R6 substituent and also with 0-3 halo or alkyl substituents;
    R3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
    R4 is selected from alkyl or haloalkyl;
    R5 is alkyl;
    R6 is selected from Ar1, (chromanyl)alkyl, (dihydrobenzodioxinyl)alkyl, or cyanocycloalkyl; and
    Ar1 is phenyl substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxy)alkoxy, (alkoxy)alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanocycloalkyl;
    or a pharmaceutically acceptable salt thereof.
  • In an aspect of the invention, there is provided a compound of Formula I:
  • Figure US20190092754A1-20190328-C00006
  • wherein:
    R1 is selected from hydrogen, alkyl, or cycloalkyl;
    R2 is selected from tetrahydroisoquinolinyl and is substituted with 1 R6 substituent and also with 0-3 halo or alkyl substituents;
    R3 is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
    R4 is selected from alkyl or haloalkyl;
    R5 is alkyl;
    R6 is selected from Ar1, (Ar1)alkyl, (chromanyl)alkyl, cyanocycloalkyl or (dihydrobenzodioxinyl)alkyl; and
    Ar1 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, cycloalkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, (hydroxy)alkoxy, (alkoxy)alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanocycloalkyl;
    or a pharmaceutically acceptable salt thereof.
  • For a particular compound of Formula I, the scope of any instance of a variable substituent, including R1, R2, R3, R4, R5, R6 and Ar1 can be used independently with the scope of any other instance of a variable substituent. As such, the invention includes combinations of the different aspects.
  • In an aspect of the invention, there is provided a composition useful for treating HIV infection comprising a therapeutic amount of a compound of Formula I and a pharmaceutically acceptable carrier. In an aspect of the invention, the composition further comprises a therapeutically effective amount at least one other agent used for treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors, and a pharmaceutically acceptable carrier. In an aspect of the invention, the other agent is dolutegravir.
  • In an aspect of the invention, there is provided a method for treating HIV infection comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need thereof. In an aspect of the invention, the method further comprises administering a therapeutically effective amount of at least one other agent used for treatment of AIDS or HIV infection selected from nucleoside HIV reverse transcriptase inhibitors, non-nucleoside HIV reverse transcriptase inhibitors, HIV protease inhibitors, HIV fusion inhibitors, HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV budding or maturation inhibitors, and HIV integrase inhibitors. In an aspect of the invention, the other agent is dolutegravir.
  • In an aspect of the invention, the other agent is administered to the patient prior to, simultaneously with, or subsequently to the compound of Formula I.
  • Preferred compounds in accordance with the present invention include the following:
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(4-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-3-((6-(5-(tert-butoxy(carboxy)methyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid;
    • (S)-2-(5-(2-([1,1′-biphenyl]-3-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (2S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(5-(2-([1,1′-biphenyl]-4-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2-methyl-3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(4-methyl-3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,4-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-4-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,3-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-3-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,5-dichlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-(tert-butyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,5-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-6-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,5-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,6-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(3,4,5-trifluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-isopropylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,4-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,5-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,3-dichlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2,3,4-trifluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(5-chloro-2-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-5-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2,3,6-trifluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-5-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-5-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluoro-3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2,4,5-trifluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2-methyl-5-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-dichlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-chlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2,4,6-trimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2,4,6-trifluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-isopropylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-ethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-cyanobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-cyanobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(5-cyano-2-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-cyanobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-cyano-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-fluoro-2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-5-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-5-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-2,3-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,3-difluoro-4-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-5-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-3,5-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,4-difluoro-5-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-isopropylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2,4,5-trimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,5-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1l-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,3-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-(tert-butyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,5-difluoro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluoro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(5-(2-(2-(benzyloxy)-3,5-dichlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4,5-difluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,3-difluoro-6-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-(2-hydroxyethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluoro-6-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-dichloro-6-ethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,3-dichloro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluoro-3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1l-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2-fluoro-5-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluoro-5-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,5-difluoro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2,3,5-trifluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-methoxy-3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(5-chloro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-5-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-ethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-(difluoromethoxy)-2-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluoro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluoro-6-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-methoxy-4-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-5-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-methoxy-5-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-5-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-(difluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-6-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-5-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-(difluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-methoxy-5-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-5-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-fluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-ethoxy-2,4-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,6-dichlorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-2-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(5-chloro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2,6-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-isopropyl-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-methoxy-4-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-methoxy-3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-isopropyl-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluoro-6-hydroxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-methoxy-2,3-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-methoxy-2,5-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-ethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-isopropoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-methoxy-5-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-isopropoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-isobutoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-isopropoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(chroman-6-ylmethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(5-(2-(3,4-bis(difluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-((2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-6-phenoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-isopropoxy-2,6-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,4-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(4-(1-cyanocyclopropyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(4-(nonyloxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-Butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-Butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2-methyl-5-(2-(2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-Butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(2-(3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3,4-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2,3-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-fluoro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-fluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid;
    • (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-fluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid; and
    • (S)-2-(tert-Butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)acetic acid; and
    • pharmaceutically acceptable salts thereof.
  • The compounds of the invention herein described may typically be administered as pharmaceutical compositions. These compositions are comprised of a therapeutically effective amount of a compound of Formula I or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier and may contain conventional excipients and/or diluents. A therapeutically effective amount is that which is needed to provide a meaningful patient benefit. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms, including capsules, tablets, lozenges, and powders, as well as liquid suspensions, syrups, elixirs, and solutions. Compositions are made using available formulation techniques, and excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) which are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa. (1985).
  • Solid compositions which are normally formulated in dosage units and compositions providing from about 1 to 1000 milligram (“mg”) of the active ingredient per dose are typical. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is about 0.25-1000 mg/unit.
  • Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of about 1-100 milligram per milliliter (“mg/mL”). Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other antiretroviral agents will be present in a unit range similar to agents of that class used clinically. Typically, this is about 1-100 mg/mL.
  • The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other antiretroviral agents used clinically. Typically, the daily dose will be about 1-100 milligram per kilogram (“mg/kg”) body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regimen, however, will be determined by a physician using sound medical judgment.
  • The compounds of this invention desirably have activity against HIV. Accordingly, another aspect of the invention is a method for treating HIV infection in a human patient comprising administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier, excipient and/or diluent.
  • The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating AIDS and HIV infection. The compound can also be used in combination therapy wherein the compound and one or more of the other agents are physically together in a fixed-dose combination (FDC). Some of these agents include HIV attachment inhibitors, CCR5 inhibitors, CXCR4 inhibitors, HIV cell fusion inhibitors, HIV integrase inhibitors, HIV nucleoside reverse transcriptase inhibitors, HIV non-nucleoside reverse transcriptase inhibitors, HIV protease inhibitors, budding and maturation inhibitors, HIV capsid inhibitors, anti-infectives, and immunomodulators, such as, for example, PD-1 inhibitors, PD-L1 inhibitors, antibodies, and the like. In these combination methods, the compound of Formula I will generally be given in a daily dose of about 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regimen, however, will be determined by a physician using sound medical judgment.
  • Examples of nucleoside HIV reverse transcriptase inhibitors include abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine.
  • Examples of non-nucleoside HIV reverse transcriptase inhibitors include delavirdine, efavirenz, etrivirine, nevirapine, and rilpivirine.
  • Examples of HIV protease inhibitors include amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir and, tipranavir.
  • An example of an HIV fusion inhibitor is enfuvirtide or T-1249.
  • An example of an HIV entry inhibitor is maraviroc.
  • Examples of HIV integrase inhibitors include dolutegravir, elvitegravir, or raltegravir.
  • An example of an HIV attachment inhibitor is fostemsavir.
  • An example of an HIV maturation inhibitor is BMS-955176, having the following structure:
  • Figure US20190092754A1-20190328-C00007
  • Thus, as set forth above, contemplated herein are combinations of the compounds of Formula I, together with one or more agents useful in the treatment of AIDS. For example, the compounds of the invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines, such as those in the following non-limiting table:
  • Drug Name Manufacturer Indication
    ANTIVIRALS
    Rilpivirine Tibotec HIV infection, AIDS, ARC
    (non-nucleoside
    reverse transcriptase
    inhibitor)
    COMPLERA ® Gilead HIV infection, AIDS,
    ARC; combination
    with emtricitabine, rilpivirine,
    and tenofovir disoproxil
    fumarate
    097 Hoechst/Bayer HIV infection,
    AIDS, ARC
    (non-nucleoside
    reverse transcriptase (RT)
    inhibitor)
    Amprenavir Glaxo Wellcome HIV infection,
    141 W94 AIDS, ARC
    GW 141 (protease inhibitor)
    Abacavir (1592U89) Glaxo Wellcome HIV infection,
    GW 1592 AIDS, ARC
    (RT inhibitor)
    Acemannan Carrington Labs ARC
    (Irving, TX)
    Acyclovir Burroughs Wellcome HIV infection, AIDS,
    ARC
    AD-439 Tanox Biosystems HIV infection, AIDS,
    ARC
    AD-519 Tanox Biosystems HIV infection, AIDS,
    ARC
    Adefovir dipivoxil Gilead Sciences HIV infection
    AL-721 Ethigen ARC, PGL
    (Los Angeles, CA) HIV positive, AIDS
    Alpha Interferon Glaxo Wellcome Kaposi's sarcoma,
    HIV in combination w/Retrovir
    Ansamycin Adria Laboratories ARC
    LM 427 (Dublin, OH)
    Erbamont
    (Stamford, CT)
    Antibody which Advanced Biotherapy AIDS, ARC
    Neutralizes pH Concepts
    Labile alpha aberrant (Rockville, MD)
    Interferon
