Compounds having ferroptosis-inducing activity and methods of using the same

Abstract

The present disclosure relates to compounds of formula (I) having ferroptosis-inducing activity, methods for treating cancer subjects using the compounds, and combination treatments with a second therapeutic agent. In certain embodiments, the compounds, or their tautomers, stereoisomers, stereoisomer mixtures, isotopically enriched analogs, or pharmaceutically acceptable salts, or pharmaceutical compositions comprising them, exhibit GPX4 inhibitory activity, and in certain embodiments, exhibit altered or enhanced stability (e.g., metabolic stability) and / or enhanced activity or other properties compared to other GPX4 inhibitors. JPEG2022522694000139.jpg2334

Description

Technical Field

[0001] Cross - reference to Related Applications This application is a continuation - in - part of PCT Application No. PCT / US2019 / 019854, filed on February 27, 2019, and is also a continuation - in - part of U.S. Patent Application No. 16 / 287,805, filed on February 27, 2019. This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62 / 893,092, filed on August 28, 2019, the content of which is incorporated herein by reference in its entirety.

Background Art

[0002] Glutathione peroxidase 4 (GPX4) can directly reduce phospholipid hydroperoxides. Depletion of GPX4 induces lipid peroxidation - dependent cell death. Cancer cells in a drug - induced, treatment - resistant state have increased dependence on the lipid peroxidase activity of GPX4 and prevent ferroptotic cell death. Studies have shown that lipophilic antioxidants such as ferrostatin can rescue cells from ferroptosis induced by GPX4 inhibition. For example, mesenchymal GPX4 knockout cells can survive in the presence of ferrostatin, but when the supply of ferrostatin is stopped, these cells undergo ferroptosis (see, e.g., Viswanathan et al., Nature 547:453 - 7, 2017). It has also been experimentally confirmed that GPX4i can be rescued by blocking other components of the ferroptosis pathway, such as lipid ROS scavengers (ferrostatin, liproxstatin), lipoxygenase inhibitors, iron chelators, and caspase inhibitors, which apoptosis inhibitors cannot rescue. These findings suggest non - apoptotic, iron - dependent, oxidative cell death (i.e., ferroptosis). Therefore, GPX4 inhibitors may be useful for inducing ferroptotic cancer cell death and thus treating cancer.

Prior Art Documents

Non - Patent Documents

[0003]

Non-Patent Document 1

Summary of the Invention

Means for Solving the Problems

[0004] The present disclosure relates to a compound having ferroptosis-inducing activity and a method of using the compound for the treatment of cancer. In certain embodiments, a compound of formula (I):

Chemical Formula

Chemical formula

[0005] In certain embodiments, an effective amount of a compound of formula (I):

Chemical formula

[0006] In certain embodiments, provided is a method for treating cancer in a patient in need thereof, comprising administering an effective amount of a compound, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein. In certain embodiments, provided is a method for treating a solid malignant tumor in a patient in need thereof, comprising administering an effective amount of a compound, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein to the patient. In certain embodiments, the solid malignant tumor is a sarcoma, carcinoma, or lymphoma. In certain embodiments, the method is a compound of formula (I): [Chemical formula] or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof, wherein ring A is C4-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, X is -O-, -S-, -NR 9 -, -CR 5 =CR 5 -, or -CR 5 =N-, p is 0, 1, or 2, q is 0, 1, 2, or 3, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, -CN, -OR 7 , -C(O)OR 6 , -C(O)N(R 7 )2, -OC(O)R 6 , -S(O)2R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -S(O)R 8 , -N(R 7)2, -NO2, -C1-C6 alkyl-OR 7 、or -Si(R 15 )3, where R 2 is -C1-C2 haloalkyl, -C2-C3 alkenyl, -C2-C3 haloalkenyl, C2 alkynyl, or -CH2OS(O)2-phenyl, C1-C2 alkyl halo and -C2-C3 alkenyl halo are optionally substituted with one or two -CH3, C2 alkynyl and phenyl are optionally substituted with one -CH3, each R 3 is independently halo, -CN, -OH, -OR 8 , -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 12 )3, -SF5, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -NR 12 C(O)OR 8 , -OC(O)N(R 7 )2, -OC(O)R 8 , -C(O)R 6 , -OC(O)CHR 8 N(R 12 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, and R 3each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl is independently optionally substituted with 1-3 R 10 and each R 4 is independently halo, -CN, -OH, -OR 8 , -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 15 )3, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -OC(O)R 8 , -C(O)R 6 , -NR 12 C(O)OR 8 , -OC(O)N(R 7 )2, -OC(O)CHR 8 N(R 12 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, and R4 each of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl is optionally and independently substituted with 1 to 3 R 10 and each R 5 is independently hydrogen, halo, -CN, -OH, -OR 8 , -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 15 )3, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -OC(O)R 8 , -C(O)R 6 , -NR 12 C(O)OR 8 , -OC(O)N(R 7 )2, -OC(O)CHR 8 N(R 12 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, where R 5 each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl is optionally and independently substituted with 1-3 R 10 and each R 6 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, and each R 6 is independently further substituted with 1-3 R 11 and each R 7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10Is cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C6 cycloalkyl, -C2-C6 alkenyl C3-C6 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, -C1-C6 alkyl heteroaryl, -C2-C6 alkenyl heteroaryl, or two Rs 7 Together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, and each R 7 Or the ring formed thereby is independently further substituted with 1 to 3 Rs 11 And Each R 8 Is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 Cycloalkyl, -C2-C6 alkenyl C3-C 10 Cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, -C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, and each R 8 Is independently further substituted with 1 to 3 Rs 11 And R 9 Is hydrogen or C1-C6 alkyl, Each R 10 Is independently halo, -CN, -OR 12 , -NO2, -N(R 12 )2, -S(O)R 13 , -S(O)2R 13 , -S(O)N(R 12 )2, -S(O)2N(R 12 )2, -Si(R 12 )3, -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -NR 12 C(O)R 12, -OC(O)R 12 , -OC(O)OR 12 , -OC(O)N(R 12 )2, -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, and R 10 each of the C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally and independently substituted with 1-3 R 11 s, each R 11 is independently halo, -CN, -OR 12 , -NO2, -N(R 12 )2, -S(O)R 13 , -S(O)2R 13 , -S(O)N(R 12 )2, -S(O)2N(R 12 )2, -Si(R 12 )3, -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -NR 12 C(O)R 12 , -OC(O)R 12 , -OC(O)OR 12 , -OC(O)N(R 12 )2, -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R 12 is independently hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl, Each R 13 is independently C1-C6 alkyl or C3-C 10 cycloalkyl, each R 15 is independently C1-C6 alkyl, C2-C6 alkenyl, aryl, heteroaryl, -C1-C6 alkylaryl, -C2-C6 alkenylaryl, -C1-C6 alkylheteroaryl, and -C2-C6 alkenylheteroaryl, a compound of formula (I), or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof.

Brief Description of the Drawings

[0007]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0008] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a protein" includes two or more proteins, and reference to "a compound" refers to two or more compounds.

[0009] Also, the use of "or" means "and / or" unless specified otherwise. Similarly, "comprise", "comprises", "comprising", "include", "includes", and "including" are interchangeable and not intended to be limiting.

[0010] When the description of various embodiments uses the term "comprising", it should be further understood that those skilled in the art will understand that in some specific examples, the embodiments can alternatively be described using the language "consisting essentially of" or "consisting of".

[0011] It should be understood that both the foregoing general description including the drawings and the following detailed description are merely illustrative and explanatory and do not limit the present disclosure. The section headings used in this specification are for organization purposes only and should not be construed as limiting the subject matter being described.

[0012] 1. Definitions With reference to the present disclosure, the technical and scientific terms used in the description of this specification will have the meanings generally understood by those skilled in the art unless specifically defined otherwise. Accordingly, the following terms are intended to have the meanings described below.

[0013] "Ferroptosis" is understood in the art as involving the generation of reactive oxygen species mediated by iron and refers to a form of cell death characterized in part by lipid peroxidation.

[0014] "Ferroptosis inducer" or "ferroptosis activator" refers to an agent that induces, promotes, or activates ferroptosis.

[0015] "GPX4 inhibitor" refers to any agent that inhibits the activity of the enzyme glutathione peroxidase 4 (GPX4). The GPX4 inhibitor can be either a direct inhibitor or an indirect inhibitor. GPX4 is a phospholipid hydroperoxidase that catalyzes the reduction of hydrogen peroxide and organic peroxides, thereby protecting cells from membrane lipid peroxidation or oxidative stress. GPX4 has selenocysteine in its active site and is oxidized to selenic acid by peroxides to obtain lipid alcohols. Glutathione acts to reduce selenic acid (-SeOH) to selenol (-SeH). When this catalytic cycle is disrupted, cell death occurs through an iron-mediated process within the cell known as ferroptosis.

[0016] As used herein, "subject" refers to a mammal, such as a dog, cat, horse, or rabbit. In certain embodiments, the subject is a non-human primate, such as a monkey, chimpanzee, or gorilla. In certain embodiments, the subject is a human and may also be referred to herein as a patient.

[0017] As used herein, "treating" or "treatment" of a disease, disorder, or syndrome includes (i) preventing the disease, disorder, or syndrome from occurring in a subject, i.e., preventing the clinical symptoms of the disease, disorder, or syndrome from occurring, or preventing the disease, disorder, or syndrome from developing in an animal that has been exposed to or is susceptible to the disease, disorder, or syndrome but has not yet experienced or shown symptoms of the disease, disorder, or syndrome; (ii) suppressing the disease, disorder, or syndrome, i.e., preventing its occurrence; and (iii) alleviating the disease, disorder, or syndrome, i.e., causing regression of the disease, disorder, or syndrome. As is known in the art, adjustments may be necessary for systemic delivery and local delivery, age, weight, general health, gender, diet, time of administration, drug interactions, and severity of symptoms, and can be confirmed by routine experimentation by those skilled in the art, particularly in view of the guidance provided in this disclosure.

[0018] "Therapeutically effective amount" refers to an amount sufficient to effect such treatment of a disease, disorder, or condition when administered to an animal (e.g., a human) for treating the disease. In certain embodiments, the treatment provides a therapeutic benefit such as improvement of symptoms or delay of disease progression. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of a disease or condition as described herein.

[0019] "Alkyl" refers to a straight-chain or branched-chain hydrocarbon group having from 1 to 20 carbon atoms (C1-C 20 or C 1~20 ), from 1 to 12 carbon atoms (C1-C 12 or C 1~12 ), or from 1 to 8 carbon atoms (C1-C8 or C 1~8 ). Exemplary "alkyl" groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl.

[0020] "Alkenyl" refers to a straight-chain or branched-chain hydrocarbon group having from 2 to 20 carbon atoms (C2-C 20 or C 2~20 ), from 2 to 12 carbon atoms (C2-C 12 or C 2~12 ), or from 2 to 8 carbon atoms (C2-C8 or C 2~8 ), and having at least one double bond. Exemplary "alkenyl" groups include, but are not limited to, vinyl, ethenyl, allyl, isopropenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, and 5-hexenyl.

[0021] "Alkynyl" refers to a straight-chain or branched-chain hydrocarbon group having from 2 to 12 carbon atoms (C2-C 12 or C 2~12 ), from 2 to 8 carbon atoms (C2~ C8 or C 2~8 ) means a linear or branched hydrocarbon group. Exemplary "alkynyls" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl, etc.

[0022] "Alkylene", "alkenylene", and "alkynylene" each refer to a linear or branched divalent hydrocarbon radical of the corresponding alkyl, alkenyl, and alkynyl, respectively. In certain embodiments, "alkyl", "alkenyl", and "alkynyl" may represent the corresponding "alkylene", "alkenylene", and "alkynylene", by way of example and not limitation, cycloalkylalkyl-, heterocycloalkylalkyl-, arylalkyl-, heteroarylalkyl-, cycloalkylalkenyl-, heterocycloalkylalkenyl-, arylalkenyl-, heteroarylalkenyl-, cycloalkylalkynyl-, heterocycloalkylalkynyl-, arylalkynyl-, heteroarylalkynyl-, etc., and the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are connected via the corresponding alkylene, alkenylene, or alkynylene group as a substituent.

[0023] With respect to a substituent, "lower" refers to a group having 1 to 6 carbon atoms.

[0024] "Alkyl halo" or "haloalkyl" has 1 to 20 carbon atoms (C1~C 20 or C 1~20 ), 1 to 12 carbon atoms (C1~C 12 or C 1~12 ), or 1 to 8 carbon atoms (C1~C8 or C 1~8refers to a linear or branched hydrocarbon group, and one or more (e.g., 1 to 3, or 1) hydrogen atoms are replaced by a halogen (e.g., Cl, F, etc.). In certain embodiments, the term "alkyl halo" refers to an alkyl group as defined herein, and one hydrogen atom is replaced by a halogen (e.g., Cl, F, etc.). In certain embodiments, the term "alkyl halo" refers to an alkyl chloride.

[0025] "Alkenyl halo" or "haloalkenyl" refers to a linear or branched hydrocarbon group having at least one double bond and having 2 to 20 carbon atoms (C2 - C 20 or C 2~20 ), 2 to 12 carbon atoms (C2 - C 12 or C 2~12 ), or 2 to 8 carbon atoms (C2 - C8 or C 2~8 ), and one or more (e.g., 1 to 3, or 1) hydrogen atoms are replaced by a halogen (e.g., Cl, F, etc.). In certain embodiments, the term "alkenyl halo" refers to an alkenyl group as defined herein, and one hydrogen atom is replaced by a halogen (e.g., Cl, F, etc.). In certain embodiments, the term "alkenyl halo" refers to an alkenyl chloride.

[0026] "Heteroalkyl" refers to a linear or branched hydrocarbon group having 1 to 20 carbon atoms (C1 - C 20 or C 1~20 ), 1 to 12 carbon atoms (C1 - C 12 or C 1~12 ), or 1 to 8 carbon atoms (C1 - C8 or C 1~8 ), and 1 to 3 carbon atoms are replaced by a heteroatom. Heteroatoms and / or groups of heteroatoms capable of replacing carbon atoms include, but are not limited to, -O-, -S-, -NR 40 -, -PH-, -C(O)-, -S(O)-, -S(O)2-, -S(O)NR 40 -, -S(O)2NR 40 -, etc. (including combinations thereof), and each R40 is independently hydrogen or lower alkyl.

[0027] "Cycloalkyl" refers to any stable monocyclic or polycyclic system consisting of carbon atoms, with any of its rings being saturated. "Cycloalkenyl" refers to any stable monocyclic or polycyclic system consisting of carbon atoms, with at least one of its rings being partially unsaturated. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicycloalkyl, and tricycloalkyl (e.g., adamantyl).

[0028] "Heterocycloalkyl" or "heterocyclyl" refers to a 4- to 14-membered monocyclic or polycyclic (e.g., bicyclic) non-aromatic hydrocarbon ring, where 1 to 3 carbon atoms are replaced by heteroatoms. Heteroatoms and / or groups of heteroatoms capable of replacing carbon atoms include -O-, -S-, -S-O-, -NR 40 -, -PH-, -C(O)-, -S(O)-, -S(O)2-, -S(O)NR 40 -, -S(O)2NR 40 -, etc. (including combinations thereof), but not limited thereto, and each R 40 is independently hydrogen or lower alkyl. Examples include thiazolidinyl, thiadiazolyl, triazinyl, morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, 2,3-dihydrofuranyl, dihydropyranyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, etc. In certain embodiments, "heterocycloalkyl" or "heterocyclyl" is a substituted or unsubstituted 4- to 7-membered monocyclic ring, where 1 to 3 carbon atoms are replaced by the above-mentioned heteroatoms.

[0029] In certain embodiments, "heterocycloalkyl" or "heterocyclyl" is a monocyclic or polycyclic (e.g., bicyclic) ring having from 4 to 10 members, or from 4 to 9 members, or from 5 to 9 members, or from 5 to 7 members, or from 5 to 6 members, and from 1 to 3 carbon atoms are replaced with the above heteroatoms. In certain embodiments, when "heterocycloalkyl" or "heterocyclyl" is a substituted or unsubstituted bicyclic ring, one ring can be aromatic if at least one ring is non-aromatic regardless of the point of attachment to the remainder of the molecule (e.g., indolinyl, isoindolinyl, etc.).

[0030] "Aryl" refers to a monocyclic or bicyclic ring having from 6 to 14 members, the monocyclic ring being aromatic and at least one of the rings of the bicyclic ring being aromatic. Unless otherwise specified, the valence of the group may be located on any atom of any ring within the radical as permitted by valence rules. Examples of "aryl" groups include phenyl, naphthyl, indenyl, biphenyl, phenanthrenyl, naphthacenyl, and the like.

[0031] "Heteroaryl" means an aromatic heterocyclic ring containing monocyclic and polycyclic (e.g., bicyclic) ring systems, wherein at least one carbon atom of one or both of the rings is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur, or at least two carbon atoms of one or both of the rings are replaced with heteroatoms independently selected from nitrogen, oxygen, and sulfur. In certain embodiments, heteroaryl can be a 5- to 6-membered monocyclic or 7- to 11-membered bicyclic ring system. Examples of "heteroaryl" groups include pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolyl, and the like.

[0032] "Bridged bicyclic" refers to any bicyclic ring system having at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or atom valence bonds connecting two bridgeheads, and a "bridgehead" is any skeletal atom of a ring system that is bonded to three or more skeletal atoms (excluding hydrogen). In certain embodiments, the bridged bicyclic group has 5 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Such bridged bicyclic groups include those described below, wherein each group is bonded to the remainder of the molecule by a carbon or nitrogen atom that is substitutable. Representative bridged bicyclic groups include, but are not limited to: [Chemical formula] .

[0033] "Fused ring" refers to a ring system having two or more rings that share at least one bond and two atoms in common. "Fused aryl" and "fused heteroaryl" refer to ring systems having at least one aryl and heteroaryl, respectively, that share at least one bond and two atoms with another ring.

[0034] "Halogen" or "halo" refers to fluorine, chlorine, bromine, and iodine.

[0035] "Acyl" refers to -C(O)R 43 wherein R 43 is hydrogen, or as defined herein, optionally substituted alkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. Exemplary acyl groups include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, etc.

[0036] "Alkyloxy" or "alkoxy" refers to -OR44 refers to R 44 is optionally substituted alkyl.

[0037] "Aryloxy" refers to -OR 45 refers to R 45 is optionally substituted aryl.

[0038] "Carboxy" refers to -COO - or COOM, where M is H or a counter ion (e.g., a cation such as Na + Ca 2+ Mg 2+ etc.).

[0039] "Carbamoyl" refers to -C(O)NR 46 R 46 refers to each R 46 is independently selected from H or optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.

[0040] "Ester" refers to a group such as -C(=O)OR 47 or is shown as -C(O)OR 47 wherein R 47 is selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0041] "Ether" refers to the group -alkyl-O-alkyl, where the term alkyl is as defined herein.

[0042] "Sulfanyl" refers to -SR 48 refers to R 48is selected from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. For example, -SR 48 (wherein R 48 is alkyl) is alkylsulfanyl.

[0043] "Sulfonyl" refers to -S(O)2-, which can have various substituents for forming different sulfonyl groups, including sulfonic acid, sulfonamide, sulfonate ester, and sulfone. For example, -S(O)2R 49 (wherein R 49 is alkyl) refers to alkylsulfonyl. -S(O)2R 49 In certain embodiments of -S(O)2R 49 R

[0044] "Sulfinyl" refers to -S(O)-, which can have various substituents for forming different sulfinyl groups, including sulfinic acid, sulfinamide, and sulfinyl ester. For example, -S(O)R 50 (wherein R 50 is alkyl) refers to alkylsulfinyl. -S(O)R 50 In certain embodiments of -S(O)R 50 R

[0045] "Silyl" refers to Si which can have various substituents, for example, -SiR 51 R 51 R 51 and each R 51is independently selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl. As defined herein, any heterocycloalkyl or heteroaryl group present in a silyl group has 1 to 3 heteroatoms independently selected from O, N, and S.

[0046] "Amino" or "amine" refers to the group -NR 52 R 52 or -N + R 52 R 52 R 52 wherein each R 52 is independently selected from hydrogen and optionally substituted alkyl, cycloalkyl, heterocycloalkyl, alkyloxy, aryl, heteroaryl, heteroarylalkyl, acyl, -C(O)-O-alkyl, sulfanyl, sulfinyl, sulfonyl, etc. Exemplary amino groups include, but are not limited to, dimethylamino, diethylamino, trimethylammonium, triethylammonium, methylsulfonylamino, furanyl-oxy-sulfamino, etc.

[0047] "Amide" refers to groups such as -C(=O)NR 53 R 53 wherein each R 53 is independently selected from H and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0048] "Carbamate" refers to groups such as -O-C(=O)NR 53 R 53 or -NR 53 -C(=O)OR 53 wherein each R 53is independently selected from H and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl.

[0049] "Sulfonamide" is -S(O)2NR 54 R 54 wherein each R 54 is independently selected from H and optionally substituted alkyl, heteroalkyl, heteroaryl, heterocycle, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, alkylene-C(O)-OR 55 or alkylene-O-C(O)-OR 55 and R 55 is selected from H, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkenyl, alkynyl, arylalkyl, heterocycloalkyl, heteroarylalkyl, amino, and sulfinyl.

[0050] "Adamantyl" refers to tricyclo[3.3.1.1 3,7 decanyl, and the bond can be through a 3-coordinate carbon site or a 2-coordinate carbon site (i.e., 1-adamantyl or 2-adamantyl). In certain embodiments, "adamantyl" refers to a compound of the following structural formula,

Chemical formula

[0051] As used herein, "N-protecting group" refers to a group intended to protect a nitrogen atom from unwanted reactions during a synthetic procedure. Exemplary N-protecting groups include acyl groups such as acetyl and t-butylacetyl, pivaloyl, etc.; alkoxycarbonyl groups such as methyloxycarbonyl and t-butyloxycarbonyl (Boc); aryloxycarbonyl groups such as benzyloxycarbonyl (Cbz) and fluorenylmethyloxycarbonyl (Fmoc); and aroyl groups such as benzoyl, but are not limited thereto. N-protecting groups are described in Greene´s Protective Groups in Organic Synthesis, 5th Edition, P.G.M. Wuts, ed., Wiley (2014).

[0052] "Optional" or "optionally" means that the described event or circumstance may or may not occur, and the description includes both the case where the event or circumstance occurs and the case where the event or circumstance does not occur. For example, "optionally substituted alkyl" refers to an alkyl group that may or may not be substituted, and the description includes both substituted alkyl groups and unsubstituted alkyl groups.

[0053] As used herein, "substituted" means that one or more hydrogen atoms of a group are replaced by an atom or group of a substituent commonly used in pharmaceutical chemistry. Each substituent may be the same or different. Examples of suitable substituents include alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycloalkyl, heteroaryl, -OR 56 (e.g., hydroxyl, alkyloxy (e.g., methoxy, ethoxy, and propoxy), ether, ester, carbamate, etc.), hydroxyalkyl, -C(O)O-alkyl, -O-alkyl-O-alkyl, haloalkyl, alkyl-O-alkyl, SR 56 (e.g., -SH, -S-alkyl, -S-aryl, -S-heteroaryl, arylalkyl-S-, etc.), S + R56 2. S(O)R 56 . SO₂R 56 . NR 56 R 57 (e.g., primary amine (i.e., NH₂), secondary amine, tertiary amine, amide, carbamate, urea, etc.), hydrazide, halo, nitrile, nitro, sulfide, sulfoxide, sulfone, sulfonamide, -SH, carboxy, aldehyde, keto, carboxylic acid, ester, amide, imine, and imide (e.g., -C(O)NR 56 C(O)R 57 )(including their seleno and thio derivatives), but not limited thereto, each R 56 and R 57 is independently alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl, and each of the substituents may optionally be further substituted. In embodiments where a functional group having an aromatic carbocyclic ring is substituted, such substitution is typically less than about 10, or a number of substitutions of about 1 to 5, and in certain embodiments, a number of substitutions of about 1 or 2.

[0054] "Pharmaceutically acceptable salts" means salts of the active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. When the compounds disclosed herein contain relatively acidic functional groups, the neutral forms of such compounds can be converted to base addition salts by contacting the neutral form, either undiluted or in a suitable inert solvent, with a sufficient amount of the desired base. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When the compounds disclosed herein contain relatively basic functional groups, the neutral forms of such compounds can be converted to acid addition salts by contacting the neutral form, either undiluted or in a suitable inert solvent, with a sufficient amount of the desired acid. Examples of pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, phosphoric acid, partially neutralized phosphoric acid, sulfuric acid, partially neutralized sulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid. Certain compounds of the present disclosure may contain both basic and acidic functional groups that allow the compound to be converted to either a base addition salt or an acid addition salt. Lists of suitable salts can be found in Remington´s Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa., (1985) and Journal of Pharmaceutical Science, 66:2 (1977), each of which is incorporated herein by reference in its entirety.

[0055] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" refers to an excipient, carrier, or adjuvant that can be administered to a subject together with at least one compound, does not destroy its pharmacological activity, is generally safe and non-toxic, and is not biologically or otherwise undesirable when administered in a dosage sufficient to deliver a therapeutically effective amount of the agent.

[0056] Any compound or structure described herein is also intended to represent both unlabeled and isotopically labeled forms of the compound. These forms of the compound are sometimes referred to as "isotope-enriched analogs." Isotopically labeled compounds have the structures shown herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. Various isotopically labeled compounds of the present disclosure, such as 3 H, and 14 C, etc., incorporating radioactive isotopes. Such isotopically labeled compounds can be useful in metabolic studies, studies of reaction kinetics, detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in the radioactive treatment of patients.

[0057] The term "isotope enrichment analog" includes "deuterated analogs" of the compounds described herein in which one or more hydrogens are replaced by deuterium, such as hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, e.g., a human. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, e.g., by using starting materials in which one or more hydrogens are replaced by deuterium.

[0058] The deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties in relation to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium can result in certain therapeutic advantages arising from higher metabolic stability, e.g., an increase in in vivo half-life, a reduction in dosage requirements, and / or an improvement in the therapeutic index. 18 F, 3 H, 11 The 18F-, 3H-, 14C-labeled compounds may be useful in PET or SPECT or other imaging studies. The isotope-labeled compounds and their prodrugs of the present disclosure can generally be prepared by replacing readily available isotope-labeled reagents with non-isotope-labeled reagents and carrying out the schemes or procedures disclosed in the Examples and Preparations described below. Deuterium in this context is understood to be considered a substituent in the compounds described herein.

[0059] The concentration of such heavier isotopes, specifically deuterium, can be defined by an isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope means any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its natural abundance isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) means deuterium.

[0060] Some compounds exist as tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound can exist in equilibrium with its imidic acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, the compound is understood by those skilled in the art to include both the amide and imidic acid tautomers. Thus, amide-containing compounds are understood to include their imidic acid tautomers. Similarly, imidic acid-containing compounds are understood to include their amide tautomers.

[0061] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, contain asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)-, or for amino acids as (D)- or (L)-, with respect to absolute stereochemistry. The present disclosure is meant to embrace all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using a chiral synthon or chiral reagent or can be separated using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or separation of a racemic compound (or a racemic compound of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers.

[0062] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refer to two stereoisomers that are mirror images of each other that cannot be superimposed on one another.

[0063] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0064] The relative configuration of the compounds shown herein is depicted graphically using the "thick bond" style (thick lines or parallel lines), and the absolute stereochemistry is depicted using a wedge bond (thick lines or parallel lines).

[0065] 2. Compounds In certain embodiments, the present specification also provides compounds of Formula I, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts, [Chemical Formula] wherein, ring A is C4 - C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, X is -O-, -S-, -NR 9 -, -CR 5 =CR 5 -, or -CR 5 =N-, p is 0, 1, or 2, q is 0, 1, 2, or 3, R 1 is C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C1 - C6 haloalkyl, C3 - C 10 cycloalkyl, -CN, -OR 7 , -C(O)OR 6 , -C(O)N(R 7 )2, -OC(O)R 6 , -S(O)2R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -S(O)R 8 , -N(R 7 )2, -NO2, -C1 - C6 alkyl - OR 7 , or -Si(R 15 )3, R 2 is -C1 - C2 haloalkyl, -C2 - C3 alkenyl, -C2 - C3 haloalkenyl, C2 alkynyl, or -CH2OS(O)2 - phenyl, where C1 - C2 haloalkyl and -C2 - C3 alkenyl are optionally substituted with one or two -CH3, C2 alkynyl and phenyl are optionally substituted with one -CH3, each R 3 is independently halo, -CN, -OH, -OR 8, -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 12 )3, -SF5, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -NR 12 C(O)OR 8 , -OC(O)N(R 7 )2, -OC(O)R 8 , -C(O)R 6 , -OC(O)CHR 8 N(R 12 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, and R 3 each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl is independently optionally substituted with 1 to 3 R 10 s, each R 4is, independently, halo, -CN, -OH, -OR 8 , -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 15 )3, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -OC(O)R 8 , -C(O)R 6 , -NR 12 C(O)OR 8 , -OC(O)N(R 7 )2, -OC(O)CHR 8 N(R 12 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, and R 4 each of the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl is optionally independently substituted with 1 to 3 R 10 s, and each R5 is, independently, hydrogen, halo, -CN, -OH, -OR 8 , -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 15 )3, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -OC(O)R 8 , -C(O)R 6 , -NR 12 C(O)OR 8 , -OC(O)N(R 7 )2, -OC(O)CHR 8 N(R 12 )2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, and each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 5 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, -C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl of R 10 is optionally independently substituted with 1 to 3 R 10 s, Each R 6 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, -C1-C6 alkyl heteroaryl, or -C2-C6 alkenyl heteroaryl, and each R 6 is independently further substituted with 1-3 R 11 groups, Each R 7 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C6 cycloalkyl, -C2-C6 alkenyl C3-C6 cycloalkyl, -C1-C6 alkyl heterocyclyl, -C2-C6 alkenyl heterocyclyl, -C1-C6 alkyl aryl, -C2-C6 alkenyl aryl, -C1-C6 alkyl heteroaryl, -C2-C6 alkenyl heteroaryl, or two R 7 groups are joined together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl, and each R 7 or the ring formed thereby is independently further substituted with 1-3 R 11 groups, Each R 8 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, -C1-C6 alkyl C3-C 10 cycloalkyl, -C2-C6 alkenyl C3-C 10cycloalkyl, -C1-C6 alkylheterocyclyl, -C2-C6 alkenylheterocyclyl, -C1-C6 alkylaryl, -C2-C6 alkenylaryl, -C1-C6 alkylheteroaryl, or -C2-C6 alkenylheteroaryl, and each R 8 is independently substituted by 1 to 3 R 11 ; R 9 is hydrogen or C1-C6 alkyl; each R 10 is independently halo, -CN, -OR 12 , -NO2, -N(R 12 )2, -S(O)R 13 , -S(O)2R 13 , -S(O)N(R 12 )2, -S(O)2N(R 12 )2, -Si(R 12 )3, -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -NR 12 C(O)R 12 , -OC(O)R 12 , -OC(O)OR 12 , -OC(O)N(R 12 )2, -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 10 is optionally independently substituted by 1 to 3 R 11 ; each R 11 is independently halo, -CN, -OR 12 , -NO2, -N(R 12 )2, -S(O)R 13, -S(O)2R 13 , -S(O)N(R 12 )2, -S(O)2N(R 12 )2, -Si(R 12 )3, -C(O)R 12 , -C(O)OR 12 , -C(O)N(R 12 )2, -NR 12 C(O)R 12 , -OC(O)R 12 , -OC(O)OR 12 , -OC(O)N(R 12 )2, -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each R 12 is, independently, hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl, each R 13 is, independently, C1-C6 alkyl or C3-C 10 cycloalkyl, each R 15 is, independently, C1-C6 alkyl, C2-C6 alkenyl, aryl, heteroaryl, -C1-C6 alkylaryl, -C2-C6 alkenylaryl, -C1-C6 alkylheteroaryl, and -C2-C6 alkenylheteroaryl.