    AR177 Aronex Pharm HIV infection, AIDS,
    ARC
    Beta-fluoro-ddA Nat'l Cancer Institute AIDS-associated
    diseases
    CI-1012 Warner-Lambert HIV-1 infection
    Cidofovir Gilead Science CMV retinitis,
    herpes, papillomavirus
    Curdlan sulfate AJI Pharma USA HIV infection
    Cytomegalovirus MedImmune CMV retinitis
    Immune globin
    Cytovene Syntex Sight threatening
    Ganciclovir CMV
    peripheral CML
    retinitis
    Darunavir Tibotec-J & J HIV infection, AIDS, ARC
    (protease inhibitor)
    Delaviridine Pharmacia-Upjohn HIV infection,
    AIDS, ARC
    (RT inhibitor)
    Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV
    Ind. Ltd. (Osaka, positive
    Japan) asymptomatic
    ddC Hoffman-La Roche HIV infection, AIDS,
    Dideoxycytidine ARC
    ddI Bristol-Myers Squibb HIV infection, AIDS,
    Dideoxyinosine ARC; combination
    with AZT/d4T
    DMP-450 AVID HIV infection,
    (Camden, NJ) AIDS, ARC
    (protease inhibitor)
    Efavirenz Bristol Myers Squibb HIV infection,
    (DMP 266, SUSTIVA ®) AIDS, ARC
    (-)6-Chloro-4-(S)- (non-nucleoside RT
    cyclopropylethynyl- inhibitor)
    4(S)-trifluoro-
    methyl-1,4-dihydro-
    2H-3,1-benzoxazin-
    2-one, STOCRINE
    EL10 Elan Corp, PLC HIV infection
    (Gainesville, GA)
    Etravirine Tibotec/J & J HIV infection, AIDS, ARC
    (non-nucleoside
    reverse transcriptase
    inhibitor)
    Famciclovir Smith Kline herpes zoster,
    herpes simplex
    GS 840 Gilead HIV infection,
    AIDS, ARC
    (reverse transcriptase
    inhibitor)
    HBY097 Hoechst Marion HIV infection,
    Roussel AIDS, ARC
    (non-nucleoside
    reverse transcriptase
    inhibitor)
    Hypericin VIMRx Pharm. HIV infection, AIDS,
    ARC
    Recombinant Human Triton Biosciences AIDS, Kaposi's
    Interferon Beta (Almeda, CA) sarcoma, ARC
    Interferon alfa-n3 Interferon Sciences ARC, AIDS
    Indinavir Merck HIV infection, AIDS,
    ARC, asymptomatic
    HIV positive, also in
    combination with
    AZT/ddI/ddC
    ISIS 2922 ISIS Pharmaceuticals CMV retinitis
    KNI-272 Nat'l Cancer Institute HIV-assoc. diseases
    Lamivudine, 3TC Glaxo Wellcome HIV infection,
    AIDS, ARC
    (reverse
    transcriptase
    inhibitor); also
    with AZT
    Lobucavir Bristol-Myers Squibb CMV infection
    Nelfinavir Agouron HIV infection,
    Pharmaceuticals AIDS, ARC
    (protease inhibitor)
    Nevirapine Boeheringer HIV infection,
    Ingleheim AIDS, ARC
    (RT inhibitor)
    Novapren Novaferon Labs, Inc. HIV inhibitor
    (Akron, OH)
    Peptide T Peninsula Labs AIDS
    Octapeptide (Belmont, CA)
    Sequence
    Trisodium Astra Pharm. CMV retinitis, HIV
    Phosphonoformate Products, Inc. infection, other CMV
    infections
    PNU-140690 Pharmacia Upjohn HIV infection,
    AIDS, ARC
    (protease inhibitor)
    Probucol Vyrex HIV infection, AIDS
    RBC-CD4 Sheffield Med. HIV infection,
    Tech (Houston, TX) AIDS, ARC
    Ritonavir Abbott HIV infection,
    AIDS, ARC
    (protease inhibitor)
    Saquinavir Hoffmann- HIV infection,
    LaRoche AIDS, ARC
    (protease inhibitor)
    Stavudine; d4T Bristol-Myers Squibb HIV infection, AIDS,
    Didehydrodeoxy- ARC
    Thymidine
    Tipranavir Boehringer Ingelheim HIV infection, AIDS, ARC
    (protease inhibitor)
    Valaciclovir Glaxo Wellcome Genital HSV & CMV
    Infections
    Virazole Viratek/ICN asymptomatic HIV
    Ribavirin (Costa Mesa, CA) positive, LAS, ARC
    VX-478 Vertex HIV infection, AIDS,
    ARC
    Zalcitabine Hoffmann-LaRoche HIV infection, AIDS,
    ARC, with AZT
    Zidovudine; AZT Glaxo Wellcome HIV infection, AIDS,
    ARC, Kaposi's
    sarcoma, in combination with
    other therapies
    Tenofovir disoproxil, Gilead HIV infection,
    fumarate salt AIDS,
    (VIREAD ®) (reverse transcriptase
    inhibitor)
    EMTRIVA ® Gilead HIV infection,
    (Emtricitabine) (FTC) AIDS,
    (reverse transcriptase
    inhibitor)
    COMBIVIR ® GSK HIV infection,
    AIDS,
    (reverse transcriptase
    inhibitor)
    Abacavir succinate GSK HIV infection,
    (or ZIAGEN ®) AIDS,
    (reverse transcriptase
    inhibitor)
    REYATAZ ® Bristol-Myers Squibb HIV infection
    (or atazanavir) AIDs, protease
    inhibitor
    FUZEON ® Roche/Trimeris HIV infection
    (Enfuvirtide or T-20) AIDs, viral Fusion
    inhibitor
    LEXIVA ® GSK/Vertex HIV infection
    (or Fosamprenavir AIDs, viral protease
    calcium) inhibitor
    SELZENTRY ™ Pfizer HIV infection
    Maraviroc; (UK 427857) AIDs, (CCR5 antagonist, in
    development)
    TRIZIVIR ® GSK HIV infection
    AIDs, (three drug combination)
    Sch-417690 (vicriviroc) Schering-Plough HIV infection
    AIDs, (CCR5 antagonist, in
    development)
    TAK-652 Takeda HIV infection
    AIDs, (CCR5 antagonist, in
    development)
    GSK 873140 GSK/ONO HIV infection
    (ONO-4128) AIDs, (CCR5 antagonist,
    in development)
    Integrase Inhibitor Merck HIV infection
    MK-0518 AIDs
    Raltegravir
    TRUVADA ® Gilead Combination of Tenofovir
    disoproxil fumarate salt
    (VIREAD ®) and EMTRIVA ®
    (Emtricitabine)
    Integrase Inhibitor Gilead/Japan Tobacco HIV Infection
    GS917/JTK-303 AIDs
    Elvitegravir in development
    Triple drug combination Gilead/Bristol-Myers Squibb Combination of Tenofovir
    ATRIPLA ® disoproxil fumarate salt
    (VIREAD ®), EMTRIVA ®
    (Emtricitabine), and
    SUSTIVA ® (Efavirenz)
    FESTINAVIR ® Oncolys BioPharma HIV infection
    AIDs
    in development
    CMX-157 Chimerix HIV infection
    Lipid conjugate of AIDs
    nucleotide tenofovir
    G5K1349572 GSK HIV infection
    Integrase inhibitor AIDs
    TIVICAY ®
    dolutegravir
    IMMUNOMODULATORS
    AS-101 Wyeth-Ayerst AIDS
    Bropirimine Pharmacia Upjohn Advanced AIDS
    Acemannan Carrington Labs, Inc. AIDS, ARC
    (Irving, TX)
    CL246, 738 Wyeth AIDS, Kaposi's
    Lederle Labs sarcoma
    FP-21399 Fuki ImmunoPharm Blocks HIV fusion
    with CD4 + cells
    Gamma Interferon Genentech ARC, in combination
    w/TNF (tumor
    necrosis factor)
    Granulocyte Genetics Institute AIDS
    Macrophage Colony Sandoz
    Stimulating Factor
    Granulocyte Hoechst-Roussel AIDS
    Macrophage Colony Immunex
    Stimulating Factor
    Granulocyte Schering-Plough AIDS,
    Macrophage Colony combination
    Stimulating Factor w/AZT
    HIV Core Particle Rorer Seropositive HIV
    Immunostimulant
    IL-2 Cetus AIDS, in combination
    Interleukin-2 w/AZT
    IL-2 Hoffman-LaRoche AIDS, ARC, HIV, in
    Interleukin-2 Immunex combination w/AZT
    IL-2 Chiron AIDS, increase in
    Interleukin-2 CD4 cell counts
    (aldeslukin)
    Immune Globulin Cutter Biological Pediatric AIDS, in
    Intravenous (Berkeley, CA) combination w/AZT
    (human)
    IMREG-1 Imreg AIDS, Kaposi's
    (New Orleans, LA) sarcoma, ARC, PGL
    IMREG-2 Imreg AIDS, Kaposi's
    (New Orleans, LA) sarcoma, ARC, PGL
    Imuthiol Diethyl Merieux Institute AIDS, ARC
    Dithio Carbamate
    Alpha-2 Schering Plough Kaposi's sarcoma
    Interferon w/AZT, AIDS
    Methionine- TNI Pharmaceutical AIDS, ARC
    Enkephalin (Chicago, IL)
    MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma
    Muramyl-Tripeptide
    Granulocyte Amgen AIDS, in combination
    Colony Stimulating w/AZT
    Factor
    Remune Immune Response Immunotherapeutic
    Corp.
    rCD4 Genentech AIDS, ARC
    Recombinant
    Soluble Human CD4
    rCD4-IgG AIDS, ARC
    hybrids
    Recombinant Biogen AIDS, ARC
    Soluble Human CD4
    Interferon Hoffman-La Roche Kaposi's sarcoma
    Alfa 2a AIDS, ARC,
    in combination w/AZT
    SK&F106528 Smith Kline HIV infection
    Soluble T4
    Thymopentin Immunobiology HIV infection
    Research Institute
    (Annandale, NJ)
    Tumor Necrosis Genentech ARC, in combination
    Factor; TNF w/gamma Interferon
    ANTI-INFECTIVES
    Clindamycin with Pharmacia Upjohn PCP
    Primaquine
    Fluconazole Pfizer Cryptococcal
    meningitis,
    candidiasis
    Pastille Squibb Corp. Prevention of
    Nystatin Pastille oral candidiasis
    Ornidyl Merrell Dow PCP
    Eflomithine
    Pentamidine LyphoMed PCP treatment
    Isethionate (IM & IV) (Rosemont, IL)
    Trimethoprim Antibacterial
    Trimethoprim/sulfa Antibacterial
    Piritrexim Burroughs Wellcome PCP treatment
    Pentamidine Fisons Corporation PCP prophylaxis
    Isethionate for
    Inhalation
    Spiramycin Rhone-Poulenc Cryptosporidial
    diarrhea
    Intraconazole- Janssen-Pharm. Histoplasmosis;
    R51211 cryptococcal
    meningitis
    Trimetrexate Warner-Lambert PCP
    Daunorubicin NeXstar, Sequus Kaposi's sarcoma
    Recombinant Human Ortho Pharm. Corp. Severe anemia
    Erythropoietin assoc. with AZT
    therapy
    Recombinant Human Serono AIDS-related
    Growth Hormone wasting, cachexia
    Megestrol Acetate Bristol-Myers Squibb Treatment of
    anorexia assoc.
    W/AIDS
    Testosterone Alza, Smith Kline AIDS-related wasting
    Total Enteral Norwich Eaton Diarrhea and
    Nutrition Pharmaceuticals malabsorption
    related to AIDS
    • Methods of Synthesis
  • The compounds of this invention can be made by various methods known in the art including those of the following schemes and in the specific embodiments section. The structure numbering and variable numbering shown in the synthetic schemes are distinct from, and should not be confused with, the structure or variable numbering in the claims or the rest of the specification. The variables in the schemes are meant only to illustrate how to make some of the compounds of this invention. The disclosure is not limited to the foregoing illustrative examples and the examples should be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced.
  • Abbreviations used in the schemes and examples generally follow conventions used in the art. Chemical abbreviations used in the specification and examples are defined as follows: “KHMDS” for potasium bis(trimethylsilyl)amide; “DMF” for N,N-dimethylformamide; “HATU” for O-(t-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, “MeOH” for methanol; “Ar” for aryl; “TFA” for trifluoroacetic acid, “DMSO” for dimethylsulfoxide; “h” for hours; “rt” for room temperature or retention time (context will dictate); “min” for minutes; “EtOAc” for ethyl acetate; “THF” for tetrahydrofuran; “Et2O” for diethyl ether; “DMAP” for 4-dimethylaminopyridine; “DCE” for 1,2-dichloroethane; “ACN” for acetonitrile; “DME” for 1,2-dimethoxyethane; “HOBt” for 1-hydroxybenzotriazole hydrate; and “DIEA” for diisopropylethylamine.
  • Certain other abbreviations as used herein, are defined as follows: “1×” for once, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” for equivalent or equivalents, “g” for gram or grams, “mg” for milligram or milligrams, “L” for liter or liters, “mL” for milliliter or milliliters, “μL” for microliter or microliters, “N” for normal, “M” for molar, “mmol” for millimole or millimoles, “atm” for atmosphere, “psi” for pounds per square inch, “conc.” for concentrate, “sat” or “sat'd “for saturated, “MW” for molecular weight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR” for high resolution, “HRMS” for high resolution mass spectrometry, “LCMS” for liquid chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” for nuclear magnetic resonance spectroscopy, “1H” for proton, “8” for delta, “s” for singlet, “d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” for hertz, and “a”, “3”, “R”, “S”, “E”, and “Z” are stereochemical designations familiar to one skilled in the art.
  • Some compounds of this invention can be prepared by the methods outlined in the Scheme I
  • Figure US20190092754A1-20190328-C00008
    Figure US20190092754A1-20190328-C00009
  • Some compounds of this invention can be prepared by the methods outlined in the Scheme II.
  • Figure US20190092754A1-20190328-C00010
  • The compounds described herein were purified by the methods well known to those skilled in art by normal phase column chromatography on silica gel column using appropriate solvent system described. Preparative HPLC purifications mentioned in this experimentation section were carried out gradient elution either on Sunfire Prep C18 ODB column (5 μm; 19 or 30×100 mm) or Waters Xbridge C18 column (5 μM; 19×200 or 30×100 mm) or Water Atlantis (5 μm; 19 or 30×100 mm) using the following mobile phases. Mobile phase A: 9:1 H2O/acetonitrile with 10 mM NH4OAc and mobile phase B:A:9:1 acetonitrile/H2O with 10 mM NH4OAc; or mobile phase A: 9:1 H2O/acetonitrile with 0.1% TFA and mobile phase B:A:9:1 acetonitrile/H2O with 0.1% TFA; or mobile phase A: water/MeOH (9:1) with 20 mM NH4OAc and mobile phase B: 95:5 MeOH/H2O with 20 mM NH4OAc or mobile phase A: water/MeOH (9:1) with 0.1% TFA and mobile phase B: 95:5 MeOH/H2O with 0.1% TFA or mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate.
  • All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS or LC-20AS liquid chromotograph using a SPD-10AV or SPD-20A UV-Vis detector and Mass Spectrometry (MS) data were determined with a Micromass Platform for LC in electrospray mode.
  • Compounds purified by preparative HPLC were diluted in methanol (1.2 mL) or DMF and purified using a Shimadzu LC-8A or LC-10A automated preparative HPLC system.
  • Figure US20190092754A1-20190328-C00011
    • 3,5-Dibromo-2,6-dimethylpyridin-4-ol
  • A 3-neck R.B-flask equipped with mechanical stirrer, addition funnel and condenser is charged with 2,6-dimethylpyridin-4-ol (100 g, 812 mmol), CH2Cl2 (1000 mL) and MeOH (120 mL). To the resulting light brown or tan solution was added tert-BuNH2 (176 ml, 1665 mmol), cooled in water bath maintained between 5-10° C. (ice-water) and added drop wise Br2 (84 ml, 1624 mmol) over 70 min. After the addition was complete cold bath was removed and stirred for 1.5 h at rt. Then, the light orange slurry was filtered and the filter cake was washed with ether (250 mL) and dried to afford 3,5-dibromo-2,6-dimethylpyridin-4-ol, hydrobromide (280.75 g, 776 mmol, 96% yield) as white solid which was used in the next step without further purification. 1H NMR (500 MHz, DMSO-d6) δ 12.08 (br. s., 1H), 2.41 (s, 6H). LCMS (M+H)=281.9.
  • Alternative Procedure:
  • Bromine (72.8 mL, 1.4 mol) was added via addition funnel over 60 min to a mechanically stirred cold (ice-water bath) solution of 2,6-dimethylpyridin-4-ol (87 g, 706 mmol) and 4-methylmorpholine (156 mL, 1.4 mol) in dichloromethane (1 L) and methanol (100 mL) and then stirred for 2 h at rt. Additional bromine (˜15 mL) was added based on monitoring by LCMS. The product was filtered, washed with ether, and dried under vacuum to give 3,5-dibromo-2,6-dimethylpyridin-4-ol 176.8 g (88%).
  • Figure US20190092754A1-20190328-C00012
    • 3,5-Dibromo-4-chloro-2,6-dimethylpyridine
  • Triethylamine (28.8 mL, 206 mmol) was added to a nitrogen purged solution of 3,5-dibromo-2,6-dimethylpyridin-4-ol (58 g, 206 mmol) and phosphorous oxychloride (57.7 mL, 619 mmol) in chloroform (450 mL) and stirred for 1 h at rt, then 3 h at 80° C. The reaction was removed from heating and immediately concentrated under house vacuum; then under high vacuum. The appearance was a cream colored solid, which was azeotroped with toluene (2×100 mL); treated with ice (200 g) for 10 min and carefully neutralized with NaHCO3 (powder), and 1N NaOH solution, and extracted with DCM (2×400 mL). The combined organic layers were dried (MgSO4), concentrated, and a beige solid was obtained that was washed with hexanes and dried under high vacuum to give 3,5-dibromo-4-chloro-2,6-dimethyl-pyridine 52.74 g (85.1%). Concentration of the hexanes gave 3.5 g of less pure product. 1H NMR (500 MHz, CDCl3) δ 2.59 (s, 6H). LCMS (M+H)=300.0.
  • Figure US20190092754A1-20190328-C00013
    • Ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate
  • To a stirred mixture of 3,5-dibromo-4-chloro-2,6-dimethylpyridine (14.94 g, 49.9 mmol) and Cu(I)Br Me2S (0.513 g, 2.495 mmol) in THF (50 mL) was added drop wise 2M iPrMgCl/THF (26.2 ml, 52.4 mmol) at −30° C. over 5 min. Then, the resulting slurry was warmed to −10° C. over 30 min and stirred for 30 min. The homogeneous brown reaction mixture was rapidly transferred via cannula to a solution of ethyl 2-chloro-2-oxoacetate (6.14 ml, 54.9 mmol, degassed for 5 min by bubbling N2 through the solution) in THF (50 mL) maintained at −30° C. The resulting reaction mixture was stirred (1.5 h) while warming to 0° C. Then, taken up in to Et2O (200 mL), washed with 1:1 sat Na2CO3/1M NH4Cl (3×50 mL), dried (MgSO4), filtered and concentrated to give brown viscous oil. Flash chromatography using 2.5, 5 and 7.5% EtOAc/Hex afforded ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (14.37 g, 44.8 mmol, 90% yield) as white solid. 1H NMR (400 MHz, CDCl3) δ 4.42 (q, J=7.0 Hz, 2H), 2.76 (s, 3H), 2.46 (s, 3H), 1.41 (t, J=7.2 Hz, 3H). LCMS (M+H)=322.1.
  • Figure US20190092754A1-20190328-C00014
    • Ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate
  • To a solution of 4,4-dimethylpiperidine (1.245 g, 11.00 mmol) and DIEA (3.49 ml, 20.00 mmol) in anhydrous CH3CN (40 mL) was added ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (3.21 g, 10 mmol) at rt. The resulting mixture was placed in a pre-heated oil bath (80° C.). After 22 h, the reaction mixture was concentrated and the residue was purified by flash chromatography using 1-lit each 2.5, 5, 7.5 and 10% EtOAc/Hex to afford ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.846 g, 7.16 mmol, 71.6% yield) as yellow solid. 1H NMR (500 MHz, CDCl3) δ 4.37 (q, J=7.1 Hz, 2H), 3.67-2.75 (br.s., 4H), 2.71 (s, 3H), 2.44 (s, 3H), 1.42 (t, J=7.1 Hz, 3H), 1.38 (t, J=5.6 Hz, 4H), 1.00 (s, 6H). LCMS (M+H)=399.4.
  • Figure US20190092754A1-20190328-C00015
    • (S)-Ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate
  • To stirred yellow solution of ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (2.25 g, 5.66 mmol) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (0.314 g, 1.133 mmol) in toluene (30 mL) at −35° C. was added drop wise 50% catecholborane (1.819 ml, 8.49 mmol) over 10 min. The reaction mixture was slowly warmed to −15° C. over 1 h and then left for 2 h at −15° C. Then, diluted with EtOAc (100 mL), washed with sat Na2CO3 (4×25 mL) by vigorously stirring and separating aqueous layers. The organic layer dried (MgSO4), filtered, concentrated and purified by flash chromatography using 10, 20 and 25% EtOAc/Hex to afford desired (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (2.2596 g, 5.66 mmol, 100% yield) contaminated with about 10% of (S)-ethyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate. Used in the next step without further purification. 1H NMR (500 MHz, CDCl3) δ 5.71 (d, J=7.3 Hz, 1H), 5.54 (d, J=7.4 Hz, 1H), 4.29 (dq, J=10.8, 7.1 Hz, 1H), 4.16 (dq, J=10.8, 7.1 Hz, 1H), 3.94-3.83 (m, 2H), 2.71 (d, J=11.9 Hz, 1H), 2.67 (s, 3H), 2.59 (s, 3H), 2.54 (d, J=12.0 Hz, 1H), 1.71 (td, J=12.7, 4.7 Hz, 1H), 1.62 (td, J=13.0, 4.7 Hz, 1H), 1.42 (dd, J=13.1, 2.2 Hz, 1H), 1.37 (dd, J=12.9, 2.4 Hz, 1H), 1.25 (t, J=7.1 Hz, 3H), 1.09 (s, 3H), 1.04 (s, 3H). LCMS (M+H)=401.3.
  • Figure US20190092754A1-20190328-C00016
    • (S)-Ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate
  • A stirred ice-cold yellow mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (2.45 g, 6.14 mmol) and 70% HClO4 (1.054 ml, 12.27 mmol) in CH2Cl2 (100 mL) was saturated with isobutylene gas by bubbling through the reaction mixture (10 min). After 2 h, cold bath was removed and the turbid reaction mixture stirred for 22 h at rt. LCMS at this point showed 4:1 product to sm. So, saturated with isobutylene (5 min) at rt and stirred for additional 24 h. Then, neutralized with sat. Na2CO3 (30 mL), organic layer separated and aqueous layer extracted with CH2Cl2 (25 mL). The combined organic layers dried (MgSO4), filtered, concentrated and purified by flash chromatography using 5, 10, 15, 20 and 40% EtOAc/hex to afford (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (2.3074 g, 5.07 mmol, 83% yield) as yellow oil: 1H NMR (500 MHz, CDCl3) δ 6.19 (br. s., 1H), 4.17-4.24 (m, 1H), 4.08-4.14 (m, 1H), 4.04 (dt, J=2.5, 12.1 Hz, 1H), 3.51 (dt, J=2.5, 12.1 Hz, 1H), 2.85-2.91 (m, 1H), 2.64 (s, 3H), 2.57-2.62 (m, 1H), 2.55 (s, 3H), 1.55-1.66 (m, 2H), 1.41-1.46 (m, 1H), 1.32-1.37 (m, 1H), 1.21 (s, 9H), 1.20 (t, J=7.2 Hz, 2H), 1.08 (s, 3H), 1.03 (s, 3H). LCMS (M+H)=457.4. And (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (0.3 g, 0.751 mmol, 12.24% yield) as pale yellow paste: LCMS (M+H)=401.3.
  • Figure US20190092754A1-20190328-C00017
    • Isopropyl 2-chloro-2-oxoacetate
  • The propan-2-ol (38.2 mL, 499 mmol) was added drop wise over 15 min to a cold (0° C.), nitrogen purged solution of oxalyl dichloride (101 g, 799 mmol) and the reaction was stirred at room temperature for 2.5 h. Then a reflux condenser was fitted and a slight vacuum was applied for about 1 h until HCl gas was removed (the HCl was trapped in by a sat'd solution of NaHCO3). The reflux condenser was removed and the flask was fitted with a short path distillation head. Excess reagent was removed by distillation under house vacuum (oil bath heated to 65° C.), and then the temperature was raised to between 85-95° C. and the product was distilled (NOTE: The 1st fraction of ˜5 mL was discarded) to provide isopropyl 2-chloro-2-oxoacetate 52.62 g (70%).
  • Figure US20190092754A1-20190328-C00018
    • Isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate
  • A solution of 2M isopropyl magnesium chloride (84 mL, 168 mmol) was added drop wise over 20 min to a cold (−70° C.), nitrogen purged solution of 3,5-dibromo-4-chloro-2,6-dimethylpyridine (48 g, 160 mmol) and copper(I)bromide-dimethyl sulfide complex (1.65 g, 8.02 mmol) in THF (240 mL), which was then allowed to warm to −10° C. over 60 min. The reaction mixture was transferred via cannula into a 1 L RB-flask containing isopropyl 2-chloro-2-oxoacetate (26.6 g, 176 mmol) in THF (160 mL) maintained at −60° C., and the reaction stirred an additional 2.5 h while being allowed to warm to −10° C. The reaction was quenched upon diluted with a mixture of 10% NH4Cl solution (80 mL) in ether (320 mL). The organic layer was washed with 160 mL of sat'd NaHCO3/10% NH4Cl solution (1:1), brine, and dried (Na2SO4). The crude product was charged (DCM solution) to a 330 g ISCO silica gel cartridge and gradient eluted (5-20% EtOAc/hexanes) using an Isolera chromatography station gave isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate 40.38 g (76%). 1H NMR (500 MHz, CDCl3) δ 5.28-5.21 (m, 1H), 2.77 (s, 3H), 2.47 (s, 3H), 1.40 (d, J=6.3 Hz, 6H). LCMS (M+H)=336.04.
  • Figure US20190092754A1-20190328-C00019
    • Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate
  • To a stirred solution of isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (7.2 g, 21.52 mmol) and DIEA (4.13 mL, 23.67 mmol) in anhydrous acetonitrile (15 mL) was added 4,4-dimethylpiperidine (2.68 g, 23.67 mmol) in acetonitrile (15 mL). The resulting solution was placed in a pre-heated oil bath at 75° C. After heating (75-78° C.) for 24 h and the temperature was raised to 85° C. for 24 h. Another portion of DIEA (3.5 mL, 20.04 mmol) and 4,4-dimethylpiperidine (0.27 g, 2.4 mmol) in acetonitrile (3 mL) was added and hearted at 85° C. for a day. The reaction mixture was diluted with ether (100 mL), washed with water (100 mL), brine (50 mL), dried (MgSO4), filtered, concentrated and purified by ISCO 120 g cartridge (EtOAc/hex: 0 to 20%) to afford isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (6.8 g, 16.53 mmol, 77% yield. 1H NMR (500 MHz, CDCl3) δ 5.25-5.11 (m, 1H), 3.17 (br. s., 4H), 2.71 (s, 3H), 2.41 (s, 3H), 1.42-1.37 (m, 10H), 1.00 (s, 6H).). LCMS (M+H)=413.3.
  • Figure US20190092754A1-20190328-C00020
    • (S)-Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate
  • To a yellow solution of isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (7.7 g, 18.72 mmol) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (7.5 mL, 7.50 mmol) in anhydrous toluene (100 mL) was added drop wise 50% catecholborane/toluene (6 mL, 28.0 mmol) over 5 min at −50° C. Then, the reaction mixture was slowly warmed to −30° C. over 1 h and left in refrigerator (−20° C.) for 3 days. Then, the reaction mixture was diluted with EtOAc (100 mL) and 20 mL of 1M Na2CO3, and vigorously stirred for 30 min. Aqueous layer separated and organic layer washed with sat'd Na2CO3 (2×25 mL) by vigorously stirring for 15 each time, then dried (MgSO4), filtered and concentrated to give crude product as light purple paste which was purified by flash chromatography using 0 to 40% EtOAc/hex to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (6.7 g, 15.72 mmol, 84% yield) as colorless thick paste. 1H NMR (500 MHz, CDCl3) δ 5.85 (d, J=5.7 Hz, 1H), 5.59 (d, J=7.4 Hz, 1H), 5.08 (dt, J=12.5, 6.3 Hz, 1H), 3.98-3.88 (m, 1H), 3.88-3.78 (m, 1H), 2.76-2.68 (m, 1H), 2.67 (s, 3H), 2.64-2.58 (m, 1H), 2.57 (s, 3H), 1.73 (td, J=12.8, 4.8 Hz, 1H), 1.65-1.59 (m, 1H), 1.47-1.35 (m, 2H), 1.27 (d, J=6.3 Hz, 3H), 1.17 (d, J=6.1 Hz, 3H), 1.09 (s, 3H), 1.04 (s, 3H). LCMS (M+H)=414.6.
  • Figure US20190092754A1-20190328-C00021
    • (S)-Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate
  • A stirred ice-cold yellow mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (6.7 g, 16.21 mmol) and 70% HClO4 (2.2 mL, 25.6 mmol) in dichloromethane (400 mL) was saturated with isobutylene gas by bubbling through the reaction mixture (10 min). The reaction mixture was cloudy sealed in a seal tube, stirred for 24 h at rt. The reaction mixture was recooled in a −10° C. bath, bubbled additional isobutylene (˜15 min). The reaction mixture became a clear solution at this point. The tube was sealed and stirred at rt for 16 h. LCMs at this point showed incomplete reaction. So, the reaction mixture was cooled down to −30° C. and bubbled isobutene (˜15 min). After 24 h, reaction mixture was neutralized with sat. Na2CO3 (20 mL), organic layer separated and aqueous layer was extracted with CH2Cl2 (25 mL). The combined organic layers were dried (MgSO4), filtered, concentrated and purified on a ISCO 120 g column (EtOAc/hex: 0 to 40%) to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (5.43 g, 9.83 mmol, 60.7% yield) as a viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.26 (br. s., 1H), 5.09-4.97 (m, 1H), 4.06 (br. s., 1H), 3.51 (br. s., 1H), 2.90 (br. s., 1H), 2.65 (s, 3H), 2.56 (s, 3H), 1.72-1.54 (m, 3H), 1.47 (br. s., 1H), 1.37 (br. s., 1H), 1.23-1.20 (m, 12H), 1.15 (d, J=6.1 Hz, 3H), 1.09 (br. s., 3H), 1.04 (br. s., 3H). LCMS (M+H)=471.3.
  • Figure US20190092754A1-20190328-C00022
    • 6-Bromo-2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline
  • To a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline (1.25 g, 5.88 mmol) in DCM (25 mL) was added 2-chloro-6-methylbenzaldehyde (1.0 g, 6.5 mmol) and acetic acid (0.337 mL, 5.88 mmol) in DCM (25 mL). Then sodium triacetoxyborohydride (1.62 g, 7.64 mmol) was added. The mixture was stirred at r.t for 16 hrs. The mixture was quenched with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by recrystallization with EtOAc to give 6-bromo-2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline (1.44 g, 4.11 mmol, 69.8% yield). LCMS (M+H): 350.00, 352.00. 1H NMR (400 MHz, DMSO-d6) δ 7.32-7.14 (m, 5H), 6.99 (d, J=8.1 Hz, 1H), 3.77 (s, 2H), 3.56 (s, 2H), 2.78-2.72 (m, 2H), 2.71-2.66 (m, 2H), 2.41 (s, 3H).
  • Figure US20190092754A1-20190328-C00023
    • 6-Bromo-2-(2-fluoro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline
  • This compound is prepared by the procedure described above for 6-bromo-2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline. 1H NMR (400 MHz, DMSO-d6) δ 7.30-7.19 (m, 3H), 7.01 (dd, J=17.4, 7.6 Hz, 3H), 3.63 (d, J=2.2 Hz, 2H), 3.52 (s, 2H), 2.79-2.73 (m, 2H), 2.69-2.63 (m, 2H), 2.38 (s, 3H). LCMS (M+H)=336.1
  • Figure US20190092754A1-20190328-C00024
    • 2-(2-Chloro-6-methylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline
  • 6-Bromo-2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline (1.00 g, 2.85 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.09 g, 4.28 mmol), Pd(dppf)Cl2 (0.209 g, 0.285 mmol) and potassium acetate (0.840 g, 8.55 mmol) were combined in dioxane (10 mL) in a sealed bottle. The mixture was degassed and heated at 85° C. for 8 hrs. The mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel column (EtOAc/hexanes gradient) to give 2-(2-chloro-6-methylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (1.05 g, 2.64 mmol, 93% yield). 1H NMR (400 MHz, CDCl3) δ 7.57-7.51 (m, 2H), 7.23 (d, J=7.6 Hz, 1H), 7.14-7.06 (m, 2H), 7.02 (d, J=7.6 Hz, 1H), 3.83 (s, 2H), 3.71 (s, 2H), 2.88-2.76 (m, 4H), 2.46 (s, 3H), 1.34 (s, 12H). LCMS (M+H): 398.05.
  • Figure US20190092754A1-20190328-C00025
    • 2-(2-Fluoro-6-methylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline
  • This compound is prepared using 6-bromo-2-(2-fluoro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinoline by following the procedure described above for 2-(2-chloro-6-methylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline. LCMS (M+H)=382.2.
    • Preparation of Intermediates (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate and (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid from (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate
  • Figure US20190092754A1-20190328-C00026
  • Step 1: To a mixture of (S)-ethyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (500 mg), (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid (365 mg) and Cs2CO3 (715 mg) in 1,4-dioxane (25 mL) and water (5 mL) was added Pd(PPh3)4 (127 mg). The mixture was flushed with nitrogen and then heated at 85° C. for 3 hours. The mixture was diluted with water (20 mL) and then extracted with EtOAc (2×20 mL). The organic layers were combined, washed with brine and concentrated under vacuum to give a crude of (S)-tert-butyl 6-(5-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate which was used as was. LCMS: MS (M+H)+ calcd. 608.4; observ. 608.5.
  • Step 2: To a solution of (S)-tert-butyl 6-(5-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg) in CH2Cl2 (20 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 3 hours. All the solvents were removed under vacuum to give rude (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate which was used without further purification. LCMS: MS (M+H)+ calcd. 508.4; observ. 508.3.
  • Step 3: To a solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate (10 mg) in MeOH (1 mL) and THF (1 mL) was added sodium hydroxide (0.158 mL, 1N). The reaction was stirred at 80° C. for 2 hours. The mixture was acidified by 1N HCl to pH ˜4. All the solvents were removed under vacuum to give a residue was purified by preparative HPLC system. LCMS: MS (M+H)+ calcd. 480.3; observ. 480.3.
    • Preparation of Intermediates (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate and (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid from (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate
  • Figure US20190092754A1-20190328-C00027
  • Step 1: To a mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (1.1 g), (2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)boronic acid (0.649 g) and Cs2CO3 (1.527 g) in 1,4-dioxane (40 mL) and water (8 mL) was added Pd(PPh3)4 (0.271 g). The mixture was flushed with nitrogen and then heated at 85° C. for 5 hours. The mixture was diluted with water (50 mL) and then extracted with EtOAc (2×50 mL). The organic layers were combined, washed with brine and concentrated under vacuum to give a residue which was purified by silica gel chromatography (hexane/EtOAc=10:1 to 3:1) to give (S)-tert-butyl 6-(5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. LCMS: MS (M+H)+ calcd. 622.4; observ. 622.4.
  • Step 2: To a solution of (S)-tert-butyl 6-(5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (420 mg) in CH2Cl2 (5 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 4 hours. All the solvents were removed under vacuum to give (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate which was used without further purification. LCMS: MS (M+H)+ calcd. 522.4; observ. 522.3.
  • Step 3: To a solution of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate (50 mg) in ethanol (4 mL) was added KOH (43.0 mg) and water (0.4 mL). The reaction mixture was heated at 85° C. for 6 hours. The mixture was acidified by 1N HCl to pH=4. All the solvents were removed under vacuum. The residue was used without further purification. LCMS: MS (M+H)+ calcd. 480.3; observ. 480.2.
    • General Procedure A for the preparation of Claim I, from (S)-ethyl or (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate
  • Figure US20190092754A1-20190328-C00028