[0066] In certain embodiments, compounds of formula I, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts are also provided,

Chemical formula

Chemical formula

[0067] In certain embodiments, R 1 is other than -C(O)OR 6 or R 2is -C2 alkynyl optionally substituted with one -CH3. In certain embodiments, R 1 is other than -C(O)OCH3, or R 2 is -C2 alkynyl optionally substituted with one -CH3. In certain embodiments, R 1 is other than -C(O)OR 6 , and R 2 is -C2 alkynyl optionally substituted with one -CH3. In certain embodiments, R 1 is other than -C(O)OCH3, and R 2 is -C2 alkynyl optionally substituted with one -CH3. In certain embodiments, R 1 is other than -C(O)OR 6 . In certain embodiments, R 1 is other than -C(O)OCH3. In certain embodiments, R 2 is -C2 alkynyl optionally substituted with one -CH3. In certain embodiments, R 2 is -C2 alkynyl.

[0068] Also provided are compounds of formula IA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0069] Also provided are compounds of formula IB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0070] Also provided are compounds of formula II, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0071] Also provided are compounds of formula IIA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0072] Also provided are compounds of formula IIB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0073] Also provided are compounds of formula III, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chem.

[0074] Also provided are compounds of formula IIIA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chem.

[0075] Also provided are compounds of formula IIIB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chem.

[0076] In certain embodiments, ring A is aryl or heteroaryl, X is -O-, -S-, -NH-, -CH=CH-, or -CH=N-, p is 0, 1, or 2, q is 1, R 1 is C1-C6 alkyl, -C(O)O-C1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2, R 3 is halo, -NHR 8 , -S(O)2N(R 7 )2, -C(O)OR 6 , -C(O)N(R 7 )2, or heterocyclyl, each R 4 is independently -OR 8 wherein, R 6 is C1-C6 alkyl, each R 7 is independently hydrogen, C1-C6 alkyl, or C3-C 10 cycloalkyl, and each R 7 is independently further substituted with 1 to 3 R 11 groups, each R 8 is independently C1-C6 alkyl or C3-C 10 cycloalkyl, and each R 8 is independently further substituted with 1 to 3 R 11 groups, each R 11 is independently -O-C1-C6 alkyl, R 14 is halo.

[0077] In certain embodiments, ring A is aryl or heteroaryl, X is -O-, -S-, -NH-, -CH=CH-, or -CH=N-, p is 0, 1, or 2, q is 1, R 1 is C1-C6 alkyl or -C(O)N(C1-C6 alkyl)2, R 3 is halo, -NHR 8, -S(O)2N(R 7 )2, -C(O)OR 6 , -C(O)N(R 7 )2, or is heterocyclyl, each R 4 is independently -OR 8 wherein, R 6 is C1-C6 alkyl, each R 7 is independently hydrogen, C1-C6 alkyl, or C3-C 10 cycloalkyl, each R 7 is independently 1-3 R 11 and is further substituted by, each R 8 is independently C1-C6 alkyl or C3-C 10 cycloalkyl, each R 8 is independently 1-3 R 11 and is further substituted by, each R 11 is independently -O-C1-C6 alkyl, R 14 is halo.

[0078] In certain embodiments, X is -O-, -S-, or -NR 9 -. In certain embodiments, X is -O-, -S-, or -NH-. In certain embodiments, X is -O-. In certain embodiments, X is -S-. In certain embodiments, X is -NR 9 -. In certain embodiments, X is -NH-.

[0079] In certain embodiments, X is -CR 5 =CR 5 -, or -CR 5 =N-. In certain embodiments, X is -CH=CH- or -CH=N-. In certain embodiments, X is -CR 5 =CR 5 -. In certain embodiments, X is -CR 5 =N-.

[0080] In certain embodiments, R 5 is R 4 .

[0081] In certain embodiments, X is -CH=CH-, p is 1 or 2, each R 4 is methoxy, ring A is phenyl, and when q is 1, R 3 is other than adamantylamine, fluoro, or -C(O)NH-cyclopropyl. In certain embodiments, X is -CH=CH-, p is 1 or 2, each R 4 is methoxy, R 1 is methyl, n-butyl, or -C(O)OCH3, ring A is phenyl, and when q is 1, R 3 is other than adamantylamine, fluoro, and -C(O)NH-cyclopropyl. In certain embodiments, X is -CH=CH-, p is 1 or 2, each R 4 is methoxy, R 1 is methyl, n-butyl, or -C(O)OCH3, R 2 is -CH2Cl or C2 alkynyl, ring A is phenyl, and when q is 1, R 3 is other than adamantylamine, fluoro, or -C(O)NH-cyclopropyl.

[0082] In certain embodiments, X is -CR 5 =CR 5 -, p is 1 or 2, ring A is phenyl, cyclohexyl, or furyl, and when q is 0 or 1, at least one R 4 is other than methoxy. In certain embodiments, R 1 is -C(O)OCH3, R 2 is -CH2Cl, ring A is phenyl, cyclohexyl, or furyl, q is 0 or 1, and R 3is -NO2, Br, or -OCH3, and when p is 1 or 2, at least one R 4 is other than methoxy. In certain embodiments, R 2 is -CH2Cl, X is -CR 5 =CR 5 -, p is 1 or 2, ring A is phenyl, cyclohexyl, or furyl, and when q is 0 or 1, at least one R 4 is other than methoxy. In certain embodiments, R 1 is -C(O)OCH3, R 2 is -CH2Cl, X is -CR 5 =CR 5 -, p is 1 or 2, ring A is phenyl, cyclohexyl, or furyl, and when q is 0 or 1, at least one R 4 is other than methoxy.

[0083] In certain embodiments, R 1 is -C(O)OCH3, and when R 2 is -CH2Cl, X is other than -CR 5 =CR 5 -. In certain embodiments, when X is -CH=CH-, p is 1 or 2, ring A is phenyl, and q is 1, at least one R 4 is other than methoxy.

[0084] In certain embodiments, the compound is not N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-propionoyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide, 4-((1S,3S)-2-(2-chloroacetyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclopropylbenzamide, 1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-chloroethan-1-one, 4-((1S,3S)-3-butyl-2-(2-chloroacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclopropylbenzamide, 4-((1S,3S)-3-butyl-6-methoxy-2-propionoyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclopropylbenzamide, 1-((1S,3S)-1-(4-(adamantan-1-ylamino)phenyl)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-chloroethan-1-one, 1-((1S,3S)-1-(4-(adamantan-1-ylamino)phenyl)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one, methyl (1S,3R)-1-(4-(adamantan-1-ylamino)phenyl)-2-(2-chloroacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, methyl (1S,3R)-1-(4-(adamantan-1-ylamino)phenyl)-6-methoxy-2-propionoyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate, 4-((1S,3S)-3-butyl-2-(2-chloroacetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclopropylbenzamide, or 4-((1S,3S)-3-butyl-6,7-dimethoxy-2-propionoyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclopropylbenzamide.

[0085] In certain embodiments, R2 When it is -C1 to C2 haloalkyl, ring A is not benzo[d][1,3]dioxole.

[0086] In certain embodiments, R 5 is R 4 as defined below.

[0087] Also provided are compounds of formula IV, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0088] Also provided are compounds of formula IV, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0089] Also provided are compounds of formula IVA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotope-enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0090] Also provided are compounds of formula IVB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotope-enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0091] Also provided are compounds of formula V, or their tautomers, stereoisomers, mixtures of stereoisomers, isotope-enriched analogs, or pharmaceutically acceptable salts, [Chemical formula] In the formula, ring A, R 1 , R 3 , R 4 , p, and q each independently are as defined herein, and R 14 is halo.

[0092] Also provided are compounds of formula V, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts, [Chemical formula] In the formula, ring A is aryl or heteroaryl, p is 0, 1, or 2, q is 1, R 1 is C1-C6 alkyl, -C(O)O-C1-C6 alkyl, or -C(O)N(C1-C6 alkyl)2, R 3 is halo, -NHR 8 , -S(O)2N(R 7 )2, -C(O)OR 6 , -C(O)N(R 7 )2, or heterocyclyl, each R 4 is independently -OR 8 , R 6 is C1-C6 alkyl, each R 7 is independently hydrogen, C1-C6 alkyl, or C3-C 10 cycloalkyl, and each R 7 is independently further substituted with 1 to 3 R 11 , each R 8 is independently C1-C6 alkyl or C3-C 10 cycloalkyl, and each R 8 is independently further substituted with 1 to 3 R11 and is further substituted with each R 11 is independently -O-C1-C6 alkyl, R 14 is halo.

[0093] In certain embodiments, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, -CN, -OR 7 , -C(O)OR 6 , -C(O)N(R 7 )2, -OC(O)R 6 , -S(O)2R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -S(O)R 8 , -N(R 7 )2, -NO2, -C1-C6 alkyl-OR 7 , or -Si(R 15 )3. In certain embodiments, R 1 is C1-C6 alkyl.

[0094] Also provided are compounds of formula VA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0095] Also provided are compounds of formula VB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0096] In certain embodiments, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, -CN, -OR 7 , -C(O)OR 6 , -C(O)N(R 7 )2, -OC(O)R 6 , -S(O)2R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -S(O)R 8 , -N(R 7 )2, -NO2, -C1-C6 alkyl-OR 7 , or -Si(R 15 )3. In certain embodiments, R 1 is C1-C6 alkyl.

[0097] Also provided are compounds of Formula VI, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical Formula

[0098] Also provided are compounds of Formula VI, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical Formula

[0099] Also provided are compounds of formula VIA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts, [Chemical formula] In the formula, ring A, R 1 , R 3 , R 4Each of p and q is, independently, as defined herein.

[0100] Also provided are compounds of Formula VIB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chem.

[0101] Also provided are compounds of Formula VII, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chem.

[0102] Also provided are compounds of Formula VII, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chem.

[0103] Also provided are compounds of formula VIIA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotope-enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0104] Also provided are compounds of formula VIIB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotope-enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0105] Also provided are compounds of formula VIII, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts, [Chemical formula] In the formula, ring A, R 1 , R 2 , R 3 , R 4 , p, and q each independently are as defined herein.

[0106] In certain embodiments, ring A, or moiety [Chemical formula] is [Chemical formula] where 0 to 3 of U, V, W, X, Y, and Z are independently N, S, or O, and the remaining variables are CH or CR 3 and each [Chemical formula] independently represents a single bond or double bond conforming to the valence requirements based on U, V, W, X, Y, and Z.

[0107] In certain embodiments, ring A, or moiety [Chemical formula] is,

Chem.

Chem.

[0108] In certain embodiments, ring A is aryl or heteroaryl. In certain embodiments, ring A is monocyclic aryl or monocyclic heteroaryl. In certain embodiments, ring A is heterocyclyl. In certain embodiments, ring A is a 4- to 7-membered heterocyclyl. In certain embodiments, ring A is aryl. In certain embodiments, ring A is phenyl. In certain embodiments, ring A is heteroaryl. In certain embodiments, ring A is pyridyl. In certain embodiments, ring A is pyrazolyl. In certain embodiments, ring A is phenyl, pyridyl, piperidinyl, piperazinyl, or morpholinyl.

[0109] In certain embodiments, ring A is aryl or heteroaryl, each being substituted by one to three R 3 In certain embodiments, ring A is aryl or heteroaryl, each being substituted by one to three R 3 and at least one R 3 is C3-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each of the C3-C 3 cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 10 is optionally substituted by one to three R 10 ​

[0110] In certain embodiments, ring A is aryl or heteroaryl, each substituted by 1 to 3 R 3 and at least one R 3 is C3-C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C3-C 3 cycloalkyl, heterocyclyl, aryl, and heteroaryl of R 10 is optionally substituted by 1 to 3 R 10 . Each R 10 is independently -OR 12 , -N(R 12 )2, -S(O)2R 13 , -OC(O)CHR 12 N(R 12 )2, or C1-C6 alkyl, and the C1-C6 alkyl of R 10 is optionally independently substituted by 1 to 3 R 11 . Each R 11 is independently halo, -OR 12 , -N(R 12 )2, -Si(R 12 )3, -C(O)OR 12 , -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, or heterocyclyl. Each R 12 is independently hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl. Each R 13 is independently C1-C6 alkyl or C3-C 10 cycloalkyl.

[0111] In certain embodiments, ring A is bicyclo[1.1.1]pentan-1-yl, phenyl, piperidinyl, pyrazolyl, pyridyl, or quinolinyl, each substituted by one, two, or three R 3is optionally replaced. In certain embodiments, ring A is bicyclo[1.1.1]pentan-1-yl, phenyl, piperidinyl, pyrazolyl, pyridyl, or quinolinyl, each being substituted by one, two, or three R 3 substituted by. In certain embodiments, ring A is bicyclo[1.1.1]pentan-1-yl, phenyl, piperidinyl, pyrazolyl, pyridyl, or quinolinyl, each being substituted by two or three R 3 substituted by.

[0112] In certain embodiments, ring A is aryl or heteroaryl, each being substituted by two or three R 3 substituted by. In certain embodiments, ring A is aryl or heteroaryl, each being substituted by two or three R 3 substituted by, and at least one R 3 is halo.

[0113] In certain embodiments, ring A is cyclohexyl. In certain embodiments, ring A is C4-C 10 cycloalkyl. In certain embodiments, ring A is C4-C7 cycloalkyl. In certain embodiments, ring A is bicyclo[1.1.1]pentanyl. In certain embodiments, ring A is selected from cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0114] In certain embodiments, ring A, or moiety

Chemical formula

Chemical formula

[0115] In certain embodiments, ring A, or a moiety

Chem.

Chem.

[0116] In certain embodiments, ring A is

Chem.

Chem.

[0117] In certain embodiments, ring A, or a moiety

Chem.

Chem.

[0118] Also provided are compounds of Formula VIII, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chem.

[0119] Also provided are compounds of Formula VIIIA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts, [Chemical formula] wherein R 1 , R 2 , R 3 , R 4 Each of R, p, and q is, independently, as defined herein.

[0120] Also provided are compounds of Formula VIIIB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts, [Chemical formula] wherein R 1 , R 2 , R 3 , R 4 Each of R, p, and q is, independently, as defined herein.

[0121] In certain embodiments, R 1 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, -CN, -C(O)OR 6 , -C(O)N(R 7 )2, -N(R 7 )2, -OR 7 , or -C1-C6 alkyl-OR 7 .

[0122] In certain embodiments, R 1 is -C(O)OR 6or -C(O)N(R 7 )2.

[0123] In certain embodiments, R 1 is C1-C6 alkyl. In certain embodiments, in certain embodiments, R 1 is C2-C6 alkyl. In certain embodiments, R 1 is C3-C6 alkyl. In certain embodiments, R 1 is C5-C6 alkyl. In certain embodiments, R 1 is C2-C3 alkyl. In certain embodiments, R 1 is C4-C6 alkyl. In certain embodiments, R 1 is methyl. In certain embodiments, R 1 is n-butyl.

[0124] In certain embodiments, R 1 is -CH2-R 16 and R 16 is C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, C1-C5 haloalkyl, or -C1-C5 alkyl-OR 7 .

[0125] In certain embodiments, R 1 is C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C 10 cycloalkyl, -CN, -OR 7 , -C(O)N(R 7 )2, -OC(O)R 6 , -S(O)2R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -S(O)R 8 , -N(R 7 )2, -NO2, -C1-C6 alkyl-OR 7 , or -Si(R 15 )3.

[0126] In certain embodiments, R1 is other than methyl. In certain embodiments, R 1 is other than n-butyl. In certain embodiments, R 1 is other than -C(O)OR 6 . In certain embodiments, R 1 is other than -C(O)OCH3.

[0127] Also provided are compounds of formula IX, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0128] Also provided are compounds of formula IXA, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0129] Also provided are compounds of formula IXB, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts,

Chemical formula

[0130] In certain embodiments, R 2 is -C1-C2 haloalkyl, -C2-C3 alkenyl, -C2-C3 haloalkenyl, C2 alkynyl, C1-C2 haloalkyl and -C2-C3 alkenyl halo are optionally substituted with one or two -CH3, and C2 alkynyl is optionally substituted with one -CH3. In certain embodiments, R 2 is -C1-C2 haloalkyl. In certain embodiments, R 2 is -C2-C3 alkenyl. In certain embodiments, R 2 is C2-C3 alkenyl. In certain embodiments, R 2 is C2 alkynyl.

[0131] In certain embodiments, at least one R 3 is halo, -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 12 )3, -SF5, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -NR 12 C(O)OR 8 , -OC(O)R 8 , -C(O)R 6 , or -OC(O)CHR 8 N(R 12 )2.

[0132] In certain embodiments, at least one R 3 is a halo.

[0133] In certain embodiments, at least one R 3 is -NHR 8 In certain embodiments, at least one R 3 is -N(R 8 )2. In certain embodiments, q is 2, one R 3 is a halo, and the other R 3 is -N(R 8 )2. In certain embodiments, q is 3, two Rs 3 are independently a halo, and one R 3 is -N(R 8 )2.

[0134] In certain embodiments, at least one R 3 is -C(O)OR 6 or -C(O)R 6 .

[0135] In certain embodiments, at least one R 3 is -S(O)2N(R 7 )2, -S(O)N(R 7 )2, or -C(O)N(R 7 )2.

[0136] In certain embodiments, at least one R 3 is -S(O)2R 8 , -S(O)R 8 , -NR 12 C(O)R 8 , -NR 12 C(O)OR 8 , -OC(O)R 8 or -OC(O)CHR 8 N(R 12 )2.

[0137] In certain embodiments, each R 3 is independently a halo, -CN, -OR8 , -NHR 8 , -S(O)2R 8 , -S(O)2N(R 7 )2, -NO2, -Si(R 12 )3, -SF5, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -NR 12 C(O)OR 8 , -OC(O)R 8 , -OC(O)CHR 8 N(R 12 )2, C1-C6 alkyl, C3-C 10 cycloalkyl, heterocyclyl, heteroaryl, or -C1-C6 alkylheterocyclyl, and each C1-C6 alkyl, C3-C 3 of the cycloalkyl, heterocyclyl, heteroaryl, or -C1-C6 alkylheterocyclyl is independently optionally substituted with 1-3 R 10 s. 10

[0138] In certain embodiments, each R 3 is independently halo, -CN, -OR 8 , -NHR 8 , -S(O)2R 8 , -S(O)2N(R 7 )2, -NO2, -Si(R 12 )3, -SF5, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -NR 12 C(O)OR 8 , -OC(O)R 8 , -OC(O)CHR 8 N(R 12 )2, C1-C6 alkyl, C3-C 10 cycloalkyl, heterocyclyl, heteroaryl, or -C1-C6 alkylheterocyclyl, and each C1-C6 alkyl, C3-C 10Cycloalkyl, heterocyclyl, heteroaryl, or -C1-C6 alkylheterocyclyl is independently -OR 12 , -N(R 12 )2, -S(O)2R 13 , -OC(O)CHR 12 N(R 12 )2, and one to three halo, -OR 12 , -N(R 12 )2, -Si(R 12 )3, -C(O)OR 12 , -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, or C1-C6 alkyl optionally substituted with heterocyclyl and is independently optionally substituted with one to three substituents selected from each R 12 is independently hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl, each R 13 is independently C1-C6 alkyl or C3-C 10 cycloalkyl.

[0139] In certain embodiments, each R 3 is independently -NH2, fluoro, methyl, pyridine-4-carboxamide, pyridine-3-amino, pentyloxycarbonylamino, N-(3-aminobicyclo[1.1.1]pentan-1-yl)amino, morpholin-4-yl, methoxycarbonyl, dimethylcarbamoyl, cyclopropylcarbamoyl, cyclohexyl, cyclobutylcarbamoyl, cyclobutylaminosulfonyl, adamantylamino, (adamantan-1-ylamino)methyl, 3-methyl-1,2,4-oxadiazol-5-yl, 2-methylpyridine-4-carboxamide, (bicyclo[1.1.1]pentan-1-ylamino)methyl, (adamantan-1-yl)carbamoyl, or (2-methoxyethyl)carbamoyl.

[0140] In certain embodiments, q is 0 or 1 and R3 is -NH2, fluoro, methyl, pyridine-4-carboxamide, pyridine-3-amino, pentyloxycarbonylamino, N-(3-aminobicyclo[1.1.1]pentan-1-yl)amino, morpholin-4-yl, methoxycarbonyl, dimethylcarbamoyl, cyclopropylcarbamoyl, cyclohexyl, cyclobutylcarbamoyl, cyclobutylaminosulfonyl, adamantylamino, (adamantan-1-ylamino)methyl, 3-methyl-1,2,4-oxadiazol-5-yl, 2-methylpyridine-4-carboxamide, (bicyclo[1.1.1]pentan-1-ylamino)methyl, (adamantan-1-yl)carbamoyl, or (2-methoxyethyl)carbamoyl.

[0141] In certain embodiments, each R 4 is independently halo, -CN, -OH, -OR 8 , -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 15 )3, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -OC(O)R 8 , -C(O)R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 10 cycloalkyl, and each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 4 cycloalkyl of R 10 is independently optionally substituted with 1-3 R 10 s.

[0142] In certain embodiments, each R 4 is independently halo, -CN, -OR 7, C1-C6 alkyl, C2-C6 alkynyl, or C3-C 10 is cycloalkyl, and R 4 each C1-C6 alkyl, C2-C6 alkynyl, or C3-C 10 cycloalkyl is independently optionally substituted with 1-3 R 10 .

[0143] In certain embodiments, each R 4 is independently halo, -CN, -OH, C1-C6 alkyl, C2-C6 alkynyl, or C3-C 10 cycloalkyl.

[0144] In certain embodiments, each R 4 is independently halo, -CN, -OH, -OR 8 , C1-C6 alkyl, or C2-C6 alkynyl, and the C1-C6 alkyl of R 4 is optionally substituted with 1-3 R 10 .

[0145] In certain embodiments, each R 4 is independently halo, -CN, -OH, -OR 8 , C1-C6 alkyl, C2-C6 alkynyl, and the C1-C6 alkyl of R 4 is independently -OR 12 , -N(R 12 )2, -S(O)2R 13 , -OC(O)CHR 12 N(R 12 )2, and 1-3 halo, -OR 12 , -N(R 12 )2, -Si(R 12 )3, -C(O)OR 12 , -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, or C1-C6 alkyl optionally substituted with heterocyclyl, and is optionally substituted with 1-3 substituents selected from each R 12is, independently, hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl, each R 13 is, independently, C1-C6 alkyl or C3-C 10 cycloalkyl.

[0146] In certain embodiments, each R 5 is, independently, halo, -CN, -OH, -OR 8 , -NH2, -NHR 8 , -N(R 8 )2, -S(O)2R 8 , -S(O)R 8 , -S(O)2N(R 7 )2, -S(O)N(R 7 )2, -NO2, -Si(R 15 )3, -C(O)OR 6 , -C(O)N(R 7 )2, -NR 12 C(O)R 8 , -OC(O)R 8 , -C(O)R 6 , C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 10 cycloalkyl, and each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or C3-C 5 cycloalkyl of R 10 is independently optionally substituted with 1-3 R 10 s.

[0147] In certain embodiments, each R 5 is, independently, halo, -CN, -OR 7 , C1-C6 alkyl, C2-C6 alkynyl, or C3-C 10 cycloalkyl, and each C1-C6 alkyl, C2-C6 alkynyl, or C3-C 5 cycloalkyl of R 10 is independently optionally substituted with 1-3 R 10 s.

[0148] In certain embodiments, each R 5is independently halo, -CN, -OH, C1-C6 alkyl, C2-C6 alkynyl, or C3-C 10 cycloalkyl.

[0149] In certain embodiments, each R 5 is independently halo, -CN, -OH, -OR 8 , C1-C6 alkyl, or C2-C6 alkynyl, and the C1-C6 alkyl of R 5 is optionally substituted with 1-3 R 10 .

[0150] In certain embodiments, each R 5 is independently halo, -CN, -OH, -OR 8 , C1-C6 alkyl, C2-C6 alkynyl, and the C1-C6 alkyl of R 5 is independently -OR 12 , -N(R 12 )2, -S(O)2R 13 , -OC(O)CHR 12 N(R 12 )2, and 1-3 halo, -OR 12 , -N(R 12 )2, -Si(R 12 )3, -C(O)OR 12 , -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, or C1-C6 alkyl optionally substituted with 1-3 substituents selected from heteroaryl, each R 12 is independently hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl, each R 13 is independently C1-C6 alkyl or C3-C 10 cycloalkyl.

[0151] In certain embodiments, each R 6is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or -C1-C6 alkyl C3-C 10 cycloalkyl, and each R 6 is independently further substituted with 1 to 3 R 11 .

[0152] In certain embodiments, each R 6 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, or -C1-C6 alkyl C3-C 10 cycloalkyl, and each R 6 is independently further substituted with 1 to 3 halo, -OR 12 , -N(R 12 )2, -Si(R 12 )3, -C(O)OR 12 , -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, or heterocyclyl, and each R 12 is independently hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl.

[0153] In certain embodiments, each R 7 is independently hydrogen, C1-C6 alkyl, C3-C 10 cycloalkyl, heterocyclyl, heteroaryl, -C1-C6 alkyl C3-C6 cycloalkyl, -C1-C6 alkyl heterocyclyl, or two R 7 are taken together with the nitrogen atom to which they are attached to form a 4- to 7-membered heterocyclyl, and each R 7 or the ring formed thereby is independently further substituted with 1 to 3 R 11 .

[0154] In certain embodiments, each R 7 is independently hydrogen, C1-C6 alkyl, C3-C 10Is cycloalkyl, heterocyclyl, heteroaryl, -C1-C6 alkyl C3-C6 cycloalkyl, -C1-C6 alkyl heterocyclyl, or two Rs 7 Together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, and each R 7 Or the ring formed thereby is independently 1 to 3 halos, -OR 12 , -N(R 12 )2, -Si(R 12 )3, -C(O)OR 12 , -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, or heterocyclyl, and is further substituted with Each R 12 Is independently hydrogen, C1-C6 alkyl or C3-C 10 Cycloalkyl.

[0155] In certain embodiments, each R 8 Is independently C1-C6 alkyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -C1-C6 alkyl C3-C 10 Cycloalkyl, or -C1-C6 alkyl aryl, and each R 8 Is independently further substituted with 1 to 3 Rs 11 .

[0156] In certain embodiments, each R 8 Is independently C1-C6 alkyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, -C1-C6 alkyl C3-C 10 Cycloalkyl, or -C1-C6 alkyl aryl, and each R 8 Is independently 1 to 3 halos, -OR 12 , -N(R 12 )2, -Si(R 12 )3, -C(O)OR 12 , -NR 12 C(O)OR 12 , -OC(O)CHR12 N(R 12 )2, C1-C6 alkyl, or heterocyclyl, further substituted with each R 12 is, independently, hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl.

[0157] In certain embodiments, each R 10 is, independently, -OR 12 , -N(R 12 )2, -S(O)2R 13 , -OC(O)CHR 12 N(R 12 )2, or C1-C6 alkyl, and the C1-C6 alkyl of R 10 is optionally independently substituted with 1 to 3 R 11 . each R 11 is, independently, halo, -OR 12 , -N(R 12 )2, -Si(R 12 )3, -C(O)OR 12 , -NR 12 C(O)OR 12 , -OC(O)CHR 12 N(R 12 )2, C1-C6 alkyl, or heterocyclyl. each R 12 is, independently, hydrogen, C1-C6 alkyl or C3-C 10 cycloalkyl. each R 13 is, independently, C1-C6 alkyl or C3-C 10 cycloalkyl.

[0158] In certain embodiments, each R 15 is, independently, C1-C6 alkyl.

[0159] In certain embodiments, p is 0. In certain embodiments, p is 0 or 1. In certain embodiments, p is 1 or 2. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0160] In certain embodiments, q is 0. In certain embodiments, q is 0 or 1. In certain embodiments, q is 1 or 2. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0161] Also provided are compounds selected from Table 1, or their tautomers, stereoisomers, mixtures of stereoisomers, isotopically enriched analogs, or pharmaceutically acceptable salts. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

Table 1-11

Table 1-12

Table 1-13

[0162] 3. Method of Use In certain embodiments, the compounds described herein are used in a method of treating cancer. In certain embodiments, a method of treating cancer comprises administering to a subject in need thereof a therapeutically effective amount of any of the compounds described herein.

[0163] In certain embodiments, a compound is used in a method of inhibiting GPX4 in a cell, comprising contacting the cell with an effective amount of a compound or composition described herein to inhibit GPX4 in the cell. In certain embodiments, the cell is a cancer cell. In certain embodiments, the method comprises administering to a patient in need thereof an effective amount of a compound or composition described herein.

[0164] In certain embodiments, a compound is used in a method of inducing ferroptosis in a cell, comprising contacting the cell with an effective amount of a compound or composition described herein. In certain embodiments, the method comprises administering to a patient in need thereof an effective amount of a compound or composition described herein.

[0165] In certain embodiments, a method for treating cancer in a patient in need of treatment is provided, comprising administering an effective amount of a compound or composition provided herein.

[0166] In certain embodiments, the compound is used in a method of treating cancer in a subject in need thereof, comprising administering to the subject having cancer a therapeutically effective amount of the ferroptosis-inducing compound described herein. Various cancers for treatment with the compound include, but are not limited to, adrenocortical cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, glioma, astrocytoma, neuroblastoma, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, kidney cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, and soft tissue cancer. In certain embodiments, the compound is used to treat pancreatic cancer.

[0167] In certain embodiments, the cancer is renal cell carcinoma (RCC), pancreatic cancer, lung cancer, breast cancer, or prostate cancer. In certain embodiments, a method for treating renal cell carcinoma (RCC) in a patient in need thereof is provided, comprising administering an effective amount of the compound or composition provided herein. In certain embodiments, a method for treating pancreatic cancer in a patient in need thereof is provided, comprising administering an effective amount of the compound or composition provided herein. In certain embodiments, a method for treating lung cancer in a patient in need thereof is provided, comprising administering an effective amount of the compound or composition provided herein. In certain embodiments, a method for treating breast cancer in a patient in need thereof is provided, comprising administering an effective amount of the compound or composition provided herein. In certain embodiments, a method for treating prostate cancer in a patient in need thereof is provided, comprising administering an effective amount of the compound or composition provided herein.

[0168] In certain embodiments, provided is a method for treating a malignant solid tumor in a patient in need of treatment, comprising administering to the patient an effective amount of a compound or composition provided herein. In certain embodiments, the malignant solid tumor is a cancer tumor. In certain embodiments, the malignant solid tumor is a lymphoma. In certain embodiments, the malignant solid tumor is a sarcoma.

[0169] In certain embodiments, cancers for treatment with the compound can be selected from, among others, adrenal cortex cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer (e.g., osteosarcoma), brain cancer (e.g., glioma, astrocytoma, neuroblastoma, etc.), breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, blood cancer (e.g., leukemia and lymphoma), intestinal cancer (small intestine), liver cancer, lung cancer (e.g., bronchial cancer, small cell lung cancer, non-small cell lung cancer, etc.), oral cancer, ovarian cancer, pancreatic cancer, kidney cancer, prostate cancer, salivary gland cancer, skin cancer (e.g., basal cell cancer, melanoma), stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, and soft tissue cancer. In certain embodiments, the cancer is renal cell carcinoma (RCC). In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is prostate cancer.

[0170] In certain embodiments, the cancer for treatment with the compound is pancreatic cancer. In certain embodiments, the pancreatic cancer for treatment with the compound is pancreatic adenocarcinoma or metastatic pancreatic cancer. In certain embodiments, the cancer for treatment with the compound is stage I, stage II, stage III, or stage IV pancreatic adenocarcinoma.

[0171] In certain embodiments, the cancer for treatment with the compound is lung cancer. In certain embodiments, the lung cancer for treatment with the compound is small cell lung cancer or non-small cell lung cancer. In certain embodiments, the non-small cell lung cancer for treatment with the compound is adenocarcinoma, squamous cell carcinoma, or large cell carcinoma. In certain embodiments, the lung cancer for treatment with the compound is metastatic lung cancer.

[0172] In certain embodiments, the cancer for treatment with the compound is blood cancer. In certain embodiments, the blood cancer is selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell chronic myeloid leukemia (CML), and multiple myeloma.

[0173] In certain embodiments, the cancer for treatment with the compound is leukemia selected from acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell chronic myeloid leukemia (CML), and multiple myeloma.

[0174] In certain embodiments, the cancer for treatment with the compound is lymphoma selected from Hodgkin lymphoma, non-Hodgkin lymphoma, and Burkitt lymphoma.

[0175] In certain embodiments, the cancer for treatment by the compounds is a cancer characterized by mesenchymal features or a mesenchymal phenotype. In some cancers, the acquisition of mesenchymal features is associated with cancer motility (e.g., intravascular invasion) and invasiveness. Mesenchymal features include, among other things, enhanced migratory ability, invasiveness, increased resistance to apoptosis, and increased production of extracellular matrix (ECM) components. In addition to these physiological properties, mesenchymal features can include the expression of certain biomarkers, including, among others, E-cadherin, N-cadherin, integrin, FSP-1, α-SMA, vimentin, β-catenin, collagen I, collagen II, collagen III, collagen IV, fibronectin, laminin 5, SNAIL-1, SNAIL-2, Twist-1, Twist-2, and Lef-1. In certain embodiments, the cancers selected for treatment with the compounds herein include, among others, breast cancer, lung cancer, head and neck cancer, prostate cancer, and colon cancer. In certain embodiments, the mesenchymal features can be specific to the cancer type or can be induced or selected by treatment of the cancer with chemotherapy and / or radiation therapy.

[0176] In certain embodiments, the cancer for treatment by the compounds is identified or determined to have activated or oncogenic RAS activity. In certain embodiments, RAS is K-RAS, H-RAS, or N-RAS. In certain embodiments, the activated or oncogenic RAS is an activated or oncogenic RAS mutation.

[0177] In certain embodiments, the cancer selected for treatment by the compounds is determined or identified as having activated or oncogenic RAS activity. In certain embodiments, the activated or oncogenic RAS activity is an activated or oncogenic RAS mutation. In certain embodiments, the activated or oncogenic RAS activity is activated or activated K-RAS activity, particularly an activated or oncogenic K-RAS mutation. In certain embodiments, the activated or oncogenic RAS activity is activated or activated N-RAS activity, particularly an activated or oncogenic N-RAS mutation. In certain embodiments, the activated or oncogenic RAS activity is activated or activated H-RAS activity, particularly an activated or oncogenic H-RAS mutation.

[0178] In certain embodiments, the compounds can be used to treat cancers that are refractory to one or more other chemotherapeutic agents, particularly cytotoxic chemotherapeutic agents, or cancers that are resistant to radiation therapy. In certain embodiments, the compounds are used to treat cancers that have developed resistance to chemotherapeutic agents that activate other cell death pathways such as apoptosis, mitotic catastrophe, necrosis, senescence, and / or autophagy.

[0179] In certain embodiments, the cancer for treatment by the compounds is identified as being refractory or resistant to chemotherapy. In certain embodiments, the cancer is identified as being refractory or resistant to one or more of alkylating agents, anti-cancer antibiotic formulations, antimetabolites (e.g., folic acid antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase inhibitors, anti-microtubule agents (e.g., taxanes, vinca alkaloids), hormonal agents (e.g., aromatase inhibitors), plant-derived agents and their synthetic derivatives, anti-angiogenic agents, differentiation inducers, cell growth arrest inducers, apoptosis inducers, cytotoxic agents, agents that affect cellular bioenergies, i.e., agents that affect the ATP levels of cells and the molecules / activities that regulate these levels, biological agents, e.g., monoclonal antibodies, kinase inhibitors, and inhibitors of growth factors and their receptors.

[0180] In certain embodiments, cancers for treatment with a compound are afatinib, afuresertib, alectinib, alisertib, albosidib, amsacrine, amonafide, ambatiniib, axitinib, azacitidine, azathioprine, bafetinib, barasertib, bendamustine, bleomycin, bosutinib, bortezomib, busulfan, cabozantinib, camptothecin, canertinib, capecitabine, cabazitaxel, carboplatin, carmustine, cenicriviroc, ceritinib, chlorambucil, cisplatin, cladribine, clofarabine, clevulanib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dacomitinib, dactinomycin, danusertib, dasatinib, daunorubicin, decitabine, dinaciclib, docetaxel, dovitinib, doxorubicin, epirubicin, epitinib, eribulin mesylate, erlotinib, etirinotecan, etoposide, everolimus, exemestane, floxuridine, fludarabine, fluorouracil, gefitinib, gemcitabine, hydroxyurea, ibrutinib, icotinib, idarubicin, ifosfamide, imatinib, imetelstat, ipatasertib, irinotecan, ixabepilone, lapatinib, lenalidomide, lestaurtinib, lomustine, lucitanib, masitinib, mechlorethamine, melphalan, mercaptopurine, methotrexate, midostaurin, mitomycin, mitoxantrone, mubritinib, nelarabine, neratinib, nilotinib, nintedanib, omacetaxine, olantinib, oxaliplatin, paclitaxel, palbociclib, parifosfamide tris, pazopanib, peritinib, pemetrexed, pentostatin, plicamycin, ponatinib, pozitinib, pralatrexate, procarbazine, quizartinib, raltitrexed, regorafenib, luxolitinib, seribantumab, sorafenib, streptozocin, sulfatinib, sunitinib, tamoxifen, tanzisertib, temozolomide, temsirolimus, teniposide, teratinib, thioguanine, thiotepa, topotecan, uramustine, valrubicin, vandetanib, vemurafenib (Zelborae), vincristine, vinblastine, vinorelbine,A cancer that has been identified as being refractory or resistant to one or more of vincristine and vinblastine.,

[0181] In certain embodiments, the cancer for treatment with the compound is identified as being refractory or resistant to one or more chemotherapeutic agents selected from cyclophosphamide, chlorambucil, melphalan, mechlorethamine, ifosfamide, busulfan, lomustine, streptozocin, temozolomide, dacarbazine, cisplatin, carboplatin, oxaliplatin, procarbazine, uracil mustard, methotrexate, pemetrexed, fludarabine, cytarabine, fluorouracil, floxuridine, gemcitabine, capecitabine, vinblastine, vincristine, vinorelbine, etoposide, paclitaxel, docetaxel, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone, bleomycin, mitomycin, hydroxyurea, topotecan, irinotecan, amsacrine, teniposide, and erlotinib.

[0182] In certain embodiments, the cancer for treatment with the compound is a cancer that is resistant to ionizing radiation therapy. The radiation resistance of the cancer can be intrinsic or can be the result of radiation therapy. In certain embodiments, the cancer for treatment with the compound is, inter alia, radiation-resistant adrenocortical cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer (e.g., osteosarcoma), brain cancer (e.g., glioma, astrocytoma, neuroblastoma, etc.), breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, blood cancer (e.g., leukemia and lymphoma), intestinal cancer (small intestine), liver cancer, lung cancer (e.g., bronchial, small cell lung cancer, non-small cell lung cancer, etc.), oral cancer, ovarian cancer, pancreatic cancer, kidney cancer, prostate cancer, salivary gland cancer, skin cancer (e.g., basal cell cancer, melanoma), stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, uterine cancer, or vaginal cancer. In certain embodiments, the cancer is pancreatic cancer, breast cancer, glioblastoma, advanced non-small cell lung cancer, bladder cancer, sarcoma, or soft tissue cancer.

[0183] 4. Combination Therapy In certain embodiments, the compounds described herein are used in combination with one or more of other (e.g., second) therapeutic treatments for cancer. In certain embodiments, the compounds can be used as monotherapy or in combination therapy with one or more therapeutic treatments, particularly in combination with one or more chemotherapeutic agents, as further provided below. In certain embodiments, the compounds are used in combination with a second therapeutic agent, and the compounds are used at a level that sensitizes cancer or cancer cells to the second therapeutic agent, e.g., a level of the compound that does not cause significant cell death. In certain embodiments, the compounds can be used in combination with radiation therapy to sensitize cells to radiation therapy or as an adjunct to radiation therapy (e.g., at a dose sufficient to activate cell death pathways).

[0184] In certain embodiments, a subject having cancer is treated with a combination of a compound described herein and radiation therapy. In certain embodiments, the method comprises administering to a subject having cancer a therapeutically effective amount of a compound of the present disclosure and adjunctively treating the subject with an effective amount of radiation therapy. In certain embodiments, the compound is administered to a subject in need thereof before, concurrently with, or after radiation treatment.

[0185] In certain embodiments, the method comprises administering an effective amount of a compound described herein to a subject having cancer to sensitize the cancer to radiation treatment and administering a therapeutically effective amount of radiation therapy to treat the cancer. In certain embodiments, an effective amount of X-rays and γ-rays are administered to the subject. In certain embodiments, an effective amount of particle radiation is administered to the subject, and the particle radiation is selected from electron beam, proton beam, and neutron beam radiation. In certain embodiments, the radiation therapy is fractionated.

[0186] In certain embodiments, a subject having cancer is administered a therapeutically effective amount of a compound described herein, or a first pharmaceutical composition thereof, and adjunctively administered a therapeutically effective amount of a second chemotherapeutic agent, or a second pharmaceutical composition thereof.

[0187] In certain embodiments, the second chemotherapeutic agent is selected from platinum agents, alkylating agents, anti-cancer antibiotic agents, antimetabolites (e.g., folic acid antagonists, purine analogs, pyrimidine analogs, etc.), topoisomerase I inhibitors, topoisomerase II inhibitors, antimicrotubule agents (e.g., taxanes, vinca alkaloids), hormonal agents (e.g., aromatase inhibitors), plant-derived agents and their synthetic derivatives, anti-angiogenic agents, differentiation-inducing agents, cell growth arrest-inducing agents, apoptosis-inducing agents, cytotoxic agents, agents that affect cell bioenergy, i.e., agents that affect the cell's ATP levels and the molecules / activities that regulate these levels, anti-cancer biological agents (e.g., monoclonal antibodies), kinase inhibitors, and inhibitors of growth factors and their receptors.

[0188] In certain embodiments, the second chemotherapeutic agent is an angiogenesis inhibitor such as, but not limited to, soluble VEGFR-1, NRP-1, angiopoietin 2, TSP-1, TSP-2, angiostatin and related molecules, endostatin, vasostatin, calreticulin, platelet factor-4, TIMP, CDAI, Meth-1, Meth-2, IFN-α, IFN-β, IFN-γ, CXCL10, IL-4, IL-12, IL-18, prothrombin (kringle domain-2), antithrombin III fragment, prolactin, VEGI, SPARC, osteopontin, maspin, canstatin (fragment of COL4A2), or an inhibitor of prolferin-related protein. In certain embodiments, the angiogenesis inhibitor is bevacizumab (Avastin), itraconazole, carboxyamidotriazole, TNP-470 (analog of fumagillin), CM101, IFN-α, IL-12, platelet factor-4, suramin, SU5416, thrombospondin, VEGFR antagonist, angiogenesis inhibitory steroid + heparin, cartilage-derived angiogenesis inhibitor factor (CDAI), matrix metalloproteinase inhibitor, angiostatin, endostatin, 2-methoxyestradiol, tecogalan, tetrathiomolybdate, thalidomide, thrombospondin, prolactin, αVβ3 inhibitor, linomide, ramucirumab, tasquinimod, ranibizumab, sorafenib (Nexavar), sunitinib (Sutent), pazopanib (Votrient), or everolimus (Afinitor).

[0189] In certain embodiments, the second chemotherapeutic agent is a cyclin-dependent kinase (CDK) inhibitor (e.g., a CDK4 / CDK6 inhibitor). Examples include, but are not limited to, palbociclib (Ibrance), ribociclib (optionally further combined with letrozole), abemaciclib (LY2835219, Verzenio), P1446A-05, and trilaciclib (G1T28).

[0190] In certain embodiments, the second chemotherapeutic agent is a Bruton's tyrosine kinase (BTK) inhibitor, such as, but not limited to, ibrutinib (PCI-32765), acalabrutinib, ONO-4059 (GS-4059), spebrutinib (AVL-292, CC-292), BGB-3111, and HM71224.

[0191] In certain embodiments, the second chemotherapeutic agent is a BRAF inhibitor. Examples include, but are not limited to, BAY43-9006 (sorafenib, Nexavar), PLX-4032 (vemurafenib), GDC-0879, PLX-4720, dabrafenib, and LGX818.

[0192] In certain embodiments, the second chemotherapeutic agent is an EGFR inhibitor. Examples include, but are not limited to, gefitinib, erlotinib, afatinib, brigatinib, icotinib, cetuximab, osimertinib, panitumumab, brigatinib, lapatinib, cimaVax-EGF, and belinostat.

[0193] In certain embodiments, the second chemotherapeutic agent is a human epidermal growth factor receptor 2 (HER2) inhibitor. Examples include, but are not limited to, trastuzumab, pertuzumab (optionally in further combination with trastuzumab), margetuximab, and NeuVax.

[0194] In certain embodiments, a method for enhancing a subject's responsiveness to an immunotherapeutic agent or an immunogenic chemotherapeutic agent is disclosed herein, the method comprising administering to a subject in need thereof an effective amount of a compound described herein and an effective amount of an immunotherapeutic agent and / or an immunogenic chemotherapeutic agent. In certain embodiments, the method further comprises administering to the subject a lipoxygenase inhibitor. In certain embodiments, the subject has a tumor whose cellular microenvironment is rich in stromal cells. In certain embodiments, administration of the compound described herein results in killing of one or more stromal cells in the microenvironment of tumor cells. In certain embodiments, administration of an effective amount of an immunotherapeutic agent and / or an immunogenic chemotherapeutic agent results in killing of one or more tumor cells. Also provided herein is a combination comprising a compound described herein and an immunotherapeutic agent, a lipoxygenase inhibitor, or an immunogenic chemotherapeutic agent. In certain embodiments, the immunotherapeutic agent is selected from a CTLA4, PDL1, or PD1 inhibitor. In certain embodiments, the immunotherapeutic agent can be selected from a CTLA4 inhibitor such as ipilimumab, a PD1 inhibitor such as pembrolizumab or nivolumab, or a PDL1 inhibitor such as atezolizumab or durvalumab. In certain embodiments, the immunotherapeutic agent is pembrolizumab. In other embodiments, the immunogenic chemotherapeutic agent is a compound selected from anthracycline, doxorubicin, cyclophosphamide, paclitaxel, docetaxel, cisplatin, oxaliplatin, or carboplatin. In certain embodiments, a combination comprising a compound described herein and a lipoxygenase inhibitor is provided herein. In certain embodiments, the lipoxygenase inhibitor is selected from PD147176 and / or ML351. In certain embodiments, the lipoxygenase inhibitor may be a 15-lipoxygenase inhibitor (see, e.g., Sadeghian et al., Expert Opinion on Therapeutic Patents, 2015, 26:1, 65-88).

[0195] In certain embodiments, the second chemotherapeutic agent is an alkylating agent including, but not limited to, adozelesin, altretamine, bendamustine, bizelesin, busulfan, carboplatin, carboquone, carmofur, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, etoglucid, fotemustine, hepsulfam, ifosfamide, improsulfan, lomustine, mannosulfan, mechlorethamine, melphalan, mitobronitol, nedaplatin, nimustine, oxaliplatin, piposulfan, prednimustine, procarbazine, ranimustine, satraplatin, semustine, streptozocin, temozolomide, thiotepa, treosulfan, triaziquone, triethylenemelamine, triplatin tetranitrate, trofosfamide, and uramustine; an antibiotic including, but not limited to, aclarubicin, amrubicin, bleomycin, dactinomycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, idarubicin, menogaril, mitomycin, neocarzinostatin, pentostatin, pirarubicin, plicamycin, valrubicin, and zorubicin; an antimetabolite including, but not limited to, aminopterin, azacitidine, azathioprine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, tegafur-uracil, thioguanine, trimethoprim, trimetrexate, and vidarabine; immunotherapy, alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, brentuximab, tositumomab, trastuzumab, 90YAntibody therapies including, but not limited to, ipritumomab tiuxetan, ipilimumab, tremelimumab, and anti-CTLA-4 antibodies; hormones or hormone antagonists including, but not limited to, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, megestrol, raloxifene, tamoxifen, and toremifene; taxanes including, but not limited to, DJ-927, docetaxel, TPI 287, larotaxel, ortataxel, paclitaxel, DHA-paclitaxel, and tesetaxel; retinoids including, but not limited to, alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; alkaloids including, but not limited to, dexamethasone, homoharringtonine, vinblastine, vincristine, vindesine, vinflunine, and vinorelbine; anti-angiogenic agents including, but not limited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; topoisomerases including, but not limited to, amsacrine, belotecan, edotecarin, etoposide, etoposide phosphate, exatecan, irinotecan (and the active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), lucanthone, mitoxantrone, pixantrone, rubitecan, teniposide, topotecan, and 9-aminocamptothecin; axitinib (AG 013736), dasatinib (BMS 354825), erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, motesanib diphosphate (AMGKinase inhibitors including, but not limited to, nilotinib (AMN107), seliciclib, sorafenib, sunitinib malate, AEE-788, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, celsemitinib, paradox breakers (such as PLX8394 or PLX7904 etc.), LGX818, BGB-283, pexidartinib (PLX3397), and batatinib; target signal transduction inhibitors including, but not limited to, bortezomib, geldanamycin, and rapamycin; biological response modifiers including, but not limited to, imiquimod, interferon-α, and interleukin-2; and 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrenatant, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, siramesine, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguazone, oblimersen, sulindac, tetrathiomolybdate, thiazofurin, mTOR inhibitors (e.g., sirolimus, temsirolimus, everolimus, deforolimus, INK28, AZD8055), PI3K inhibitors (e.g., BEZ235, GDC-0941, XL147, XL765, BMK120), cyclin-dependent kinase (CDK) inhibitors (e.g., CDK4 inhibitors or CDK6 inhibitors, such as palbociclib (PD-0332991), ribociclib (LEE011), abemaciclib (LY2835219), P1446A-05, abemaciclib (LY2835219), trilaciclib (G1T28), etc.), AKT inhibitors, Hsp90 inhibitors (e.g., geldanamycin, radicicol, tanespimycin), farnesyltransferase inhibitors (e.g., tipifarnib), aromatase inhibitors (anastrozole letrozole exemestane), and other chemotherapeutic agents including, but not limited to, AS703026, AZD6244 (celsemitinib), AZD8330, BIXMEK inhibitors including, but not limited to, 02188, CI-1040 (PD184352), GSK1120212 (also known as trametinib or JTP-74057), cobimetinib, PD0325901, PD318088, PD98059, RDEA119 (BAY 869766), TAK-733, and U0126-EtOH; AEE788, AG-1478 (Tyrphostin AG-1478), AG-490, apatinib (YN968D1), AV-412, AV-951 (tifosiban), axitinib, AZD8931, BIBF1120 (Vargatef), BIBW2992 (Afatinib), BMS794833, BMS-599626, brivanib (BMS-540215), brivanib alaninate (BMS-582664), cediranib (AZD2171), chrysophanic acid (chrysophanol), clearnolaniib (CP-868569), CUDC-101, CYC116, dovitinib D-lactate (TKI258 D-lactate), E7080, erlotinib hydrochloride (Tarceva, CP-358774, OSI-774, NSC-718781), foretinib (GSK1363089, XL880), gefitinib (ZD-1839 or Iressa), imatinib (Gleevec), imatinib mesylate, Ki8751, KRN 633, lapatinib (Tykerb), lenvatinib (ABT-869), masitinib (Masivet, AB1010), MGCD-265, motesanib (AMG-706), MP-470, mubritinib (TAK 165), neratinib (HKI-272), NVP-BHG712, OSI-420 (desmethylerlotinib, CP-473420), OSI-930, pazopanib HCl, PD-153035 HCl, PD173074, pelitinib (EKB-569), PF299804, ponatinib (AP24534), PP121, RAF265 (CHIR-265), Raf265 derivatives, regorafenib (BAY 73-4506), sorafenib tosylate (Nexavar), sunitinib malate (Sutent), teratinib (BAYSelected from tyrosine kinase inhibitors including, but not limited to, sunitinib (SU11248), sorafenib (BAY 43-9006), axitinib (AG-013736), pazopanib (GW786034), lapatinib (Tykerb), nilotinib (AMN107), dasatinib (Sprycel), imatinib (Gleevec), gefitinib (Iressa), erlotinib (Tarceva), vandetanib (Zactima), brivanib alaninate (PTK787), WZ3146, WZ4002, WZ8040, quizartinib, cabozantinib, XL647, EGFR siRNA, FLT4 siRNA, KDR siRNA; antidiabetic drugs such as metformin; PPAR agonists (rosiglitazone, pioglitazone, bezafibrate, ciprofibrate, clofibrate, gemfibrozil, fenofibrate, indiglitazone); DPP4 inhibitors (sitagliptin, vildagliptin, saxagliptin, dutogliptin, gemigliptin, alogliptin); or EGFR inhibitors including, but not limited to, AEE-788, AP-26113, BIBW-2992 (Tovok), CI-1033, GW-572016, Iressa, LY2874455, RO-5323441, Tarceva (erlotinib, OSI-774), CUDC-101, and WZ4002.

[0196] In certain embodiments, the second chemotherapeutic agent is selected from afatinib, afuresertib, alectinib, alisertib, albosidib, amsacrine, amonafide, ambatiniib, axitinib, azacitidine, azathioprine, bafetinib, barasertib, bendamustine, bleomycin, bosutinib, bortezomib, busulfan, cabozantinib, camptothecin, canertinib, capecitabine, cabazitaxel, carboplatin, carmustine, cenicriviroc, ceritinib, chlorambucil, cisplatin, cladribine, clofarabine, clearnolaniib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dacarbazine, dacomitinib, dactinomycin, danusertib, dasatinib, daunorubicin, decitabine, dinaciclib, docetaxel, dovitinib, doxorubicin, epirubicin, epitinib, eribulin mesylate, erlotinib, etirinotecan, etoposide, everolimus, exemestane, floxuridine, fludarabine, fluorouracil, gefitinib, gemcitabine, hydroxyurea, ibrutinib, icotinib, idarubicin, ifosfamide, imatinib, imetelstat, ipatasertib, irinotecan, ixabepilone, lapatinib, lenalidomide, lestaurtinib, lomustine, lucitanib, masitinib, mechlorethamine, melphalan, mercaptopurine, methotrexate, midostaurin, mitomycin, mitoxantrone, mubritinib, nelarabine, neratinib, nilotinib, nintedanib, omacetaxine, olantinib, oxaliplatin, paclitaxel, palbociclib, parifosfamide tris, pazopanib, pelitinib, pemetrexed, pentostatin, plicamycin, ponatinib, poziotinib, pralatrexate, procarbazine, quizartinib, raltitrexed, regorafenib, luxolitinib, seribantumab, sorafenib, streptozocin, sulfatinib, sunitinib, tamoxifen, tanespimycin, temozolomide, temsirolimus, teniposide, teratinib, thioguanine, thiotepa, topotecan, uramustine, valrubicin, vandetanib, vemurafenib (Zelboraf), vincristine, vinblastine, vinorelbine, and vindesine, and the like.In certain embodiments, the compounds of the present specification are administered before, simultaneously with, or after treatment with a chemotherapeutic agent.

[0197] In certain embodiments, a method of treating cancer comprises administering a therapeutically effective amount of a compound described herein and a therapeutically effective amount of a biological agent used in the treatment of cancer.In certain embodiments, the biological agent is selected from anti-BAFF (e.g., belimumab), anti-CCR4 (e.g., mogamulizumab), anti-CD19 / CD3 (e.g., blinatumomab), anti-CD20 (e.g., ofatumumab, rituximab, ibritumomab tiuxetan, obinutuzumab, tositumomab), anti-CD22 (e.g., moxetumomab pasudotox), anti-CD30 (e.g., brentuximab vedotin), anti-CD33 (e.g., gemtuzumab), anti-CD37 (e.g., otrexup), anti-CD38 (e.g., daratumumab), anti-CD52 (e.g., alemtuzumab), anti-CD56 (e.g., lorbevizumab mertansine), anti-CD74 (e.g., mirvetuximab), anti-CD105, anti-CD248 (TEM1) (e.g., ontuxizumab), anti-CTLA4 (e.g., tremelimumab, ipilimumab), anti-EGFL7 (e.g., parsaclisib), anti-EGFR (HER1 / ERBB1) (e.g., panitumumab, nimotuzumab, necitumumab, cetuximab, imiglucerase, fuzulizumab), anti-FZD7 (e.g., vantictumab), anti-HER2 (ERBB2 / neu) (e.g., margetuximab, pertuzumab, ado-trastuzumab emtansine, trastuzumab), anti-HER3 (ERBB3), anti-HGF (e.g., rilotumumab, ficlatuzumab), anti-IGF-1R (e.g., ganitumab, figitumumab, cixutumumab, darolutamide), anti-IGF-2R, anti-KIR (e.g., lirilumab, onalizumab), anti-MMP9, anti-PD-1 (e.g., nivolumab, pidilizumab, ramucirumab), anti-PD-L1 (e.g., atezolizumab), anti-PDGFRa (e.g., ramucirumab, toveratinib), anti-PD-L2, anti-PIGF (e.g., ziv-aflibercept), anti-RANKL (e.g., denosumab), anti-TNFRSF 9 (CD 137 / 4-1BB) (e.g., urelumab), anti-TRAIL-RI / DR4, R2 / D5 (e.g., durvalumab), anti-TRAIL-R1 / D4 (e.g., mapatumumab), anti-TRAIL-R2 / D5 (e.g., conatumumab, lexatumumab, apomab), anti-VEGFA (e.g., bevacizumab, ziv-aflibercept); and anti-VEGFB (e.g., ziv-aflibercept); and anti-VEGFR2 (e.g., ramucirumab).

[0198] 5. Formulation and Administration In certain embodiments, the pharmaceutical compositions of the compounds can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in Remington: The Science and Practice of Pharmacy, 21 st Ed. (2005). The therapeutic compounds and their physiologically acceptable salts, hydrates and solvates can be formulated for administration by any suitable route, including, inter alia, topical, nasal, oral, parenteral, rectal, or inhalation. In certain embodiments, administration of the pharmaceutical composition can be by intradermal, subcutaneous, intravenous, intramuscular, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary, or intratumoral injection using a syringe or other device. Transdermal administration is also contemplated, as is inhalation or aerosol administration. Tablets, capsules, and liquids can be administered orally, rectally, or vaginally.

[0199] In the case of oral administration, the pharmaceutical composition can take the form of tablets or capsules prepared by conventional means using, for example, pharmaceutically acceptable excipients. Tablets and capsules containing the active ingredient can contain (a) diluents or fillers such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylate, and / or calcium hydrogen phosphate, calcium sulfate, (b) lubricants such as silica, talcum, stearic acid, its magnesium or calcium salts, metal stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate, and / or polyethylene glycol, (c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, and / or hydroxypropyl methyl cellulose, (d) disintegrants such as starch (including potato starch or sodium starch), glycolic acid, agar, alginic acid or its sodium salt, or effervescent mixtures, (e) wetting agents such as sodium lauryl sulfate, and / or (f) absorbents, coloring agents, flavors, and sweeteners, etc., and can be prepared together with excipients. The composition is prepared according to conventional mixing, granulating, or coating methods.

[0200] In certain embodiments, the carrier is, for example, cyclodextrin for enhancing the solubility and / or bioavailability of the compounds of the present specification. In certain embodiments, the cyclodextrin for use in the pharmaceutical composition can be selected from α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, their derivatives, and combinations thereof. In certain embodiments, the cyclodextrin is selected from β-cyclodextrin, γ-cyclodextrin, their derivatives, and combinations thereof.

[0201] In certain embodiments, the compound can be formulated using a cyclodextrin or derivative thereof selected from carboxyalkyl cyclodextrin, hydroxyalkyl cyclodextrin, sulfoalkyl ether cyclodextrin, and alkyl cyclodextrin. In various embodiments, the alkyl group in the cyclodextrin is methyl, ethyl, propyl, butyl, or pentyl.

[0202] When used in a formulation comprising a compound of the present disclosure, the cyclodextrin can be present at about 0.1 w / v to about 30% w / v, about 0.1 w / v to about 20% w / v, about 0.5% w / v to about 10% w / v, or about 1% w / v to about 5% w / v. In certain embodiments, the cyclodextrin is present at about 0.1% w / v, about 0.2% w / v, about 0.5% w / v, about 1% w / v, about 2% w / v, about 3% w / v, about 4% w / v, about 5% w / v, about 6% w / v, about 7% w / v, about 8% w / v, about 9% w / v, about 10% w / v, about 12% w / v, about 14% w / v, about 16% w / v, about 18% w / v, about 20% w / v, about 25% w / v, or about 30% w / v or more.