  • Step 1: Na2CO3 or K2C03 or Cs2CO3 or NaH (1-20 eq.) was added into a solution of (S)-ethyl of (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate (1 eq.) and an electrophile (1-20 eq.) in acetonitrile or THF or DMF or dioxane. The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). After removal of solvents under vacuum, the residue was used as was or purified by the preparative HPLC system.
  • Step 2: To a solution of the product from the step 1 (1 eq.) in MeOH or EtOH and THF (volume ratio 20:1 to 1:20) was added NaOH or KOH (1 to 100 eq.). The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). The mixture was acidified by 1N HCl to pH ˜4. Removal of the solvents under vacuum gave a residue which was purified by the preparative HPLC system.
    • General Procedure B for the preparation of Claim I, from (S)-ethyl or (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate
  • Figure US20190092754A1-20190328-C00029
  • Step 1: A solution of (S)-Ethyl or (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetate (1 eq.) and an aldehyde (1-10 eq.) in DMF was stirred at room temperature for 2-24 hours, before NaCNBH3 (1-20 eq.) and AcOH (1-200 eq.) were added. The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). After the reaction was quenched with water, it was extracted with EtOAc. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated under vacuum. The residue was used as was or purified by the preparative HPLC system.
  • Step 2: To a solution of the product from the step 1 (1 eq.) in MeOH or EtOH and THF (volume ratio 20:1 to 1:20) was added NaOH or KOH (1 to 100 eq.). The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). The mixture was acidified by 1N HCl to pH ˜4. Removal of the solvents under vacuum gave a residue which was purified by the preparative HPLC system.
    • General Procedure C for the preparation of Claim I, from (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
  • Figure US20190092754A1-20190328-C00030
  • A solution of (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid (1 eq.) and an aldehyde (1-10 eq.) in DMF was stirred at room temperature for 2-24 hours, before NaCNBH3 (1-20 eq.) and AcOH (1-200 eq.) were added. The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). After the reaction was quenched with water, it was extracted with EtOAc. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated under vacuum. The residue was used as was or purified by the preparative HPLC system.
    • General Procedure D for the preparation of Claim I, from (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
  • Figure US20190092754A1-20190328-C00031
  • Step 1: To a mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (1 equiv), 2-(arylalkyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (1 to 5 equiv.) and cesium carbonate (2 to 10 equiv.) in 1,4-dioxane/water was added Pd(Ph3P)4 (0.1 to 1 equiv.). The mixture was flushed with nitrogen and then heated at 90° C. until reaction complete (1 to 24 h). The mixture was diluted with water and then extracted with EtOAc. The organic layers were combined, washed with brine and concentrated to give a residue, which was purified by silicagel column (EtOAc/Hex; gradient elution) to give (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(arylalkyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetate
  • Step 2: To a solution of the product from the step 1 (1 eq.) in MeOH or EtOH and THF (volume ratio 20:1 to 1:20) was added NaOH or KOH (1 to 100 eq.). The reaction was carried out at room temperature or at an increased temperature (up to 150° C.) for a period of time (10 minutes to 72 hours). The mixture was acidified by 1N HCl to pH ˜4. Removal of the solvents under vacuum gave a residue which was purified by the preparative HPLC system.
  • Name
    General Method Used LCMS
    Compound Structure (M + H)+
    1 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00032
    Method A: LCMS (M + H) = 588.7
    2 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(3-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00033
    Method A: LCMS (M + H) = 638.8
    3 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00034
    Method A: LCMS (M + H) = 584.8
    4 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00035
    Method A: LCMS (M + H) = 584.2
    5 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(4-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00036
    Method A: LCMS (M + H) = 584.4
    6 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00037
    Method A: LCMS (M + H) = 600.3
    7 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00038
    Method A: LCMS (M + H) = 588.2
    8 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(4-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00039
    Method A: LCMS (M + H) = 638.4
    9 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00040
    Method A: LCMS (M + H) = 588.8
    10 (S)-3-((6-(5-(tert-butoxy(carboxy)methyl)-4-(4,4-
    dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-3,4-
    dihydroisoquinolin-2(1H)-yl)methyl)benzoic acid
    Figure US20190092754A1-20190328-C00041
    Method A: LCMS (M + H) = 614.2
    11 (S)-2-(5-(2-([1,1′-biphenyl]-3-ylmethyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid
    Figure US20190092754A1-20190328-C00042
    Method A: LCMS (M + H) = 646.4
    12 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00043
    Method A: LCMS (M + H) = 638.3
    13 (2S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(1-phenylethyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00044
    Method A: LCMS (M + H) = 584.3
    14 (S)-2-(5-(2-([1,1′-biphenyl]-4-ylmethyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid
    Figure US20190092754A1-20190328-C00045
    Method A: LCMS (M + H) = 646.4
    15 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2-methyl-3-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00046
    Method A: LCMS (M + H) = 652.1
    16 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(4-methyl-3-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00047
    Method A: LCMS (M + H) = 652.1
    17 (S)-2-(tert-butoxy)-2-(5-(2-(3,4-dimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00048
    Method A: LCMS (M + H) = 598.1
    18 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-4-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00049
    Method A: LCMS (M + H) = 602.3
    19 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-dimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00050
    Method A: LCMS (M + H) = 598.5
    20 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00051
    Method C: 1H NMR (500 MHz, DMSO-d6) δ 7.56-7.49 (m, 1H),
    7.23 (t, J = 9.7 Hz, 1H), 7.12-7.03 (m, 3H), 6.88 (s, 1H), 5.82 (d,
    J = 10.6 Hz, 1H), 3.71 (s, 2H), 3.64 (br. s., 2H), 3.32 (br. s., 1H),
    2.89 (s, 1H), 2.83 (d, J = 4.8 Hz, 2H), 2.74-2.70 (m, 2H), 2.54 (s,
    1H), 2.42 (s, 3H), 2.09-2.04 (m, 3H), 1.90 (s, 6H), 1.11 (s, 9H),
    0.84 (br. s., 3H), 0.60 (br. s., 3H). LCMS (M + H) = 606.3
    21 (S)-2-(tert-butoxy)-2-(5-(2-(2,3-difluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00052
    Method C: 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.28 (m, 2H),
    7.22 (d, J = 5.5 Hz, 1H), 7.16-7.08 (m, 1H), 7.07-7.01 (m, 1H),
    6.88 (s, 1H), 5.79 (d, J = 10.3 Hz, 1H), 3.81-3.75 (m, 2H), 3.66
    (br. s., 2H), 3.40-3.36 (m, 1H), 2.91-2.68 (m, 6H), 2.54 (s, 1H),
    2.42 (s, 3H), 2.12-2.01 (m, 3H), 1.90 (s, 5H), 1.11 (s, 9H), 0.84
    (br. s., 3H), 0.60 (br. s., 3H). LCMS (M + H) = 606.3
    22 (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-3-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00053
    Method C: LCMS (M + H) = 622.3
    23 (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00054
    Method C, D: 1H NMR (500 MHz, METHANOL-d4) δ 7.32-7.25
    (m, 1H), 7.25-7.07 (m, 4H), 6.99-6.90 (m, 1H), 5.60-5.41 (m,
    1H), 3.94 (s, 2H), 3.80 (s, J = 15.1 Hz, 2H), 2.91 (m, 4H), 2.81-
    2.60 (m, 7H), 2.52 (s, 3H), 2.31 (s, 3H), 1.35 (br. s., 4H), 1.20 (s,
    9H), 0.85 (s, 6H). LCMS (M + H) = 618.3
    24 (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00055
    Method C: 1H NMR (500 MHz, DMSO-d6) δ 7.60-7.53 (m, 1H),
    7.39 (d, J = 8.8 Hz, 2H), 7.15-7.02 (m, 2H), 6.90-6.84 (m, 1H),
    5.82 (d, J = 11.0 Hz, 1H), 3.70-3.58 (m, 4H), 2.91-2.66 (m, 8H),
    2.42 (s, 3H), 2.12-2.04 (m, 3H), 1.90 (s, 4H), 1.11 (s, 9H), 0.85
    (br. s., 3H), 0.61 (br. s., 3H). LCMS (M + H) = 622.3
    25 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00056
    Method C: 1H NMR (500 MHz, DMSO-d6) δ 7.36-7.26 (m, 1H),
    7.13-6.93 (m, 4H), 6.85 (br. s., 1H), 5.77 (d, J = 12.5 Hz, 1H),
    3.59 (br. s., 4H), 2.90-2.66 (m, 6H), 2.42 (s, 3H), 2.35 (br. s.,
    3H), 2.12-2.03 (m, 3H), 1.90 (s, 7H), 1.10 (br. s., 9H), 0.84 (br.
    s., 3H), 0.59 (br. s., 3H). LCMS (M + H) = 602.4
    26 (S)-2-(tert-butoxy)-2-(5-(2-(3,5-dichlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00057
    Method A: LCMS (M + H) = 638.4
    27 (S)-2-(tert-butoxy)-2-(5-(2-(4-(tert-butyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00058
    Method A: LCMS (M + H) = 626.5
    28 (S)-2-(tert-butoxy)-2-(5-(2-(3-chlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00059
    Method A: LCMS (M + H) = 604.4
    29 (S)-2-(tert-butoxy)-2-(5-(2-(2,5-dimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00060
    Method A: LCMS (M + H) = 598.4
    30 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-6-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00061
    Method C: LCMS (M + H) = 656.5
    31 (S)-2-(tert-butoxy)-2-(5-(2-(3,5-difluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00062
    Method C: LCMS (M + H) = 606.3
    32 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00063
    Method C: LCMS (M + H) = 656.3
    33 (S)-2-(tert-butoxy)-2-(5-(2-(2,6-dimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00064
    Method C: LCMS (M + H) = 598.4
    34 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(3,4,5-trifluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00065
    Method A, C: LCMS (M + H) = 624.3
    35 (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-4-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00066
    Method C: LCMS (M + H) = 622.0
    36 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    isopropylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00067
    Method C: LCMS (M + H) = 612.5
    37 (S)-2-(tert-butoxy)-2-(5-(2-(3,4-difluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00068
    Method A: LCMS (M + H) = 606.5
    38 (S)-2-(tert-butoxy)-2-(5-(2-(2,5-difluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00069
    Method A: LCMS (M + H) = 606.5
    39 (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00070
    Method A: LCMS (M + H) = 622.4
    40 (S)-2-(tert-butoxy)-2-(5-(2-(2,3-dichlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00071
    Method A: LCMS (M + H) = 638.3
    41 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2,3,4-trifluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00072
    Method A, C: LCMS (M + H) = 624.3
    42 (S)-2-(tert-butoxy)-2-(5-(2-(5-chloro-2-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00073
    Method A: LCMS (M + H) = 622.3
    43 (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-5-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00074
    Method A: LCMS (M + H) = 622.4
    44 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2,3,6-trifluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00075
    Method A: LCMS (M + H) = 624.5
    45 (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-5-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00076
    Method A: LCMS (M + H) = 622.4
    46 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-5-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00077
    Method A: LCMS (M + H) = 602.5
    47 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-
    fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00078
    Method A: LCMS (M + H) = 602.5
    48 (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluoro-3-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00079
    Method A: LCMS (M + H) = 620.5
    49 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2,4,5-trifluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00080
    Method A: LCMS (M + H) = 624.4
    50 (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00081
    Method A: LCMS (M + H) = 606.5
    51 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00082
    Method A, D: 1H NMR (400 MHz, DMSO-d6) δ 7.28-7.19 (m,
    1H), 7.15-6.98 (m, 4H), 6.87 (s, 1H), 5.96 (br. s., 1H), 4.94 (td,
    J = 6.2, 3.4 Hz, 1H), 3.68 (br. s., 2H), 3.64 (br. s., 2H), 2.88-2.67
    (m, 6H), 2.44-2.39 (m, 6H), 2.10 (s, 2H), 2.05 (s, 1H), 1.82 (t,
    J = 11.4 Hz, 1H), 1.51- 1.41 (m, 1H), 1.25 (d, J = 13.2 Hz, 1H),
    1.17 (dd, J = 6.2, 1.3 Hz, 4H), 1.15-1.09 (m, 14H), 0.84 (s, 3H),
    0.59 (s, 3H). LCMS (M + H) = 644.3. LCMS (M + H) = 602.5
    52 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2-methyl-5-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00083
    Method A: LCMS (M + H) = 652.5
    53 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-dichlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00084
    Method A: LCMS (M + H) = 638.4
    54 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00085
    Method A: LCMS (M + H) = 602.5
    55 (S)-2-(tert-butoxy)-2-(5-(2-(2-chlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00086
    Method A: LCMS (M + H) = 604.5
    56 (S)-2-(tert-butoxy)-2-(5-(2-(4-chlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00087
    Method A: LCMS (M + H) = 604.4
    57 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2,4,6-trimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00088
    Method A: LCMS (M + H) = 612.5
    58 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2,4,6-trifluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00089
    Method A: LCMS (M + H) = 624.5
    59 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    isopropylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00090
    Method A: LCMS (M + H) = 612.6
    60 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    ethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00091
    Method A: LCMS (M + H) = 598.2
    61 (S)-2-(tert-butoxy)-2-(5-(2-(3-cyanobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00092
    Method C: LCMS (M + H) = 595.3
    62 (S)-2-(tert-butoxy)-2-(5-(2-(2-cyanobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00093
    Method C: LCMS (M + H) = 595.3
    63 (S)-2-(tert-butoxy)-2-(5-(2-(5-cyano-2-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00094
    Method C: LCMS (M + H) = 613.3
    64 (S)-2-(tert-butoxy)-2-(5-(2-(4-cyanobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00095
    Method C: LCMS (M + H) = 595.3
    65 (S)-2-(tert-butoxy)-2-(5-(2-(4-cyano-2-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00096
    Method C: LCMS (M + H) = 609.3
    66 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-
    fluoro-2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00097
    Method C: LCMS (M + H) = 656.3
    67 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-3-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00098
    Method C: LCMS (M + H) = 656.3
    68 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-5-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00099
    Method C: LCMS (M + H) = 656.3
    69 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-2-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00100
    Method C: LCMS (M + H) = 656.3
    70 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-5-(trifluoromethyl)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00101
    Method C: LCMS (M + H) = 656.3
    71 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00102
    Method C: LCMS (M + H) = 602.3
    72 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-2,3-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-
    2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00103
    Method C: LCMS (M + H) = 616.2
    73 (S)-2-(tert-butoxy)-2-(5-(2-(2,3-difluoro-4-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00104