[0203] Tablets may be either film-coated or enteric-coated according to methods known in the art. Liquid formulations for oral administration can take, for example, the form of solutions, syrups, or suspensions, or be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid formulations can be prepared by conventional means using pharmaceutically acceptable carriers and additives such as suspending agents, such as sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, such as lecithin or acacia; non-aqueous media, such as almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, such as methyl or propyl-p-hydroxybenzoate or sorbic acid. The formulations may also contain buffering salts, flavoring agents, coloring agents, and / or sweetening agents as required. Optionally, the formulations for oral administration can be suitably formulated to control the release of the active compound.

[0204] The compound can be formulated for parenteral administration, for example, by bolus injection or continuous infusion. Injectable formulations can be presented in unit dosage form, for example, in ampoules or multi-dose containers, optionally with the addition of preservatives. Injectable compositions can be aqueous isotonic solutions or suspensions. In certain embodiments of parenteral administration, the compound can be prepared using a surfactant such as Cremaphor, or a lipophilic solvent such as triglycerides or liposomes. The composition can be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, solubilizing agents, salts for adjusting osmotic pressure, and / or buffers. Alternatively, the compound can be in powder form for reconstitution before use with a suitable vehicle, such as pyrogen-free sterile water. Furthermore, they can also contain other therapeutically active substances.

[0205] For administration by inhalation, the compound can conveniently be delivered in the form of an aerosol spray from a pressurized pack or a nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gases. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges, for example, of gelatin for use in an inhaler or insufflator can be formulated to contain a powder mixture of the compound and a suitable powder base, such as lactose or starch.

[0206] Formulations suitable for transdermal application contain an effective amount of the compound together with a carrier. Preferred carriers include absorbable pharmacologically acceptable solvents to assist passage through the subject's skin. For example, a transdermal device is in the form of a dressing or patch that includes a backing member, a reservoir containing the compound, optionally with a carrier, a rate control barrier for delivering the compound to the skin of the host over an extended period at a predetermined, optionally controlled rate, and means for securing the device to the skin. Matrix transdermal formulations can also be used.

[0207] For example, formulations suitable for topical application to the skin and eyes are preferably aqueous solutions, ointments, creams, or gels well known in the art. The formulation may contain solubilizing agents, stabilizers, tonicity enhancing agents, buffers, and preservatives.

[0208] In certain embodiments, the compound can also be formulated as a rectal composition, such as a suppository or retention enema, which includes, for example, conventional suppository bases such as cocoa butter or other glycerides, or a gel former such as carbomer.

[0209] In certain embodiments, the compound can be formulated as a depot formulation. Such long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. The compound can be formulated as a suitable polymer or hydrophobic substance (e.g., as an emulsion in an acceptable oil), an ion exchange resin, a biodegradable polymer, or a poorly soluble derivative, such as a poorly soluble salt.

[0210] The pharmaceutical composition can be provided in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient, as required. The pack can include, for example, a metal or plastic foil, such as a blister pack. Instructions for administration can be attached to the pack or dispenser device.

[0211] 6. Effective Amount and Dosage In certain embodiments, the pharmaceutical composition of the compound is administered to a subject, preferably a human, in a therapeutically effective amount for preventing, treating, or controlling the conditions or diseases described herein. The pharmaceutical composition is administered to the subject in an amount sufficient to elicit an effective therapeutic response in the subject. An effective therapeutic response is a response that at least partially blocks or delays the symptoms or complications of the condition or disease. The amount sufficient to achieve this is defined as a "therapeutically effective dosage" or "therapeutically effective amount". The dosage of the compound can take into account, inter alia, the species of warm-blooded animal (mammal), body weight, age, the condition being treated, the severity of the condition being treated, the dosage form, and the route of administration. The size of the dosage is also determined by the presence, nature, and extent of any adverse effects associated with the administration of the particular therapeutic compound in a particular subject.

[0212] In certain embodiments, suitable dosages of the compounds or compositions thereof of the present disclosure are from about 1 ng / kg to about 1000 mg / kg, 0.01 mg / kg to 900 mg / kg, 0.1 mg / kg to 800 mg / kg, from about 1 mg / kg to about 700 mg / kg, from about 2 mg / kg to about 500 mg / kg, from about 3 mg / kg to about 400 mg / kg, 4 mg / kg to about 300 mg / kg, or from about 5 mg / kg to about 200 mg / kg. In certain embodiments, suitable dosages of the compound can be about 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 250 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, or 1000 mg / kg. In certain embodiments, the dosage of the compound can be administered once daily or divided into sub-dosages and administered in multiple dosages, for example, 2, 3, or 4 times a day.

[0213] In certain embodiments, the compounds can be administered, sequentially or simultaneously, with one or more second compounds, either by the same route of administration or different routes of administration. When administered sequentially, the time between administrations is selected, inter alia, to provide benefits to the therapeutic efficacy and / or safety of the combination therapy. In certain embodiments, the compounds of the present specification can be administered first, followed by administration of a second compound, or a second compound can be administered first, followed by administration of the compounds of the present disclosure. By way of example and not limitation, the time between administrations can be about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 12 hours, about 16 hours, or about 20 hours. In certain embodiments, the time between administrations is about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days or more. In certain embodiments, the time between administrations is about 1 week, 2 weeks, 3 weeks, or 4 weeks or more. In certain embodiments, the time between administrations is about 1 month or 2 months or more.

[0214] When administered simultaneously, the compounds can be administered separately by the same or different routes simultaneously with the second compound, or as a single composition by the same route. In certain embodiments, the amounts and frequencies of administration of the second compound can use the standard dosages and standard frequencies of administration used for the particular compound. See, for example, Physicians´ Desk Reference, 70th Ed., PDR Network, 2015, which is incorporated herein by reference.

[0215] In certain embodiments where the compounds of the present disclosure are administered in combination with a second compound, the dosage of the second compound is administered at a therapeutically effective dosage. In certain embodiments, suitable dosages can be from about 1 ng / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 900 mg / kg, from about 0.1 mg / kg to about 800 mg / kg, from about 1 mg / kg to about 700 mg / kg, from about 2 mg / kg to about 500 mg / kg, from about 3 mg / kg to about 400 mg / kg, from about 4 mg / kg to about 300 mg / kg, or from about 5 mg / kg to about 200 mg / kg. In certain embodiments, suitable dosages of the second compound can be about 1 mg / kg, 5 mg / kg, 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, 45 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 125 mg / kg, 150 mg / kg, 175 mg / kg, 200 mg / kg, 250 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, 600 mg / kg, 700 mg / kg, 800 mg / kg, 900 mg / kg, or 1000 mg / kg. In certain embodiments, guidance regarding the dosage of the second compound is provided in Physicians´ Desk Reference, 70th Ed, PDR Network (2015), which is incorporated herein by reference. th is provided by

[0216] The optimal dosage, toxicity, and therapeutic effect of such compounds can vary depending on the relative potency of the individual compound and can be determined by standard pharmaceutical procedures in cell culture or experimental animals, for example, by determining the 50 LD 50 (the dose lethal to 50% of the population) and the 50 ED 50It can be expressed as a ratio. Compounds or combinations thereof that exhibit a large therapeutic index are preferred. Certain agents that exhibit toxic side effects can be used, but care must be taken in designing a delivery system that targets such agents to the site of the diseased tissue in order to minimize potential damage to normal cells and thereby reduce side effects.

[0217] For example, data obtained from cell culture assays and animal studies can be used to establish a dosage range for use in humans. The dosage of such small molecule compounds is preferably within a range of circulating concentrations that have little or no toxicity, i.e., ED 50 The dosage can vary within this range depending on the dosage form and route of administration used. For any compound used in the methods disclosed herein, a therapeutically effective amount can first be estimated from cell culture assays. The IC determined in cell culture 50 (concentration of the test compound that achieves half-maximal inhibition of the symptom) to achieve a range of circulating plasma concentrations can be determined in an animal model. Such information can be used to more accurately determine a useful dosage in humans. Plasma levels can be measured, for example, by high performance liquid chromatography (HPLC).

[0218] 7. Methods of Preparation The following examples are provided to further illustrate the methods of the present disclosure, as well as the compounds and compositions for use in the methods. The examples described are merely illustrative and are not intended to limit the scope of the invention in any way. The disclosures of all papers and references mentioned in this application, including patents, are hereby incorporated by reference in their entirety.

[0219] The compounds of the present disclosure can be synthesized by incorporating known chemical reactions and related procedures such as separation and purification, considering the guidance provided herein. Representative methods and procedures for the preparation of the compounds in the present disclosure are described below and in the examples. The acronyms are abbreviations used according to the conventions that can be found in the literature and scientific journals.

[0220] In certain embodiments, a process for preparing a compound of Formula I, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or salt thereof, is provided,

Chemical Formula

Chemical Formula

[0221] In certain embodiments, a process for preparing a compound of Formulas 1-5, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or salt thereof, is provided,

Chemical Formula

Chemical Formula

[0222] As demonstrated by the following examples, it is understood that starting materials and reaction conditions can vary, the order of reactions can vary, and additional steps can be used to produce the compounds encompassed by the present disclosure. General references for known chemical reactions useful for synthesizing the disclosed compounds are available (see, for example, Smith and March, March´s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley Interscience, 2001, or Carey and Sundberg, Advanced Organic Chemistry, Part B. Reaction and Synthesis; Fifth Edition, Springer, 2007, or Li, J.J. Name Reactions, A Collection of Detailed Mechanisms and Synthetic Applications; Fifth Edition, Springer, 2014).

[0223] It will be understood that other process conditions can be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, unless otherwise specified. The optimal reaction conditions can vary depending on the specific reactants or solvents used, but such conditions can be determined by one of ordinary skill in the art by routine optimization procedures.

[0224] Furthermore, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. Protecting groups suitable for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in Wuts, P.G.M., Greene, T.W., & Greene, T.W. (2006). Greene’s protective groups in organic synthesis. Hoboken, N.J., Wiley-Interscience, and the references cited therein.

[0225] Furthermore, the compounds of the present disclosure may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as a stereoisomer-rich mixture. Unless otherwise specified, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) may be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, chiral resolvants, etc.

[0226] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd’s Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March’s Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989) or obvious modifications thereof.

[0227] General synthesis In certain embodiments, the compounds disclosed herein can follow the general schemes shown below. For example, the compounds of formula I can be prepared according to the general synthesis outlined below in Scheme 1, and suitable reagents can be purchased from commercial sources or synthesized by known methods or methods adapted from the examples provided herein. In Scheme 1, ring A, X, R 1 , R 2 , R 3 , R 4 , p, and q each are, independently, as defined herein. [Chemical formula]

[0228] In Scheme 1, under standard amide bond formation reaction conditions, compound 1-3 can be provided by coupling amine 1-1 with acid 1-2. Cyclizing compound 1-3 to provide compound 1-5 can be achieved by first forming compound 1-4 and subsequently reducing it using a hydride (e.g., NaBH4, LiAlH4, etc.). Alternatively, compound 1-5 can be provided directly from compound 1-3 under appropriate conditions such as in an aprotic solvent in the presence of an acid catalyst. Then, the compound of formula I can be provided by coupling compound 1-5 with compound 1-6 under reaction conditions suitable for providing the compound of formula I. At the end of each reaction, each of the intermediates or final compounds can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc.

[0229] Suitable starting materials and reagents for use in Scheme 1 can be purchased or prepared by methods known to those skilled in the art. As shown in Scheme 2, chiral or enantiomerically enriched starting materials can be provided for use in the method of Scheme 1 by converting a chiral or enantiomerically enriched amino alcohol to oxathiazolidinedioxide 2-2. In Scheme 2, X, R 1 , R 4 , and p are, independently, as defined herein, M is a metal halide (e.g., MgBr), and PG is a protecting group (e.g., Boc). [Chemical formula]

[0230] Referring to Scheme 2, compound 2-1 is coupled to compound 2-2 under standard coupling conditions to produce compound 2-3. The reaction is typically carried out in the presence of a suitable catalyst (e.g., CuI) using an appropriate solvent / solvent mixture. Deprotection of compound 2-3 gives compound 2-4. At the end of the reaction, each intermediate can be recovered by conventional techniques such as neutralization, extraction, precipitation, chromatography, filtration, etc.

[0231] In some embodiments of the methods of Scheme 1 and Scheme 2, various substituents on the starting compounds (e.g., compounds I-1 and I-2, (e.g., ring A, R 1 、R 2 、R 3 、etc.) are as defined for formula I. However, it should also be understood that either compound of Scheme 1 or Scheme 2 can be further modified using chemical derivatization and / or functional group interconversion to obtain various compounds of formula I.

[0232] Other compounds of the present disclosure can be synthesized using the synthetic routes described above and adapting chemical synthesis procedures available to those skilled in the art. Exemplary methods of synthesis are provided in the Examples. Each of the procedures describing the synthesis of the exemplary compounds is part of the specification and is therefore to be understood as incorporated herein in the detailed description of the present disclosure.

Examples

[0233] Synthesis Examples Intermediate 1: Synthesis of Intermediate (S)-1-(3-Methoxyphenyl)hexan-2-amine

Chem.

[0234] tert-Butyl (S)-(1-hydroxyhexan-2-yl)carbamate: To a solution of (S)-2-aminohexan-1-ol (24.5 g, 209.06 mmol, 1 equiv) in DCM (250 mL) was added TEA (58.76 mL, 418.12 mmol, 2 equiv) dropwise at 0 °C, and after stirring for 5 min, di-tert-butyl dicarbonate (57.63 mL, 250.87 mmol, 1.2 equiv) was added. After stirring at room temperature for 14 h, it was diluted with water (30 mL) and extracted with DCM (2×150 mL). The combined organic layers were washed with water, then an aqueous NaHCO3 solution (ca. 30 mL), and finally a brine solution (75 mL), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combiflash silica gel chromatography using MeOH in DCM as eluent to give tert-butyl (S)-(1-hydroxyhexan-2-yl)carbamate. 1 H NMR (400 MHz, CDCl3) δ ppm 0.90 (s, 3H), 1.25 - 1.33 (m, 6H), 1.38 - 1.41 (m, 9H), 3.48 - 3.55 (m, 1H), 3.62 - 3.68 (m, 2H), 4.57 (bs, 1H).

[0235] 1H-Imidazole (25 g, 368.1 mmol, 4 equiv) and triethylamine (39 mL, 276.1 mmol, 3 equiv) were dissolved in anhydrous dichloromethane (200 mL, commercially available dry solvent) at room temperature, and the mixture was cooled to 0 °C (external temperature, maintained with ice). Then, thionyl chloride (7.3 mL, 101.2 mmol, 1.1 equiv) was slowly added dropwise over about 30 minutes via an additional funnel while maintaining the bath temperature at 0 °C. The reaction mixture was then stirred at 0 °C for an additional 10 minutes. The reaction mixture was then cooled to -78 °C. Then, a solution of tert-butyl (S)-(1-hydroxyhexan-2-yl)carbamate (20 g, 92.03 mmol, 1 equiv) prepared at room temperature in anhydrous dichloromethane (100 mL, commercially available dry solvent) was added dropwise via an additional funnel to the reaction mixture stirred at -78 °C over 45 minutes. The reaction mixture was stirred at -78 °C for an additional 3 hours. Then, the dry ice-acetone bath was removed, and the reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction (TLC, 10% EA in hexane), the mixture was diluted with DCM and washed with water (200 mL × 3) and brine (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure on a rotary evaporator to obtain the crude product. The crude product was purified by silica gel column chromatography using ethyl acetate in hexane as the eluent. The product was eluted with 10 - 25% EA in hexane to obtain tert-butyl (4S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide. 1 H NMR (400 MHz, CDCl3) δ ppm 0.91 (t, J = 6.8 Hz, 3H), 1.27 - 1.38 (m, 4H), 1.52 (s, 9H), 1.67 - 1.73 (m, 1H), 1.99 - 2.10 (m, 1H), 3.97 - 4.02 (m, 1H), 4.70 - 4.78 (m, 2H).

[0236] tert-Butyl (S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide: This reaction was carried out in 2 batches of 20 g. Ruthenium(III) chloride (0.463 g, 2.23 mmol, 0.014 equiv) was added to a stirred solution of tert-butyl (4S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (42.0 g, 159.48 mmol, 1 equiv) in acetonitrile (400 mL) and water (200 mL) at 0 °C, followed by the addition of sodium metaperiodate (37.43 g, 175.43 mmol, 1.1 equiv) in portions. The biphasic mixture was stirred at room temperature for 2 h. The reaction mixture was filtered through sinter and washed with ethyl acetate. Water (250 mL) was added and the mixture was extracted with ethyl acetate (2 × 150 mL). The combined organics were washed with water (150 mL), brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography using 10% ethyl acetate in hexane as the eluent to give tert-butyl (S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. 1 H NMR (400 MHz, CDCl3) δ ppm 0.89 - 0.92 (m, 3H), 1.24 - 1.37 (m, 4H), 1.53 (s, 9H), 1.77 - 1.83 (m, 1H), 1.88 - 1.89 (m, 1H), 4.26 - 4.30 (m, 2H), 4.59 - 4.63 (m, 1H).

[0237] tert-Butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate: To a solution of copper(I) iodide (0.95 g, 5.017 mmol, 0.1 equiv) in diethyl ether (150 mL) was added dropwise (3-methoxyphenyl)magnesium bromide (1 M in THF) (98.5 mL, 100.35 mmol, 2 equiv) at -20 °C over 15 min (salt and ice bath). The reaction mixture was stirred at -20 °C for 30 min (salt and ice bath). Then, a solution of tert-butyl (S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (14 g, 50.172 mmol, 1 equiv) in diethyl ether (100 mL) was added dropwise to the reaction mass at -20 °C (salt and ice bath) over 25 min. The resulting mixture was stirred at -20 °C for 4 h. Finally, the reaction was quenched at -20 °C with 10% aqueous citric acid (70 mL) (salt and ice bath). The mixture was warmed to room temperature and stirred for 10 min. The mixture was filtered through a pad of celite and washed thoroughly with ethyl acetate. The filtrate was washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column chromatography using 15% ethyl acetate in n-hexane as the eluent to give tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate. LCMS (ES) m / z = 208.2 [M+H] + The boc mass was not observed. 1 H NMR (400 MHz, CDCl3) δ ppm 0.86 - 0.87 (m, 3H), 1.25 - 1.28 (m, 6H), 1.40 (s, 9H), 2.73 (bs, 2H), 3.79 (s, 3H), 4.29 (bs, 1H), 6.71 - 6.76 (m, 3H), 7.17 - 7.21 (m, 1H). The amide NH was not observed.

[0238] (S)-1-(3-Methoxyphenyl)hexan-2-amine: To a solution of tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate (12.0 g, 39.033 mmol, 1 equiv) in dichloromethane (50 mL) was slowly added 4 M HCl in 1,4-dioxane (150 mL) at 0 °C. The mixture was stirred at room temperature for 5 h. After completion of the reaction, the progress of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The resulting crude was basified with a saturated aqueous solution of NaHCO3. The compound was extracted with EtOAc (3 × 200 mL). The organic layer was separated, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-1-(3-methoxyphenyl)hexan-2-amine. LCMS(ES) m / z = 208.1 [M + H] +

[0239] Procedure 1: Synthesis of Compound 1 [Chemical Structure] To a stirred mixture of (R)-2-methyloxirane (10 g, 172 mmol, 1 equiv) in dry tetrahydrofuran (100 mL) was added phenylmagnesium bromide (3 M in diethyl ether) (63 mL, 183 mmol, 1.1 equiv) at -10 °C under a nitrogen atmosphere. The resulting mixture was gradually warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC (15% ethyl acetate in hexanes). The reaction mixture was quenched with saturated ammonium chloride solution. The crude product was extracted with ethyl acetate (3x300 mL), and the combined organics were washed with water (200 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude product, which was purified by flash column chromatography using 15% ethyl acetate in hexanes as the eluent to give (R)-1-phenylpropan-2-ol. 11H NMR (400 MHz, CDCl3) δ ppm 1.23 (d, J = 2.0 Hz, 3H), 1.48 (s, 1H), 2.66 - 2.71 (m, 1H), 2.77 - 2.80 (m, 1H), 4.02 (bs, 1H), 7.21 - 7.31 (m, 5H).

[0240] (R)-1-Phenylpropan-2-ol (0.5 g, 3.671 mmol, 1 eq) and triethylamine (1.54 mL, 11 mmol, 3 eq) in dichloromethane (10 mL) were stirred. Methanesulfonyl chloride (0.42 mL, 5.5 mmol, 1.5 eq) was added thereto at 0 °C under a nitrogen atmosphere. The resulting mixture was gradually warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC (50% dichloromethane in hexane). The reaction mixture was quenched with water. The crude product was extracted with dichloromethane (3 x 30 mL), and the combined organics were washed with water (50 mL), brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain crude product (R)-1-phenylpropan-2-yl methanesulfonate, which was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (d, J = 6.4 Hz, 3H), 2.51 (s, 3H), 2.89 - 2.99 (m, 2H), 4.85 - 4.95 (m, 1H), 7.16 - 7.40 (m, 5H).

[0241] Sodium azide (0.18 g, 2.80 mmol, 1.2 eq) was added to a stirred solution of (R)-1-phenylpropan-2-yl methanesulfonate (0.5 g crude, 2 mmol, 1 eq) in N,N-dimethylformamide (10 mL) at room temperature under a nitrogen atmosphere. The resulting mixture was heated to 80 °C and stirred for 16 h. The progress of the reaction was monitored by TLC (5% ethyl acetate in hexane). After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with water. The mixture was extracted with ethyl acetate (3 x 30 mL), and the combined organics were washed with water (4 x 30 mL), brine (20 mL), dried over anhydrous Na 2 SO 4It was dried above, concentrated under reduced pressure to obtain a crude product, and this was purified by flash column chromatography using 5% ethyl acetate in hexane as an eluent to obtain (S)-(2-azidopropyl)benzene. 1 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (d, J = 6.8 Hz, 3H), 2.69 - 2.74 (m, 1H), 2.81 - 2.86 (m, 1H), 3.66 - 3.72 (m, 1H), 7.18 - 7.32 (m, 5H).

[0242] To a stirred solution of (S)-(2-azidopropyl)benzene (0.24 g, 1.5 mmol, 1 equivalent) in ethyl acetate (10 mL), palladium (10%, 50% hydrophilic on activated carbon powder) (0.05 g) was added at room temperature under a nitrogen atmosphere. The resulting mixture was subjected to hydrogenation by stirring for 8 hours using a hydrogen pressure (a balloon is appropriate if a large-scale parr apparatus is available). The progress of the reaction was monitored by TLC (10% ethyl acetate in hexane). After completion of the reaction, the reaction mixture was filtered through a celite pad, the celite pad was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain (S)-1-phenylpropan-2-amine. 1 1H NMR (400 MHz, CDCl3) δ ppm 1.12 (d, J = 6.8 Hz, 3H), 2.49 - 2.59 (m, 1H), 2.68 - 2.77 (m, 1H), 3.12 - 3.20 (m, 1H), 4.68 (s, 2H), 7.09 - 7.31 (m, 5H).

[0243] To a solution of (S)-1-phenylpropan-2-amine (0.2 g, 1.5 mmol, 1 equivalent) and 4-morpholinobenzaldehyde (0.28 g, 1.5 mmol, 1 equivalent) in toluene (10 mL), anhydrous MgSO4 (0.2 g) was added at room temperature. The reaction mixture was stirred at 110 °C for 4 hours. TLC (70% ethyl acetate in hexane) indicated that the reaction was complete. The solid portion was removed from the reaction mixture by filtration, and the filtrate was concentrated under reduced pressure. The resulting crude (S)-1-(4-morpholinophenyl)-N-(1-phenylpropan-2-yl)methanimine was carried on to the next step without further purification.

[0244] A solution of (S)-1-(4-morpholinophenyl)-N-(1-phenylpropan-2-yl)methanimine (0.5 g crude) in trifluoromethanesulfonic acid (0.5 mL) was stirred at 130 °C for 24 h. TLC 5% (methanol in dichloromethane) indicated completion of the reaction. The reaction mixture was cooled to room temperature, diluted with ice-cold water (5 mL), and then basified to pH = 12 with 10% aqueous sodium hydroxide solution. The product was extracted with ethyl acetate (30 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The obtained crude product was purified by flash chromatography using 5% methanol in dichloromethane as the eluent. The isolated product was further purified by preparative HPLC [analysis conditions: column: Inertsil ODS 3V (250 mm × 4.6 mm × 5 μm), mobile phase (A): 0.1% ammonia in water, mobile phase (B): CH3CN, flow rate: 1.0 mL / min, composition of B: 0 / 10, 12 / 80, 25 / 90, 27 / 10, 30 / 10] to give 4-(4-((3S)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)morpholine. LCMS (ES) m / z = 309.2 [M+H]+, 1H NMR (400 MHz, CDCl3): δ ppm 1.24 (d, J = 4.4 Hz, 3H), 2.69 - 2.81 (m, 2H), 3.14 - 3.20 (m, 5H), 3.85 (bs, 4H), 5.05 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 6.8 Hz, 2H), 6.99 (s, 1H), 7.09 (s, 2H), 7.21 - 7.25 (m, 2H).

[0245] A solution of 4-(4-((3S)-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)morpholine (0.04 g, 0.129 mmol, 1 equiv) in chloroform (5 mL) was added with sodium bicarbonate (0.021 g, 0.259 mmol, 2.0 equiv) at 0 °C, and then 2-chloroacetyl chloride (0.015 mL, 0.194 mmol, 1.5 equiv) was added. The mixture was warmed to room temperature and stirred for 3 h under N2 atmosphere. TLC (40% ethyl acetate in hexane) indicated the completion of the reaction. The reaction was then diluted with dichloromethane (20 mL), washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography using 50% EtOAc in n-hexane as the mobile phase to obtain 2-chloro-1-((3S)-3-methyl-1-(4-morpholinophenyl)-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one. LCMS (ES) m / z = 385.3 [M+H] + , 1 H NMR (400 MHz, CDCl3): δ ppm 1.25 (bs, 3H), 2.3 - 2.5 (m, 1H), 2.75 - 2.95 (m, 1H), 3.14 (bs, 4H), 3.85 (bs, 4H), 4.16 - 4.26 (m, 3H), 5.97 (bs, 1H), 6.83 (bs, 2H), 7.07 (bs, 2H), 7.19 - 7.25 (m, 4H). Chiral HPLC purity: 48.93 (trans), 47.12% (cis).

[0246] Procedure 2: Synthesis of Compounds 2 and 3

Chemical Structure

[0247] To a solution of methyl D-phenylalaninate (0.1 g, 0.557 mmol, 1 equiv) in toluene (10 mL) was added methyl 4-formylbenzoate (0.09 g, 0.557 mmol, 1 equiv). The reaction mixture was heated to 120 °C and stirred for 1 hour. The mixture was concentrated under reduced pressure to give methyl (R,E)-4-(((1-methoxy-1-oxo-3-phenylpropan-2-yl)imino)methyl)benzoate, and the crude product obtained was carried on to the next step without further purification.

[0248] Methyl (R,E)-4-(((1-methoxy-1-oxo-3-phenylpropan-2-yl)imino)methyl)benzoate (0.3 g crude) was mixed with trifluoromethanesulfonic acid (2 mL), and the mixture was heated to 130 °C and stirred for 18 hours. The mixture was analyzed by LCMS (LCMS showed the hydrolysis product (3R)-1-(4-carboxyphenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid). The mixture was cooled to 0 °C, and 10 mL of anhydrous methanol was added. The resulting mixture was heated to 80 °C and stirred for 2 hours. The mixture was cooled to 0 °C, neutralized with triethylamine, and concentrated under reduced pressure. The obtained crude product was dissolved in ethyl acetate, washed with water (3 × 20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 20% ethyl acetate in hexane as the eluent to obtain methyl (3R)-1-(4-(methoxycarbonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate. LCMS (ES) m / z = 326.2 [M+H] +

[0249] To a stirred mixture of methyl (3R)-1-(4-(methoxycarbonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (0.12 g, 0.368 mmol, 1 eq) and sodium bicarbonate (0.06 g, 0.737 mmol, 2 eq) in chloroform (5 mL), 2-chloroacetyl chloride (0.044 mL, 0.553 mmol, 1.5 eq) was added at 0 °C under a nitrogen atmosphere. The resulting mixture was warmed to room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC (20% ethyl acetate in hexanes). After completion of the reaction, the mixture was diluted with dichloromethane (50 mL), washed with water (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative HPLC [analytical conditions: column: Inertsil ODS 3V (250 mm × 4.6 mm × 5 μm), mobile phase (A): 0.1% ammonia in water, mobile phase (B): CH3CN, flow rate: 1.0 mL / min, composition of B: 0 / 20, 12 / 80, 25 / 90, 27 / 20, 30 / 20] to give methyl (1S,3R)-2-(2-chloroacetyl)-1-(4-(methoxycarbonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (3). Polar spots in TLC compared to those corresponding to other isomers. LCMS (ES) m / z = 402 [M+H]+, 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.04 - 3.15 (m, 1H), 3.30 (m, 1H), 3.46 (m, 3H), 3.78 - 3.79 (s, 3H), 3.98, 4.30 (m, 0.5H, 0.5H), 4.67 - 4.73 (m, 1H), 5.21, 5.37 (m, 0.5H, 0.5H), 6.28, 6.52 (s, 0.5H, 0.5H), 7.11 - 7.21 (m, 3H), 7.51 - 7.60 (m, 3H), 7.88 - 7.89 (m, 2H). Chiral HPLC purity with two peaks at 61.1% and 36.7%, and methyl (1R,3R)-2-(2-chloroacetyl)-1-(4-(methoxycarbonyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (2). In TLC, a non-polar spot corresponding to that of other isomers. LCMS (ES) m / z = 402 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ ppm 2.98 - 3.02 (m, 0.5H), 3.07 - 3.12 (m, 1H), 3.21 - 3.22 (m, 0.5H), 3.27 (s, 1H), 3.66 (s, 2H), 3.80 (s, 3H), 4.22 - 4.26 (m, 1H), 4.31 - 4.40 (m, 1H), 4.65 - 4.75, 5.02 (m, 1H), 6.42, 6.77 (m, 0.8H, 0.3H), 7.11 - 7.38 (m, 4H), 7.63 (d, J = 7.2 Hz, 2H), 7.83 - 7.89 (m, 2H). Chiral HPLC purity with two peaks of 74.37% and 25.6%,

[0250] Procedure 3: Synthesis of Compounds 4 and 5 [Chemical Structure] To a solution of compound methyl 4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (0.35 g, 1.12 mmol, 1.0 equiv) in DCM (10 mL), triethylamine (0.45 g, 4.49 mmol, 4.0 equiv) and di-tert-butyl dicarbonate (0.715 g, 2.24 mmol, 2.0 equiv) were added at room temperature and the mixture was stirred for 16 h. TLC (50% EtOAc in hexane) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, the crude product was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product tert-butyl (1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z): 356.0 [M - t Bu + H] + .