    Method C: LCMS (M + H) = 620.1
    74 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-5-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00105
    Method C: LCMS (M + H) = 602.3
    75 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-3,5-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-
    2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00106
    Method C: LCMS (M + H) = 616.3
    76 (S)-2-(tert-butoxy)-2-(5-(2-(3,4-difluoro-5-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00107
    Method C: LCMS (M + H) = 620.3
    77 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    isopropylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00108
    Method C: LCMS (M + H) = 612.4
    78 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2,4,5-trimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00109
    Method C: LCMS (M + H) = 612.2
    79 (S)-2-(tert-butoxy)-2-(5-(2-(3,5-dimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00110
    Method C: LCMS (M + H) = 598.3
    80 (S)-2-(tert-butoxy)-2-(5-(2-(2,3-dimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00111
    Method C: LCMS (M + H) = 598.3
    81 (S)-2-(tert-butoxy)-2-(5-(2-(3-(tert-butyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00112
    Method C: LCMS (M + H) = 626.4
    82 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00113
    Method C: LCMS (M + H) = 602.3
    83 (S)-2-(tert-butoxy)-2-(5-(2-(2,5-difluoro-4-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00114
    Method C: LCMS (M + H) = 636.2
    84 (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluoro-4-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00115
    Method C: LCMS (M + H) = 636.2
    85 (S)-2-(5-(2-(2-(benzyloxy)-3,5-dichlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid
    Figure US20190092754A1-20190328-C00116
    Method C: LCMS (M + H) = 744.4
    86 (S)-2-(tert-butoxy)-2-(5-(2-(4,5-difluoro-2-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00117
    Method C: LCMS (M + H) = 636.2
    87 (S)-2-(tert-butoxy)-2-(5-(2-(2,3-difluoro-6-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00118
    Method A, C: LCMS (M + H) = 636.2
    88 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-(2-
    hydroxyethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00119
    Method C: LCMS (M + H) = 630.2
    89 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluoro-6-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00120
    Method C: LCMS (M + H) = 636.2
    90 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-dichloro-6-ethoxybenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00121
    Method C: LCMS (M + H) = 682.1
    91 (S)-2-(tert-butoxy)-2-(5-(2-(2,3-dichloro-4-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00122
    Method C: LCMS (M + H) = 668.1
    92 (S)-2-(tert-butoxy)-2-(5-(2-(2,6-difluoro-3-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00123
    Method C: LCMS (M + H) = 636.3
    93 (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2-fluoro-5-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00124
    Method C: LCMS (M + H) = 652.3
    94 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluoro-5-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00125
    Method A, C: LCMS (M + H) = 636.3
    95 (S)-2-(tert-butoxy)-2-(5-(2-(3,5-difluoro-4-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00126
    Method A, C: LCMS (M + H) = 636.5
    96 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2,3,5-trifluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00127
    Method C: LCMS (M + H) = 624.3
    97 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00128
    Method A, : LCMS (M + H) = 618.2
    98 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    methoxy-3-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00129
    Method A: LCMS (M + H) = 668.7
    99 (S)-2-(tert-butoxy)-2-(5-(2-(5-chloro-2-methoxybenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00130
    Method A: LCMS (M + H) = 634.4
    100 (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-5-methoxybenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00131
    Method A: LCMS (M + H) = 634.5
    101 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-3-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00132
    Method A: LCMS (M + H) = 618.5
    102 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(4-(trifluoromethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00133
    Method A: LCMS (M + H) = 654.1
    103 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    ethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00134
    Method A: LCMS (M + H) = 614.3
    104 (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-
    (trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-
    (4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00135
    Method A: LCMS (M + H) = 688.1
    105 (S)-2-(tert-butoxy)-2-(5-(2-(4-(difluoromethoxy)-2-fluorobenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00136
    Method A: LCMS (M + H) = 654.2
    106 (S)-2-(tert-butoxy)-2-(5-(2-(2,6-(difluoro-4-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00137
    Method A: LCMS (M + H) = 636.7
    107 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-(difluoro-6-methoxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00138
    Method A: LCMS (M + H) = 636.7
    108 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-4-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-
    6-yl)-2,6-dimethylpiperidin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00139
    Method A: LCMS (M + H) = 672.2
    109 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    methoxy-4-(trifluoromethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-2,6-dimethylpiperidin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00140
    Method A: LCMS (M + H) = 668.2
    110 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(3-(trifluoromethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00141
    Method A, C: LCMS (M + H) = 654.4
    111 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-5-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-
    6-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00142
    Method A: LCMS (M + H) = 672.2
    112 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    methoxy-5-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00143
    Method A: LCMS (M + H) = 668.2
    113 (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-5-
    (trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-
    (4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00144
    Method A: LCMS (M + H) = 688.3
    114 (S)-2-(tert-butoxy)-2-(5-(2-(2-(difluoromethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00145
    Method A: LCMS (M + H) = 636.4
    115 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-6-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00146
    Method C: LCMS (M + H) = 618.2
    116 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-5-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00147
    Method C: LCMS (M + H) = 618.2
    117 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00148
    Method C: 1H NMR (500 MHz, DMSO-d6) δ 7.37 (t, J = 7.7 Hz,
    1H), 7.15-7.01 (m, 2H), 6.94-6.83 (m, 2H), 6.75 (t, J = 8.3 Hz,
    1H), 5.75 (d, J = 9.5 Hz, 1H), 3.84-3.77 (m, 3H), 3.62 (br. s., 1H),
    2.91-2.62 (m, 8H), 2.42 (s, 3H), 2.11-2.03 (m, 3H), 1.89 (s,
    8H), 1.10 (s, 9H), 0.84 (br. s., 3H), 0.61 (br. s., 3H). LCMS (M +
    H) = 618.2
    118 (S)-2-(tert-butoxy)-2-(5-(2-(3-(difluoromethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00149
    Method C: LCMS (M + H) = 636.2
    119 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    methoxy-5-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-
    2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00150
    Method A: LCMS (M + H) = 614.4
    120 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    fluoro-3-(trifluoromethoxy)benzyl)-1,2,3,4-tetrahydroisoquinolin-
    6-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00151
    Method C: LCMS (M + H) = 672.2
    121 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(3-(1,1,2,2-tetrafluoroethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00152
    Method C: LCMS (M + H) = 686.2
    122 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-5-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00153
    Method C: LCMS (M + H) = 618.2
    123 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(2-(trifluoromethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00154
    Method A: LCMS (M + H) = 654.3
    124 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-
    fluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00155
    Method A: LCMS (M + H) = 618.4
    125 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(4-(1,1,2,2-tetrafluoroethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00156
    Method C: LCMS (M + H) = 686.2
    126 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-
    ethoxy-2,4-difluorobenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-
    2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00157
    Method A: LCMS (M + H) = 650.4
    127 (S)-2-(tert-butoxy)-2-(5-(2-(3,4-dichlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00158
    Method C: LCMS (M + H) = 638.1
    128 (S)-2-(tert-butoxy)-2-(5-(2-(2,6-dichlorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00159
    Method C: LCMS (M + H) = 638.1
    129 (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-3-methoxybenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00160
    Method C: LCMS (M + H) = 634.2
    130 (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-2-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00161
    Method C: LCMS (M + H) = 622.1
    131 (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00162
    Method C: LCMS (M + H) = 618.1
    132 (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00163
    Method C: LCMS (M + H) = 618.1
    133 (S)-2-(tert-butoxy)-2-(5-(2-(5-chloro-2-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00164
    Method C: LCMS (M + H) = 618.1
    134 (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-3-methylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00165
    Method C: LCMS (M + H) = 618.1
    135 (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-2,6-difluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00166
    Method C: LCMS (M + H) = 640.1
    136 (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-fluorobenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00167
    Method C: LCMS (M + H) = 622.1
    137 (S)-2-(tert-butoxy)-2-(5-(2-(3-chloro-4-methoxybenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00168
    Method C: LCMS (M + H) = 634.1
    138 (S)-2-(tert-butoxy)-2-(5-(2-(4-chloro-3-methoxybenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00169
    Method C: LCMS (M + H) = 634.1
    139 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(5-
    isopropyl-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-
    2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00170
    Method C: LCMS (M + H) = 642.2
    140 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    methoxy-4-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-
    2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00171
    Method C: LCMS (M + H) = 614.2
    141 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    methoxy-3-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-
    2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00172
    Method C: LCMS (M + H) = 614.2
    142 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    fluoro-2-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00173
    Method C: LCMS (M + H) = 618.3
    143 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    isopropyl-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-
    2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00174
    Method C: LCMS (M + H) = 642.4
    144 (S)-2-(tert-butoxy)-2-(5-(2-(2,4-difluoro-6-hydroxybenzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00175
    Method C: LCMS (M + H) = 622.3
    145 (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methoxybenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00176
    Method C: LCMS (M + H) = 634.5
    146 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00177
    Method C: LCMS (M + H) = 618.5
    147 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    methoxy-2,3-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00178
    Method C: LCMS (M + H) = 628.2
    148 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    methoxy-2,5-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00179
    Method C: LCMS (M + H) = 628.4
    149 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    ethoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00180
    Method C: LCMS (M + H) = 614.1
    150 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    isopropoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00181
    Method C: LCMS (M + H) = 628.2
    151 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    methoxy-5-(trifluoromethyl)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00182
    Method C: LCMS (M + H) = 668.3
    152 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    isopropoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00183
    Method C: LCMS (M + H) = 628.4
    153 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    isobutoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00184
    Method C: LCMS (M + H) = 642.4
    154 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(3-
    isopropoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00185
    Method C: LCMS (M + H) = 628.4
    155 (S)-2-(tert-butoxy)-2-(5-(2-(chroman-6-ylmethyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00186
    Method C: LCMS (M + H) = 626.2
    156 (S)-2-(tert-butoxy)-2-(5-(2-((2,3-dihydrobenzo[b][1,4]dioxin-6-
    yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-
    dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00187
    Method C: LCMS (M + H) = 628.2
    157 (S)-2-(5-(2-(3,4-bis(difluoromethoxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)-2-(tert-butoxy)acetic acid
    Figure US20190092754A1-20190328-C00188
    Method C: LCMS (M + H) = 702.1
    158 (S)-2-(tert-butoxy)-2-(5-(2-((2,3-dihydrobenzo[b][1,4]dioxin-5-
    yl)methyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-
    dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00189
    Method C: LCMS (M + H) = 628.2
    159 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(2-
    fluoro-6-phenoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00190
    Method C: LCMS (M + H) = 680.2
    160 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(2-(4-
    isopropoxy-2,6-dimethylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00191
    Method C: LCMS (M + H) = 656.2
    161 (S)-2-(tert-butoxy)-2-(5-(2-(3,4-dimethylbenzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00192
    Method A: LCMS (M + H) = 598.4
    162 (S)-2-(tert-butoxy)-2-(5-(2-(4-(1-cyanocyclopropyl)benzyl)-
    1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-
    yl)-2,6-dimethylpyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00193
    Method C: LCMS (M + H) = 635.2
    163 (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-
    dimethyl-5-(2-(4-(nonyloxy)benzyl)-1,2,3,4-
    tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
    Figure US20190092754A1-20190328-C00194
    Method C: LCMS (M + H) = 712.3
  • Figure US20190092754A1-20190328-C00195
    • (S)-3-Bromo-5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridine 1-oxide
  • To a stirred solution of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (16 g, 34 mmol) in DCM (170 ml) was added mCPBA (77% max) (11.7 g, 51.1 mmol) at rt over 5 min. After 4 h, the reaction mixture was washed with sat aq Na2CO3 (3×50 mL), dried (Na2SO4), filtered and concentrated to give (S)-3-bromo-5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridine 1-oxide (14.6 g, 30.1 mmol, 88% yield). 1H NMR (500 MHz, chloroform-d) δ 6.28 (br. s., 1H), 5.03 (spt, J=6.3 Hz, 1H), 4.00 (t, J=11.4 Hz, 1H), 3.50 (td, J=12.1, 2.4 Hz, 1H), 2.91-2.79 (m, 1H), 2.76 (s, 3H), 2.67-2.60 (m, 1H), 2.56 (s, 3H), 1.60 (br s, 1H), 1.45 (d, J=12.1 Hz, 1H), 1.38-1.31 (m, 1H), 1.22-1.17 (m, 13H), 1.14 (d, J=6.1 Hz, 3H), 1.10-1.05 (m, 3H), 1.04-1.00 (m, 3H). LCMS (M+)=485.10, 487.10.