[0251] To a solution of tert-butyl (1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.650 g, 1.57 mmol, 1.0 equiv) in a mixture of THF:MeOH:H2O (9 mL:1 mL), lithium hydroxide (0.331 g, 7.89 mmol, 5.0 equiv) was added and the mixture was stirred at room temperature for 16 h. TLC (50% EtOAc in hexanes) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure and the crude product was acidified with 5% citric acid solution (pH = 9). The reaction mixture was diluted with EtOAc (50 mL), the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude 4-((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid. LC-MS (m / z): 396.0 [M+H] + .

[0252] To a solution of 4-((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid (0.38 g, 0.957 mmol, 1.0 equiv) in DCM (10 mL), triethylamine (0.4 mL, 2.87 mmol, 3.0 equiv) and cyclopropanamine (0.65 g, 1.14 mmol, 1.2 equiv) were added at 0 °C and the mixture was stirred for 15 min. To the above reaction mixture, T3P (50 wt% in EtOAc) (1.4 mL, 1.97 mmol, 1.2 equiv) was added at the same temperature and the mixture was stirred for 16 h. TLC (50% EtOAc in hexanes) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure and the crude product was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude tert-butyl (1S,3S)-1-(4-(cyclopropylcarbamoyl)phenyl)-6-methoxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z): 381.0[M- tBu+H] + .

[0253] A solution of tert-butyl (1S,3S)-1-(4-(cyclopropylcarbamoyl)phenyl)-6-methoxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.27 g, 0.61 mmol, 1.0 equiv) in DCM (10 mL) was added trifluoroacetic acid (0.084 g, 0.74 mmol, 1.2 equiv) at 0 °C, and the mixture was stirred for 2 h. TLC (50% EtOAc in hexane) indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to give crude N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-2λ 4 -isoquinolin-1-yl)benzamide. LC-MS (m / z): 337.0 [M+H] + .

[0254] N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-2λ 4A solution of N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide (0.2 g, 0.59 mmol, 1.0 equiv) was added with TEA (0.12 g, 1.18 mmol, 2.0 equiv) at 0 °C and stirred for 15 minutes. Then, 2-chloroacetyl chloride (0.08 g, 0.71 mmol, 1.2 equiv) was added at 0 °C. The mixture was stirred at room temperature for 1 hour. LCMS and TLC (50% EtOAc in hexane) indicated the completion of the reaction. The reaction mixture was diluted with saturated NaHCO3 solution (10 mL) and extracted with DCM (2 × 50 mL). The organic layer was dried over Na2SO4 and concentrated to obtain the crude product. The crude product was purified by flash column chromatography using 15% EtOAc / hexane as the eluent, followed by preparative TLC using 30% EtOAc in hexane as the eluent to obtain 4-((1S,3S)-2-(2-chloroacetyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclopropylbenzamide. LC-MS (m / z): 413.3 [M+H] + , 1 H NMR (400 MHz, DMSO-d6): δ 0.49 - 0.52 (m, 2H), 0.52 - 0.64 (m, 2H), 0.66 (bs, 3H), 2.65 - 2.66 (m, 1H), 2.77 - 2.81 (m, 1H), 3.71 (s, 3H), 4.37 - 4.74 (bs, 3H), 6.13 (s, 1H), 6.74 - 6.75 (m, 1H), 6.79 - 6.81 (m, 1H), 7.320 - 7.302 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.64 (s, 2H), 8.13 (s, 1H).

[0255] N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-2λ 4To a solution of (isoquinolin-1-yl)benzamide (0.2 g, 0.59 mmol, 1.0 eq), triethylamine (0.162 g, 1.42 mmol, 2.4 eq) and propiolic acid (0.041 mL, 0.59 mmol, 1.0 eq) were added and stirred for 15 minutes. To the above reaction mixture, 2-chloro-1-methylpyridin-1-ium iodide (0.182 g, 0.71 mmol, 1.2 eq) was added and stirred for 16 hours. LCMS and TLC (5% MeOH in DCM) indicated completion of the reaction. The reaction mixture was diluted with water (10 mL), the organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure to give the crude product. The crude product was purified by preparative TLC using 70% EtOAc in hexane as the eluent to give N-cyclopropyl-4-((1S,3S)-6-methoxy-3-methyl-2-propionoyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide. LC-MS (m / z): 389.0 [M+H] + , 1 H NMR (400 MHz, DMSO-d6): δ 0.49 - 0.51 (m, 2H), 0.52 - 0.65 (m, 2H), 0.66 (bs, 3H), 2.65 - 2.66 (m, 1H), 2.78 - 2.82 (m, 1H), 3.71 (s, 3H), 4.37 - 4.74 (bs, 3H), 6.13 (s, 1H), 6.75 - 6.78 (m, 1H), 6.79 - 6.81 (m, 1H), 7.32 - 7.30 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 7.64 (s, 2H), 8.13 (s, 1H).

[0256] Procedure 4: Synthesis of Compounds 6 and 7

Chemical Structure

[0257] To a solution of (R)-1-(3-methoxyphenyl)propan-2-ol (2.8 g, 16.86 mmol, 1.0 equiv) in DCM (30 mL) were added triethylamine (5.1 g, 50.58 mmol, 3.0 equiv) and then methanesulfonyl chloride (2.8 g, 25.30 mmol, 1.5 equiv) at 0 °C. The mixture was stirred at 0 °C for 1.0 h under a N2 atmosphere. TLC (30% EtOAc in n-hexane) indicated that the reaction was complete. The reaction was diluted with a saturated aqueous solution of NaHCO3 (15 mL) and extracted with DCM (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain (R)-1-(3-methoxyphenyl)propan-2-yl methanesulfonate. 11H NMR (400 MHz, CDCl3) δ ppm 1.47 (d, J = 6.0 Hz, 3H), 2.56 (s, 3H), 2.84 - 2.89 (m, 1H), 2.93 - 2.99 (m, 1H), 3.79 (s, 3H), 4.87 - 4.92 (m, 1H), 6.77 - 6.82 (m, 3H), 7.21 - 7.23 (m, 1H).

[0258] To a solution of (R)-1-(3-methoxyphenyl)propan-2-yl methanesulfonate (3.8 g, 15.57 mmol, 1.0 equiv) in DMF (38 mL) was added sodium azide (1.2 g, 18.68 mmol, 1.2 equiv) at room temperature. The reaction mixture was stirred at 80 °C for 16 h. TLC (5% EtOAc in n-hexane) indicated completion of the reaction. The reaction mixture was diluted with water (15 mL) and EtOAc (50 mL), the organic layer was separated, washed with water (5 X 25 mL), brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford the crude product. The crude product was purified by flash column chromatography (n-hexane / EtOAc = 9.7:0.2, R f = 0.6) to give (S)-1-(2-azidopropyl)-3-methoxybenzene. 1 1H NMR (400 MHz, CDCl3) δ ppm 1.26 (d, J = 6.0 Hz, 3H), 2.66 - 2.71 (m, 1H), 2.78 - 2.83 (m, 1H), 3.62 - 3.71 (m, 1H), 3.80 (s, 3H), 6.74 - 6.79 (m, 3H), 7.20 - 7.22 (m, 1H).

[0259] To a solution of (S)-1-(2-azidopropyl)-3-methoxybenzene (2.37 g, 12.40 mmol, 1.0 equiv) in ethyl acetate (23 mL) was added Pd / C (150 mg of 10% Pd) at room temperature. The resulting reaction mixture was hydrogenated at room temperature for 20 h at 100 PSI in a Parr shaker. The catalyst was then removed by filtration through celite, and the filtrate was concentrated under reduced pressure to give (S)-1-(3-methoxyphenyl)propan-2-amine. LCMS (ES) m / z = 343.3 [M+H] +11H NMR (400 MHz, CDCl3) δ ppm 1.13 (d, J = 6.0 Hz, 3H), 2.44 - 2.54 (m, 1H), 2.67 - 2.72 (m, 1H), 3.16 - 3.21 (m, 1H), 3.79 (s, 3H), 6.74 - 6.78 (m, 3H), 7.21 (t, J = 7.8 Hz, 1H). The NH2 proton was 1 not observed in the 1H NMR.

[0260] A solution of (S)-1-(3-methoxyphenyl)propan-2-amine (0.3 g, 1.81 mmol, 1.0 equiv) and methyl 4-formylbenzoate (0.36 g, 2.18 mmol, 1.2 equiv) in toluene (4 mL) was irradiated with microwave at 90 °C for 20 minutes. After that, the volatile part was concentrated under reduced pressure to obtain methyl (S)-4-(((1-(3-methoxyphenyl)propan-2-yl)imino)methyl)benzoate. This product was directly advanced for the cyclization step.

[0261] A solution of methyl (S)-4-(((1-(3-methoxyphenyl)propan-2-yl)imino)methyl)benzoate (product of the previous step) in TFA (2 mL) was irradiated with microwave at 140 °C for 45 minutes. After that, the volatile part was concentrated under reduced pressure and diluted with a saturated aqueous solution of NaHCO3 (10 mL) and EtOAc (40 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel flash column chromatography (n-hexane / EtOAc = 3:2, R f = 0.4 - for non-polar spots, R f = 0.3 - for polar spots)) to obtain methyl 4-((1R,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (less polar spot) and methyl 4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (polar spot).

[0262] Methyl 4-((1R,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate: LCMS(ES) m / z = 312.2 [M+H]+, 1 H NMR(400 MHz, CDCl3) δ ppm 1.26 (d, J = 6.0 Hz, 3H), 2.74 - 2.76 (m, 2H), 3.19 - 3.20 (m, 1H), 3.76 (s, 3H), 3.90 (s, 3H), 5.12 (s, 1H), 6.49 - 6.64 (m, 3H), 7.41 (d, J = 8.0 Hz, 2H), 8.00 (d, J = 7.6 Hz, 2H). The NH proton was 1 not observed in the 1H NMR.

[0263] Methyl 4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate: LCMS(ES) m / z = 312.2 [M+H] + . 1 H NMR(400 MHz, CDCl3) δ ppm 1.11 (d, J = 6.4 Hz, 3H), 2.53 - 2.60 (m, 1H), 2.82 - 2.87 (m, 1H), 3.04 - 3.07 (m, 1H), 3.80 (s, 3H), 3.89 (s, 3H), 5.24 (s, 1H), 6.67 - 6.69 (m, 2H), 6.79 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.0 Hz, 2H). The NH proton was 1 not observed in the 1H NMR.

[0264] To a solution of methyl 4-((1R,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (0.2 g, 0.64 mmol, 1 equiv) in DCM (5.0 mL), triethylamine (0.19 g, 1.92 mmol, 3.0 equiv) was added at 0 °C, followed by the addition of 2-chloroacetyl chloride (0.095 g, 0.83 mmol, 1.3 equiv). The mixture was stirred at 0 °C for 2.0 h under a N2 atmosphere. TLC (35% EtOAc in n-hexane) indicated that the reaction was complete. The reaction was then diluted with saturated aqueous NaHCO3 (5 mL) and extracted with DCM (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC using 40% EtOAc in n-hexane as the mobile phase to give methyl 4-((1R,3S)-2-(2-chloroacetyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (6): LCMS (ES) m / z = 388.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) (at 70 °C) δ ppm 1.10 (d, J = 5.6 Hz, 3H), 3.00 (bs, 2H), 3.77 (m, 3H), 3.82 (s, 3H), 4.21 (bs, 1H), 4.47 (q, J = 13.6 Hz, 2H), 6.45 (bs, 1H), 6.83 - 6.85 (m, 2H), 7.16 (bs, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.0 Hz, 2H).

[0265] A solution of methyl 4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (0.11 g, 0.35 mmol, 1 equiv) in DCM (4.0 mL) was added with triethylamine (0.1 g, 1.05 mmol, 3.0 equiv) at 0 °C, followed by the addition of 2-chloroacetyl chloride (0.05 g, 0.45 mmol, 1.3 equiv). The mixture was stirred at 0 °C for 2.0 h under a N2 atmosphere. TLC (35% EtOAc in n-hexane) indicated the completion of the reaction. Then, the reaction was diluted with saturated aqueous solution of NaHCO3 (5 mL) and extracted with DCM (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative TLC using 40% EtOAc in n-hexane as the mobile phase to afford methyl 4-((1S,3S)-2-(2-chloroacetyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (7): LCMS (ES) m / z = 388.0 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) (at 70 °C) δ ppm 0.97 (bs, 3H), 2.65 (bs, 2H), 3.71 (s, 3H), 3.79 (s, 3H), 4.40 (bs, 1H), 4.75 (bs, 2H), 6.17 (bs, 1H), 6.76 - 6.82 (m, 2H), 7.40 - 7.49 (m, 3H), 7.81 (bs, 2H).

[0266] Procedure 5: Synthesis of Compounds 8, 9 and 10

Chemical formula

[0267] Compound 8: LC-MS (m / z): 348.3 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (d, J = 5.2 Hz, 3H), 2.58 - 2.65 (m, 1H), 3.02 - 3.12 (m, 1H), 3.71 (s, 3H), 4.41 - 4.72 (m, 3H), 6.11 (s, 1H), 6.76 (s, 1H), 6.80 (d, J = 8.4 Hz, 1H), 7.04 (bs, 2H), 7.27 (dd, J = 8.4, 5.6 Hz, 2H), 7.45 (d, J = 8.4 Hz, 1H). This NMR was recorded at 60 °C.

[0268] Compound 9: LC-MS (m / z): 324.0 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ ppm 0.92 (d, J = 6.0 Hz, 1H), 1.07 (d, J = 6.0 Hz, 2H), 2.57 - 2.73 (m, 1H), 2.82 - 2.90 (m, 1H), 3.72 - 3.73 (m, 3H), 4.22 (s, 0.4H), 4.49 (s, 0.6H), 4.70 (bs, 0.5H), 4.92 (bs, 0.5H), 6.09 (s, 0.6H), 6.31 (s, 0.4H), 6.78 - 6.85 (m, 2H), 7.01 (t, J = 9.0 Hz, 1H), 7.08 (t, J = 8.4 Hz, 1H), 7.21 - 7.23 (m, 2H), 7.40 (d, J = 8.0 Hz, 0.6H), 7.57 (d, J = 8.4 Hz, 0.4H). This NMR was recorded at 60 °C.

[0269] Compound 10: LC-MS (m / z): 324.3 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 - 1.13 (m, 3H), 2.21 - 2.28 (m, 0.5H), 2.90 - 2.94 (m, 0.5H), 3.07 - 3.08 (m, 1H), 3.77 (s, 3H), 4.07 (bs, 0.5H), 4.49 - 4.57 (m, 1.5H), 6.53 - 6.56 (m, 1H), 6.82 - 6.88 (m, 2H), 7.02 - 7.14 (m, 4.5H), 7.32 - 7.36 (m, 0.5H). This NMR was recorded at 60 °C.

[0270] Procedure 6: Synthesis of Compound 11

Chem.

[0271] TEA (10 mL, 71.67 mmol, 2 equiv) was added dropwise at 0 °C to a solution of (S)-2-aminohexan-1-ol (4.2 g, 35.83 mmol, 1 equiv) in DCM (40 mL), and after stirring for 5 min, di-tert-butyl dicarbonate (9.86 mL, 43.00 mmol, 1.2 equiv) was added. After stirring at room temperature for 18 h, it was washed with water (75 mL) and brine (75 mL), dried over Na2SO4, and concentrated in vacuo. The residue was subjected to combiflash silica gel chromatography using MeOH in DCM as the eluent to obtain tert-butyl (S)-(1-hydroxyhexan-2-yl)carbamate. 1 1H NMR (400 MHz, CDCl3) δ ppm 0.89 (s, 3H), 1.32 - 1.43 (m, 6H), 1.44 (s, 9H), 3.50 - 3.54 (m, 1H), 3.61 - 3.67 (m, 2H), 4.59 (bs, 1H).

[0272] A solution of 1H-imidazole (5.1 g, 75.57 mmol, 4 eq) and triethylamine (7.9 mL, 56.68 mmol, 3 eq) in anhydrous dichloromethane (30 mL) was cooled to -78 °C, and thionyl chloride (1.5 mL, 20.78 mmol, 1.1 eq) was added dropwise. The reaction mixture was stirred for 5 minutes while cooling to -78 °C, and tert-butyl (S)-(1-hydroxyhexan-2-yl)carbamate (4.1 g, 18.89 mmol, 1 eq) in anhydrous dichloromethane (30 mL) was added dropwise over 30 minutes. The reaction mixture was stirred at -78 °C for 3 hours. The reaction mixture was stirred overnight while warming to room temperature. Water (100 mL) was added, and the phases were separated. The aqueous phase was further extracted with dichloromethane (150 mL), and the combined organics were washed with water (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. tert-Butyl (4S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide was used in the next step without further purification.

[0273] Ruthenium(III) chloride hydrate (0.002 g, 0.013 mmol, 0.007 eq) was added to a stirred solution of tert-butyl (4S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2-oxide (5 g, 19 mmol, 1 eq) in acetonitrile (50 mL) and water (50 mL) at 0 °C, followed by the addition of sodium periodate (4.4 g, 20.91 mmol, 1.1 eq) portionwise. The biphasic mixture was stirred at 20 °C for 2 hours. Water (250 mL) was added, and the mixture was extracted with ethyl acetate (2 × 150 mL). The combined organics were washed with water (150 mL), brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by column chromatography using 10% ethyl acetate in hexane as the eluent to give tert-butyl (S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide. 11H NMR (400 MHz, CDCl3) δ ppm 0.90 - 1.25 (m, 3H), 1.31 - 1.38 (m, 6H), 1.48 (s, 9H), 1.75 - 1.95 (m, 2H), 4.27 - 4.32 (m, 2H), 4.61 - 4.65 (m, 1H).

[0274] To a solution of copper(I) iodide (0.238 g, 1.25 mmol, 0.1 eq) in diethyl ether (25 mL) was added dropwise (3-methoxyphenyl)magnesium bromide (1 M in THF) (25 mL, 25.08 mmol, 2.0 eq) at -12 °C over 10 minutes. The reaction mixture was stirred at -12 °C for 30 minutes. Then, a solution of tert-butyl (S)-4-butyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (3.5 g, 12.54 mmol, 1.0 eq) in diethyl ether (15 mL) was added dropwise to the reaction at -12 °C. The resulting mixture was stirred at -12 °C for 4 hours. Finally, the reaction was quenched with 10% aqueous citric acid solution (15 mL) at -12 °C and diluted with ethyl acetate (100 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product, which was purified by flash column chromatography using 15% ethyl acetate in n-hexane as the eluent to give tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate. LC-MS (m / z) = 252.0 [M+H] + . 1 1H NMR (400 MHz, CDCl3) δ ppm 0.86 - 0.87 (m, 3H), 1.23 - 1.35 (m, 6H), 1.40 (s, 9H), 2.73 (bs, 2H), 3.78 (s, 3H), 4.29 (bs, 1H), 6.71 - 6.76 (m, 3H), 7.19 (t, J = 7.8 Hz, 1H). The amide NH was not observed.

[0275] A solution of tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate (3.7 g, 12.05 mmol, 1 equiv) in dichloromethane (30 mL) was added trifluoroacetic acid (2.7 g, 24.10 mmol, 2 equiv) at 0 °C. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the progress of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The resulting product was dissolved in ice-cold water (10 mL) and basified with a saturated aqueous solution of NaHCO3. The compound was extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-1-(3-methoxyphenyl)hexan-2-amine. LC-MS (m / z) = 208.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.82 - 0.90 (m, 3H), 1.23 - 1.42 (m, 4H), 1.57 - 1.62 (m, 2H), 2.69 - 2.91 (m, 2H), 3.25 - 3.58 (m, 1H), 3.80 (s, 3H), 6.69 - 6.78 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H). The NH2 proton was not observed.

[0276] To a solution of 4-fluorobenzoic acid (1.62 g, 11.59 mmol, 1.2 equiv) in DCM (25 mL) was added TEA (3.9 g, 38.64 mmol, 4 equiv), and after stirring for 15 minutes, T3P (50 wt% in EtOAc) (4.6 g, 14.49 mmol, 1.5 equiv) was added at 0 °C, and stirring was continued for an additional 5 minutes. (S)-1-(3-Methoxyphenyl)hexan-2-amine (2.0 g, 9.66 mmol, 1 equiv) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature. The progress of the reaction was monitored by TLC (20% ethyl acetate in hexane). After 16 hours, the reaction mixture was diluted with DCM (50 mL) and saturated sodium bicarbonate solution (20 mL). The organic layer was separated, washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (S)-4-fluoro-N-(1-(3-methoxyphenyl)hexan-2-yl)benzamide. LC-MS (m / z) = 330.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.88 - 0.89 (m, 3H), 1.26 - 1.48 (m, 6H), 2.83 - 2.93 (m, 2H), 3.76 (s, 3H), 4.36 - 4.38 (m, 1H), 5.74 (d, J = 7.6 Hz, 1H), 6.69 - 6.80 (m, 3H), 7.08 (t, J = 8.4 Hz, 2H), 7.21 (t, J = 7.6 Hz, 1H), 7.68 (t, J = 6.4 Hz, 2H).

[0277] Trifluoromethanesulfonic anhydride (2.5 mL, 14.89 mmol, 2.0 equiv) was added via syringe over 1 minute to a stirred mixture of amide (S)-4-fluoro-N-(1-(3-methoxyphenyl)hexan-2-yl)benzamide (2.45 g, 7.44 mmol, 1 equiv) and 2-chloropyridine (1.4 mL, 14.89 mmol, 2.0 equiv) in dichloromethane (25 mL) at -78 °C. After 5 minutes, the reaction mixture was placed in an ice bath and warmed to 0 °C. After 5 minutes, the resulting solution was warmed to 23 °C. After 1 hour, an aqueous sodium hydroxide solution (5 mL, 1 N) was introduced to neutralize the trifluoromethanesulfonate salt. Dichloromethane (50 mL) was added to dilute the mixture, and the layers were separated. The organic layer was washed with brine (2 mL), dried over anhydrous sodium sulfate, and filtered. The volatiles were removed under reduced pressure to afford (S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline. LC-MS (m / z) = 312.0 [M+H] + .

[0278] A solution of (S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinoline (0.8 g, 2.57 mmol, 1 equiv) in anhydrous THF (5 mL) was added dropwise under a nitrogen atmosphere at -78 °C to a mixture of 1 M lithium aluminum hydride in THF (25.7 mL, 25.72 mmol, 10 equiv) and 25% w / w trimethylaluminum in hexane in THF (20 mL) (3.7 mL, 12.85 mmol, 5 equiv). The suspension was stirred at -78 °C for 1 hour and warmed to 0 °C over 3 hours. The reaction mixture was quenched with saturated aqueous sodium chloride solution (5 mL), followed by dilution with EtOAc (30 mL), and the precipitate was filtered off. Finally, the filtrate was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography (EtOAc / n-hexane = 75 / 25) to afford (1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (trans was confirmed by nOe experiment).

[0279] The isolated pure water product was treated with the metal scavenger Quadrasil® TA (the compound was dissolved in THF (5 mL), Quadrasil® TA (100 mg) was added, the mixture was stirred for 0.5 h, and filtered. This was repeated once more and concentrated). LC-MS (m / z) = 314.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ ppm 0.85 (bs, 3H), 1.26 (bs, 4H), 1.45 (bs, 2H), 2.60 - 2.69 (m, 1H), 2.87 - 2.92 (m, 2H), 3.80 (s, 3H), 5.20 (s, 1H), 6.69 (s, 2H), 6.79 - 6.81 (m, 1H), 6.97 - 7.05 (m, 2H), 7.13 (s, 2H).

[0280] To a solution of (1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (0.1 g, 0.31 mmol, 1 equiv) in DCM (4 mL) was added triethylamine (0.08 g, 0.77 mmol, 2.5 equiv) at 0 °C, followed by the addition of 2-chloroacetyl chloride (0.054 g, 0.47 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 1 h under a N2 atmosphere. TLC (25% EtOAc in hexane) indicated the completion of the reaction. The reaction was then diluted with a saturated aqueous solution of NaHCO3 (5 mL), and the product was extracted with DCM (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by preparative TLC using 25% EtOAc in n-hexane as the mobile phase to obtain 1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-2-chloroethan-1-one. LC-MS (m / z) = 390.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6): (Since the behavior of rotational isomers was observed in RT NMR, it was recorded at 70 °C) δ 0.79 - 0.81 (m, 3H), 1.00 (bs, 1H), 1.20 (bs, 4H), 1.40 (bs, 1H), 2.78 - 2.83 (m, 1H), 2.87 - 2.90 (m, 2H), 3.71 (s, 3H), 4.50 (bs, 2H), 6.09 (s, 1H), 6.77 - 6.80 (m, 2H), 7.03 (bs, 2H), 7.28 (t, J = 6.6 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H).

[0281] Procedure 7: Synthesis of Compound 12

Chemical Structure

[0282] To a solution of (1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (0.15 g, 0.47 mmol, 1.0 equiv) in acetonitrile (3.5 mL) was added sodium bicarbonate (0.3 g, 3.57 mmol, 7.5 equiv) at 0 °C. After stirring for 5 minutes, a solution of 3-(trimethylsilyl)prop-2-ynoyl chloride (0.113 g, 0.69 mmol, 1.5 equiv) in acetonitrile (1.5 mL) was added. The resulting mixture was stirred at 0 °C for 15 minutes and the progress of the reaction was monitored by TLC (20% ethyl acetate in n-hexane). Thereafter, the solid portion was removed from the reaction mass by passing through a pad of celite, which was washed with acetonitrile. The resulting filtrate was concentrated under reduced pressure to give 1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one, which was carried on to the next step without further purification. LC-MS (m / z) = 438.2 [M+H] + .

[0283] A solution of 1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.2 g, 0.45 mmol, 1 equiv) in THF (4.0 mL) was added tetrabutylammonium fluoride (1 M in THF solution) (0.5 mL, 0.5 mmol, 1.1 equiv) at -78 °C. The reaction mixture was stirred at -78 °C for 15 minutes. The progress of the reaction was monitored by TLC (20% ethyl acetate in n-hexane). Thereafter, the reaction mixture was diluted with water (5 mL), and the product was extracted with ethyl acetate (25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC using 20% ethyl acetate in n-hexane as the eluent to obtain 1-((1S,3S)-3-butyl-1-(4-fluorophenyl)-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LC-MS (m / z) = 366.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.81 - 0.88 (m, 3H), 1.20 - 1.24 (m, 5H), 1.50 (bs, 1H), 2.78 - 2.89 (s, 2H), 3.72 (s, 3H), 4.18 (s, 0.3H), 4.54 (s, 0.5H), 4.50 (bs, 0.5H), 4.70 (bs, 0.7H), 6.05 (s, 0.6H), 6.31 (s, 0.4H), 6.77 - 6.84 (m, 2H), 6.98 - 7.10 (m, 2H), 7.23 - 7.24 (m, 2H), 7.36 (d, J = 8.0 Hz, 0.7H), 7.53 (d, J = 7.6 Hz, 0.3H).

[0284] Procedure 8: Synthesis of Compound 13

Chemical formula

[0285] To a solution of 4-((3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylbenzamide (0.5 g, 1.27 mmol, 1 equiv) in DCM (10 mL), TEA (0.4 g, 3.18 mmol, 2.5 equiv) was added, followed by 2-chloroacetyl chloride (0.091 mL, 1.14 mmol, 0.9 equiv), and the mixture was stirred at 0 °C for 6 h. TLC 30% (ethyl acetate in hexane) indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by preparative HPLC [analysis conditions: column: Inertsil ODS 3V (250 mm × 4.6 mm × 5 μm), mobile phase (A): 0.1% ammonia in water, mobile phase (B): CH3CN, flow rate: 1.0 mL / min, composition of B: 0 / 10, 12 / 80, 25 / 90, 27 / 10, 30 / 10] to obtain 4-((1S,3S)-3-butyl-2-(2-chloroacetyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylbenzamide. LCMS (ES) m / z: 469.0 [M+H] + , HPLC purity: 99.8%, chiral HPLC purity: 99.92%. 1 H NMR (400 MHz, CDCl3): δ ppm 0.78 - 0.81 (m, 3H), 1.22 - 1.41 (m, 6H), 1.60 - 1.69 (m, 2H), 1.99 - 2.06 (m, 2H), 2.18 - 2.20 (m, 2H), 2.80 - 2.84 (m, 2H), 3.09 - 3.10 (m, 1H), 3.71 (s, 3H), 4.31 - 4.37 (m, 1H), 4.55 (bs, 2H), 6.13 (s, 1H), 6.77 - 6.81 (m, 2H), 7.32 - 7.34 (m, 2H), 7.43 (m, 1H), 7.66 (s, 1H).

[0286] Procedure 9: Synthesis of Compound 14

Chemical Structure

[0287] A solution of tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate (10 g, 32.57 mmol, 1 equiv) in dichloromethane (50 mL) was added 4 M HCl in 1,4-dioxane (20 mL, 64.10 mmol, 2 equiv) at 0 °C. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the progress of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The resulting crude was dissolved in ice-cold water (10 mL) and basified with a saturated aqueous solution of NaHCO3. The compound was extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-1-(3-methoxyphenyl)hexan-2-amine. LC-MS (m / z): 208.1 [M+H] + . 1 1H NMR (400 MHz, CDCl3): δ ppm 0.82 - 0.90 (m, 3H), 1.23 - 1.42 (m, 4H), 1.57 - 1.62 (m, 2H), 2.69 - 2.91 (m, 2H), 3.25 - 3.58 (m, 1H), 3.80 (s, 3H), 6.69 - 6.78 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H) (NH2 proton was not observed).

[0288] A solution of (S)-1-(3-methoxyphenyl)hexan-2-amine (0.7 g, 3.37 mmol, 1 equiv) and methyl 4-formylbenzoate (0.664 g, 4.05 mmol, 1 equiv) in toluene (4 mL) was irradiated with microwave at 90 °C for 20 minutes. Thereafter, the volatile portion was concentrated under reduced pressure and directly advanced to the cyclization step with TFA (4 mL), and irradiated with microwave at 140 °C for 45 minutes. Thereafter, the volatile portion was concentrated under reduced pressure, and the obtained crude product was diluted with a saturated aqueous solution of NaHCO3 (10 mL) and EtOAc (40 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by flash column chromatography (n-hexane / EtOAc) to obtain methyl 4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate. LC-MS (m / z): 208.1 [M+H] + . 1 H NMR (400 MHz, CDCl3): δ ppm 0.84 - 0.86 (m, 3H), 1.23 - 1.24 (m, 6H), 2.55 - 2.59 (m, 1H), 2.85 - 2.88 (m, 2H), 3.75 (s, 3H), 3.80 (s, 3H), 5.29 (s, 3H), 6.67 - 6.69 (m, 2H), 6.70 - 6.80 (m, 1H), 7.21 - 7.26 (s, 2H), 7.94 - 8.0 (m, 2H).

[0289] To a solution of methyl 4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (0.35 g, 1.12 mmol, 1 equiv) in DCM (10 mL) was added triethylamine (0.45 g, 4.49 mmol, 4 equiv) and di-tert-butyl dicarbonate (0.715 g, 2.24 mmol, 2 equiv) at room temperature, and the mixture was stirred for 16 h. TLC (50% EtOAc in hexane) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product tert-butyl (1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z): 356.0 [M- t Bu+H] + .

[0290] To a solution of tert-butyl (1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.650 g, 1.57 mmol, 1 equiv) in a mixture of THF:MeOH:H2O (9 mL:1 mL) was added lithium hydroxide (0.331 g, 7.89 mmol, 5 equiv), and the mixture was stirred at room temperature for 16 h. TLC (50% EtOAc in hexane) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was acidified with 5% citric acid solution (pH = 9). The reaction mixture was diluted with EtOAc (50 mL), the organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product 4-((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid. LC-MS (m / z): 396.0 [M+H] + .

[0291] To a solution of compound 4-((1S,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid (0.520 g, 1.18 mmol, 1 equiv) in DCM (10 mL) were added triethylamine (0.6 mL, 4.73 mmol, 4 equiv) and 2-methoxyethan-1-amine (0.106 g, 1.42 mmol, 1.2 equiv) at 0 °C, and the mixture was stirred for 15 min. To the above reaction mixture was added T3P (50 wt% in EtOAc) (1.4 mL, 1.7 mmol, 1.5 equiv) at the same temperature, and the mixture was stirred for 16 h. TLC (30% EtOAc in hexane) indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product tert-butyl (1S,3S)-3-butyl-6-methoxy-1-(4-((2-methoxyethyl)carbamoyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z): 497.0 [M- t Bu+H] + 。

[0292] A solution of tert-butyl (1S,3S)-3-butyl-6-methoxy-1-(4-((2-methoxyethyl)carbamoyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.380 g, 0.76 mmol, 1 eq) in dichloromethane (50 mL) was added 4M HCl in 1,4-dioxane (10 mL, 1.52 mmol, 2 eq) at 0 °C. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the progress of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The obtained crude product was dissolved in ice-cold water (20 mL) and basified with a saturated aqueous solution of NaHCO3. The compound was extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(2-methoxyethyl)benzamide. LC-MS (m / z): 397.0 [M+H] + .

[0293] 3-(Trimethylsilyl)propionic acid (0.172 g, 1.20 mmol, 1 equiv), DMF (0.003 g, 0.048 mmol, 0.04 equiv), and oxalyl chloride (0.114 mL, 1.33 mmol, 1.1 equiv) were added and stirred for 30 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure to obtain crude 3-(trimethylsilyl)propionyl chloride, which was diluted with ACN (1 mL) and added to a stirred solution of 4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(2-methoxyethyl)benzamide (0.320 g, 0.807 mmol, 1 equiv) and NaHCO3 (0.508 g, 6.05 mmol, 7.5 equiv) in ACN (5 mL) at 0 °C and stirred for 15 minutes. LCMS and TLC (70% EtOAc in hexanes) indicated completion of the reaction. The reaction was filtered and concentrated under reduced pressure to obtain the crude product 4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propionyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(2-methoxyethyl)benzamide, which was carried on to the next step without further purification. LC-MS (m / z): 521.0 [M+H] + .

[0294] 4-((1S,3S)-3-Butyl-6-methoxy-2-(3-(trimethylsilyl)propionoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(2-methoxyethyl)benzamide (0.360 g, 0.69 mmol, 1 eq) in THF (10.0 mL) was added dropwise with TBAF (1 M solution in THF) (0.48 mL, 0.48 mmol, 2 eq), and the mixture was stirred for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL), and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4, concentrated, and further purified by preparative TLC chromatography using 70% EtOAc in hexane as the eluent to obtain 4-((1S,3S)-3-butyl-6-methoxy-2-propionoyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-(2-methoxyethyl)benzamide. LC-MS (m / z): 449.2 [M+H] + , HPLC purity: 98.6%, chiral HPLC purity: 99.98%. 1 1H NMR (400 MHz, DMSO-d6): δ 0.80 - 0.83 (m, 3H), 0.92 - 1.24 (m, 5H), 1.50 (bs, 1H), 2.80 - 2.90 (m, 2H), 3.10 (s, 1H), 3.24 (s, 3H), 3.38 - 3.42 (m, 4H), 3.71 - 3.72 (m, 2H), 4.16 - 4.46 (s, 1H), 4.58 - 4.75 (bs, 1H), 6.07 - 6.34 (s, 1H), 6.77 - 6.84 (m, 2H), 7.29 - 7.31 (m, 2H), 7.38 - 7.58 (m, 1H), 7.64 - 7.73 (m, 2H), 8.13 - 8.19 (m, 1H).

[0295] Procedure 10: Synthesis of Compound 15

Chemical Structure

[0296] To a solution of methyl 5-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)picolinate (0.320 g, 0.18 mmol, 1 equiv) in DCM (10 mL) was added triethylamine (0.50 g, 3.61 mmol, 4 equiv) and di-tert-butyl dicarbonate (0.394 g, 1.80 mmol, 2 equiv) at room temperature, and the mixture was stirred for 16 h. TLC (50% EtOAc in hexanes) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude product tert-butyl (1R,3S)-3-butyl-6-methoxy-1-(6-(methoxycarbonyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z): 455.0 [M- t Bu+H] + .

[0297] To a solution of tert-butyl (1R,3S)-3-butyl-6-methoxy-1-(6-(methoxycarbonyl)pyridin-3-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.450 g, 0.99 mmol, 1 equiv) in a mixture of THF:MeOH:H2O (9 mL:1 mL) was added lithium hydroxide (0.208 g, 4.96 mmol, 5 equiv), and the mixture was stirred at room temperature for 16 h. TLC (50% EtOAc in hexanes) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was acidified with 5% citric acid solution (pH = 9). The reaction mixture was diluted with EtOAc (50 mL), the organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product 5-((1R,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)picolinic acid. LC-MS (m / z): 441.0 [M+H] + .

[0298] To a solution of compound 5-((1R,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)picolinate (0.300 g, 0.68 mmol, 1 equiv) in DCM (10 mL) were added triethylamine (0.38 mL, 2.72 mmol, 4 equiv) and cyclobutanamine (0.058 g, 0.817 mmol, 1.2 equiv) at 0 °C, and the mixture was stirred for 15 minutes. To the above reaction mixture was added T3P (50 wt% in EtOAc) (0.72 mL, 0.81 mmol, 1.5 equiv) at the same temperature, and the mixture was stirred for 16 hours. TLC (30% EtOAc in hexane) indicated the completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product tert-butyl (1R,3S)-3-butyl-1-(6-(cyclobutylcarbamoyl)pyridin-3-yl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z): 494.0 [M- t Bu+H] + .

[0299] A solution of tert-butyl (1R,3S)-3-butyl-1-(6-(cyclobutylcarbamoyl)pyridin-3-yl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.220 g, 0.445 mmol, 1 equiv) in dichloromethane (50 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 0.89 mmol, 2 equiv) at 0 °C. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the progress of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The obtained crude product was dissolved in ice-cold water (20 mL) and basified with a saturated aqueous solution of NaHCO3. The compound was extracted with EtOAc (100 mL). The combined organics were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylpicolinamide. LC-MS (m / z): 394.0 [M+H] + .

[0300] 3-(Trimethylsilyl)propionic acid (0.084 g, 0.59 mmol, 1 equiv), DMF (0.003 g, 0.048 mmol, 0.04 equiv), and oxalyl chloride (0.055 mL, 0.64 mmol, 1.1 equiv) were added and stirred for 30 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure to obtain the crude product 3-(trimethylsilyl)propionyl chloride, which was diluted with ACN (1 mL) and added to a stirred solution of 5-((1R,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylpicolinamide (0.155 g, 0.394 mmol, 1 equiv) and NaHCO3 (0.248 g, 2.95 mmol, 7.5 equiv) in ACN (5 mL) at 0 °C and stirred for 15 minutes. LCMS and TLC (70% EtOAc in hexane) indicated completion of the reaction. The reaction was filtered and concentrated under reduced pressure to obtain the crude product 5-((1R,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propionyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylpicolinamide, which was advanced to the next step without further purification. LC-MS (m / z): 518.0 [M+H] + .

[0301] 5-((1R,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propionoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylpicolinamide (0.210 g, 0.405 mmol, 1 equiv) in THF (10.0 mL) was added to TBAF (1 M solution in THF) (0.81 mL, 0.81 mmol, 2 equiv), and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure, diluted with ethyl acetate (100 mL), and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4 and concentrated, and the resulting crude product was further purified by preparative TLC chromatography using 70% EtOAc in hexanes as the eluent to afford 5-((1R,3S)-3-butyl-6-methoxy-2-propionoyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-N-cyclobutylpicolinamide. LC-MS (m / z): 446.2 [M+H] + , HPLC purity: 99.45%, chiral HPLC purity: 99.8%. 1 1H NMR (400 MHz, DMSO-d6): δ 0.79 - 0.83 (m, 3H), 1.20 - 1.24 (m, 5H), 1.46 (bs, 1H), 1.57 - 1.63 (m, 2H), 2.09 - 2.16 (m, 4H), 2.81 - 2.95 (m, 1H), 3.15 - 3.19 (m, 1H), 4.35 - 4.41 (m, 1H), 4.63 (s, 1H), 4.77 (bs, 1H), 6.15 (s, 0.7H), 6.47 (s, 0.39H), 6.78 - 6.83 (m, 2H), 7.42 - 7.44 (m, 1H), 7.78 - 7.88 (m, 3H), 8.56 - 8.60 (m, 1H), 8.68 - 8.70 (m, 1H).

[0302] Procedure 11: Synthesis of Compounds 40 and 41

Chemical Structure

[0303] To a solution of 40-2 (80 mg, 382.33 umol, 1 equiv), 4A MS (700 mg, 382.33 umol, 1 equiv), and methyl 4-formylbenzoate (62.76 mg, 382.33 umol, 1 equiv) in DCM (15 mL) was added a yellow solution with stirring at 20 °C for 0.5 h. TLC (eluting with PE / EA = 3 / 1) indicated completion of the reaction. The reaction solution was diluted with DCM (10 mL) and washed with water (10 mL * 3). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 40-3.

[0304] To a solution of 40-3 (150 mg, 422.08 umol, 1 equiv) in TFA (4.81 g, 42.21 mmol, 3.13 mL, 100 equiv) was added a yellow solution with stirring at 80 °C for 16 h. TLC (quenched with water, eluting with PE / EA = 3 / 1) indicated completion of the reaction. The reaction solution was diluted with DCM (10 mL) and washed with NaHCO3 solution to pH = 8. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 40-4.

[0305] To a solution of 40-4 (150 mg, 422.08 umol, 1 equiv) and Et3N (85.42 mg, 844.16 umol, 117.50 μL, 2 equiv) in DCM (5 mL) was added 2-chloroacetyl chloride (71.51 mg, 633.12 umol, 50.36 μL, 1.5 equiv) at 0 °C for 1 h to afford a yellow solution. TLC (quenched with water, eluting with PE / EA = 3 / 1) indicated completion of the reaction. The reaction product was purified by preparative TLC to give 40 and 41.

[0306] Compound 40: LC-MS (m / z): 432.0 [M] + 。 1 H NMR (400 MHz, chloroform-d) δ ppm 3.08 - 3.13 (m, 1H) 3.28 (brs, 1H) 3.59 (s, 4H) 3.77 (s, 4H) 3.85 - 3.90 (m, 5H) 3.93 - 3.99 (m, 1H) 4.07 (brs, 1H) 4.11 - 4.18 (m, 1H) 5.17 (brs, 1H) 5.28 (brs, 1H) 6.13 (s, 1H) 6.42 (s, 1H) 6.61 - 6.69 (m, 2H) 6.77 - 6.86 (m, 2H) 7.28 - 7.36 (m, 5H) 7.91 (brd, J = 8.28 Hz, 1H) 7.98 (brd, J = 8.03 Hz, 2H).

[0307] Compound 41: LC-MS (m / z): 432.0 [M] + 。 1 H NMR (400 MHz, chloroform-d) δ ppm 2.59 - 2.71 (m, 1H) 2.99 (brdd, J = 14.81, 4.52 Hz, 1H) 3.20 (brs, 1H) 3.33 (brs, 1H) 3.79 (s, 3H) 3.77 - 3.80 (m, 1H) 3.83 (s, 4H) 3.89 (s, 4H) 4.07 - 4.26 (m, 3H) 4.40 (brdd, J = 12.92, 4.64 Hz, 1H) 4.68 - 4.77 (m, 1H) 4.73 (brs, 1H) 6.10 (s, 1H) 6.76 - 6.85 (m, 2H) 6.89 (brd, J = 8.53 Hz, 1H) 7.00 (brd, J = 7.28 Hz, 1H) 7.35 (brd, J = 8.28 Hz, 1H) 7.63 (brd, J = 8.28 Hz, 2H) 7.89 (brd, J = 7.53 Hz, 1H) 7.99 (brd, J = 8.28 Hz, 2H).

[0308] Procedure 12: Synthesis of Compounds 42 and 43

Chemical Structure

[0309] To a solution of 42-3 (50 mg, 269.92 μmol, 1 equiv) and methyl 4-formylbenzoate (44.31 mg, 269.92 μmol, 1 equiv) in toluene (3 mL) was added TFA (15.39 mg, 134.96 μmol, 9.99 μL, 0.5 equiv) at 20 °C. The mixture was stirred at 80 °C for 16 h to give a yellow solution. TLC indicated the completion of the reaction. The reaction mixture was purified by preparative TLC to give 42-4 and 42-5. 1 H NMR (400 MHz, chloroform-d) δ ppm 2.96 - 3.05 (m, 1H) 3.10 - 3.18 (m, 1H) 3.73 (s, 3H) 3.83 - 3.88 (m, 1H) 3.86 (dd, J = 7.15, 5.65 Hz, 1H) 3.91 (s, 3H) 5.44 (s, 1H) 6.85 (d, J = 5.02 Hz, 1H) 7.19 (d, J = 5.02 Hz, 1H) 7.40 (d, J = 8.28 Hz, 2H) 8.00 (d, J = 8.28 Hz, 2H).

[0310] To a solution of 42-4 (40 mg, 120.71 μmol, 1 equiv) and TEA (18.32 mg, 181.06 μmol, 25.20 μL, 1.5 equiv) in DCM (3 mL) was added 2-chloroacetyl chloride (20.45 mg, 181.06 μmol, 14.40 μL, 1.5 equiv) at 0 °C. The mixture was stirred at 30 °C for 1 h to give a yellow solution. TLC (quenched with water, eluting with PE / EA = 0 / 1) indicated completion of the reaction. The reaction product was purified by preparative TLC to give 42. 1 H NMR (400 MHz, chloroform-d) δ ppm 3.02 - 3.59 (m, 2H) 3.60 - 3.70 (m, 3H) 3.88 (brd, J = 5.52 Hz, 3H) 4.06 (brd, J = 13.30 Hz, 1H) 5.03 - 5.27 (m, 1H) 6.27 (brs, 1H) 6.77 (d, J = 5.02 Hz, 1H) 7.09 - 7.20 (m, 1H) 7.32 - 7.52 (m, 2H) 7.88 - 8.10 (m, 2H). LC-MS (m / z): 407.9 [M] + 。

[0311] To a solution of 42-5 (60.00 mg, 181.06 μmol, 1 equiv) and TEA (27.48 mg, 271.59 μmol, 37.80 μL, 1.5 equiv) in DCM (3 mL) was added 2-chloroacetyl chloride (30.67 mg, 271.59 μmol, 21.60 μL, 1.5 equiv) at 0 °C. The mixture was stirred at 30 °C for 1 h to give a yellow solution. TLC (quenched with water, eluting with PE / EA = 3 / 1) indicated completion of the reaction. The mixture was re-purified by preparative TLC to give 43. 1 H NMR (400 MHz, chloroform-d) δ ppm 2.01 (s, 1H) 2.99 - 3.17 (m, 5H) 3.56 (brd, J = 16.06 Hz, 1H) 3.89 (s, 4H) 4.18 (d, J = 12.30 Hz, 1H) 4.30 (brs, 1H) 4.87 (brs, 1H) 6.88 - 7.05 (m, 2H) 7.28 (brs, 1H) 7.39 (brs, 2H) 7.94 (brs, 2H). LC-MS (m / z): 407.9 [M] + 。

[0312] Procedure 13: Synthesis of Compounds 44 and 45 [Chemical formula] To this solution of 2-methylpropan-2-sulfonamide (6.24 g, 51.49 mmol, 2 equiv) in THF (120 mL) was added Ti(OEt)4 (58.72 g, 257.43 mmol, 53.38 mL, 10 equiv), 44-1 (5 g, 25.74 mmol, 1 equiv) in THF (100 mL). The brown solution was heated to 75 °C and monitored by TLC. After 5 h, the reaction was cooled to 25 °C to afford crude 44-2. The reaction was then cooled to -20 °C, NaBH4 (973.93 mg, 25.74 mmol, 1 equiv) was added, and the reaction was stirred at -20 °C for 3 h, then warmed to 25 °C and stirred for 12 h. LCMS indicated completion of the reaction. An equivalent of saturated aqueous NaCl (60 mL) was added to precipitate the titanium salts. After stirring for 5 min, the suspension was filtered through Celite and the filter cake was washed with EtOAc (100 mL × 2). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 × 100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give a residue. The residue was purified by flash chromatography (silica) eluting with ethyl acetate in petroleum ether (0% - 80%) to afford 44-3. 1 1H NMR (400 MHz, CDCl3) δ = 6.77 - 6.62 (m, 3H), 3.80 (d, J = 4.8 Hz, 6H), 3.64 - 3.49 (m, 1H), 3.18 (brd, J = 4.8 Hz, 1H), 2.78 - 2.59 (m, 2H), 1.14 - 1.05 (m, 12H).

[0313] To a mixture of 44-3 (2 g, 6.68 mmol, 1 equiv) in MeOH (20 mL) was added dropwise HCl / dioxane (4 M, 20 mL, 11.98 equiv). The mixture was stirred at 20 °C for 12 h to give a brown mixture. LCMS indicated that the reaction was complete. The reaction mixture was diluted with 60 mL of HCl (0.1 M). The resulting mixture was extracted with ethyl acetate (30 mL × 2). The aqueous phase was adjusted to pH = 8. The aqueous phase was extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 44-4. 1 H NMR (400 MHz, CDCl3) δ = 6.78 - 6.83 (m, 1H), 6.70 - 6.75 (m, 2H), 3.86 (d, J = 4.4 Hz, 6H), 3.07 - 3.21 (m, 1H), 2.78 - 2.59 (m, 2H), 2.67 (m, 1H), 2.44 (m, 1H), 1.64 (brs, 2H), 1.12 (d, J = 6.4 Hz, 3H).

[0314] 4A molecular sieve (3 g, 2.56 mmol, 1 equiv) was added to a solution of 44-4 (500 mg, 2.56 mmol, 1 equiv) and 4-morpholinobenzaldehyde (489.68 mg, 2.56 mmol, 1 equiv) in toluene (20 mL), and the mixture was stirred at 120 °C for 4 h. LCMS indicated that the starting materials were not completely consumed. The reaction mixture was stirred at 120 °C for an additional 4 h. LCMS indicated that the starting materials were completely consumed. The reaction mixture was filtered, and the filter was concentrated in vacuo. The residue was dissolved in TFA (32.58 g, 285.73 mmol, 21.16 mL, 111.58 equiv), and the solution was heated at 120 °C for 20 h. LC-MS indicated that the starting materials were completely consumed. The reaction mixture was concentrated under reduced pressure. The mixture was adjusted to pH = 9 with 2N aqueous NaOH and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, dichloromethane:methanol = 100:1 - 100:5) to give N136-6 and 44-5. 11H NMR (400 MHz, chloroform-d) δ ppm 1.25 (d, J = 6.4 Hz, 3H), 2.58 - 2.80 (m, 2H), 3.12 - 3.22 (m, 5H), 3.57 - 3.64 (m, 3H), 3.84 - 3.91 (m, 7H), 5.01 (s, 1H), 6.18 - 6.25 (m, 1H), 6.57 - 6.66 (m, 1H), 6.89 (d, J = 8.8 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H).

[0315] To a mixture of 44 - 6 (122 mg, 331.10 μmol, 1 eq) and TEA (335.04 mg, 3.31 mmol, 460.85 μL, 10 eq) in DCM (6 mL) was added 2 - chloroacetyl chloride (112.19 mg, 993.30 μmol, 79.00 μL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 30 minutes to give a brown mixture. LCMS indicated that the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC and then dried by lyophilization to give 44 and 45.

[0316] Compound 44: LC - MS (m / z): 445.0 [M + H] + 。 1 1H NMR (400 MHz, chloroform-d) δ 0.99 (brs, 3H), 2.41 (brd, J = 14.8 Hz, 1H), 2.80 - 3.28 (m, 5H), 3.60 - 4.57 (m, 12H), 4.83 (brs, 1H), 5.74 (brs, 1H), 6.57 (s, 1H), 6.65 - 6.90 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H)

[0317] Compound 45: LC - MS (m / z): 445.0 [M + H] + 。 11H NMR (400 MHz, chloroform-d) δ 0.99 (brs, 3H), 2.41 (brd, J = 14.8 Hz, 1H), 2.80 - 3.28 (m, 5H), 3.60 - 4.57 (m, 12H), 4.83 (brs, 1H), 5.74 (brs, 1H), 6.57 (s, 1H), 6.65 - 6.90 (m, 3H), 7.03 (d, J = 8.8 Hz, 2H)

[0318] Procedure 14: Synthesis of Compound 46

Chemical Structure

[0319] To a solution of 46-2 (1 g, 6.02 mmol, 1 equiv) and Et3N (1.83 g, 18.05 mmol, 2.51 mL, 3 equiv) in DCM (20 mL) was added MsCl (1.03 g, 9.02 mmol, 698.48 μL, 1.5 equiv) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. TLC indicated the completion of the reaction. The reaction mixture was poured into saturated NaHCO3 (50 mL) solution and the mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 46-3, which was used directly in the next step without further purification. 1 1H NMR (400 MHz, CDCl3) δ = 7.22 - 7.12 (m, 1H), 6.82 - 6.62 (m, 3H), 4.89 - 4.73 (m, 1H), 3.73 (s, 3H), 2.95 - 2.74 (m, 2H), 2.49 (s, 3H), 1.40 (d, J = 6.0 Hz, 3H).

[0320] To a solution of 46-3 (1.5 g, 6.14 mmol, 1 equiv) in DMF (8 mL) was added NaN3 (798.30 mg, 12.28 mmol, 2 equiv). The mixture was heated at 80 °C for 2 h. TLC indicated the completion of the reaction. 90 mL of water was added and the mixture was extracted with 120 mL of EtOAc / hexane (1:1) mixture. The extract was dried over anhydrous Na2SO4 and evaporated to give crude 46-4, which was used directly in the next step without further purification.

[0321] To a solution of 46-4 (1.1 g, 5.75 mmol, 1 equiv) in EtOAc (100 mL) was added Pd / C (500 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 25 °C for 1 h under H2 (15 psi). TLC indicated the completion of the reaction. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by flash chromatography (silica) eluting with MeOH in CH2Cl2 (0% - 20%) to give 46-5. 11H NMR (400 MHz, CDCl3) δ = 7.20 - 7.08 (m, 1H), 6.74 - 6.61 (m, 3H), 3.72 (s, 3H), 3.17 - 3.03 (m, 1H), 2.62 (dd, J = 5.6, 13.6 Hz, 1H), 2.42 (dd, J = 8.0, 13.2 Hz, 1H), 1.42 (s, 2H), 1.05 (d, J = 6.4 Hz, 3H).

[0322] 4A MS (600 mg) was added to a solution of 46 - 5 (100 mg, 605.21 μmol, 1 equiv) and 4 - morpholinobenzaldehyde (115.73 mg, 605.21 μmol, 1 equiv) in toluene (4 mL), and the mixture was stirred at 120 °C for 4 h. The reaction mixture was filtered, and the filter was concentrated in vacuo. The residue was dissolved in TFA (5.00 mL), and the solution was heated at 120 °C for 20 h. TLC indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The mixture was basified with 2N aqueous NaOH and extracted with EtOAc (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 46 - 6, which was used directly in the next step without further purification. 1 1H NMR (400 MHz, CDCl3) δ = 7.19 - 7.13 (m, 2H), 6.80 (d, J = 8.4 Hz, 2H), 6.58 - 6.47 (m, 3H), 4.93 (s, 1H), 3.80 - 3.77 (m, 4H), 3.69 (s, 3H), 3.16 - 3.11 (m, 1H), 3.10 - 3.05 (m, 4H), 2.71 - 2.63 (m, 2H), 1.97 (s, 1H), 1.16 (d, J = 6.0 Hz, 3H)

[0323] To a solution of 46-6 (250.00 mg, 738.68 μmol, 1 equiv) and Et3N (224.24 mg, 2.22 mmol, 308.45 μL, 3 equiv) in DCM (5 mL) was added 2-chloroacetyl chloride (166.86 mg, 1.48 mmol, 117.51 μL, 2 equiv) at 0 °C. The reaction mixture was stirred at 25 °C for 1 h. LCMS indicated that the reaction was complete. The reaction mixture was poured into saturated NaHCO3 (50 mL) solution and the mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica) eluting with ethyl acetate in petroleum ether (0% - 40%) to afford 46. 1 H NMR (400 MHz, DMSO-d6) δ = 7.15 (brd, J = 8.8 Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.90 - 6.79 (m, 4H), 6.31 (brs, 1H), 4.53 - 4.35 (m, 2H), 4.28 - 4.18 (m, 1H), 3.79 (s, 3H), 3.76 - 3.70 (m, 2H), 3.76 - 3.70 (m, 1H), 3.76 - 3.70 (m, 1H), 3.12 - 3.08 (m, 4H), 3.01 - 2.93 (m, 1H), 2.49 - 2.37 (m, 1H), 1.14 (d, J = 6.4 Hz, 3H).

[0324] Procedure 15: Synthesis of Compound 47

Chemical Structure

[0325] To a solution of 47-2 (1 g, 6.02 mmol, 1 equiv) and Et3N (1.83 g, 18.05 mmol, 2.51 mL, 3 equiv) in DCM (20 mL) was added MsCl (1.03 g, 9.02 mmol, 698.48 μL, 1.5 equiv) at 0 °C. The reaction was stirred at 25 °C for 1 hour. TLC indicated that the reaction was complete. The reaction was poured into saturated NaHCO3 (50 mL) solution and the mixture was extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 47-3, which was used directly in the next step without further purification. 1 1H NMR (400 MHz, CDCl3) δ = 7.22 - 7.12 (m, 1H), 6.82 - 6.62 (m, 3H), 4.89 - 4.73 (m, 1H), 3.73 (s, 3H), 2.95 - 2.74 (m, 2H), 2.49 (s, 3H), 1.40 (d, J = 6.0 Hz, 3H).

[0326] To a solution of 47-3 (1.5 g, 6.14 mmol, 1 equiv) in DMF (8 mL) was added NaN3 (798.30 mg, 12.28 mmol, 2 equiv). The mixture was heated at 80 °C for 2 h. TLC indicated that the reaction was complete. 90 mL of water was added and the mixture was extracted with 120 mL of an EtOAc / hexane (1:1) mixture. The extract was dried over anhydrous Na2SO4 and evaporated to give crude 47-4, which was used directly in the next step without further purification.

[0327] To a solution of 47-4 (1.1 g, 5.75 mmol, 1 equiv) in EtOAc (100 mL) was added Pd / C (500 mg, 10% purity) under N2. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 25 °C for 1 h under H2 (15 psi). TLC indicated that the reaction was complete. The reaction mixture was filtered and the filtrate was concentrated. The crude product was purified by flash chromatography (silica) eluting with MeOH in CH2Cl2 (0% - 20%) to give 47-5. 1 H NMR (400 MHz, CDCl3) δ = 7.20 - 7.08 (m, 1H), 6.74 - 6.61 (m, 3H), 3.72 (s, 3H), 3.17 - 3.03 (m, 1H), 2.62 (dd, J = 5.6, 13.6 Hz, 1H), 2.42 (dd, J = 8.0, 13.2 Hz, 1H), 1.42 (s, 2H), 1.05 (d, J = 6.4 Hz, 3H).

[0328] 4A molecular sieve (3 g, 3.03 mmol, 1.00 equiv) was added to a solution of 47-5 (500 mg, 3.03 mmol, 1 equiv) and 4-morpholinobenzaldehyde (578.66 mg, 3.03 mmol, 1 equiv) in toluene (25 mL), and the mixture was stirred at 120 °C for 4 h. LCMS indicated that the reaction was complete. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to a small volume under vacuum to give crude N135-6A, which was used directly in the next step without further purification.

[0329] 47-6A (1 g, 2.95 mmol, 1 equiv) was dissolved in TFA (46.20 g, 405.19 mmol, 30.00 mL, 137.13 equiv), and the solution was heated at 120 °C for 20 h to obtain a brown solution. LCMS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The mixture was basified with 2N aqueous NaOH and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica) eluting with MeOH in CH2Cl2 (0% - 5%). The crude product was purified by preparative TLC (DCM / MeOH = 10 / 1, Rf1 = 0.5, Rf2 = 0.45) to obtain the cis product as the major product.

[0330] A trace amount of the trans product was obtained by further preparative TLC purification (purity 95%), and the structure was clearly confirmed by 2D NMR.

[0331] To a solution of 47-6B (10 mg, 29.55 μmol, 1 equiv) and Et3N (8.97 mg, 88.64 μmol, 12.34 μL, 3 equiv) in DCM (2 mL) was added 2-chloroacetyl chloride (6.67 mg, 59.09 μmol, 4.70 μL, 2 equiv) at 0 °C. The mixture was stirred at 25 °C for 1 h to obtain a brown solution. LCMS indicated that the reaction was complete. The reaction was concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 2 / 1, Rf = 0.4) to obtain 47. 1 1H NMR (400 MHz, CDCl3) δ = 7.24 (brd, J = 8.0 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.78 - 6.69 (m, 3H), 6.61 (s, 1H), 5.78 (brs, 1H), 4.84 (brs, 1H), 4.04 (brd, J = 12.4 Hz, 1H), 3.81 (brd, J = 12.4 Hz, 1H), 3.77 - 3.73 (m, 4H), 3.72 (s, 3H), 3.06 - 2.99 (m, 4H), 2.96 (brs, 1H), 2.44 (brd, J = 16.0 Hz, 1H), 0.97 (brd, J = 5.6 Hz, 3H).

[0332] Step 16: Synthesis of Compound 39

Chemical Structure

[0333] 1 H NMR (400 MHz, CDCl3) δ ppm 0.84 - 0.92 (m, 3H), 1.16 - 1.38 (m, 9H), 1.49 - 1.51 (m, 1H), 1.65 - 1.80 (m, 6H), 1.92 - 2.03 (m, 1H), 2.70 - 2.79 (m, 2H), 3.78 (s, 3H), 4.12 - 4.17 (m, 1H), 5.11 (d, J = 8.4 Hz, 1H), 6.70 - 6.75 (m, 3H), 7.18 (t, J = 7.8 Hz, 1H).

[0334] (S)-3-Butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinoline: Trifluoromethanesulfonic anhydride (1.45 mL, 8.64 mmol, 2.0 equiv) was added via syringe over 1 minute to a stirred mixture of (S)-N-(1-(3-methoxyphenyl)hexan-2-yl)cyclohexanecarboxamide (1.37 g, 4.32 mmol, 1 equiv) and 2-chloropyridine (0.81 mL, 8.64 mmol, 2.0 equiv) in dichloromethane (13 mL) at -78 °C. After 5 minutes, the reaction mixture was placed in an ice bath and warmed to 0 °C. After 5 minutes, the resulting solution was warmed to 23 °C. After 1 hour, aqueous sodium hydroxide solution (5 mL, 1 N) was introduced to neutralize the trifluoromethanesulfonate salt. Dichloromethane (50 mL) was added to dilute the mixture and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure to give the crude product. The crude product obtained was carried forward to the next step without further purification. LC-MS (m / z) = 300.3 [M+H] + .

[0335] (1S,3S)-3-Butyl-1-cyclohexyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline: A solution of (S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinoline (1.37 g, 4.58 mmol, 1 equiv) in anhydrous THF (20 mL) was added dropwise to a mixture of 1 M lithium aluminum hydride in THF (22.9 mL, 22.90 mmol, 5.0 equiv) and a 2 M solution of trimethylaluminum in toluene in THF (20 mL) at -78 °C under a nitrogen atmosphere. The suspension was stirred at -78 °C for 1 h and warmed to 0 °C over 30 min. The reaction mixture was quenched with saturated aqueous sodium chloride solution (5 mL), followed by dilution with EtOAc (30 mL), and the resulting precipitate was filtered off. Finally, the filtrate was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc / n-hexane = 20 / 80) to give (1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (trans was confirmed by nOe experiment). The isolated pure product was treated with the metal scavenger Quadrasil® AP (the compound was dissolved in THF (10 mL), Quadrasil® AP (1 g) was added, the mixture was stirred for 0.5 h, and filtered. This was repeated once more and concentrated). LC-MS (m / z) = 302.3 [M+H] +

[0336] 1 H NMR (400 MHz, CDCl3) δ ppm 0.90 - 0.93 (m, 3H), 1.02 - 1.04 (m, 1H), 1.17 (bs, 3H), 1.25 - 1.29 (m, 1H), 1.34 - 1.35 (s, 3H), 1.36 - 1.42 (m, 3H), 1.66 - 1.68 (m, 3H), 1.68 - 1.77 (m, 3H), 2.41 - 2.47 (m, 1H), 2.80 - 2.85 (m, 1H), 3.10 (bs, 1H), 3.58 (d, J = 6.4 Hz, 1H), 3.76 (s, 3H), 6.60 (s, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H).

[0337] 1-((1S,3S)-3-Butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: First step: A solution of 3-(trimethylsilyl)propionic acid (141 mg, 0.99 mmol, 1.5 equiv) in DMF (1.9 mg, 0.026 mmol, 0.04 equiv) was added with oxalyl chloride (0.13 g, 1.05 mmol, 1.6 equiv) at room temperature and stirred for 30 minutes. Then, the reaction mixture was concentrated under reduced pressure to obtain 3-(trimethylsilyl)propionyl chloride. This acid chloride was carried on to the next step without further purification.

[0338] Second step: Sodium bicarbonate (0.42 g, 4.98 mmol, 7.5 equiv) was added to a solution of (1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline (0.2 g, 0.66 mmol, 1.0 equiv) in acetonitrile (5.0 mL) at 0 °C. After stirring for 5 minutes, a solution of 3-(trimethylsilyl)propionyl chloride in acetonitrile (2.0 mL) was added to the above reaction mass. The resulting mixture was stirred at 0 °C for 15 minutes and the progress of the reaction was monitored by TLC (15% ethyl acetate in n-hexane). Then, the reaction mass was diluted with EtOAc (30 mL) and water (5 mL). The organic layer was separated, washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was carried on to the next step without further purification. LC-MS (m / z) = 426.7 [M+H] +

[0339] 1-((1S,3S)-3-Butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one: To a solution of 1-((1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.29 g, 0.68 mmol, 1.0 equiv) in THF (5.0 mL) was added TBAF (1 M solution in THF) (0.75 mL, 0.75 mmol, 1.1 equiv) at -78 °C. The reaction mixture was stirred at -78 °C for 15 minutes. The progress of the reaction was monitored by TLC (15% ethyl acetate in n-hexane). Thereafter, the reaction mixture was quenched with saturated aqueous NaHCO3 (5 mL), and the product was extracted with ethyl acetate (30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC using 15% ethyl acetate in n-hexane as the eluent to afford 1-((1S,3S)-3-butyl-1-cyclohexyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LC-MS (m / z) = 354.6 [M+H] +

[0340] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 0.54 - 0.68 (m, 1H), 0.76 - 0.77 (m, 3H), 0.82 - 0.99 (m, 3H), 1.08 - 1.14 (m, 6H), 1.38 - 1.66 (m, 7H), 2.74 - 2.78 (m, 1H), 2.96 - 3.08 (m, 1H), 3.72 (s, 3H), 4.16 (bs, 0.5H), 4.35 - 4.38 (m, 0.5H), 4.50 - 4.52 (m, 1H), 4.75 - 4.78 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 12.8 Hz, 1H), 7.01 - 7.08 (m, 1H).

[0341] Procedure 17: Synthesis of Compound 28

Chemical Structure

[0342] 1 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (t, J = 7.0 Hz, 3H), 1.67 - 1.74 (m, 6H), 1.97 (s, 6H), 2.14 (s, 3H), 4.29 (q, J = 6.9 Hz, 2H), 6.67 (d, J = 8.4 Hz, 2H), 7.80 (d, J = 8.4 Hz, 2H).

[0343] 4-(((3s,5s,7s)-Adamantan-1-yl)amino)benzoic acid: To a solution of ethyl 4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoate (1.6 g, 5.37 mmol, 1 eq) in EtOH (29 mL) and water (11 mL) was added sodium hydroxide (0.43 g, 10.70 mmol, 2 eq), and the mixture was stirred at 80 °C for 6 h. TLC (15% ethyl acetate in hexane) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the resulting crude was acidified with 5% citric acid solution (pH = 4). Finally, the product was extracted from the aqueous layer with EtOAc (75 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the product 4-(((3s,5s,7s)-adamantan-1-yl)amino)benzoic acid. LC-MS (m / z) = 272.0 [M+H] +

[0344] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.61 - 1.68 (m, 6H), 1.91 (s, 6H), 2.06 (s, 3H), 5.87 (bs, 1H), 6.72 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 8.8 Hz, 2H), 12.00 (bs, 1H).

[0345] 4-(((3R,5R,7R)-Adamantan-1-yl)amino)-N-((S)-1-(3-methoxyphenyl)hexan-2-yl)benzamide: To a solution of 4-(((3S,5S,7S)-adamantan-1-yl)amino)benzoic acid (1.05 g, 3.88 mmol, 1.2 eq) in DCM (20 mL), TEA (1.3 g, 12.92 mmol, 4 eq) was added and stirred for 5 minutes. Then, T3P (50 wt% in EtOAc) (1.53 g, 4.84 mmol, 1.5 eq) was added at 0 °C and stirred for an additional 5 minutes. Next, (S)-1-(3-methoxyphenyl)hexan-2-amine (0.67 g, 3.23 mmol, 1 eq) was added to the reaction mixture, and then the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mixture was diluted with DCM (50 mL) and saturated sodium bicarbonate solution (20 mL), the organic layer was separated, washed with brine solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by flash chromatography using ethyl acetate in hexane as the eluent to obtain 4-(((3R,5R,7R)-adamantan-1-yl)amino)-N-((S)-1-(3-methoxyphenyl)hexan-2-yl)benzamide. LC-MS (m / z) = 461.0 [M+H] +

[0346] 1 H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (bs, 3H), 1.22 (bs, 4H), 1.45 (bs, 2H), 1.64 (s, 6H), 1.89 (s, 6H), 2.05 (s, 3H), 2.65 - 2.76 (m, 2H), 3.16 (d, J = 4.0 Hz, 1H), 3.66 (s, 3H), 4.07 (bs, 1H), 5.49 (s, 1H), 6.68 - 6.75 (m, 4H), 7.11 - 7.12 (m, 1H), 7.50 (d, J = 7.2 Hz, 2H), 7.57 - 7.64 (m, 1H).

[0347] (3R,5R,7R)-N-(4-((S)-3-Butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)adamantan-1-amine: Trifluoromethanesulfonic anhydride (0.547 mL, 3.26 mmol, 3.0 equiv) was added via syringe over 1 minute to a stirred mixture of 4-(((3R,5R,7R)-adamantan-1-yl)amino)-N-((S)-1-(3-methoxyphenyl)hexan-2-yl)benzamide (0.5 g, 1.08 mmol, 1 equiv) and 2-chloropyridine (0.3 mL, 3.26 mmol, 3.0 equiv) in dichloromethane (3.6 mL) at -78 °C. After 5 minutes, the reaction mixture was placed in an ice bath and warmed to 0 °C. After 5 minutes, the resulting solution was warmed to 23 °C. After 1 hour, aqueous sodium hydroxide solution (5 mL, 1 N) was introduced to neutralize the trifluoromethanesulfonate salt. Dichloromethane (50 mL) was added to dilute the mixture and the layers were separated. The organic layer was washed with brine (7 mL), dried over anhydrous sodium sulfate, and filtered. Volatiles were removed under reduced pressure to give the crude product. The crude product obtained was purified by flash chromatography using ethyl acetate in hexane as the eluent to give the desired product ((3R,5R,7R)-N-(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)adamantan-1-amine. LC-MS (m / z) = 443.3 [M+H] +

[0348] (3R,5R,7R)-N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)adamantan-1-amine: A solution of (3R,5R,7R)-N-(4-((S)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-1-yl)phenyl)adamantan-1-amine (0.5 g, 1.13 mmol, 1 equiv) in methanol (9 mL) was added sodium borohydride (0.128 g, 33.93 mmol, 3 equiv) at 0 °C. The suspension was stirred at room temperature for 16 h. Thereafter, the reaction mixture was concentrated and the resulting crude was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated, washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by flash chromatography using ethyl acetate in hexane as the eluent to obtain (3R,5R,7R)-N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)adamantan-1-amine. The isolated pure product was treated with the metal scavenger Quadrasil® AP (the compound was dissolved in THF (5 mL), Quadrasil® AP (50 mg) was added, the mixture was stirred for 0.5 h, and filtered. This was repeated once more and concentrated). LC-MS (m / z) = 445.3 [M+H] +

[0349] 1 H NMR (400 MHz, CDCl3) δ ppm 0.84 - 088 (m, 3H), 1.22 - 1.30 (m, 4H), 1.42 - 1.43 (m, 2H), 1.60 - 1.70 (m, 6H), 1.85 (s, 6H), 2.09 (bs, 3H), 2.53 - 2.60 (m, 1H), 2.82 - 2.86 (m, 1H), 2.87 - 2.97 (m, 1H), 3.78 (s, 3H), 5.13 (s, 1H), 6.66 - 6.70 (m, 4H), 6.84 - 6.90 (m, 3H).

[0350] 1-((1S,3S)-1-(4-(((3R,5R,7R)-Adamantan-1-yl)amino)phenyl)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: First step: To a solution of 3-(trimethylsilyl)propionic acid (11.8 mg, 0.083 mmol, 1.0 eq) in DMF (0.24 mg, 0.003 mmol, 0.04 eq) was added oxalyl chloride (11.5 mg, 0.091 mmol, 1.1 eq) at room temperature and stirred for 30 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure to obtain 3-(trimethylsilyl)propionyl chloride. This acid chloride was advanced to the next step without further purification.

[0351] Second step: To a solution of (3R,5R,7R)-N-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)adamantan-1-amine (37 mg, 0.083 mmol, 1.0 eq) in acetonitrile (1.0 mL) was added sodium bicarbonate (52.5 mg, 0.62 mmol, 7.5 eq) at 0 °C. After stirring for 5 minutes, a solution of 3-(trimethylsilyl)propionyl chloride in acetonitrile (1.0 mL) was added to the above reaction mass. The resulting mixture was stirred at 0 °C for 15 minutes and the progress of the reaction was monitored by TLC (70% ethyl acetate in n-hexane). Thereafter, the reaction mass was diluted with EtOAc (30 mL) and water (10 mL). The organic layer was separated, washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. This crude product was advanced to the next step without further purification. LC-MS (m / z) = 569.4 [M+H] +

[0352] 1-((1S,3S)-1-(4-(((3R,5R,7R)-Adamantan-1-yl)amino)phenyl)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one: To a solution of 1-((1S,3S)-1-(4-(((3R,5R,7R)-Adamantan-1-yl)amino)phenyl)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (48 mg, 0.084 mmol, 1.0 equiv) in THF (1.5 mL) was added TBAF (1 M solution in THF) (0.092 mL, 0.092 mmol, 1.1 equiv) at -78 °C. The reaction mixture was stirred at -78 °C for 15 min. The progress of the reaction was monitored by TLC (25% ethyl acetate in n-hexane). Then, the reaction mixture was quenched with saturated aqueous NaHCO3 (5 mL), and the product was extracted with ethyl acetate (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC using 25% ethyl acetate in n-hexane as the eluent to give 1-((1S,3S)-1-(4-(((3R,5R,7R)-Adamantan-1-yl)amino)phenyl)-3-butyl-6-methoxy-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LC-MS (m / z) = 497.3 ([M+H] +

[0353] 1 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79 - 0.80 (m, 3H), 1.18 - 1.24 (m, 6H), 1.51 (bs, 1H), 1.61 (s, 5H), 1.79 (s, 6H), 2.01 (s, 3H), 2.71 - 2.83 (m, 1H), 3.00 - 3.09 (m, 2H), 3.72 - 3.73 (m, 3H), 4.15 (bs, 0.3H), 4.40 (bs, 1H), 4.61 (bs, 0.7H), 5.95 (s, 0.5H), 6.16 (s, 0.5H), 6.59 - 6.66 (m, 2H), 6.76 - 6.85 (m, 4H), 7.29 (d, J = 8.4 Hz, 0.5H), 7.40 (d, J = 7.6 Hz, 0.5H).

[0354] Step 18: Synthesis of Compound 55

Chem.

[0355] 1 H NMR (400 MHz, CDCl3): δ ppm 0.86 - 0.87 (m, 3H), 1.23 - 1.35 (m, 6H), 1.40 (s, 9H), 2.73 (bs, 2H), 3.78 (s, 3H), 4.29 (bs, 1H), 6.71 - 6.76 (m, 3H), 7.19 (t, J = 7.8 Hz, 1H). Amide NH was not observed.

[0356] (S)-1-(3-Methoxyphenyl)hexan-2-amine: To a solution of tert-butyl (S)-(1-(3-methoxyphenyl)hexan-2-yl)carbamate (10 g, 32.57 mmol, 1 equiv) in dichloromethane (50 mL) was added 4 M HCl in 1,4-dioxane (20 mL, 64.10 mmol, 2 equiv) at 0 °C. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the progress of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The obtained crude product was dissolved in ice-cold water (10 mL) and basified with a saturated aqueous solution of NaHCO3. The compound was extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give (S)-1-(3-methoxyphenyl)hexan-2-amine. LC-MS (m / z): 208.1 [M+H] + .

[0357] 1 1H NMR (400 MHz, CDCl3): δ ppm 0.82 - 0.90 (m, 3H), 1.23 - 1.42 (m, 4H), 1.57 - 1.62 (m, 2H), 2.69 - 2.91 (m, 2H), 3.25 - 3.58 (m, 1H), 3.80 (s, 3H), 6.69 - 6.78 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H) (NH2 proton was not observed).

[0358] Methyl 4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate: A solution of (S)-1-(3-methoxyphenyl)hexan-2-amine (0.7 g, 3.37 mmol, 1 equiv) and methyl 4-formylbenzoate (0.664 g, 4.05 mmol, 1 equiv) in toluene (4 mL) was irradiated with microwave at 90 °C for 20 minutes. Thereafter, the volatile portion was concentrated under reduced pressure and directly advanced to the cyclization step with TFA (4 mL), and irradiated with microwave at 140 °C for 45 minutes. Thereafter, the volatile portion was concentrated under reduced pressure, and the obtained crude product was diluted with a saturated aqueous solution of NaHCO3 (10 mL) and EtOAc (40 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by flash column chromatography (n-hexane / EtOAc) to obtain methyl 4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate. LC-MS (m / z): 208.1 [M+H] + .

[0359] 1 1H NMR (400 MHz, CDCl3): δ ppm 0.84 - 0.86 (m, 3H), 1.23 - 1.24 (m, 6H), 2.55 - 2.59 (m, 1H), 2.85 - 2.88 (m, 2H), 3.75 (s, 3H), 3.80 (s, 3H), 5.29 (s, 3H), 6.67 - 6.69 (m, 2H), 6.70 - 6.80 (m, 1H), 7.21 - 7.26 (s, 2H), 7.94 - 8.0 (m, 2H).

[0360] tert-Butyl (1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate: To a solution of compound methyl 4-((1S,3S)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoate (0.35 g, 1.12 mmol, 1 equiv) in DCM (10 mL) were added triethylamine (0.45 g, 4.49 mmol, 4 equiv) and di-tert-butyl dicarbonate (0.715 g, 2.24 mmol, 2 equiv) at room temperature, and the mixture was stirred for 16 h. TLC (50% EtOAc in hexanes) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was diluted with EtOAc (50 mL) and washed with water (2 × 50 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product tert-butyl (1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z): 356.0 [M- t Bu+H] + 。

[0361] 4-((1S,3S)-2-(tert-Butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid: To a solution of compound tert-butyl (1S,3S)-6-methoxy-1-(4-(methoxycarbonyl)phenyl)-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.650 g, 1.57 mmol, 1 equiv) in a mixture of THF:MeOH:H2O (9 mL:1 mL) was added lithium hydroxide (0.331 g, 7.89 mmol, 5 equiv), and the mixture was stirred at room temperature for 16 h. TLC (50% EtOAc in hexanes) indicated completion of the reaction. The reaction mixture was concentrated under reduced pressure, and the crude product was dissolved in 5% citric acid solution ( pIt was acidified with H = 9). The reaction mixture was diluted with EtOAc (50 mL), the organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product 4 - ((1S,3S)-2-(tert-butoxycarbonyl)-6-methoxy-3-methyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid. LC-MS (m / z): 396.0 [M+H].

[0362] tert-Butyl (1S,3S)-3-butyl-1-(4-(((E)-1-(hydroxyimino)ethyl)carbamoyl)phenyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate: To a solution of 4 - ((1S,3S)-2-(tert-butoxycarbonyl)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzoic acid (0.2 g, 0.45 mmol, 1 equiv) in DMF (10 mL) were added DIPEA (0.15 mL, 0.91 mmol, 2 equiv) and HATU (0.207 g, 5.46 mmol, 1.2 equiv) at room temperature, and the mixture was stirred for 15 minutes. Then, (E)-N'-hydroxyacetimidamide (0.043 g, 0.591 mmol, 1.3 equiv) was added, and the reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by TLC (30% EtOAc in hexane). After completion of the reaction, the reaction mixture was poured into crushed ice and then extracted with EtOAc (2 × 50 mL). The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain tert-butyl (1S,3S)-3-butyl-1-(4-(((E)-1-(hydroxyimino)ethyl)carbamoyl)phenyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z) = 496.0 [M+H] + .

[0363] tert-Butyl (1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate: To a solution of tert-butyl (1S,3S)-3-butyl-1-(4-(((E)-1-(hydroxyimino)ethyl)carbamoyl)phenyl)-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.3 g, 0.606 mmol, 1 eq) in ACN (10 mL) was added 4 Å MS (0.1 g), and the reaction mixture was stirred in a sealed tube at 120 °C for 3 h. The progress of the reaction was monitored by TLC (50% EtOAc in hexane). After completion of the reaction, the reaction mixture was filtered through a sintered funnel, and the resulting filtrate was concentrated under reduced pressure to give the crude product. It was purified by silica gel column chromatography using 25 - 30% EtOAc in hexane as the eluent to give tert-butyl (1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. LC-MS (m / z) = 478.0 [M+H] + .

[0364] 5-(4-((1S,3S)-3-Butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)-3-methyl-1,2,4-oxadiazole: To a solution of tert-butyl (1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.185 g, 0.387 mmol, 1 eq) in dichloromethane (20 mL) was added 4 M HCl in 1,4-dioxane (10 mL, 1.52 mmol, 2 eq) at 0 °C. The mixture was stirred at room temperature for 16 h. After completion of the reaction, the progress of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The obtained crude product was dissolved in ice-cold water (20 mL) and basified with a saturated aqueous solution of NaHCO3. The compound was extracted with EtOAc (100 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 5-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)-3-methyl-1,2,4-oxadiazole. LC-MS (m / z): 378.0 [M+H] + .

[0365] 1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: Oxalyl chloride (0.05 mL, 0.969 mmol, 1.1 eq) was added to 3-(trimethylsilyl)propionic acid (0.090 g, 0.260 mmol, 1 eq) and DMF (0.0008 g, 0.010 mmol, 0.04 eq), and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure to obtain crude 3-(trimethylsilyl)propionyl chloride, which was diluted with ACN (1 mL) and added to a stirred solution of 5-(4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl)-3-methyl-1,2,4-oxadiazole (0.160 g, 0.424 mmol, 1 eq) and NaHCO3 (0.267 g, 3.181 mmol, 7.5 eq) in ACN (5 mL) at 0 °C, and the mixture was stirred for 15 minutes. LCMS and TLC (30% EtOAc in hexanes) indicated completion of the reaction. The reaction was filtered and concentrated under reduced pressure to obtain the crude product 1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one, which was carried on to the next step without further purification. LC-MS (m / z): 502.0 [M+H] + .

[0366] 1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one: To 1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.100 g, 0.199 mmol, 1 equiv) in THF (10.0 mL), TBAF (1 M solution in THF) (0.104 mL, 0.399 mmol, 2 equiv) was added and stirred for 30 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (100 mL), and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4, concentrated, and further purified by preparative TLC chromatography using 20% EtOAc in hexane as the eluent to obtain 1-((1S,3S)-3-butyl-6-methoxy-1-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LC-MS (m / z): 430.1 [M+H] + .

[0367] 1 1H NMR (400 MHz, DMSO-d6): δ 0.80 - 0.81 (m, 3H), 0.83 - 1.49 (m, 6H), 2.31 (s, 3H), 2.81 - 2.92 (m, 1H), 2.93 - 3.13 (m, 1H), 3.71 (s, 3H), 4.35 (s, 0.5H), 4.59 (s, 0.5H), 4.65 - 4.77 (bs, 1H), 6.13 (s, 0.7H), 6.41 (s, 0.5H), 6.78 - 6.86 (m, 2H), 7.49 - 7.53 (m, 2H), 7.68 - 7.70 (m, 1H), 7.92 - 8.00 (m, 2H).

[0368] Procedure 19: Synthesis of Compound 38

Chemical Structure

[0369] 1 H NMR (400 MHz, DMSO-d6): δ ppm 0.81 (s, 3H), 0.98 - 1.40 (m, 15H), 1.62 (s, 6H), 2.00 (s, 9H), 2.75 (s, 1H), 3.03 (s, 1H), 3.68 (s, 3H), 4.30 - 4.44 (m, 1H), 5.87 (s, 1H), 6.73 (s, 2H), 7.28 (s, 2H), 7.41 (s, 2H), 7.59 (s, 2H).

[0370] N-((3R,5R,7R)-Adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide: To a solution of tert-butyl (1S,3S)-1-(4-(((3R,5R,7R)-adamantan-1-yl)carbamoyl)phenyl)-3-butyl-6-methoxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.23 g, 0.401 mmol, 1 equiv) in dichloromethane (10 mL) was added 4 M HCl in 1,4-dioxane (7 mL) at 0 °C. The mixture was stirred at room temperature for 3 h. After completion of the reaction, the progress of the reaction was monitored by TLC and the reaction mixture was concentrated under reduced pressure. The obtained crude was dissolved in ice-cold water (10 mL) and basified with a saturated aqueous solution of NaHCO3. The compound was extracted with EtOAc (30 mL). The organic layer was separated, washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide. LC-MS (m / z): 473.7 [M+H] + .

[0371] N-((3R,5R,7R)-Adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propionoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide: Oxalyl chloride (0.061 mL, 0.717 mmol, 1.2 eq) was added to 3-(trimethylsilyl)propionic acid (0.085 g, 0.59 mmol, 1 eq) and DMF (0.001 mL, 0.023 mmol, 0.04 eq), and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure to obtain the crude product 3-(trimethylsilyl)propionoyl chloride, which was diluted with ACN (1 mL) and added to a stirred solution of N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide (0.19 g, 0.401 mmol, 1 eq) and NaHCO3 (0.253 g, 3.01 mmol, 7.5 eq) in ACN (5 mL) at 0 °C, and the mixture was stirred for 15 minutes. LCMS and TLC (40% EtOAc in hexane) indicated completion of the reaction. The reaction was filtered and concentrated under reduced pressure to obtain the crude product N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propionoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide, which was carried on to the next step without further purification. LC-MS (m / z): 597.3 [M+H] + .

[0372] N-((3R,5R,7R)-Adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-propionoyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide: To N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-(3-(trimethylsilyl)propionoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide (0.17 g, 0.284 mmol, 1 equiv) in THF (10.0 mL), TBAF (1 M solution in THF) (0.081 mL, 0.313 mmol, 1.1 equiv) was added and stirred for 15 minutes. Thereafter, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate (30 mL), and washed with water (2 × 10 mL). The organic layer was dried over Na2SO4, concentrated, and further purified by flash column chromatography using 20% EtOAc in hexane as the eluent to obtain N-((3R,5R,7R)-adamantan-1-yl)-4-((1S,3S)-3-butyl-6-methoxy-2-propionoyl-1,2,3,4-tetrahydroisoquinolin-1-yl)benzamide. LC-MS (m / z): 525.8 [M+H] + .

[0373] 1 1H NMR (400 MHz, DMSO-d6): δ 0.81 (t, J = 6.0 Hz, 3H), 1.22 (s, 6H), 1.48 - 1.61 (m, 7H), 2.00 (s, 8H), 2.85 - 2.89 (m, 1H), 3.10 - 3.13 (m, 1H), 3.69 (d, J = 6.0 Hz, 3H), 4.29 (s, 1H), 4.59 (bs, 1H), 6.06 (s, 1H), 6.76 - 6.84 (m, 2H), 7.25 - 7.29 (m, 2H), 7.41 - 7.47 (m, 2H), 7.55 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H).

[0374] Procedure 20: Synthesis of Compound 48

Chemical Structure

[0375] 1 H NMR (400 MHz, CDCl3) δ ppm 0.87 - 0.89 (m, 3H), 1.36 - 1.46 (m, 4H), 1.60 - 1.69 (m, 2H), 2.59 (s, 3H), 2.81 - 2.93 (m, 2H), 3.76 (s, 3H), 4.36 - 4.37 (m, 1H), 5.83 (d, J = 7.2 Hz, 1H), 6.74 - 6.78 (m, 3H), 7.21 (t, J = 7.6 Hz, 2H), 7.37 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H).

[0376] (S)-3-Butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinoline: Trifluoromethanesulfonic anhydride (1.28 mL, 7.65 mmol, 2 eq) was added via syringe over 1 minute to a stirred mixture of (S)-N-(1-(3-methoxyphenyl)hexan-2-yl)-2-methylisonicotinamide (1.25 g, 3.82 mmol, 1 eq) and 2-chloropyridine (0.72 mL, 7.65 mmol, 2 eq) in dichloromethane (10 mL) at -78 °C. After 5 minutes, the reaction mixture was placed in an ice bath and warmed to 0 °C. After 5 minutes, the resulting solution was warmed to 23 °C. TLC (5% MeOH in DCM) indicated completion of the reaction. After 1 hour, aqueous sodium hydroxide solution (12 mL, 1 N) was introduced to neutralize the trifluoromethanesulfonate salt. Dichloromethane (70 mL) was added to dilute the mixture and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure to afford the crude product. The crude product obtained was purified by flash chromatography using ethyl acetate in hexane as eluent to give the desired product (S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinoline. LCMS (ES) m / z = 309.4 [M+H] +

[0377] (1S,3S)-3-Butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline: A solution of (S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinoline (0.54 g, 1.78 mmol, 1 equiv) in anhydrous THF (4 mL) was added dropwise to a mixture of 1 M lithium aluminum hydride in THF (17.8 mL, 17.8 mmol, 10 equiv) and trimethylaluminum (2 M in THF) (4.46 mL, 12.85 mmol, 5 equiv) at -78 °C under a nitrogen atmosphere. The suspension was stirred at -78 °C for 1 h and warmed to 0 °C over 1 h. TLC (5% MeOH in DCM) indicated completion of the reaction. The reaction mixture was quenched with saturated aqueous sodium chloride solution (8 mL), followed by dilution with EtOAc (30 mL), and the precipitate was filtered off. Finally, the filtrate was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography using ethyl acetate in hexane as the eluent to afford (1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline. LCMS (ES) m / z = 311.3 [M+H] +

[0378] 1-((1S,3S)-3-Butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: First step: Oxalyl chloride (0.13 mL, 1.59 mmol, 1.1 equiv) was added to a solution of 3-(trimethylsilyl)propionic acid (206 mg, 1.44 mmol, 3 equiv) in DMF (0.014 mL, 0.05 mmol, 0.04 equiv) at room temperature and stirred for 30 min. The reaction mixture was then concentrated under reduced pressure to afford 3-(trimethylsilyl)propionyl chloride. This acid chloride was carried on to the next step without further purification.

[0379] Second Step: Sodium bicarbonate (0.30 g, 3.62 mmol, 7.5 eq) was added to a solution of (1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline (0.15 g, 0.48 mmol, 1.0 eq) in acetonitrile (5.0 mL) at 0 °C. After stirring for 5 minutes, a solution of 3-(trimethylsilyl)propionyl chloride in acetonitrile (3.0 mL) was added to the above reaction mass. The resulting mixture was stirred at 0 °C for 15 minutes and the progress of the reaction was monitored by TLC (55% ethyl acetate in n-hexane). Thereafter, the reaction mass was diluted with EtOAc (15 mL) and water (5 mL). The organic layer was separated, washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. This crude product was carried forward to the next step without further purification. LCMS (ES) m / z = 435.3 [M+H] +

[0380] 1-((1S,3S)-3-Butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one: To a solution of 1-((1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.25 g, 0.576 mmol, 1 equiv) in THF (5.0 mL) was added TBAF (1 M solution in THF) (0.63 mL, 0.63 mmol, 1.1 equiv) at -78 °C. The reaction mixture was stirred at -78 °C for 15 minutes. The progress of the reaction was monitored by TLC (60% ethyl acetate in n-hexane). Thereafter, the reaction mixture was quenched with saturated aqueous NaHCO3 (8 mL), and the product was extracted with ethyl acetate (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC using 55% ethyl acetate in n-hexane as the eluent to afford 1-((1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LCMS (ES) m / z = 363.4 [M+H] +

[0381] 1 1H NMR (400 MHz, DMSO-d6) ppm δ 0.80 (d, 3H), 1.24 (s, 4H), 1.50 (s, 2H), 2.38 (s, 3H), 2.80 - 2.88 (m, 1H), 3.12 - 3.15 (m, 1H), 3.72 (s, 3H), 4.38 (s, 1H), 4.57 - 4.74 (m, 1H), 5.97 (s, 1H), 6.78 (s, 2H), 6.99 - 7.07 (m, 2H), 7.40 - 7.55 (m, 1H), 8.23 - 8.29 (m, 1H).

[0382] Procedure 21: Synthesis of Compound 49

Chemical Structure

[0383] 1 H NMR (400 MHz, CDCl3) δ ppm 0.84 (t, J = 6.8 Hz, 3H), 1.23 - 1.60 (m, 6H), 2.81 - 2.94 (m, 2H), 3.74 (s, 3H), 4.35 - 4.36 (m, 1H), 6.73 - 6.82 (m, 3H), 7.17 (t, J = 8.0 Hz, 1H), 7.39 (t, J = 6.0 Hz, 1H), 7.82 (t, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 7.6 Hz, 1H), 8.52 (d, J = 4.0 Hz, 1H).

[0384] (S)-3-Butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinoline: Trifluoromethanesulfonic anhydride (1.55 mL, 9.28 mmol, 2.0 equiv) was added via syringe over 1 minute to a stirred mixture of (S)-N-(1-(3-methoxyphenyl)hexan-2-yl)picolylamide (1.4 g, 4.64 mmol, 1 equiv) and 2-chloropyridine (0.87 mL, 9.28 mmol, 2.0 equiv) in dichloromethane (15 mL) at -78 °C. After 5 minutes, the reaction mixture was placed in an ice bath and warmed to 0 °C. After 5 minutes, the resulting solution was warmed to 23 °C. TLC (40% ethyl acetate in n-hexane) indicated completion of the reaction. After 1 hour, aqueous sodium hydroxide solution (12 mL, 1 N) was introduced to neutralize the trifluoromethanesulfonate salt. Dichloromethane (50 mL) was added to dilute the mixture and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure to afford the crude product. The crude product obtained was purified by flash chromatography using ethyl acetate in hexane as the eluent to afford the desired product (S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinoline. LC-MS (m / z) = 295.1 [M+H] +

[0385] 1 1H NMR (400 MHz, CDCl3) δ ppm 0.93 (t, J = 7.2 Hz, 3H), 1.26 - 1.43 (m, 4H), 1.65 - 1.88 (m, 2H), 2.58 - 2.65 (m, 1H), 2.79 - 2.87 (m, 1H), 3.58 (bs, 1H), 3.83 (s, 3H), 6.73 - 6.75 (m, 2H), 7.32 - 7.37 (m, 2H), 7.77 - 7.83 (m, 2H), 8.64 - 8.70 (m, 1H).

[0386] (1R,3S)-3-Butyl-6-methoxy-1-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline: A solution of (S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinoline (0.1 g, 0.34 mmol, 1 eq) in anhydrous THF (4 mL) was added dropwise to a mixture of 1M lithium aluminum hydride in THF (3.4 mL, 3.40 mmol, 10 eq) and trimethylaluminum (2M in toluene) (0.85 mL, 1.70 mmol, 5 eq) at -78 °C under a nitrogen atmosphere. The suspension was stirred at -78 °C for 1 h and warmed to 0 °C over 1 h. TLC (5% MeOH in DCM) indicated completion of the reaction. The reaction mixture was quenched with saturated aqueous sodium chloride solution (4 mL), followed by dilution with EtOAc (15 mL), and the precipitate was filtered off. Finally, the filtrate was dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by silica gel flash chromatography using ethyl acetate in hexane as the eluent to afford (1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline. LC-MS (m / z) = 311.3 [M+H] +

[0387] 1-((1R,3S)-3-Butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one: First step: Oxalyl chloride (0.02 mL, 0.26 mmol, 1.1 eq) was added to a solution of 3-(trimethylsilyl)propionic acid (0.10 g, 0.709 mmol, 3.0 eq) in -DMF (0.0007 mL 0.009 mmol, 0.04 eq) at room temperature, and the reaction was stirred for 30 min. The reaction mixture was then concentrated under reduced pressure to afford 3-(trimethylsilyl)propionyl chloride. This acid chloride was carried on to the next step without further purification.

[0388] Second step: To a solution of (1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline (0.07 g, 0.236 mmol, 1.0 equiv) in acetonitrile (3.0 mL) was added sodium bicarbonate (0.149 g, 1.77 mmol, 7.5 equiv) at 0 °C. After stirring for 5 minutes, a solution of 3-(trimethylsilyl)propionyl chloride in acetonitrile (2.0 mL) was added to the above reaction mass. The resulting mixture was stirred at 0 °C for 15 minutes and the progress of the reaction was monitored by TLC (60% ethyl acetate in n-hexane). Thereafter, the reaction mass was diluted with EtOAc (15 mL) and water (5 mL). The organic layer was separated, washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. This crude product was carried forward to the next step without further purification. LC-MS (m / z) = 421.3 [M+H] +

[0389] 1-((1R,3S)-3-Butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one: To a solution of 1-((1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(trimethylsilyl)prop-2-yn-1-one (0.07 g, 0.166 mmol, 1.0 equiv) in THF (4.0 mL) was added TBAF (1 M solution in THF) (0.183 mL, 0.183 mmol, 1.1 equiv) at -78 °C. The reaction mixture was stirred at -78 °C for 15 minutes. The progress of the reaction was monitored by TLC (50% ethyl acetate in n-hexane). Thereafter, the reaction mixture was quenched with saturated aqueous NaHCO3 (2 mL), and the product was extracted with ethyl acetate (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative TLC using 50% ethyl acetate in n-hexane as the eluent to give 1-((1R,3S)-3-butyl-6-methoxy-1-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)prop-2-yn-1-one. LC-MS (m / z) = 349.4 [M+H] +

[0390] 1 1H NMR (400 MHz, DMSO-d6): δ 0.80 (t, J = 6.8 Hz, 3H), 1.20 - 1.44 (m, 6H), 2.71 - 2.83 (m, 1H), 3.03 (s, 1H), 3.43 - 3.47 (m, 1H), 3.67 - 3.69 (m, 3H), 4.56 - 4.70 (m, 2H), 6.01 - 6.28 (m, 2H), 6.72 - 6.79 (m, 1H), 7.09 - 7.18 (m, 1H), 7.35 - 7.44 (m, 1H), 7.56 - 7.69 (m, 1H), 8.32 - 8.42 (m, 1H).

[0391] Procedure 22: Synthesis of Compound 50

Chemical Structure

[0392] 1 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (t, J = 7.2 Hz, 3H), 3.97 (s, 3H), 4.38 (q, J = 6.8 Hz, 2H), 6.79 (d, J = 1.6 Hz, 1H), 7.37 (d, J = 1.2 Hz, 1H).

[0393] 1-Methyl-1H-pyrazole-3-carboxylic acid: To a solution of ethyl 1-methyl-1H-pyrazole-3-carboxylate (2.0 g, 13.0 mmol, 1 eq) in THF (10 mL) and methanol (10 mL) was added 2 M sodium hydroxide solution (15 mL). The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC (70% ethyl acetate in n-hexane). After completion of the reaction, the reaction mixture was concentrated to remove the solvent. The reaction mixture was acidified using 1N HCl solution (pH 3) and extracted with ethyl acetate (120 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude 1-methyl-1H-pyrazole-5-carboxylic acid. LCMS (m / z) = 127.1 [M+H] +

[0394] 11H NMR (400 MHz, DMSO-d6) δ ppm 3.87 (s, 3H), 6.63 - 6.64 (m, 1H), 7.75 (s, 1H), 12.54 (s, 1H).

[0395] (S)-N-(1-(3-Methoxyphenyl)hexan-2-yl)-1-methyl-1H-pyrazole-3-carboxamide: To a solution of (2S)-1-(3-methoxyphenyl)hexan-2-amine (1.6 g, 7.72 mmol, 1.0 equiv) in DCM (10 mL) was added 1-methyl-1H-pyrazole-3-carboxylic acid (1.17 g, 9.26 mmol, 1.2 equiv) and triethylamine (4.3 mL, 30.9 mmol, 4.0 equiv). This was added to propanephosphonic anhydride (7.37 mL, 11.6 mmol, 1.5 equiv) at 0 °C. After addition, the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC (70% ethyl acetate in n-hexane). After completion of the reaction, the reaction mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with DCM (70 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]-1-methyl-1H-pyrazole-5-carboxamide. LCMS (m / z) = 316.2 [M+H] +

[0396] (3S)-3-Butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinoline: Trifluoromethanesulfonic anhydride (3.19 mL, 19.0 mmol, 2.0 equiv) was added via syringe over 10 min to a stirred mixture of N-[(2S)-1-(3-methoxyphenyl)hexan-2-yl]-1-methyl-1H-pyrazole-3-carboxamide (3.0 g, 9.51 mmol, 1.0 equiv) and 2-chloropyridine (1.8 mL, 19.0 mmol, 2.0 equiv) in dichloromethane (20 mL) at -78 °C. After 5 min, the reaction mixture was placed in an ice bath and warmed to 0 °C. After 5 min, the resulting solution was warmed to 23 °C. The progress of the reaction was monitored by TLC (70% ethyl acetate in n-hexane). After 15 min, aqueous sodium hydroxide solution (12 mL, 1 N) was added to the reaction mixture at 0 °C to neutralize the trifluoromethanesulfonate salt. Dichloromethane (50 mL) was added to dilute the mixture and the layers were separated. The organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the volatiles were removed under reduced pressure to give the crude product. The crude product obtained was purified by flash chromatography using ethyl acetate in hexane as the eluent to give the desired product (3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinoline. LCMS (m / z) = 298.1 [M+H] +

[0397] 1 1H NMR (400 MHz, CDCl3) δ ppm: 0.88 (t, J = 6.4 Hz, 3H), 1.24 - 1.44 (m, 4H), 1.54 - 2.03 (m, 2H), 2.76 - 2.88 (m, 1H), 3.01 - 3.20 (m, 1H), 3.92 (s, 3H), 4.04 (s, 4H), 6.85 (d, J = 1.2 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 7.10 (s, 1H), 7.56 (s, 1H), 8.13 (d, J = 8.8 Hz, 1H).

[0398] (1R,3S)-3-Butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydroisoquinoline at -78 °C: To a solution of trimethylaluminum (7.82 mL, 15.6 mmol, 5 eq) in tetrahydrofuran (8 mL), lithium aluminum hydride (31.3 mL, 31.3 mmol, 10 eq) was added at -78 °C, followed by the addition of (3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-3,4-dihydroisoquinoline (0.93 g, 3.13 mmol, 1 eq) in THF (3 mL). The reaction mixture was stirred at -78 °C for 1 h. The progress of the reaction was monitored by TLC (70% ethyl acetate in n-hexane). After 1 h, the reaction was complete. The reaction mixture was quenched with brine solution (10 mL) at 0 °C and diluted with ethyl acetate (15 mL). Then it was filtered through a celite bed and washed with ethyl acetate (20 mL). The organic layer was separated from the aqueous layer and concentrated under reduced pressure to obtain the crude product. The crude product was purified by flash column chromatography on silica gel with increasing the polarity of 2 - 3% MeOH in DCM as the solvent to give (1R,3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydroisoquinoline (a mixture of cis and trans). LCMS (m / z) = 300.2 [M + H] +

[0399] 1-[(3S)-3-Butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-3-(trimethylsilyl)prop-2-yn-1-one: First step: To a solution of 3-(trimethylsilyl)propionic acid (0.2 g, 1.41 mmol, 1 eq) in DMF (0.004 mL, 0.056 mmol, 0.04 eq), oxalyl chloride (0.13 mL, 1.55 mmol, 1.1 eq) was added at room temperature and the reaction mixture was stirred for 30 min. Thereafter, the reaction mixture was concentrated under reduced pressure to obtain 3-(trimethylsilyl)propionyl chloride. This acid chloride was carried on to the next step without further purification.

[0400] Second Step: To a solution of (1S,3S)-3-butyl-6-methoxy-1-(2-methylpyridin-4-yl)-1,2,3,4-tetrahydroisoquinoline (0.42 g, 1.40 mmol, 1 equiv) in acetonitrile (3.0 mL) was added sodium bicarbonate (0.88 g, 10.5 mmol, 7.5 equiv) at 0 °C. After stirring for 5 minutes, a solution of 3-(trimethylsilyl)propiolyl chloride in acetonitrile (2 mL) was added to the above reaction mass. The resulting mixture was stirred at 0 °C for 15 minutes and the progress of the reaction was monitored by TLC (60% ethyl acetate in n-hexane). Thereafter, the reaction mass was diluted with EtOAc (20 mL) and water (5 mL). The organic layer was separated, washed with brine solution (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. This crude product was carried forward to the next step without further purification. LCMS (m / z) = 424.3 [M+H] + .

[0401] 1-[(1R,3S)-3-Butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl]prop-2-yn-1-one: To a solution of [(3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl]-3-(trimethylsilyl)prop-2-yn-1-one (0.5 g, 1.18 mmol, 1 equiv) in THF (8.0 mL) was added TBAF (1 M solution in THF) (1.30 mL, 1.30 mmol, 1.1 equiv) at -78 °C. The reaction mixture was stirred at -78 °C for 15 minutes. The progress of the reaction was monitored by TLC (50% ethyl acetate in n-hexane). Thereafter, the reaction mixture was quenched with saturated aqueous NaHCO3 (2 mL), and the product was extracted with ethyl acetate (25 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative TLC using 50% ethyl acetate in n-hexane as the eluent to give 1-[(1R,3S)-3-butyl-6-methoxy-1-(1-methyl-1H-pyrazol-3-yl)-1,2,3,4-tetrahydroisoquinolin-2-yl]prop-2-yn-1-one. LCMS (m / z) = 352.4 [M+H] + 。

[0402] 1 1H NMR (400 MHz, DMSO-d6): δ 0.79 (t, J = 6.0 Hz, 3H), 0.94 - 1.43 (m, 6H), 2.71 - 2.83 (m, 1H), 2.93 - 2.98 (m, 0.5H), 3.25 - 3.26 (m, 0.5H), 3.64 - 3.70 (m, 6H), 4.30 - 4.56 (m, 2H), 5.91 - 6.20 (m, 2H), 6.73 - 6.79 (m, 2H), 7.26 - 7.47 (m, 2H).

[0403] Procedure 23: Synthesis of Compound 76

Chemical Structure

[0404] 1 H NMR (400 MHz, CDCl3) δ ppm 0.86 (bs, 3H), 1.25 - 1.28 (m, 6H), 1.43 (s, 9H), 2.17 (s, 6H), 2.68 - 2.81 (m, 2H), 3.86 (s, 3H), 4.11 - 4.13 (m1H), 4.93 (bs, 1H), 5.16 (d, J = 8.4 Hz, 1H), 6.67 - 6.76 (m, 3H), 7.19 (t, J = 8.0 Hz, 1H).

[0405] tert-Butyl (S)-(3-(3-butyl-6-methoxy-3,4-dihydroisoquinolin-...

Claims

1. A compound of formula I, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof, wherein 【Chemical 1】 wherein Ring A is C ４ to C １０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, X is -S- or -CR ５ =CR ５ - and p is 0, 1, or 2; q is 0, 1, 2, or 3; R １ is C １ -C ６ alkyl, C ２ -C ６ alkenyl, C ２ -C ６ alkynyl, C １ -C ６ haloalkyl, C ３ -C １０ cycloalkyl, -CN, -OR ７ ,-C(O)OR ６ ,-C(O)N(R ７ ２ ,-OC(O)R ６ ,-S(O) ２ R ８ ,-S(O) ２ N(R ７ ２ ,-S(O)N(R ７ ２ ,-S(O)R ８ ,-N(R ７ ２ ,-NO ２ ,-C １ -C ６ alkyl-OR ７ or -Si(R １５ ３ and​​​​​ R ２ is -CH ２ -halo or C ２ alkynyl, and Each R ３ is independently halo, -CN, -OH, -OR ８ , -NH ２ , -NHR ８ , -N(R ８ ) ２ , -S(O) ２ R ８ , -S(O)R ８ , -S(O) ２ N(R ７ ) ２ , -S(O)N(R ７ ) ２ , -NO ２ , -Si(R １２ ) ３ , -SF ５ , -C(O)OR ６ , -C(O)N(R ７ ) ２ , -NRC(O)R １２ ８ , -NR １２ C(O)OR ８ , -OC(O)N(R ７ ) ２ , -OC(O)R ８ , -C(O)R ６ , -OC(O)CHR ８ N(R １２ ) ２ , C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C ３ ~C １０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -C １ ~C ６ alkyl C ３ ~C １０ cycloalkyl, -C ２ ~C ６ alkenyl C ３ ~C １０ cycloalkyl, -C １ ~C ６ alkyl heterocyclyl, -C ２ ~C ６ alkenyl heterocyclyl, -C １ ~C ６ ​Alkylaryl, -C ２ ~C ６ Alkenylaryl, C １ ~C ６ Alkylheteroaryl, or -C ２ ~C ６ Alkenylheteroaryl, and each C of R ３ each C of １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C １０ Cycloalkyl, heterocyclyl, aryl, heteroaryl, -C １ ~C ６ Alkyl C ３ ~C １０ Cycloalkyl, -C ２ ~C ６ Alkenyl C ３ ~C １０ Cycloalkyl, -C １ ~C ６ Alkylheterocyclyl, -C ２ ~C ６ Alkenylheterocyclyl, -C １ ~C ６ Alkylaryl, -C ２ ~C ６ Alkenylaryl, C １ ~C ６ Alkylheteroaryl, or -C ２ ~C ６ Alkenylheteroaryl is independently unsubstituted or substituted with 1 to 3 R １０ and Each R ４ is independently halo, -CN, -OH, -OR ８ , -NH ２ , -NHR ８ , -N(R ８ ), ２ , -S(O) ２ R ８ , -S(O)R ８ , -S(O) ２ N(R ７ ), ２ , -S(O)N(R ７ ), ２ , -NO ２ , -Si(R １５ ), ３ , -C(O)OR ６ , -C(O)N(R ７ ), ２ , -NRC(O)R １２ , -OC(O)R ８ , -C(O)R ８ , -NRC(O)OR ６ , -OC(O)N(R １２ ), ８ , -OC(O)CHRN(R ７ ), ２ , -OC(O)CHRN(R ８ ), １２ ), ２ , C １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C ３ ~C １０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -C １ ~C ６ alkyl C ３ ~C １０ cycloalkyl, -C ２ ~C ６ alkenyl C ３ ~C １０ cycloalkyl, -C １ ~C ６ alkyl heterocyclyl, -C ２ ~C ６ alkenyl heterocyclyl, -C １ ~C ６ alkyl aryl, -C ２ ~C ６ alkenylaryl, C １ ~C ６ alkylheteroaryl, or -C ２ ~C ６ alkenylheteroaryl, and each C of R ４ is １ ~C ６ alkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C ３ ~C １０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -C １ ~C ６ alkylC ３ ~C １０ cycloalkyl, -C ２ ~C ６ alkenylC ３ ~C １０ cycloalkyl, -C １ ~C ６ alkylheterocyclyl, -C ２ ~C ６ alkenylheterocyclyl, -C １ ~C ６ alkylaryl, -C ２ ~C ６ alkenylaryl, C １ ~C ６ alkylheteroaryl, or -C ２ ~C ６ alkenylheteroaryl is independently unsubstituted or substituted with 1 to 3 R １０ 's, Each R ５ independently represents hydrogen, halo, -CN, -OH, -OR ８ , -NH ２ , -NHR ８ , -N(R ８ ) ２ , -S(O) ２ R ８ , -S(O)R ８ , -S(O) ２ N(R ７ ) ２ , -S(O)N(R ７ ) ２ , -NO ２ , -Si(R １５ ) ３ , -C(O)OR ６ , -C(O)N(R ７ ) ２ , -NRC(O)R １２ , -OC(O)R ８ , -C(O)R ８ , -NR ６ C(O)OR １２ , -OC(O)N(R ８ ) ７ , -OC(O)CHRN(R ２ ) ８ , C １２ ~C ２ alkyl, C １ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C ２ ~C ６ cycloalkyl, heterocyclyl, aryl, heteroaryl, -C ３ ~C １０ alkyl C １ ~C ６ cycloalkyl, -C ３ ~C １０ alkenyl C ２ ~C ６ cycloalkyl, -C ３ ~C １０ alkyl heterocyclyl, -C １ ~C ６ alkenyl heterocyclyl, -C ２ ~C ６ alkyl aryl, -C １ ~C ６ ~C ２ to C ６ alkenylaryl, C １ to C ６ alkylheteroaryl, or -C ２ to C ６ is alkenylheteroaryl, and each C of R ５ to C １ alkyl, C ６ to C ２ alkenyl, C ６ to C ２ alkynyl, C ６ to C ３ cycloalkyl, heterocyclyl, aryl, heteroaryl, -C １０ to C １ alkylC ６ to C ３ cycloalkyl, -C １０ to C ２ alkenylC ６ to C ３ cycloalkyl, -C １０ to C １ alkylheterocyclyl, -C ６ to C ２ alkenylheterocyclyl, -C ６ to C １ alkylaryl, -C ６ to C ２ alkenylaryl, C ６ to C １ alkylheteroaryl, or -C ６ to C ２ alkenylheteroaryl is independently unsubstituted or substituted with 1 to 3 R ６ and １０ is substituted Each R ６ is, independently, hydrogen, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C ３ to C １０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -C １ to C ６ alkyl C ３ to C １０ cycloalkyl, -C ２ to C ６ alkenyl C ３ to C １０ cycloalkyl, -C １ to C ６ alkyl heterocyclyl, -C ２ to C ６ alkenyl heterocyclyl, -C １ to C ６ alkyl aryl, -C ２ to C ６ alkenyl aryl, C １ to C ６ alkyl heteroaryl, or -C ２ to C ６ alkenyl heteroaryl, and each R ６ is, independently, unsubstituted or further substituted by 1 to 3 R １１ s, Each R ７ is, independently, hydrogen, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C ３ to C １０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -C １ to C ６ alkyl C ３ to C ６ cycloalkyl, -C ２ to C ６ alkenyl C ３ to C ６ cycloalkyl, -C １ to C ６ alkyl heterocyclyl, -C ２ to C ６ alkenyl heterocyclyl, -C １ to C ６ alkyl aryl, -C ２ to C ６ alkenyl aryl, -C １ to C ６ alkyl heteroaryl, -C ２ to C ６ alkenyl heteroaryl, or two Rs ７ together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, and each R ７ or the ring formed thereby is, independently, unsubstituted or further substituted with 1 to 3 Rs １１ . Each R ８ is independently C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C ３ to C １０ cycloalkyl, heterocyclyl, aryl, heteroaryl, -C １ to C ６ alkyl C ３ to C １０ cycloalkyl, -C ２ to C ６ alkenyl C ３ to C １０ cycloalkyl, -C １ to C ６ alkyl heterocyclyl, -C ２ to C ６ alkenyl heterocyclyl, -C １ to C ６ alkyl aryl, -C ２ to C ６ alkenyl aryl, -C １ to C ６ alkyl heteroaryl, or -C ２ to C ６ alkenyl heteroaryl, and each R ８ is independently unsubstituted or further substituted by 1 to 3 R １１ 's, R ９ is hydrogen or C １ to C ６ alkyl, and Each R １０ is independently halo, -CN, -OR １２ , -NO ２ , -N(R １２ ), ２ , -S(O)R １３ , -S(O) ２ R １３ , -S(O)N(R １２ ), ２ , -S(O) ２ N(R １２ ), ２ , -Si(R １２ ), ３ , -C(O)R １２ , -C(O)OR １２ , -C(O)N(R １２ ), ２ , -NR １２ C(O)R １２ , -OC(O)R １２ , -OC(O)OR １２ , -OC(O)N(R １２ ), ２ , -NR １２ C(O)OR １２ , -OC(O)CHR １２ N(R １２ ), ２ , C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C ３ ~C １０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each C １０ of R １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C ３ ~C １０ cycloalkyl, heterocyclyl, aryl, or heteroaryl is unsubstituted or independently has 1 to 3 R １１ is replaced by, Each R １１ is, independently, halo, -CN, -OR １２ , -NO ２ , -N(R １２ ), ２ , -S(O)R １３ , -S(O) ２ R １３ , -S(O)N(R １２ ), ２ , -S(O) ２ N(R １２ ), ２ , -Si(R １２ ), ３ , -C(O)R １２ , -C(O)OR １２ , -C(O)N(R １２ ), ２ , -NR １２ C(O)R １２ , -OC(O)R １２ , -OC(O)OR １２ , -OC(O)N(R １２ ), ２ , -NR １２ C(O)OR １２ , -OC(O)CHR １２ N(R １２ ), ２ , C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C ２ ~C ６ alkenyl, C ２ ~C ６ alkynyl, C ３ ~C １０ cycloalkyl, heterocyclyl, aryl, or heteroaryl, and Each R １２ is, independently, hydrogen, C １ to C ６ alkyl or C ３ to C １０ cycloalkyl, and Each R １３ is independently C １ to C ６ alkyl or C ３ to C １０ cycloalkyl, Each R １５ is, independently, C １ to C ６ alkyl, C ２ to C ６ alkenyl, aryl, heteroaryl, -C １ to C ６ alkylaryl, -C ２ to C ６ alkenylaryl, -C １ to C ６ alkylheteroaryl, and -C ２ to C ６ alkenylheteroaryl, of the compound of formula I, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, represented by a compound of formula II, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof. 【Chemical Formula 5】 。

3. The compound according to claim 1, represented by a compound of formula IIA, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof. 【Chemical Formula 6】 。

4. The compound according to claim 1, represented by a compound of formula IIB, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof. 【Chemical Formula 7】 。

5. The compound of formula III, wherein R １４ is halo), or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof, as claimed in claim 1. 【Chemical Formula 8】

6. The compound of formula IIIA, wherein R １４ is halo), or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof, according to claim 1. 【Chemical Formula 9】

7. The compound of formula IIIB (wherein R １４ is halo), or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof, of the compound according to claim 1. 【Chemical Formula 10】

8. Ring A is C ４ - C １０ The compound according to any one of claims 1 to 7, or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof, wherein Ring A is cycloalkyl.

9. The compound according to any one of claims 1 to 7, wherein ring A is heterocyclyl, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof.

10. The compound according to any one of claims 1 to 7, wherein ring A is aryl, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 1 to 7, wherein ring A is heteroaryl, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, represented by a compound of formula VIII, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof. 【Chemical 11】 。

13. The compound according to claim 1, represented by a compound of formula VIIIA, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof. 【Chemical Formula 12】 。

14. The compound according to claim 1, represented by a compound of formula VIIIB, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof. 【Chemical 13】 。

15. R １ is C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ haloalkyl, C ３ to C １０ cycloalkyl, -CN, -C(O)OR ６ , -C(O)N(R ７ ) ２ , -N(R ７ ) ２ , -OR ７ , or -C １ to C ６ alkyl-OR ７ The compound according to any one of claims 1 to 14

16. R １ is -C(O)OR ６ or -C(O)N(R ７ ), ２ A compound according to any one of claims 1 to 14, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof.

17. R １ is C １ -C ６ alkyl, a compound according to any one of claims 1 to 14, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof.

18. The compound according to any one of claims 1 to 14, or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof, wherein p is 0 or 1.

19. A compound of formula IX (wherein R １６ is hydrogen or C ２ to C ５ alkyl), or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof, according to claim 1. 【Chemical 14】

20. A compound of formula IX A (wherein R １６ is hydrogen or C ２ to C ５ alkyl), the compound according to claim 1, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof. 【Chemical Formula 15】

21. A compound of formula IXB, wherein R １６ is hydrogen or C ２ -C ５ alkyl), or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof, according to claim 1. 【Chemical 16】

22. The compound according to any one of claims 1 to 21, or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof, wherein q is 2 or 3.

23. Each R ４ is, independently, halo, -CN, -OR ７ , C １ ~C ６ alkyl, C ２ ~C ６ alkynyl, or C ３ ~C １０ cycloalkyl, and each C ４ ~C １ alkyl, C ６ ~C ２ alkynyl, or C ６ ~C ３ cycloalkyl of １０ is, independently, unsubstituted or substituted with 1 to 3 R １０ s, a compound according to any one of claims 1 to 22, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analogue, or pharmaceutically acceptable salt thereof.​

24. The compound according to any one of claims 1 to 23, or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof, wherein q is 1.

25. 【Fig. 17-1】 【Chemical 17-2】 【Chemical 17-3】 【Chemical 17-4】 【Chemical 17-5】 【Chemical 17-6】 【Chemical 17-7】 【Chemical 17-8】 【Chemical 17-9】 【Chemical 17-10】 【Chemical Formula 17-11】 【Chemical 17-12】 【Chemical 17-13】 【Chemical Formula 17-14】 【Chemical Formula 17-15】 【Chemical 17-16】 【Chemical 17-17】 【Chemical 17-18】 【Chemical 17 - 19】 【Chemical 17-20】 【Chemical 17-21】 A compound selected from the group consisting of, or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof.

26. 【Fig. 21】 A compound selected from, or a pharmaceutically acceptable salt thereof.

27. 【Fig. 22】 A compound selected from.

28. A pharmaceutical composition comprising the compound according to any one of claims 1 to 27, or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

29. A composition for inhibiting GPX4 in cells, wherein the composition comprises the compound according to any one of claims 1 to 27, or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof.

30. The composition according to claim 29, wherein the cell is a cancer cell.

31. A composition for treating cancer in a subject, wherein the composition comprises the compound according to any one of claims 1 to 27, or a tautomer, stereoisomer, mixture of stereoisomers, isotope-enriched analog, or pharmaceutically acceptable salt thereof.

32. The composition according to claim 31, wherein the cancer is adrenocortical cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, kidney cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, pharyngeal cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, or soft tissue cancer.

33. The composition according to claim 32, wherein the cancer is osteosarcoma, glioma, astrocytoma, neuroblastoma, small intestine cancer, bronchial cancer, small cell lung cancer, non-small cell lung cancer, basal cell carcinoma, or melanoma.

34. The composition according to claim 33, wherein the cancer is a blood cancer.

35. The composition according to claim 33, wherein the blood cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), hairy cell chronic myeloid leukemia (CML), or multiple myeloma.

36. The composition according to any one of claims 29 to 35, wherein the composition is administered in combination with a second therapeutic agent.

37. The composition according to claim 36, wherein the second therapeutic agent is a platinum preparation, an alkylating agent, an anticancer antibiotic, an antimetabolite, a topoisomerase I inhibitor, a topoisomerase II inhibitor, or an antimicrotubule agent.

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