  • Figure US20190092754A1-20190328-C00196
    • Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-6-(hydroxymethyl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate
  • To a stirred solution of (S)-3-bromo-5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridine 1-oxide (12.8 g, 26.4 mmol) in anhydrous DCM (132 ml) was added, dropwise, trifluoroacetic anhydride (7.45 ml, 52.7 mmol) over 5 min at rt. After 2 h, sat NaHCO3(50 mL) was slowly added, stirred for 10 min, aq layer separated, organic layer dried (Na2SO4), filtered, concentrated, adsorbed onto Celite and was purified on silica gel (Biotage, EtOAc/hexanes gradient). The major peak was collected to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-6-(hydroxymethyl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (9.7 g, 20 mmol, 76% yield). 1H NMR (500 MHz, chloroform-d) δ 6.24 (br s, 1H), 5.04 (spt, J=6.3 Hz, 1H), 4.75 (br s, 1H), 4.72-4.59 (m, 2H), 4.05 (br s, 1H), 3.48 (t, J=11.0 Hz, 1H), 2.91 (d, J=11.5 Hz, 1H), 2.68-2.62 (m, 1H), 2.60 (s, 3H), 1.63-1.57 (m, 2H), 1.45 (d, J=15.0 Hz, 1H), 1.39-1.32 (m, 1H), 1.22-1.19 (m, 12H), 1.15-1.12 (m, 3H), 1.08 (s, 3H), 1.03 (s, 3H). LCMS (M+H)=485.17, 487.17.
  • Figure US20190092754A1-20190328-C00197
    • Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-6-formyl-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate
  • To a stirred solution of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-6-(hydroxymethyl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (1.0 g, 2.1 mmol) in CH2Cl2 (19 ml) was added Dess-Martin periodinane (1.3 g, 3.1 mmol) at once at rt. After 16 h, the reaction mixture was diluted with ether, washed with 1M NaOH followed by brine. The organic phase was dried over (Na2SO4), concentrated and purified on silica gel (Biotage, EtOAc/hexanes gradient, 0-100% over 10 CVs) to afford (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-6-formyl-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (960 mg, 1.99 mmol, 96% yield). 1H NMR (500 MHz, chloroform-d) δ 10.29 (s, 1H), 6.26 (br s, 1H), 5.12-4.97 (m, 1H), 4.15-4.05 (m, 1H), 3.54 (t, J=12.1 Hz, 1H), 2.94 (d, J=10.9 Hz, 1H), 2.71 (d, J=11.0 Hz, 1H), 2.66-2.62 (m, 3H), 1.59 (br s, 1H), 1.51 (br s, 1H), 1.41-1.35 (m, 1H), 1.30-1.25 (m, 1H), 1.22-1.18 (m, 12H), 1.16-1.13 (m, 3H), 1.11-1.03 (m, 6H). LCMS (M+H)=483.0, 485.0.
  • Figure US20190092754A1-20190328-C00198
    • (S)-3-Bromo-5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-6-methylpicolinic acid
  • To a solution of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-6-formyl-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (2.0 g, 4.1 mmol) in DMSO (41 ml) was added potassium phosphate monobasic (1.69 g, 12.4 mmol) in water (10 mL) followed by sodium chlorite (1.12 g, 12.4 mmol) in water (10 mL) and the mixture was stirred overnight. A ppt formed immediately. As the reaction stirred, the precipitated material stuck to the sides of the flask. After stirring overnight, the solution was poured away and the solids were taken up in EtOAc and were then washed with brine, dried (Na2SO4), filtered and concentrated to afford the expected product. The DMSO solution also contained some product. It was diluted with EtOAc and washed with Brine. The organic phase was dried over Na2SO4, and concentrated and was combined with the material isolated from the ppt. The combined material afforded a quantitative amount of (S)-3-bromo-5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-6-methylpicolinic acid (quantitative). LCMS (M+H)=499.04.
  • Figure US20190092754A1-20190328-C00199
    • Isopropyl (S)-2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate
  • Water (0.16 ml, 8.8 mmol) followed by diphenylphosphoryl azide (0.76 ml, 3.5 mmol) was added to a stirring solution of (S)-3-bromo-5-(1-(tert-butoxy)-2-isopropoxy-2-oxoethyl)-4-(4,4-dimethylpiperidin-1-yl)-6-methylpicolinic acid (882 mg, 1.77 mmol) in Toluene (18 ml) at rt. The reaction was stirred at 90° C. for 2 h. The mixture was then diluted with EtOAc and washed with sat aq NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated. The reaction was concentrated, adsorbed onto Celite and purified on silica gel (Biotage, EtOAc/hexanes gradient, 0-100% over 10 CVs) to give the expected product (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate in quantitative isolated yield. LCMS (M+H)=455.20, 457.20.
    • Example 164
  • Figure US20190092754A1-20190328-C00200
    • (S)-2-(tert-Butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)acetic acid
  • (S)-Isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (25 mg, 0.055 mmol), 2-(2-chloro-6-methylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (33 mg, 0.082 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (4.5 mg, 11 μmol), PdOAc2 (1.2 mg, 5.5 mol) and potassium phosphate tribasic (87 mg, 0.41 mmol) were combined under N2. 1,4-Dioxane (1 ml) and Water (0.2 ml) were added under N2. The reaction was heated at 80° C. for 1 h. The reaction was concentrated, adsorbed onto celite and was purified on silica gel (Biotage, EtOAc/hexanes gradient, 0-100% over 10 CVs) The isolated residue was subjected to hydrolysis conditions by treating with 0.1 mL of 5N NaOH, in 1.5 mL of EtOH, and was stirred at 80 C overnight. The reaction mixture containing the product was submitted to the Single Compound Purification team for purification and analysis. The crude material was purified via preparative LC/MS to give desired product (7.6 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.29 (d, J=7.3 Hz, 1H), 7.20 (d, J=9.5 Hz, 2H), 7.14-7.08 (m, 1H), 7.06-6.99 (m, 2H), 5.81 (s, 1H), 3.83 (s, 2H), 3.69 (s, 2H), 2.80 (dd, J=14.1, 4.2 Hz, 4H), 2.49 (br. s., 3H), 2.45 (s, 3H), 1.30 (br. s., 3H), 1.25 (s, 3H), 1.12 (s, 10H), 0.88-0.75 (m, 7H). LCMS (M+H)=604.18.
    • Example 165
  • Figure US20190092754A1-20190328-C00201
    • (S)-2-(tert-Butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2-methyl-5-(2-(2-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)pyridin-3-yl)acetic acid
  • (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2-methylpyridin-3-yl)-2-(tert-butoxy)acetate (50 mg, 0.11 mmol), 2-(2-chloro-6-methylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (66 mg, 0.17 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (9.01 mg, 0.022 mmol), potassium phosphate tribasic (175 mg, 0.823 mmol), PdOAc2 (2.5 mg, 11 μmol) were combined under N2. 1,4-Dioxane (1.8 ml) and Water (0.4 ml) was added under N2. The reaction was stirred at 80° C. for 1 hr. The reaction was concentrated, adsorbed onto celite and was purified on silica gel (Biotage, EtOAc/hexanes gradient 0-100% over 10 CVs). The isolated material was taken up in 1.5 mL of EtOH and treated with 5N aq NaOH (0.20 ml, 1.1 mmol). The reaction was stirred overnight at 80 C. The reaction was purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient. One of the minor peaks with a M+H matching that of titled compound was re-purified via preparative LC/MS to give desired product (7.1 mg). 1H NMR (500 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.36-7.32 (m, 1H), 7.30 (d, J=5.5 Hz, 2H), 7.18 (s, 2H), 7.13-7.08 (m, 1H), 7.04 (br. s., 1H), 5.80 (br. s., 1H), 3.64-3.59 (m, 2H), 2.84 (br. s., 1H), 2.74-2.67 (m, 1H), 2.46 (s, 3H), 2.38-2.32 (m, 3H), 1.90 (s, 2H), 1.55 (br. s., 3H), 1.29 (br. s., 3H), 1.10 (s, 13H), 0.87 (br. s., 3H), 0.73 (br. s., 3H). LCMS (M+H)=570.25.
  • Figure US20190092754A1-20190328-C00202
    • Isopropyl 2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate
  • To a stirred solution of isopropyl 2-(5-bromo-4-chloro-2,6-dimethylpyridin-3-yl)-2-oxoacetate (0.8 g, 2.391 mmol) and DIPEA (0.501 ml, 2.87 mmol) in anhydrous CH3CN (2.4 mL) was added 3,3-dimethylpiperidine (0.325 g, 2.87 mmol) and the resulting solution was placed in a pre-heated heating block at 90° C. overnight. The reaction mixture was combined with diluted with ethyl acetate (80 mL), washed with water (50 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated. The residue was purified on ISCO 80 g cartridge (0-25% EtOAC/Hex) to give an isopropyl 2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate as a bright yellow viscous oil (0.74 g, 75%). LCMS (M+H)=413.0.
  • Figure US20190092754A1-20190328-C00203
    • (S)-Isopropyl 2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate
  • To a solution of isopropyl 2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (0.92 g, 2.237 mmol) and (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (0.447 ml, 0.447 mmol) in Toluene at −50° C. was added catecholborane (0.718 ml, 3.35 mmol) slowly. The reaction mixture was slowly warmed up to −15° C. over 5 h and stirred at −10° C. overnight in a chiller. The reaction mixture was diluted with ethyl acetate and washed with 1M Na2CO3 (50 mL). The organic layer was isolated, washed with 1M Na2CO3, dried over Na2SO4 and concentrated. The residue was purified on silica (120 g isco column) using 10-50% ethyl acetate in hexanes. The desired fractions were concentrated to give isopropyl (S)-2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate as a yellow viscous oil (0.81 g, 1.95 mmol, 87% yield). LCMS (M+H)=415.2.
  • Figure US20190092754A1-20190328-C00204
    • (S)-Isopropyl 2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate
  • In a 100 ml round bottom flask fitted with a shlenk adaptor with rubber septum (with empty balloon attached), Isobutylene gas was vigorously bubbled for 20 minutes into a cooled (0° C.) solution of (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate (0.81 g, 1.960 mmol) and perchloric acid (0.168 ml, 1.960 mmol) in DCM (39 mL) until the volume doubled and the balloon filled to firmness. After 2 hrs, the isobutylene line was disconnected and needle pulled to just above the solution line then connected to a bubbler to monitor isobutylene gas exit. The reaction mixture was stirred at 0° C. for 1 h, the ice bath was removed and warmed up to rt while monitoring for conversion. After 2 hrs the reaction appeared to go to full conversion according to LCMS. The reaction mixture was poured into a 500 mL Erlenmeyer flask and made basic with 2M sodium carbonate while vigorously stirring. The organic layer was separated and washed with water, followed by brine, collected, dried (MgSO4), filtered and volatiles evaporated to give a yellow oil as the crude product. The crude product was purified on silica gel (80 g column, 10-50% EtOAc/Hex) to give the product (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.704 g, 1.50 mmol, 77% yield) as a yellow viscous oil. 1H NMR (500 MHz, CDCl3) δ 6.40 (br. s., 1H), 5.14-4.97 (m, 1H), 3.89 (t, J=10.3 Hz, 1H), 3.24 (d, J=11.2 Hz, 1H), 2.91-2.40 (m, 9H), 1.85 (d, J=11.7 Hz, 1H), 1.68 (d, J=11.5 Hz, 1H), 1.51 (d, J=12.9 Hz, 1H), 1.42-0.86 (m, 22H). LCMS (M+H)=470.1.
  • Figure US20190092754A1-20190328-C00205
    • (S)-Isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-, 2,3,4-tetrahydroisoquinolin-6-yl)-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate
  • A mixture of (S)-isopropyl 2-(5-bromo-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (0.07 g, 0.149 mmol), 2-(2-chloro-6-methylbenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroisoquinoline (0.089 g, 0.224 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.012 g, 0.030 mmol), palladium(II) acetate (3.35 mg, 0.015 mmol) and 2M K3PO4 (0.559 mL, 1.118 mmol) in 1,4-dioxane (1772 μl) under N2. The reaction mixture was degassed for 5 min and heated at 80° C. for 1 h. The organic layer was isolated and purified on silica gel (24 g, isco column) using 0-85% ethyl acetate in hexanes. The desired fractions were concentrated to give (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate as a light brown foamy solid (57 mg, 0.086 mmol, 58%). LCMS (M+H)=661.5.
    • Example 166
  • Figure US20190092754A1-20190328-C00206
    • (S)-2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid
  • NaOH (0.173 mL, 0.863 mmol) was added to a solution of (S)-isopropyl 2-(tert-butoxy)-2-(5-(2-(2-chloro-6-methylbenzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-4-(3,3-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (0.057 g, 0.086 mmol) in ethanol (1.5 mL) and the mixture was heated at 80° C. for 4 h. Additional NaOH (0.173 mL, 0.863 mmol) was added and the mixture was heated for 6 h, cooled purified by preparative LC/MS to give desired product (32.0 mg, 0.052 mmol, 60%). LCMS (M+H)=619.3.
    • Biological Methods
  • Inhibition of HIV Replication:
  • A recombinant NL-RLuc proviral clone was constructed in which a section of the nef gene from NL4-3 was replaced with the Renilla Luciferase gene. This virus is fully infectious and can undergo multiple cycles of replication in cell culture. In addition, the luciferous reporter provides a simple and easy method for quantitating the extent of virus growth and consequently, the antiviral activity of test compounds. The plasmid pNLRLuc contains the proviral NL-Rluc DNA cloned into pUC18 at the PvuII site. The NL-RLuc virus was prepared by transfection of 293T cells with the plasmid pNLRLuc. Transfections were performed using the LipofectAMINE PLUS kit from Invitrogen (Carlsbad, Calif.) according to the manufacturer and the virus generated was titered in MT-2 cells. For susceptibility analyses, the titrated virus was used to infect MT-2 cells in the presence of compound, and after 5 days of incubation, cells were processed and quantitated for virus growth by the amount of expressed luciferase. Assay media was RPMI 1640 supplemented with 10% heat inactivated fetal bovine serum (FBS), 100 units/ml penicillin G/100 units/ml streptomycin, 10 mM HEPES buffer pH 7.55 and 2 mM L-glutamine. The results from at least 2 experiments were used to calculate the EC50 values. Luciferase was quantitated using the Dual Luciferase kit from Promega (Madison, Wis.). Susceptibility of viruses to compounds was determined by incubation in the presence of serial dilutions of the compound. The 50% effective concentration (EC50) was calculated by using the exponential form of the median effect equation where (Fa)=1/[1+(ED50/drug conc.)m](Johnson V A, Byington R T. Infectivity Assay. In Techniques in HIV Research. ed. Aldovini A, Walker B D. 71-76. New York: Stockton Press. 1990). Results are shown in Table 1. Activity equal to A refers to a compound having an EC50≤100 nM, while B and C denote compounds having an EC50 between 100 nM and 1 uM (B) or >1 uM (C).
  • TABLE 1
    Compound Activity EC50 μM Compound Activity EC50 μM
     1 A 0.006  84 A
     2 A  85 A
     3 A  86 A
     4 A  87 A
     5 A  88 A 0.012
     6 A  89 A
     7 A 0.004  90 A
     8 A  91 A
     9 A  92 A
    10 C 1.475  93 A
    11 A  94 A
    12 A  95 A
    13 A  96 A 0.003
    14 A 0.034  97 A
    15 A  98 A
    16 A  99 A
    17 A 100 A
    18 A 101 A
    19 A 102 A
    20 A 103 A 0.012
    21 A 104 A
    22 A 105 A
    23 A 0.003 106 A
    24 A 107 A
    25 A 108 A
    26 A 109 A
    27 A 110 A 0.008
    28 A 111 A
    29 A 112 A
    30 A 113 A
    31 A 0.011 114 A
    32 A 115 A
    33 A 116 A 0.002
    34 A 117 A
    35 A 118 A
    36 A 119 A
    37 A 120 A
    38 A 0.006 121 A
    39 A 122 A
    40 A 123 A 0.011
    41 A 124 A
    42 A 125 A
    43 A 126 A
    44 A 127 A
    45 A 0.003 128 A
    46 A 129 A 0.003
    47 A 130 A
    48 A 131 A
    49 A 132 A
    50 A 133 A
    51 A 0.003 134 A 0.012
    52 A 135 A
    53 A 136 A
    54 A 137 A
    55 A 138 A
    56 A 139 A 0.03
    57 A 140 A
    58 A 141 A
    59 A 0.058 142 A
    60 A 143 A
    61 A 144 A 0.008
    62 A 145 A
    63 A 146 A
    64 A 147 A
    65 A 148 A
    66 A 0.013 149 A
    67 A 150 A 0.021
    68 A 151 A
    69 A 152 A
    70 A 153 A
    71 A 154 A
    72 A 155 A
    73 A 0.007 156 A 0.008
    74 A 157 A
    75 A 158 A
    76 A 159 A
    77 A 160 A
    78 A 161 A
    79 A 162 A
    80 A 0.003 163 A 0.076
    81 A 164 A 0.003
    82 A 165 A
    83 A 166 A 0.023
  • It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims (1)

We claim:
1. A compound of Formula I
Figure US20190092754A1-20190328-C00207
or a pharmaceutically acceptable salt thereof wherein:
R1 is hydrogen, C1-6alkyl, or C3-7cycloalkyl;
R2 is tetrahydroisoquinolinyl and is substituted with 1 R6 substituent and also with 0-3 halo or C1-6alkyl substituents;
R3 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or homomorpholinyl, and is substituted with 0-3 substituents selected from cyano, halo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, and C1-6haloalkoxy;
R4 is C1-6alkyl or C1-6haloalkyl;
R5 is C1-6alkyl;
R6 is Ar1, (Ar1) C1-6alkyl, (chromanyl)C1-6alkyl, cyanoC3-7cycloalkyl or (dihydrobenzodioxinyl) C1-6alkyl; and
Ar1 is phenyl substituted with 0-5 substituents selected from cyano, halo, C1-6alkyl, C3-7cycloalkyl, C1-6haloalkyl, hydroxy, C1-6alkoxy, C1-6haloalkoxy, (hydroxy)C1-6alkoxy-(C1-6alkoxy)C1-6alkoxy, phenoxy, benzyloxy, carboxy, phenyl, and cyanoC3-7cycloalkyl.
US16/202,653 2015-08-11 2018-11-28 5-(n-benzyl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication Abandoned US20190092754A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US16/202,653 US20190092754A1 (en) 2015-08-11 2018-11-28 5-(n-benzyl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201562203791P 2015-08-11 2015-08-11
PCT/IB2016/054832 WO2017025917A1 (en) 2015-08-11 2016-08-10 5-(n-benzyl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US201815749176A 2018-01-31 2018-01-31
US16/202,653 US20190092754A1 (en) 2015-08-11 2018-11-28 5-(n-benzyl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/IB2016/054832 Continuation WO2017025917A1 (en) 2015-08-11 2016-08-10 5-(n-benzyl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US15/749,176 Continuation US10189816B2 (en) 2015-08-11 2016-08-10 Substituted pyridines as inhibitors of human immunodeficiency virus replication

Publications (1)

Publication Number Publication Date
US20190092754A1 true US20190092754A1 (en) 2019-03-28

Family

ID=56851651

Family Applications (2)

Application Number Title Priority Date Filing Date
US15/749,176 Active US10189816B2 (en) 2015-08-11 2016-08-10 Substituted pyridines as inhibitors of human immunodeficiency virus replication
US16/202,653 Abandoned US20190092754A1 (en) 2015-08-11 2018-11-28 5-(n-benzyl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US15/749,176 Active US10189816B2 (en) 2015-08-11 2016-08-10 Substituted pyridines as inhibitors of human immunodeficiency virus replication

Country Status (23)

Country Link
US (2) US10189816B2 (en)
EP (1) EP3334716A1 (en)
JP (1) JP6782766B2 (en)
KR (1) KR20180032649A (en)
CN (1) CN108137534A (en)
AR (1) AR105653A1 (en)
AU (1) AU2016306089B2 (en)
CA (1) CA2994791A1 (en)
CL (1) CL2018000363A1 (en)
CO (1) CO2018001359A2 (en)
CR (1) CR20180091A (en)
DO (1) DOP2018000035A (en)
EA (1) EA033057B1 (en)
HK (1) HK1249503A1 (en)
IL (1) IL257240B (en)
MA (1) MA42614A (en)
MX (1) MX2018001722A (en)
PE (1) PE20181002A1 (en)
PH (1) PH12018500294A1 (en)
TW (1) TWI657086B (en)
UA (1) UA120464C2 (en)
WO (1) WO2017025917A1 (en)
ZA (1) ZA201800689B (en)

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3334723B1 (en) * 2015-08-12 2019-09-18 VIIV Healthcare UK (No.5) Limited 5-(n-[6,5]-fused bicyclic aryl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
TW201718537A (en) * 2015-08-12 2017-06-01 Ｖｉｉｖ醫療保健英國（Ｎｏ．５）有限公司 Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
EP3455217A1 (en) * 2016-05-11 2019-03-20 ViiV Healthcare UK (No.5) Limited Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US10407410B2 (en) 2016-05-11 2019-09-10 VIIV Healthcare UK (No.5) Limited Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US20190152957A1 (en) * 2016-05-11 2019-05-23 VIIV Healthcare UK (No.5) Limited Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US20200016136A1 (en) * 2017-01-03 2020-01-16 Viiv Healthcare Uk (No. 5) Limited Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
WO2018127800A1 (en) * 2017-01-03 2018-07-12 VIIV Healthcare UK (No.5) Limited Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Family Cites Families (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7939545B2 (en) * 2006-05-16 2011-05-10 Boehringer Ingelheim International Gmbh Inhibitors of human immunodeficiency virus replication
JP5269086B2 (en) * 2007-11-15 2013-08-21 ギリアード サイエンシス インコーポレーテッド Human immunodeficiency virus replication inhibitor
WO2009062288A1 (en) 2007-11-15 2009-05-22 Boehringer Ingelheim International Gmbh Inhibitors of human immunodeficiency virus replication
WO2009062308A1 (en) 2007-11-16 2009-05-22 Boehringer Ingelheim International Gmbh Inhibitors of human immunodeficiency virus replication
BRPI0820307A2 (en) 2007-11-16 2019-09-24 Boehringer Ingelheim Int human immunodeficiency virus replication inhibitors
US8338441B2 (en) * 2009-05-15 2012-12-25 Gilead Sciences, Inc. Inhibitors of human immunodeficiency virus replication
GB0908394D0 (en) 2009-05-15 2009-06-24 Univ Leuven Kath Novel viral replication inhibitors
GB0913636D0 (en) 2009-08-05 2009-09-16 Univ Leuven Kath Novel viral replication inhibitors
KR101483834B1 (en) 2009-12-23 2015-01-16 카트호리이케 유니버시타이트 로이펜 Novel antiviral compounds
US8633200B2 (en) 2010-09-08 2014-01-21 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
US8629276B2 (en) 2012-02-15 2014-01-14 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
US9034882B2 (en) 2012-03-05 2015-05-19 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
CN105189511B (en) 2013-03-13 2017-05-24 百时美施贵宝公司 Inhibitors of human immunodeficiency virus replication
ES2623904T3 (en) 2013-03-14 2017-07-12 VIIV Healthcare UK (No.5) Limited Human immunodeficiency virus replication inhibitors
US9193720B2 (en) * 2014-02-20 2015-11-24 Bristol-Myers Squibb Company Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
PT3116880T (en) * 2014-02-20 2018-05-10 Viiv Healthcare Uk No 5 Ltd Pyridin-3-yl acetic acid macrocycles as inhibitors of human immunodeficiency virus replication
EP3334723B1 (en) * 2015-08-12 2019-09-18 VIIV Healthcare UK (No.5) Limited 5-(n-[6,5]-fused bicyclic aryl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
TW201718537A (en) * 2015-08-12 2017-06-01 Ｖｉｉｖ醫療保健英國（Ｎｏ．５）有限公司 Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US10214516B2 (en) * 2015-08-12 2019-02-26 VIIV Healthcare UK (No.5) Limited 5-(N-fused tricyclic aryl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication

Also Published As

Publication number Publication date
DOP2018000035A (en) 2018-03-30
JP2018522927A (en) 2018-08-16
IL257240B (en) 2020-02-27
ZA201800689B (en) 2021-08-25
UA120464C2 (en) 2019-12-10
CR20180091A (en) 2018-06-13
AU2016306089A1 (en) 2018-03-01
CN108137534A (en) 2018-06-08
EP3334716A1 (en) 2018-06-20
PE20181002A1 (en) 2018-06-26
TW201718549A (en) 2017-06-01
HK1249503A1 (en) 2018-11-02
MA42614A (en) 2021-05-26
EA033057B1 (en) 2019-08-30
CO2018001359A2 (en) 2018-05-10
IL257240A (en) 2018-03-29
MX2018001722A (en) 2018-05-16
US10189816B2 (en) 2019-01-29
CA2994791A1 (en) 2017-02-16
EA201890361A1 (en) 2018-11-30
AU2016306089B2 (en) 2018-08-09
US20180230129A1 (en) 2018-08-16
JP6782766B2 (en) 2020-11-11
WO2017025917A1 (en) 2017-02-16
TWI657086B (en) 2019-04-21
KR20180032649A (en) 2018-03-30
AR105653A1 (en) 2017-10-25
PH12018500294A1 (en) 2018-08-13
CL2018000363A1 (en) 2018-07-06

Similar Documents

Publication Publication Date Title
US10189816B2 (en) Substituted pyridines as inhibitors of human immunodeficiency virus replication
US10214516B2 (en) 5-(N-fused tricyclic aryl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US10407410B2 (en) Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US10577353B2 (en) 5-(n-[6,5]-fused bicyclic aryl tetrahydroisoquinolin-6-yl) pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US10106504B2 (en) Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US20180170903A1 (en) Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US20190152957A1 (en) Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US20200325127A1 (en) Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US20180147196A1 (en) Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US20180170904A1 (en) Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US10221156B2 (en) Pyridin-3-yl acetic acid derivatives as inhibitors of human immunodeficiency virus replication
US10138253B2 (en) Imidazopyridine macrocycles as inhibitors of human immunodeficiency virus replication

Legal Events

Date Code Title Description
AS Assignment

Owner name: VIIV HEALTHCARE UK (NO.5) LIMITED, UNITED KINGDOM

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:EASTMAN, KYLE J.;KADOW, JOHN F.;NAIDU, B. NARASIMHULU;AND OTHERS;SIGNING DATES FROM 20160907 TO 20160909;REEL/FRAME:047607/0500

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION