AT2R Antagonist and its Use

Abstract

The present invention relates to certain piperidine compounds as AT2R antagonists, for example, compounds of formula (I) 【Chemical 1】 TIFF2025521119000318.tif35128 or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 3 , and X are as defined herein), its pharmaceutical composition, and its method of use for treating pain associated with AT2R activity are provided.

Description

[Technical Field]

[0001] This disclosure relates to compounds, pharmaceutical compositions, and methods comprising an angiotensin II receptor 2 (AT2R) antagonist, and their use in the treatment of chronic pain, including nociceptive, neuropathic, and mixed-type pain, particularly osteoarthritis (OA) pain, diabetic peripheral neuropathy pain (DPNP), or chronic low back pain (CLBP). Chronic pain can be classified into different categories based on its mechanism: nociceptive, neuropathic, and mixed-type. Nociceptive pain is caused by stimuli (including inflammation) that may cause damage to non-nerve tissue, or actually cause damage. This activates nociceptive receptors in the peripheral sensory system. Pain due to osteoarthritis is a typical example of somatic nociceptive pain. Neuropathic pain is caused by damage or disease of the central or peripheral nervous system and leads to maladaptive hypersensitivity of the sensory nervous system. Pain due to diabetic peripheral neuropathy is a typical example of peripheral neuropathic pain. Conditions exhibiting characteristics of both nociceptive and neuropathic pain are classified as mixed-type pain (for example, chronic low back pain may be an indefinite example). [Background technology]

[0002] Chronic pain is a very widespread condition with a significant impact on society. In 2016, an estimated 20.4% of the adult population in the United States experienced chronic pain, defined as pain on most days or daily for the past six months, based on National Health Examination data. An estimated 8% of the population had chronic pain that limited their living or working activities on most days or daily for the past six months. As a result, chronic pain is a major source of healthcare costs, with the annual cost of managing chronic pain in the United States estimated at approximately $635 billion in 2010. Despite the high disease burden and social impact, the management of chronic pain is currently unsatisfactory. Non-pharmacological therapies alone are insufficient to alleviate pain or improve function, and the available drug therapies are diverse, offer only minimal benefits, and carry significant safety risks. Currently, the most frequently used drugs to alleviate the most common types of chronic pain are acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids. Gabapentinoids, other anticonvulsants (such as sodium divalproate, carbamazepine, or lamotrigine), and some antidepressants (such as tricyclic antidepressants or duloxetine) can be used for certain pain disorders. Current pharmacological medical equipment typically offers low levels of efficacy and presents tolerability issues and / or adverse side effects. While opioids are effective for acute pain, their high risk of abuse and potential for serious adverse reactions limit treatment options for chronic pain. The physical, emotional, and economic impacts of chronic pain on patients and society, coupled with the lack of effective and tolerable treatment options, represent a significant unmet medical need.

[0003] Existing treatments for neuropathic pain exhibit moderate efficacy and undesirable side effects. The renin-angiotensin system (RAS) is involved in neuropathic pain (see, e.g., Pain Rep. 2021, 6, e869). AT2R is associated with pain mechanisms in the nervous system and is expressed in injured nerves and invading immune cells (Proc. Natl. Acad. Sci. USA, 2018, 115, E8057-E8066). Injured nerves and painful neuromas have higher AT2R expression than normal nerves. AT2R antagonists have been shown to be useful in pain relief in animal studies (Pain. Medicine. 2013, 14, 1557; Pain. Medicine. 2013, 14, 692) and clinical trials (Lancet. 2014, 383, 1637-1647). A relevant review article can be found, for example, in Expert.Opin.Ther.Targets.2015,19,25-35. Angiotensin II (Ang II) is an octapeptide substance produced by the hydrolysis of angiotensin I under the action of angiotensin-converting enzyme, and has various functions, including the regulation of blood pressure, fluid balance, and pain perception. Angiotensin receptors are G protein-coupled receptors, and Ang II activates angiotensin II receptor 1 (AT1R) and angiotensin II receptor 2 (AT2R).

[0004] Angiotensin type 2 receptors (AT2Rs) are associated with chronic neuropathic pain and inflammatory pain (see, e.g., Behav Pharmacol, 2014, 25, 137; Pain Med, 2013, 14, 1557; Pain Med, 2013, 14, 692; International Publication No. 2007 / 106938; and No. 2006 / 066361), and these conditions lack effective treatment options. EMA401 (Orodanrigan), a highly selective AT2R antagonist, has been reported to possess analgesic properties. EMA401 was studied in Phase 1 and Phase 2 clinical trials for its high selectivity for AT2Rs and good oral bioavailability (Lancet, 2014, 383, 1637), but these trials were terminated due to preclinical toxicity findings. There are no other known AT2R antagonists approved in clinical trials for the treatment of pain. There remains an unmet need for an AT2R antagonist with desired clinical properties to provide an alternative therapy for pain disorders, such as osteoarthritis (OA) pain, diabetic peripheral neuropathy (DPNP), chronic low back pain (CLBP), or other forms of chronic pain. [Overview of the project] [Means for solving the problem]

[0005] This disclosure provides compounds useful in treating pain related to AT2R activity, pharmaceutically acceptable salts thereof, and compositions thereof, including methods for preparing the compounds and compositions thereof, and methods for using the compounds and compositions thereof in the treatment of pain.

[0006] This disclosure relates to a compound of formula (I),

[0007] [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula R 1 , R 2 , R 3 , and X are as described herein.

[0008] In some embodiments, the compounds of the present disclosure are selected from the examples listed in Table I, or their stereoisomers, or their pharmaceutically acceptable salts.

[0009] In some embodiments, the compounds of the present disclosure are selected from the examples listed in Table I or from pharmaceutically acceptable salts thereof.

[0010] In some embodiments, the compounds of this disclosure are selected from the examples listed in Table I.

[0011] This disclosure provides a pharmaceutical composition comprising a compound of the disclosure and / or a salt of the compound, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0012] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a compound of the Disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.

[0013] In some embodiments, the Disclosure provides a pharmaceutical composition comprising a salt of a compound of the Disclosure and a pharmaceutically acceptable carrier, diluent, or excipient.

[0014] In some embodiments, the present disclosure provides a method for treating pain, comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0015] In some embodiments, the present disclosure provides compounds of the present disclosure, or pharmaceutically acceptable salts thereof, for use in the treatment of pain.

[0016] In some embodiments, the present disclosure provides the use of the compounds of the present disclosure, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for the treatment of pain. [Modes for carrying out the invention]

[0017] The present disclosure relates to compounds useful in the treatment of pain associated with AT2R activity, pharmaceutically acceptable salts thereof, and stereoisomers thereof, including compounds, methods of preparing compositions containing the compounds, and methods of using the compounds (e.g., in the treatment of pain).

[0018] The present disclosure relates to a compound of formula (I),

[0019]

Chemical formula

[0020] [[ID=^55]]

Chemical formula

[0021] In another embodiment, the present disclosure relates to a compound of formula (I),

[0022] [ka] During the ceremony, R 1 is methyl, ethyl, propyl, butan-2-yl, pentyl, 3-methylbutan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranil, or phenyl, and methyl, ethyl, propyl, butan-2-yl, pentyl, 3-methylbutan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranil, or phenyl is one or more R 1aIt is optionally replaced by Each R 1a However, independently, these are fluorine, chlorine, methyl, isopropyl, methoxyl, or cyclopropyl. R 2 is methyl, ethyl, propyl, butan-2-yl, pentyl, 3-methylbutan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranil, or phenyl, and methyl, ethyl, propyl, butan-2-yl, pentyl, 3-methylbutan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranil, or phenyl is one or more R 2a It is optionally replaced by Each R 2a However, independently, these are fluorine, chlorine, methyl, isopropyl, methoxyl, or cyclopropyl. R 3 H is, X is triazolyl, pyrimidinyl, pyridinyl, phenyl,

[0023] [ka] The triazolyl, pyrimidinyl, pyridinyl, and phenyl are one or more X a It is optionally replaced by each X a However, independently, these are bromine, pentyl, or cyclopropyl. R 4 is methyl, ethyl, isopropyl, pentyl, cyclopentyl, or phenyl, and methyl, ethyl, isopropyl, pentyl, cyclopentyl, or phenyl is one or more R 4a It is optionally replaced by Each R 4a However, independently, these are fluorine, methyl, methoxyl, or cyclopropyl. R 5 is methyl, ethyl, isopropyl, pentyl, cyclopentyl, or phenyl, and methyl, ethyl, isopropyl, pentyl, cyclopentyl, or phenyl is one or more R5a It is optionally replaced by Each R 5a However, independently, these are fluorine, methyl, methoxyl, or cyclopropyl. R 6 However, it is tert-butyl, R 7 However, one or more R 7a A phenyl that is optionally substituted with, Each R 7a However, independently, it is fluorine, R 8 However, it is H, F, or methyl, R 9 However, it is H, F, or methyl, or R 8 and R 9 They combine to form cyclopropyl, R 10 and R 11 However, each is either H or R 10 and R 11 They combine to form an oxo, R 12 The compounds are indolinyl, tetrahydroquinolinyl, phenyl, or isopropylphenyl, and indolinyl, tetrahydroquinolinyl, phenyl, or isopropylphenyl are one or more R 12a It is optionally replaced by Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently fluorine, cyano, isopropyl, methoxyl, or cyclopropyl.

[0024] In another embodiment, the present disclosure relates to a compound of formula (Ia),

[0025] [ka] During the ceremony, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10Aryl, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 The aryl is optionally substituted with one or more R 1a s, and each R 1a is independently halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 2 is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 aryl, and aryl, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 is optionally substituted with one or more R 2a s, and each R 2a is independently halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, X is C5-C 10 heteroaryl, C6-C 10 aryl,

[0026]

Chemical formula

[0027] In another embodiment, the present disclosure relates to a compound of formula (Ib),

[0028] [ka] During the ceremony, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 1a It is optionally replaced by Each R 1a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 3 However, it is H or C1-C6 alkyl, R 4However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 4a It is optionally replaced by Each R 4a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 5 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 5a It is optionally replaced by Each R 5a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0029] In another embodiment, the present disclosure relates to a compound of formula (Ic),

[0030] [ka] During the ceremony, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 1a It is optionally replaced by Each R 1a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 2However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 3 However, it is H or C1-C6 alkyl, R 6 The present invention provides a compound, or a pharmaceutically acceptable salt thereof, which is H or a C1-C6 alkyl group.

[0031] In another embodiment, the present disclosure relates to a compound of formula (Id),

[0032] [ka] During the ceremony, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 1a It is optionally replaced by Each R 1a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2aIt is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 3 However, it is H or C1-C6 alkyl, R 7 However, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 7a It is optionally replaced by Each R 7a However, they are independently halogens, cyanos, or C3-C6 cycloalkyls. R 8 However, it is H, halogen, or C1-C6 alkyl, R 9 However, it is H, a halogen, or a C1-C6 alkyl, or R 8 and R 9 The present invention provides compounds, or pharmaceutically acceptable salts thereof, in which these elements combine to form a C3-C6 cycloalkyl group.

[0033] In another embodiment, the present disclosure relates to a compound of formula (Ie),

[0034] [ka] During the ceremony, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 1a It is optionally replaced by Each R 1aHowever, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 3 However, it is H or C1-C6 alkyl, R 10 and R 11 However, each is either H or R 10 and R 11 They combine to form an oxo, R 12 However, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl, including C1-C6 alkyl, C3-C6 cycloalkyl, and C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 A heterocycloalkyl group contains one or more R 12a It is optionally replaced by Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0035] In another embodiment, the present disclosure relates to a compound of formula (If),

[0036] [ka] During the ceremony, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 1a It is optionally replaced by Each R 1a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 3 However, it is H or C1-C6 alkyl, R 12 However, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl, including C1-C6 alkyl, C3-C6 cycloalkyl, and C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 A heterocycloalkyl group contains one or more R 12a It is optionally replaced by Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0037] In another embodiment, the present disclosure relates to a compound of formula (Ig),

[0038] [ka] During the ceremony, R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. X is C5~C 10 Heteroaryl, C6~C 10 Ariel,

[0039] [ka] And C5~C 10 Heteroaryl or C6~C 10 Ayl is one or more X a It is optionally replaced by each X a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 4 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 4a It is optionally replaced by Each R 4a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 5 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 5a It is optionally replaced by Each R 5a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 6 However, it is H or C1-C6 alkyl, R 7 However, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 7a It is optionally replaced by Each R 7a However, they are independently halogens, cyanos, or C3-C6 cycloalkyls. R 8 However, it is H, halogen, or C1-C6 alkyl, R 9 However, it is H, a halogen, or a C1-C6 alkyl, or R 8 and R 9 These combine to form a C3-C6 cycloalkyl group, R 10 and R 11 However, each is either H or R 10 and R 11 They combine to form an oxo, R 12 However, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl, including C1-C6 alkyl, C3-C6 cycloalkyl, and C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 A heterocycloalkyl group contains one or more R12a It is optionally replaced by Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0040] In another embodiment, the present disclosure relates to a compound of formula (Ih),

[0041] [ka] During the ceremony, R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. X is C5~C 10 Heteroaryl, C6~C 10 Ariel,

[0042] [ka] And C5~C 10 Heteroaryl or C6~C 10 Ayl is one or more X a It is optionally replaced by each X a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 4 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 4a It is optionally replaced by Each R 4a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 5 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 5a It is optionally replaced by Each R 5a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 6 However, it is H or C1-C6 alkyl, R 7 However, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 7a It is optionally replaced by Each R 7a However, they are independently halogens, cyanos, or C3-C6 cycloalkyls. R 8 However, it is H, halogen, or C1-C6 alkyl, R 9 However, it is H, a halogen, or a C1-C6 alkyl, or R 8 and R 9 These combine to form a C3-C6 cycloalkyl group, R 10 and R 11 However, each is either H or R 10 and R 11 They combine to form an oxo, R 12However, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl, including C1-C6 alkyl, C3-C6 cycloalkyl, and C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 A heterocycloalkyl group contains one or more R 12a It is optionally replaced by Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0043] In another embodiment, the present disclosure relates to a compound of formula (Ih-a),

[0044] [ka] During the ceremony, R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. X is C5~C 10 Heteroaryl, C6~C 10 Ariel,

[0045] [ka] And C5~C 10 Heteroaryl or C6~C 10Ayl is one or more X a It is optionally replaced by each X a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 4 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 4a It is optionally replaced by Each R 4a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 5 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 5a It is optionally replaced by Each R 5a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 6 However, it is H or C1-C6 alkyl, R 7 However, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 7a It is optionally replaced by Each R 7a However, they are independently halogens, cyanos, or C3-C6 cycloalkyls. R 8 However, it is H, halogen, or C1-C6 alkyl, R 9 However, it is H, a halogen, or a C1-C6 alkyl, or R8 and R 9 These combine to form a C3-C6 cycloalkyl group, R 10 and R 11 However, each is either H or R 10 and R 11 They combine to form an oxo, R 12 However, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl, including C1-C6 alkyl, C3-C6 cycloalkyl, and C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 A heterocycloalkyl group contains one or more R 12a It is optionally replaced by Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0046] In another embodiment, the present disclosure relates to a compound of formula (Ih-b),

[0047] [ka] During the ceremony, R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. X is C5~C 10 Heteroaryl, C6~C10 Ariel,

[0048] [ka] And C5~C 10 Heteroaryl or C6~C 10 Ayl is one or more X a It is optionally replaced by each X a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 4 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 4a It is optionally replaced by Each R 4a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 5 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 5a It is optionally replaced by Each R 5a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 6 However, it is H or C1-C6 alkyl, R 7 However, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 7a It is optionally replaced by Each R 7a However, they are independently halogens, cyanos, or C3-C6 cycloalkyls. R 8 However, it is H, halogen, or C1-C6 alkyl, R 9 However, it is H, a halogen, or a C1-C6 alkyl, or R 8 and R 9 These combine to form a C3-C6 cycloalkyl group, R 10 and R 11 However, each is either H or R 10 and R 11 They combine to form an oxo, R 12 However, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl, including C1-C6 alkyl, C3-C6 cycloalkyl, and C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 A heterocycloalkyl group contains one or more R 12a It is optionally replaced by Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0049] In another embodiment, the present disclosure relates to a compound of formula (Ii),

[0050] [ka] During the ceremony, X is C5~C 10 Heteroaryl, C6~C 10 Ariel,

[0051] [ka] And C5~C 10 Heteroaryl or C6~C 10 Ayl is one or more X a It is optionally replaced by each X a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 4 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 4a It is optionally replaced by Each R 4a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 5 However, H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 5a It is optionally replaced by Each R 5a However, these are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, R 6 However, it is H or C1-C6 alkyl, R 7 However, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 If an aryl is one or more R 7a It is optionally replaced by Each R 7a However, they are independently halogens, cyanos, or C3-C6 cycloalkyls. R 8 However, it is H, halogen, or C1-C6 alkyl, R 9 However, it is H, a halogen, or a C1-C6 alkyl, or R 8 and R 9 These combine to form a C3-C6 cycloalkyl group, R 10 and R 11 However, each is either H or R 10 and R 11 They combine to form an oxo, R 12 However, C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl, including C1-C6 alkyl, C3-C6 cycloalkyl, and C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 A heterocycloalkyl group contains one or more R 12a It is optionally replaced by Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0052] In another embodiment, the present disclosure relates to a compound of formula (Ij),

[0053] [ka] During the ceremony, n is 0, 1, or 2, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 1a It is optionally replaced by Each R 1aHowever, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. Each R 12a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0054] In another embodiment, the present disclosure relates to a compound of formula (Ik),

[0055] [ka] During the ceremony, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 1a It is optionally replaced by Each R 1a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls.

[0056] In another embodiment, the present disclosure relates to a compound of formula (Il),

[0057] [ka] During the ceremony, R 1 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 1a It is optionally replaced by Each R 1a However, these are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls. R 2 However, C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 If an aryl is one or more R 2a It is optionally replaced by Each R 2a The present invention provides compounds, or pharmaceutically acceptable salts thereof, that are independently halogens, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls.

[0058] In some embodiments, R 1 This refers to C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 A aryl is one or more R 1a It is being replaced by an arbitrary choice.

[0059] In some embodiments, R 1 is one or more R 1a It is a C1-C6 alkyl group that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C1 alkyl group that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C2 alkyl group optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C3 alkyl group optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C4 alkyl group optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C5 alkyl group optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C6 alkyl group optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a methyl atom optionally substituted with R. In some embodiments, 1 is one or more R 1a It is ethyl optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a propyl optionally substituted with R. In some embodiments, 1 is one or more R 1a It is butyl optionally substituted with R. In some embodiments,1 is one or more R 1a It is a pentyl that is optionally substituted with R. In some embodiments, R 1 is one or more R 1a It is a hexyl that has been optionally substituted.

[0060] In some embodiments, R 1 is one or more R 1a It is a C3-C6 cycloalkyl group that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C3 cycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C4 cycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C5 cycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C6 cycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a cyclopropyl optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a cyclopentyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a cyclohexyl that has been optionally substituted.

[0061] In some embodiments, R 1 is one or more R 1a It is a C3-C9 heterocycloalkyl group that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C3 heterocycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1aIt is a C4 heterocycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C5 heterocycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C6 heterocycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C7 heterocycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C8 heterocycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C9 heterocycloalkyl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is tetrahydropyranyl that has been optionally substituted with [another compound].

[0062] In some embodiments, R 1 is one or more R 1a C6~C are optionally substituted. 10 It is an arrow. In some embodiments, R 1 is one or more R 1a It is a C6 aryl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a It is a C7 aryl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a This is a C8 aryl that is optionally substituted with R. In some embodiments, 1 is one or more R 1a This is a C9 aryl that is optionally substituted with R. In some embodiments, R 1 is one or more R 1a C is optionally replaced by 10 It is an arrow. In some embodiments, R 1 is one or more R 1aIt is a phenyl compound that has been optionally substituted.

[0063] In some embodiments, R 1a These are halogens, C1-C6 alkyl groups, C1-C6 alkoxyls, or C3-C6 cycloalkyl groups.

[0064] In some embodiments, R 1a is a halogen. In some embodiments, R 1a is fluorine. In some embodiments, R 1a is chlorine. In some embodiments, R 1a is bromine. In some embodiments, R 1a It is iodine.

[0065] In some embodiments, R 1a is a C1-C6 alkyl group. In some embodiments, R 1a is a C1 alkyl group. In some embodiments, R 1a is a C2 alkyl group. In some embodiments, R 1a is a C3 alkyl group. In some embodiments, R 1a is a C4 alkyl group. In some embodiments, R 1a is a C5 alkyl group. In some embodiments, R 1a is a C6 alkyl group. In some embodiments, R 1a is methyl. In some embodiments, R 1a is ethyl. In some embodiments, R 1a is propyl. In some embodiments, R 1a is butyl. In some embodiments, R 1a is pentill. In some embodiments, R 1a It is hexyl.

[0066] In some embodiments, R 1a R is a C1-C6 alkoxyl. In some embodiments, R 1a is a C1 alkoxyl. In some embodiments, R1a It is a C2 alkoxyl. In some embodiments, R 1a It is a C3 alkoxyl. In some embodiments, R 1a is a C4 alkoxyl. In some embodiments, R 1a It is a C5 alkoxyl. In some embodiments, R 1a It is a C6 alkoxyl. In some embodiments, R 1a It is a methoxyl.

[0067] In some embodiments, R 1a is a C3-C6 cycloalkyl group. In some embodiments, R 1a is a C3 cycloalkyl group. In some embodiments, R 1a is a C4 cycloalkyl group. In some embodiments, R 1a is a C5 cycloalkyl. In some embodiments, R 1a is a C6 cycloalkyl. In some embodiments, R 1a is cyclopropyl. In some embodiments, R 1a If the cycloalkyl group is a cycloalkyl group, then the cycloalkyl group is covalently bonded to R. 1 It may be bonded to, or the cycloalkyl ring atom may be R 1 It is understood that they may share atoms. In some embodiments, R 2 This refers to C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 A aryl is one or more R 2a It is being replaced by an arbitrary choice.

[0068] In some embodiments, R 2 is one or more R 2a It is a C1-C6 alkyl group that is optionally substituted with R. In some embodiments, 2 is one or more R 2aIt is a C1 alkyl group that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C2 alkyl group optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C3 alkyl group optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C4 alkyl group optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C5 alkyl group optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C6 alkyl group optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a methyl atom optionally substituted with R. In some embodiments, 2 is one or more R 2a It is ethyl optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a propyl optionally substituted with R. In some embodiments, 2 is one or more R 2a It is butyl optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a pentyl that is optionally substituted with R. In some embodiments, R 2 is one or more R 2a It is a hexyl that has been optionally substituted.

[0069] In some embodiments, R 2 is one or more R 2a It is a C3-C6 cycloalkyl group that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C3 cycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2aIt is a C4 cycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C5 cycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C6 cycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a cyclopropyl optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a cyclopentyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a cyclohexyl that has been optionally substituted.

[0070] In some embodiments, R 2 is one or more R 2a It is a C3-C9 heterocycloalkyl group that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C3 heterocycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C4 heterocycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C5 heterocycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C6 heterocycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C7 heterocycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C8 heterocycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2aIt is a C9 heterocycloalkyl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is tetrahydropyranyl that has been optionally substituted with [another compound].

[0071] In some embodiments, R 2 is one or more R 2a C6~C are optionally substituted. 10 It is an arrow. In some embodiments, R 2 is one or more R 2a It is a C6 aryl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a It is a C7 aryl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a This is a C8 aryl that is optionally substituted with R. In some embodiments, 2 is one or more R 2a This is a C9 aryl that is optionally substituted with R. In some embodiments, R 2 is one or more R 2a C is optionally replaced by 10 It is an arrow. In some embodiments, R 2 is one or more R 2a It is a phenyl compound that has been optionally substituted.

[0072] In some embodiments, R 2a These are halogens, C1-C6 alkyl groups, C1-C6 alkoxyls, or C3-C6 cycloalkyl groups.

[0073] In some embodiments, R 2a is a halogen. In some embodiments, R 2a is fluorine. In some embodiments, R 2a is chlorine. In some embodiments, R 2a is bromine. In some embodiments, R 2a It is iodine.

[0074] In some embodiments, R 2a is a C1-C6 alkyl group. In some embodiments, R 2a is a C1 alkyl group. In some embodiments, R 2a is a C2 alkyl group. In some embodiments, R 2a is a C3 alkyl group. In some embodiments, R 2a is a C4 alkyl group. In some embodiments, R 2a is a C5 alkyl group. In some embodiments, R 2a is a C6 alkyl group. In some embodiments, R 2a is methyl. In some embodiments, R 2a is ethyl. In some embodiments, R 2a is propyl. In some embodiments, R 2a is butyl. In some embodiments, R 2a is pentill. In some embodiments, R 2a It is hexyl.

[0075] In some embodiments, R 2a R is a C1-C6 alkoxyl. In some embodiments, R 2a is a C1 alkoxyl. In some embodiments, R 2a It is a C2 alkoxyl. In some embodiments, R 2a It is a C3 alkoxyl. In some embodiments, R 2a is a C4 alkoxyl. In some embodiments, R 2a It is a C5 alkoxyl. In some embodiments, R 2a It is a C6 alkoxyl. In some embodiments, R 2a It is a methoxyl.

[0076] In some embodiments, R 2a is a C3-C6 cycloalkyl group. In some embodiments, R 2a is a C3 cycloalkyl group. In some embodiments, R 2ais a C4 cycloalkyl group. In some embodiments, R 2a is a C5 cycloalkyl. In some embodiments, R 2a is a C6 cycloalkyl. In some embodiments, R 2a It is cyclopropyl.

[0077] In some embodiments, R 2a If the cycloalkyl group is a cycloalkyl group, then the cycloalkyl group is covalently bonded to R 2 It may be bonded to, or the cycloalkyl ring atom may be R 2 It is understood that they can share atoms.

[0078] In some embodiments, R 3 is H or C1-C6 alkyl. In some embodiments, R 3 H is H. In some embodiments, R 3 These are C1-C6 alkyl groups.

[0079] In some embodiments, X is C5~C 10 Heteroaryl, C6~C 10 Ariel,

[0080] [ka] And C5~C 10 Heteroaryl or C6~C 10 Ayl is one or more X a It is being replaced by an arbitrary choice.

[0081] In some embodiments, X is C5~C 10 Heteroaryl or C6~C 10 It is an aryl, C5~C 10 Heteroaryl or C6~C 10 Ayl is one or more X a It is being replaced by an arbitrary choice.

[0082] In some embodiments, X is one or more X a C5~C are optionally substituted. 10 It is a heteroaryl. In some embodiments, X is one or more X a It is a C5 heteroaryl that is optionally substituted with X. In some embodiments, X is one or more X a It is a C6 heteroaryl that is optionally substituted with X. In some embodiments, X is one or more X a It is a C7 heteroaryl that is optionally substituted with X. In some embodiments, X is one or more X a It is a C8 heteroaryl that is optionally substituted with X. In some embodiments, X is one or more X a It is a C9 heteroaryl that is optionally substituted with X. In some embodiments, X is one or more X a C is optionally replaced by 10 It is a heteroaryl compound. In some embodiments, X is pyridyl, pyrimidyl, or 1,2,4-triazolyl, where pyridyl, pyrimidyl, or 1,2,4-triazolyl is one or more X compounds. a It is optionally replaced by one or more X. In some embodiments, X is one or more X a It is pyridyl optionally substituted with. In some embodiments, X is one or more X a It is pyrimidyl optionally substituted with X. In some embodiments, X is one or more X a It is a triazolyl that is optionally substituted with. In some embodiments, X is one or more X a It is 1,2,4-triazolyl, optionally substituted with . In some embodiments, X is pyridyl.

[0083] In some embodiments, X is one or more X a C6~C are optionally substituted. 10 It is an arrow. In some embodiments, X is one or more X a It is a C6 aryl that is optionally substituted with. In some embodiments, X is one or more X aIt is a C7 aryl that is optionally substituted with. In some embodiments, X is one or more X a It is a C8 aryl that is optionally substituted with. In some embodiments, X is one or more X a It is a C9 aryl that is optionally substituted with. In some embodiments, X is one or more X a C is optionally replaced by 10 It is an aryl compound. In some embodiments, X is a phenyl compound.

[0084] In some embodiments, X a These are halogens, C1-C6 alkyl groups, C1-C6 alkoxyls, or C3-C6 cycloalkyl groups.

[0085] In some embodiments, X a is a halogen. In some embodiments, X a is fluorine. In some embodiments, X a is chlorine. In some embodiments, X a is bromine. In some embodiments, X a It is iodine.

[0086] In some embodiments, X a is a C1-C6 alkyl group. In some embodiments, X a is a C1 alkyl group. In some embodiments, X a is a C2 alkyl group. In some embodiments, X a is a C3 alkyl group. In some embodiments, X a is a C4 alkyl group. In some embodiments, X a is a C5 alkyl group. In some embodiments, X a is a C6 alkyl group. In some embodiments, X a is methyl. In some embodiments, X a is ethyl. In some embodiments, X a is propyl. In some embodiments, X ais butyl. In some embodiments, X a is a pentill. In some embodiments, X a It is hexyl.

[0087] In some embodiments, X a These are C1-C6 alkoxyls. In some embodiments, X a is a C1 alkoxyl. In some embodiments, X a is a C2 alkoxyl. In some embodiments, X a is a C3 alkoxyl. In some embodiments, X a is a C4 alkoxyl. In some embodiments, X a It is a C5 alkoxyl. In some embodiments, X a It is a C6 alkoxyl.

[0088] In some embodiments, X a is a C3-C6 cycloalkyl group. In some embodiments, X a is a C3 cycloalkyl group. In some embodiments, X a is a C4 cycloalkyl group. In some embodiments, X a is a C5 cycloalkyl group. In some embodiments, X a is a C6 cycloalkyl group. In some embodiments, X a It is cyclopropyl.

[0089] In some embodiments, X is

[0090] [ka] That is the case.

[0091] In some embodiments, X is

[0092] [ka] That is the case.

[0093] In some embodiments, X is

[0094] [ka] That is the case.

[0095] In some embodiments, X is

[0096] [ka] That is the case.

[0097] In some embodiments, X is

[0098] [ka] That is the case.

[0099] In some embodiments, R 4 These are C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 A aryl is one or more R 4a It is being replaced by an arbitrary choice.

[0100] In some embodiments, R 4 H is H.

[0101] In some embodiments, R 4 is one or more R 4a It is a C1-C6 alkyl group that is optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C1 alkyl group that is optionally substituted with R. In some embodiments, 4 is one or more R4a It is a C2 alkyl group optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C3 alkyl group optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C4 alkyl group optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C5 alkyl group optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C6 alkyl group optionally substituted with R. In some embodiments, 4 is methyl. In some embodiments, R 4 is ethyl. In some embodiments, R 4 is propyl. In some embodiments, R 4 is butyl. In some embodiments, R 4 is pentill. In some embodiments, R 4 It is hexyl.

[0102] In some embodiments, R 4 is one or more R 4a It is a C3-C6 cycloalkyl group that is optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C3 cycloalkyl that is optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C4 cycloalkyl that is optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C5 cycloalkyl that is optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C6 cycloalkyl that is optionally substituted with R. In some embodiments, 4 is one or more R 4aIt is a cyclopropyl optionally substituted with R. In some embodiments, 4 is one or more R 4a It is cyclobutyl optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a cyclopentyl that is optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a cyclohexyl that has been optionally substituted.

[0103] In some embodiments, R 4 is one or more R 4a C6~C are optionally substituted. 10 It is an arrow. In some embodiments, R 4 is one or more R 4a It is a C6 aryl that is optionally substituted with R. In some embodiments, 4 is one or more R 4a It is a C7 aryl that is optionally substituted with R. In some embodiments, 4 is one or more R 4a This is a C8 aryl that is optionally substituted with R. In some embodiments, 4 is one or more R 4a This is a C9 aryl that is optionally substituted with R. In some embodiments, R 4 is one or more R 4a C is optionally replaced by 10 It is an arrow. In some embodiments, R 4 is one or more R 4a It is a phenyl compound that has been optionally substituted.

[0104] In some embodiments, R 4a These are halogens, cyanos, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls.

[0105] In some embodiments, R 4a is a halogen. In some embodiments, R 4ais fluorine. In some embodiments, R 4a is chlorine. In some embodiments, R 4a is bromine. In some embodiments, R 4a It is iodine.

[0106] In some embodiments, R 4a It is cyano.

[0107] In some embodiments, R 4a is a C1-C6 alkyl group. In some embodiments, R 4a is a C1 alkyl group. In some embodiments, R 4a is a C2 alkyl group. In some embodiments, R 4a is a C3 alkyl group. In some embodiments, R 4a is a C4 alkyl group. In some embodiments, R 4a is a C5 alkyl group. In some embodiments, R 4a is a C6 alkyl group. In some embodiments, R 4a is methyl. In some embodiments, R 4a is ethyl. In some embodiments, R 4a is propyl. In some embodiments, R 4a is butyl. In some embodiments, R 4a is pentill. In some embodiments, R 4a It is hexyl.

[0108] In some embodiments, R 4a R is a C1-C6 alkoxyl. In some embodiments, R 4a is a C1 alkoxyl. In some embodiments, R 4a It is a C2 alkoxyl. In some embodiments, R 4a It is a C3 alkoxyl. In some embodiments, R 4a is a C4 alkoxyl. In some embodiments, R 4aIt is a C5 alkoxyl. In some embodiments, R 4a It is a C6 alkoxyl. In some embodiments, R 4a is a methoxyl. In some embodiments, R 4a is ethoxyl. In some embodiments, R 4a is propoxyl. In some embodiments, R 4a is butoxyl. In some embodiments, R 4a is pentoxyl. In some embodiments, R 4a It is hexoxyl.

[0109] In some embodiments, R 4a is a C3-C6 cycloalkyl group. In some embodiments, R 4a is a C3 cycloalkyl group. In some embodiments, R 4a is a C4 cycloalkyl group. In some embodiments, R 4a is a C5 cycloalkyl. In some embodiments, R 4a is a C6 cycloalkyl. In some embodiments, R 4a is cyclopropyl. In some embodiments, R 4a is cyclobutyl. In some embodiments, R 4a is cyclopentyl. In some embodiments, R 4a It is cyclohexyl.

[0110] In some embodiments, R 5 These are C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 It is an aryl group, and is a C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 A aryl is one or more R 5a It is being replaced by an arbitrary choice.

[0111] In some embodiments, R 5 H is H.

[0112] In some embodiments, R 5 is one or more R 5a It is a C1-C6 alkyl group that is optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C1 alkyl group that is optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C2 alkyl group optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C3 alkyl group optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C4 alkyl group optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C5 alkyl group optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C6 alkyl group optionally substituted with R. In some embodiments, 5 is methyl. In some embodiments, R 5 is ethyl. In some embodiments, R 5 is propyl. In some embodiments, R 5 is butyl. In some embodiments, R 5 is pentill. In some embodiments, R 5 It is hexyl.

[0113] In some embodiments, R 5 is one or more R 5a It is a C3-C6 cycloalkyl group that is optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C3 cycloalkyl that is optionally substituted with R. In some embodiments, 5 is one or more R 5a It is a C4 cycloalkyl that is optionally substituted with R. In some embodiments, 5 is one or more R5a is a C5 cycloalkyl optionally substituted with one or more R 5 . In some embodiments, R 5a is a C6 cycloalkyl optionally substituted with one or more R 5 . In some embodiments, R 5a is a cyclopropyl optionally substituted with one or more R 5 . In some embodiments, R 5a is a cyclobutyl optionally substituted with one or more R 5 . In some embodiments, R 5a is a cyclopentyl optionally substituted with one or more R 5 . In some embodiments, R 5a is a cyclohexyl optionally substituted with one or more R

[0114] . In some embodiments, R 5 is a C6-C 5a aryl optionally substituted with one or more R 10 . In some embodiments, R 5 is a C6 aryl optionally substituted with one or more R 5a . In some embodiments, R 5 is a C7 aryl optionally substituted with one or more R 5a . In some embodiments, R 5 is a C8 aryl optionally substituted with one or more R 5a . In some embodiments, R 5 is a C9 aryl optionally substituted with one or more R 5a . In some embodiments, R 5 is a C 5a aryl optionally substituted with one or more R 10 . In some embodiments, R 5 is a phenyl optionally substituted with one or more R 5a .

[0115] . In some embodiments, R 5aThese are halogens, cyanos, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls.

[0116] In some embodiments, R 5a is a halogen. In some embodiments, R 5a is fluorine. In some embodiments, R 5a is chlorine. In some embodiments, R 5a is bromine. In some embodiments, R 5a It is iodine.

[0117] In some embodiments, R 5a It is cyano.

[0118] In some embodiments, R 5a is a C1-C6 alkyl group. In some embodiments, R 5a is a C1 alkyl group. In some embodiments, R 5a is a C2 alkyl group. In some embodiments, R 5a is a C3 alkyl group. In some embodiments, R 5a is a C4 alkyl group. In some embodiments, R 5a is a C5 alkyl group. In some embodiments, R 5a is a C6 alkyl group. In some embodiments, R 5a is methyl. In some embodiments, R 5a is ethyl. In some embodiments, R 5a is propyl. In some embodiments, R 5a is butyl. In some embodiments, R 5a is pentill. In some embodiments, R 5a It is hexyl.

[0119] In some embodiments, R 5a R is a C1-C6 alkoxyl. In some embodiments, R 5a is a C1 alkoxyl. In some embodiments, R5a It is a C2 alkoxyl. In some embodiments, R 5a It is a C3 alkoxyl. In some embodiments, R 5a is a C4 alkoxyl. In some embodiments, R 5a It is a C5 alkoxyl. In some embodiments, R 5a It is a C6 alkoxyl. In some embodiments, R 5a is a methoxyl. In some embodiments, R 5a is ethoxyl. In some embodiments, R 5a is propoxyl. In some embodiments, R 5a is butoxyl. In some embodiments, R 5a is pentoxyl. In some embodiments, R 5a It is hexoxyl.

[0120] In some embodiments, R 5a is a C3-C6 cycloalkyl group. In some embodiments, R 5a is a C3 cycloalkyl group. In some embodiments, R 5a is a C4 cycloalkyl group. In some embodiments, R 5a is a C5 cycloalkyl. In some embodiments, R 5a is a C6 cycloalkyl. In some embodiments, R 5a is cyclopropyl. In some embodiments, R 5a is cyclobutyl. In some embodiments, R 5a is cyclopentyl. In some embodiments, R 5a It is cyclohexyl.

[0121] In some embodiments, R 6 is H or C1-C6 alkyl. In some embodiments, R 6 H is H. In some embodiments, R 6 is a C1-C6 alkyl group. In some embodiments, R 6is a C1 alkyl. In some embodiments, R 6 is a C2 alkyl. In some embodiments, R 6 is a C3 alkyl. In some embodiments, R 6 is a C4 alkyl. In some embodiments, R 6 is a C5 alkyl. In some embodiments, R 6 is a C6 alkyl. In some embodiments, R 6 is tert-butyl.

[0122] In some embodiments, R 7 is C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 aryl, and C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 aryl is optionally substituted with one or more R 7a .

[0123] In some embodiments, R 7 is C1-C6 alkyl optionally substituted with one or more R 7a . In some embodiments, R 7 is C1 alkyl optionally substituted with one or more R 7a . In some embodiments, R 7 is C2 alkyl optionally substituted with one or more R 7a . In some embodiments, R 7 is C3 alkyl optionally substituted with one or more R 7a . In some embodiments, R 7 is C4 alkyl optionally substituted with one or more R 7a . In some embodiments, R 7 is C5 alkyl optionally substituted with one or more R 7a . In some embodiments, R 7 is C6 alkyl optionally substituted with one or more R 7a . In some embodiments, R 7is methyl. In some embodiments, R 7 is ethyl. In some embodiments, R 7 is propyl. In some embodiments, R 7 is butyl. In some embodiments, R 7 is pentill. In some embodiments, R 7 It is hexyl.

[0124] In some embodiments, R 7 is one or more R 7a It is a C3-C6 cycloalkyl group that is optionally substituted with R. In some embodiments, 7 is one or more R 7a It is a C3 cycloalkyl that is optionally substituted with R. In some embodiments, 7 is one or more R 7a It is a C4 cycloalkyl that is optionally substituted with R. In some embodiments, 7 is one or more R 7a It is a C5 cycloalkyl that is optionally substituted with R. In some embodiments, 7 is one or more R 7a It is a C6 cycloalkyl that is optionally substituted with R. In some embodiments, 7 is one or more R 7a It is a cyclopropyl optionally substituted with R. In some embodiments, 7 is one or more R 7a It is cyclobutyl optionally substituted with R. In some embodiments, 7 is one or more R 7a It is a cyclopentyl that is optionally substituted with R. In some embodiments, 7 is one or more R 7a It is a cyclohexyl that has been optionally substituted.

[0125] In some embodiments, R 7 is one or more R 7a C6~C are optionally substituted. 10It is an arrow. In some embodiments, R 7 is one or more R 7a It is a C6 aryl that is optionally substituted with R. In some embodiments, 7 is one or more R 7a It is a C7 aryl that is optionally substituted with R. In some embodiments, 7 is one or more R 7a This is a C8 aryl that is optionally substituted with R. In some embodiments, 7 is one or more R 7a This is a C9 aryl that is optionally substituted with R. In some embodiments, R 7 is one or more R 7a C is optionally replaced by 10 It is an arrow. In some embodiments, R 7 is one or more R 7a It is a phenyl compound that has been optionally substituted.

[0126] In some embodiments, R 7a These are halogens, cyanos, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls.

[0127] In some embodiments, R 7a is a halogen. In some embodiments, R 7a is fluorine. In some embodiments, R 7a is chlorine. In some embodiments, R 7a is bromine. In some embodiments, R 7a It is iodine.

[0128] In some embodiments, R 7a It is cyano.

[0129] In some embodiments, R 7a is a C1-C6 alkyl group. In some embodiments, R 7a is a C1 alkyl group. In some embodiments, R 7ais a C2 alkyl group. In some embodiments, R 7a is a C3 alkyl group. In some embodiments, R 7a is a C4 alkyl group. In some embodiments, R 7a is a C5 alkyl group. In some embodiments, R 7a is a C6 alkyl group. In some embodiments, R 7a is methyl. In some embodiments, R 7a is ethyl. In some embodiments, R 7a is propyl. In some embodiments, R 7a is butyl. In some embodiments, R 7a is pentill. In some embodiments, R 7a It is hexyl.

[0130] In some embodiments, R 7a R is a C1-C6 alkoxyl. In some embodiments, R 7a is a C1 alkoxyl. In some embodiments, R 7a It is a C2 alkoxyl. In some embodiments, R 7a It is a C3 alkoxyl. In some embodiments, R 7a is a C4 alkoxyl. In some embodiments, R 7a It is a C5 alkoxyl. In some embodiments, R 7a It is a C6 alkoxyl. In some embodiments, R 7a is a methoxyl. In some embodiments, R 7a is ethoxyl. In some embodiments, R 7a is propoxyl. In some embodiments, R 7a is butoxyl. In some embodiments, R 7a is pentoxyl. In some embodiments, R 7a It is hexoxyl.

[0131] In some embodiments, R 7ais a C3-C6 cycloalkyl group. In some embodiments, R 7a is a C3 cycloalkyl group. In some embodiments, R 7a is a C4 cycloalkyl group. In some embodiments, R 7a is a C5 cycloalkyl. In some embodiments, R 7a is a C6 cycloalkyl. In some embodiments, R 7a is cyclopropyl. In some embodiments, R 7a is cyclobutyl. In some embodiments, R 7a is cyclopentyl. In some embodiments, R 7a It is cyclohexyl.

[0132] In some embodiments, R 8 is H or C1-C6 alkyl. In some embodiments, R 8 H is H. In some embodiments, R 8 is a halogen. In some embodiments, R 8 In some embodiments, R 8 is a C1-C6 alkyl group. In some embodiments, R 8 is a C1 alkyl group. In some embodiments, R 8 is a C2 alkyl group. In some embodiments, R 8 is a C3 alkyl group. In some embodiments, R 8 is a C4 alkyl group. In some embodiments, R 8 is a C5 alkyl group. In some embodiments, R 8 is a C6 alkyl group. In some embodiments, R 8 is methyl. In some embodiments, R 8 is ethyl. In some embodiments, R 8 is propyl. In some embodiments, R 8 is butyl. In some embodiments, R 8 is pentill. In some embodiments, R 8It is hexyl.

[0133] In some embodiments, R 9 is H or C1-C6 alkyl. In some embodiments, R 9 H is H. In some embodiments, R 9 is a halogen. In some embodiments, R 9 In some embodiments, R 9 is a C1-C6 alkyl group. In some embodiments, R 9 is a C1 alkyl group. In some embodiments, R 9 is a C2 alkyl group. In some embodiments, R 9 is a C3 alkyl group. In some embodiments, R 9 is a C4 alkyl group. In some embodiments, R 9 is a C5 alkyl group. In some embodiments, R 9 is a C6 alkyl group. In some embodiments, R 9 is methyl. In some embodiments, R 9 is ethyl. In some embodiments, R 9 is propyl. In some embodiments, R 9 is butyl. In some embodiments, R 9 is pentill. In some embodiments, R 9 It is hexyl.

[0134] In some embodiments, R 8 and R 9 These combine to form a C3-C6 cycloalkyl group. In some embodiments, R 8 and R 9 These combine to form C3. In some embodiments, R 8 and R 9 These combine to form C4. In some embodiments, R 8 and R 9 These combine to form C5. In some embodiments, R 8 and R 9These combine to form C6. In some embodiments, R 8 and R 9 These combine to form cyclopropyl.

[0135] In some embodiments, R 10 and R 11 Each is either H or R 10 and R 11 These combine to form an oxo. In some embodiments, R 10 and R 11 These are H, respectively. In some embodiments, R 10 and R 11 These combine to form an oxo.

[0136] In some embodiments, R 12 C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl, including C1-C6 alkyl, C3-C6 cycloalkyl, and C6-C 10 Aryl, C1-C3-(phenyl), or C3-C 10 Heterocycloalkyl is one or more R 12a It is being replaced by an arbitrary choice.

[0137] In some embodiments, R 12 is one or more R 12a It is a C1-C6 alkyl group that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C1 alkyl group that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C2 alkyl group optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C3 alkyl group optionally substituted with R. In some embodiments, 12 is one or more R 12aIt is a C4 alkyl group optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C5 alkyl group optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C6 alkyl group optionally substituted with R. In some embodiments, 12 is methyl. In some embodiments, R 12 is ethyl. In some embodiments, R 12 is propyl. In some embodiments, R 12 is butyl. In some embodiments, R 12 is pentill. In some embodiments, R 12 It is hexyl.

[0138] In some embodiments, R 12 is one or more R 12a It is a C3-C6 cycloalkyl group that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C3 cycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C4 cycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C5 cycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C6 cycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a cyclopropyl optionally substituted with R. In some embodiments, 12 is one or more R 12a It is cyclobutyl optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a cyclopentyl that is optionally substituted with R. In some embodiments,12 is one or more R 12a It is a cyclohexyl that has been optionally substituted.

[0139] In some embodiments, R 12 is one or more R 12a C6~C are optionally substituted. 10 It is an arrow. In some embodiments, R 12 is one or more R 12a It is a C6 aryl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C7 aryl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a This is a C8 aryl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a This is a C9 aryl that is optionally substituted with R. In some embodiments, R 12 is one or more R 12a C is optionally replaced by 10 It is an arrow. In some embodiments, R 12 is one or more R 12a It is a phenyl compound that has been optionally substituted.

[0140] In some embodiments, R 12 is C1-C3-(phenyl). In some embodiments, R 12 is C1-(phenyl). In some embodiments, R 12 is C2-(phenyl). In some embodiments, R 12 is C3-(phenyl). In some embodiments, R 12 It is isopropylphenyl.

[0141] In some embodiments, R 12 is one or more R 12a C3~C are optionally replaced by 10 It is heterocycloalkyl. In some embodiments, R12 is one or more R 12a It is a C3 heterocycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C4 heterocycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C5 heterocycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C6 heterocycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C7 heterocycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C8 heterocycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a C9 heterocycloalkyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a C is optionally replaced by 10 It is heterocycloalkyl. In some embodiments, R 12 is one or more R 12a It is a cyclopropyl optionally substituted with R. In some embodiments, 12 is one or more R 12a It is an indolinyl that is optionally substituted with R. In some embodiments, 12 is one or more R 12a It is a tetrahydroquinolinyl that has been optionally substituted with [the specified compound].

[0142] In some embodiments, R 12a These are halogens, cyanos, C1-C6 alkyls, C1-C6 alkoxyls, or C3-C6 cycloalkyls.

[0143] In some embodiments, R 12ais a halogen. In some embodiments, R 12a is fluorine. In some embodiments, R 12a is chlorine. In some embodiments, R 12a is bromine. In some embodiments, R 12a It is iodine.

[0144] In some embodiments, R 12a It is cyano.

[0145] In some embodiments, R 12a is a C1-C6 alkyl group. In some embodiments, R 12a is a C1 alkyl group. In some embodiments, R 12a is a C2 alkyl group. In some embodiments, R 12a is a C3 alkyl group. In some embodiments, R 12a is a C4 alkyl group. In some embodiments, R 12a is a C5 alkyl group. In some embodiments, R 12a is a C6 alkyl group. In some embodiments, R 12a is methyl. In some embodiments, R 12a is ethyl. In some embodiments, R 12a is propyl. In some embodiments, R 12a is butyl. In some embodiments, R 12a is pentill. In some embodiments, R 12a It is hexyl.

[0146] In some embodiments, R 12a R is a C1-C6 alkoxyl. In some embodiments, R 12a is a C1 alkoxyl. In some embodiments, R 12a It is a C2 alkoxyl. In some embodiments, R 12a It is a C3 alkoxyl. In some embodiments, R 12a is a C4 alkoxyl. In some embodiments, R12a It is a C5 alkoxyl. In some embodiments, R 12a It is a C6 alkoxyl. In some embodiments, R 12a is a methoxyl. In some embodiments, R 12a is ethoxyl. In some embodiments, R 12a is propoxyl. In some embodiments, R 12a is butoxyl. In some embodiments, R 12a is pentoxyl. In some embodiments, R 12a It is hexoxyl.

[0147] In some embodiments, R 12a is a C3-C6 cycloalkyl group. In some embodiments, R 12a is a C3 cycloalkyl group. In some embodiments, R 12a is a C4 cycloalkyl group. In some embodiments, R 12a is a C5 cycloalkyl. In some embodiments, R 12a is a C6 cycloalkyl. In some embodiments, R 12a is cyclopropyl. In some embodiments, R 12a is cyclobutyl. In some embodiments, R 12a is cyclopentyl. In some embodiments, R 12a It is cyclohexyl.

[0148] In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0149] In some embodiments, R 1 is phenyl, and R 2 It is phenyl.

[0150] In some embodiments, X is

[0151] [ka] And R 4 is phenyl, and R 5 It is methyl.

[0152] In some embodiments, X is

[0153] [ka] And R 10 and R 11 These combine to form an oxo.

[0154] In some embodiments, X is

[0155] [ka] And R 12 teeth

[0156] [ka] That is the case.

[0157] In some embodiments, X is

[0158] [ka] And R 10 and R 11 They combine to form an oxo, R 12 teeth

[0159] [ka] That is the case.

[0160] In some embodiments, R 1 and R 2 At least one of them

[0161] [ka] That is the case.

[0162] This disclosure relates to the following compounds

[0163] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0164] This disclosure relates to the following compounds

[0165] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0166] This disclosure relates to the following compounds

[0167] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0168] This disclosure relates to the following compounds

[0169] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0170] This disclosure relates to the following compounds

[0171] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0172] This disclosure relates to the following compounds

[0173] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0174] This disclosure relates to the following compounds

[0175] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0176] This disclosure relates to the following compounds

[0177] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0178] This disclosure relates to the following compounds

[0179] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0180] This disclosure relates to the following compounds

[0181] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0182] This disclosure relates to the following compounds

[0183] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0184] This disclosure relates to the following compounds

[0185] [ka] Or provide a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the compound is selected from the compounds listed in Table I, as well as their pharmaceutically acceptable salts and stereoisomers.

[0187] In some embodiments, the compound is selected from the compounds listed in Table I and their pharmaceutically acceptable salts.

[0188] In some embodiments, the compound is selected from the compounds listed in Table I.

[0189] [Table 1-1]

[0190] [Table 1-2]

[0191] [Table 1-3]

[0192] [Table 1-4]

[0193] Table 1-5

[0194] Table 1-6

[0195] Table 1-7

[0196] Table 1-8

[0197] Table 1-9

[0198] Table 1-10

[0199] Table 1-11

[0200] Table 1-12

[0201] Table 1-13

[0202] Table 1-14

[0203] Table 1-15

[0204] Table 1-16

[0205] Table 1-17

[0206] Table 1-18

[0207] Table 1-19

[0208] Table 1-20

[0209] Table 1-21

[0210] Table 1-22

[0211] Table 1-23

[0212] Table 1-24

[0213] Table 1-25

[0214] [Table 1-26]

[0215] [Table 1-27]

[0216] [Table 1-28]

[0217] [Table 1-29]

[0218] [Table 1-30]

[0219] [Table 1-31]

[0220] [Table 1-32]

[0221] [Table 1-33]

[0222] In some embodiments, the Disclosure provides compounds that are isotopic derivatives (e.g., isotope-labeled compounds) of any one of the compounds disclosed herein.

[0223] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table I, and a pharmaceutically acceptable salt thereof.

[0224] In some embodiments, the compound is an isotopic derivative of any one of the compounds listed in Table I.

[0225] It is understood that isotopic derivatives can be prepared using any of the various techniques recognized in the art. For example, isotopic derivatives can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using an isotopic labeling reagent instead of a non-isotopic labeling reagent.

[0226] In some embodiments, the isotopic derivative is a deuterium-labeled compound.

[0227] In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of the formulas disclosed herein.

[0228] In some embodiments, the compound is a deuterium-labeled compound from any one of the compounds listed in Table I, and a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the compound is one of the deuterium-labeled compounds listed in Table I.

[0230] It is understood that deuterium-labeled compounds contain deuterium atoms in substantially higher amounts than the naturally occurring abundance of deuterium, which is approximately 0.015%.

[0231] It is understood that deuterium-labeled compounds can be prepared using any of the various techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and / or examples described herein, by using a deuterium-labeled reagent instead of a non-deuterium-labeled reagent.

[0232] The compounds of the present invention containing the aforementioned deuterium atom or their pharmaceutically acceptable salts are within the scope of the present invention. Furthermore, deuterium (i.e., 2 Substitution with H) may result in certain therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced required dosage).

[0233] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. In this specification, singular nouns also include plural nouns unless the context explicitly indicates otherwise. Similar or equivalent methods and materials may be used in the practice or testing of this disclosure, but preferred methods and materials are described below. References cited herein are not considered prior art to the claimed invention. In case of any conflict, this specification, including definitions, shall prevail. Materials, methods, and examples are illustrative and not intended to limit the scope of the invention.

[0234] Other features and advantages of this disclosure will be apparent from the following detailed description and claims.

[0235] To avoid misunderstanding, please understand that in this specification, when a base is modified by "as described herein," it encompasses the broadest definition in which the base first appears, as well as any specific definition of that base.

[0236] Suitable pharmaceutically acceptable salts of the compounds of this disclosure are, for example, acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citric acid, methanesulfonic acid, or maleic acid. In addition, suitable pharmaceutically acceptable salts of the compounds of this disclosure that are sufficiently acidic are salts with alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or organic bases that yield pharmaceutically acceptable cations, such as methylamine, dimethylamine, diethylamine, trimethylamine, piperidine, morpholine, or tris(2-hydroxyethyl)amine.

[0237] It will be understood that the compounds of this disclosure and any pharmaceutically acceptable salts thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomeric forms of the compounds.

[0238] As used herein, the term “isomer” means a compound having the same molecular formula but differing in the order of its atoms or the spatial arrangement of its atoms. Isomers with different spatial arrangements of atoms are called “stereoisomers.” Stereoiomers that are not mirror images of each other are called “diastereoisomers,” and stereoisomers that are mirror images of each other but cannot be superimposed are called “enantiomers,” or sometimes optical isomers. A mixture containing equal amounts of individual enantiomer forms with opposite chiralities is called a “racemic mixture.”

[0239] As used herein, the term “chiral center” refers to a carbon atom bonded to four non-identical substituents.

[0240] As used herein, the term “chiral isomer” means a compound having at least one chiral center. Compounds having two or more chiral centers may exist as individual diastereomers or as a mixture of diastereomers called a “diastereomer mixture.” When one chiral center is present, the stereoisomers may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of substituents attached to the chiral center. Substituents attached to the chiral center under consideration are ranked according to the Cahn, Ingold, and Prelog sequence rule. (Cahn et al.,Angew.Chem.Inter.Edit.1966,5,385;errata 511;Cahn et al.,Angew.Chem.1966,78,413;Cahn and Ingold,J.Chem.Soc.1951(London),612;Cahn et al.,Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

[0241] As used herein, the term “geometric isomer” means a diastereomer whose existence is due to rotational hindrance around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These arrangements are distinguished by the prefixes cis and trans or Z and E, which indicate that their groups are on the same side or opposite side of the double bond in the molecule according to the Kahn-Ingold-Prelogue rule.

[0242] Please understand that the compounds disclosed herein may be represented as different chiral or geometric isomers. Where a compound exists in chiral or geometric isomeric form, all isomeric forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any of the isomeric forms. Please also understand that not all isomers possess the same level of activity.

[0243] It should be understood that the structures and other compounds discussed in this disclosure include all of their atropic isomers. It should also be understood that not all atropic isomers have the same level of activity.

[0244] As used herein, the term “atropisomer” refers to a type of stereoisomer in which two isomers differ in the spatial arrangement of their atoms. The existence of atropisomers is due to rotational limitations caused by rotational hindrance of a large group around a central bond. While such atropisomers typically exist as a mixture, recent advances in chromatography techniques have made it possible to separate mixtures of two atropisomers in selected cases.

[0245] As used herein, a “tautomer” is one of two or more structural isomers that exist in equilibrium and are readily converted from one isomer to another. This conversion results in a formal transfer of hydrogen atoms, accompanied by the switching of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of sets of tautomers. Chemical equilibrium of tautomers is reached in a solution in which tautomerization is possible. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. The concept of tautomers that can be interconverted by tautomerization is called tautomerism. Of the various types of tautomerism possible, two are commonly observed. Keto-enol tautomerism involves a simultaneous shift of electrons and hydrogen atoms. Ring-chain tautomerism occurs as a result of an aldehyde group (-CHO) in a sugar chain molecule reacting with one of the hydroxyl groups (-OH) in the same molecule, forming the cyclic (ring-shaped) form represented by glucose.

[0246] It should be understood that the compounds of this disclosure may be described as different tautomers. Where a compound has tautomer forms, it is intended that all tautomer forms are included within the scope of this disclosure, and that the naming of the compound does not exclude any tautomer form. It will be understood that certain tautomers may have higher levels of activity than others.

[0247] Compounds having the same molecular formula but differing in the nature or order of atomic bonding or the spatial arrangement of atoms are called "isomers." Isomers with different spatial arrangements of atoms are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while stereoisomers that are mirror images of each other but cannot be superimposed are called "enantiomers." If a compound has a chiral center, for example, if the compound is bonded to four different groups, then pairs of enantiomers are possible. Enantiomers can be characterized by the absolute configuration of their chiral center and are described by the Cahn and Prelog R and S sequence rules, or by the rotation of the plane of polarization of the molecule, specifying it as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing enantiomers in equal proportions is called a "racemic mixture."

[0248] The compounds of this disclosure may have one or more chiral centers. Therefore, such compounds can be prepared as individual (R) or (S) stereoisomers, or as mixtures thereof. Unless otherwise indicated, the descriptions or nomenclature of specific compounds in this specification and the claims are intended to include both individual enantiomers and mixtures thereof, racemates, or other forms. Planar bonds in the chemical structure are intended to include any isomer (e.g., enantiomers or diastereomers) and mixtures thereof. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see the discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolution of racemates. Some of the compounds of this disclosure may have geometric isomers (E and Z isomers). It should be understood that this disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers, as well as mixtures thereof, that possess inflammasome inhibitory activity.

[0249] The example compounds 1 to 112 of the present invention represent chiral compounds and were prepared and tested as individual stereoisomers or as racemic mixtures, as described in the examples herein (see, for example, Examples 2 to 5 below). The absolute stereochemical characterization and determination of the individual stereoisomers of the examples provided herein are within the scope of the art of the art, and methods for such determinations are well known in the literature of medicinal chemistry (see, for example, Chiral Analysis (Second Edition) Advances in Spectroscopy, Chromatography and Emerging Methods, 2018). For example, the absolute configuration is generally determined by NMR based on the use of CDA, and diastereomer derivatives containing a covalent bond between a chiral auxiliary and an enantiomer substrate adopt a preferred conformation that can be predicted based on differential shielding caused by the aromatic ring incorporated into the chiral identification reagent.

[0250] This disclosure also includes compounds of the disclosure as defined herein that include one or more isotopic substitutions.

[0251] It should be understood that any compound of any of the formulas described herein, where applicable, includes the compound itself, as well as its salts and solvates. For example, salts may be formed between an anion and a positively charged group (e.g., amino) on a substituted compound disclosed herein.

[0252] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" refers to one or more relatively non-toxic inorganic and organic salts of the compounds of the present invention. It will be understood by those skilled in the art that the compounds of the present invention can form salts. The compounds of the present invention contain basic heterocycles and therefore react with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable acid addition salts and general methodologies for preparing them are well known in the art. See, for example, P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2008) and SMBerge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol 66, No. 1, January 1977.

[0253] It should be understood that the compounds of this disclosure, for example, salts thereof, may exist in either a hydrated or unhydrated (anhydrous) form, or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates and dihydrates. Non-limiting examples of solvates include ethanol solvate and acetone solvate.

[0254] As used herein, the term “solvate” means a solubilated form containing either a stoichiometric or non-stoichiometric amount of solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in a crystalline solid state, and thus form solvates. When the solvent is water, the solvate formed is a hydrate; when the solvent is an alcohol, the solvate formed is an alcoholate. Hydrates are formed by a combination of one or more molecules of water and one molecule of a substance in which the water retains its molecular state as H2O.

[0255] It should be understood that certain compounds in this disclosure may exhibit polymorphism, and that this disclosure encompasses all such forms or mixtures thereof. It is generally known that crystalline materials can be analyzed using techniques known to those skilled in the art, such as X-ray powder diffraction, differential scanning calorimetry, thermogravimetric analysis, diffuse reflection infrared Fourier transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, and solution and / or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

[0256] The compounds of this disclosure may exist in several different tautomer forms, and references to the compounds of this disclosure include all such forms. To avoid misunderstanding, even if a compound may exist in one of several tautomer forms and only one is specifically described or shown, all the others are also encompassed in formula (I). Examples of tautomer forms include, for example, the following tautomer pairs: keto / enol (illustrated below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enthiol, and keto, enol, and enolate forms such as nitro / acy-nitro.

[0257] [ka]

[0258] Compounds of the Disclosure containing amine functional groups may also form N-oxides. References herein to compounds containing amine functional groups also include N-oxides. If a compound contains several amine functional groups, one or more nitrogen atoms may be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. N-oxides may also be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., a peroxycarboxylic acid), see, for example, the page in Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More specifically, N-oxides may be prepared by the procedure of LWDeady (Syn.Comm.1977,7,509-514), in which the amine compound is reacted with meta-chloroperoxybenzoic acid (mCPBA) in an inert solvent such as dichloromethane.

[0259] The compounds of this disclosure may be administered in the form of a prodrug, which is broken down in the body of a human or animal to release the compound. The prodrug can be used to alter the physical and / or pharmacokinetic properties of the compound. A prodrug may be formed when the compound contains a suitable group or substituent to which a character-modifying group can be attached. Examples of prodrugs include derivatives containing an in vivo cleavable alkyl or acyl substituent on the sulfonylurea group in any one of the compounds of the formulas disclosed herein.

[0260] Accordingly, the Disclosure includes the compounds of the Disclosure as defined above herein, when made available by organic synthesis and when made available in the body of a human or animal by cleavage of its prodrug. Accordingly, the Disclosure includes the compounds of the Disclosure produced by organic synthesis means, and such compounds (i.e., compounds of the Disclosure) produced in the body of a human or animal by the metabolism of precursor compounds may also be synthetically produced or metabolically produced compounds.

[0261] The preferred pharmaceutically acceptable prodrugs of the compounds disclosed herein are based on reasonable medical judgment that they are suitable for administration to the human or animal body without undesirable pharmacological activity and excessive toxicity. Various forms of prodrugs are described, for example, in the following literature. a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of "Pro-drugs", by H. Bundgaard p.113-191(1991);d) H. Bundgaard,Advanced Drug Delivery Reviews,8,1-38(1992);e) H. Bundgaard,et al.,Journal of Pharmaceutical Sciences,77,285(1988);f)N. Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984);g)T.Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems," ACSSymposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design," Pergamon Press, 1987.

[0262] A preferred pharmaceutically acceptable prodrug of a compound of the disclosure having a hydroxyl group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the disclosure containing a hydroxyl group is, for example, a pharmaceutically acceptable ester or ether that is cleaved in the body of a human or animal to produce a hydroxyl-parent compound. A preferred pharmaceutically acceptable ester-forming group for the hydroxyl group is an inorganic ester such as a phosphate ester (including a phosphoramide cyclic ester). A further preferred pharmaceutically acceptable ester-forming group for the hydroxyl group is C1-C 10 Alkanoyl groups, for example, acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C 10 Examples of alkoxycarbonyl groups include ethoxycarbonyl, N,N-(C1-C6 alkyl)2-carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl groups. Examples of ring substituents on phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include acetoxymethyl and α-acyloxyalkyl groups such as pivaloyloxymethyl.

[0263] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a carboxyl group include, for example, amides formed using amides that can be cleaved in vivo, such as amines such as ammonia, C1-C4 alkylamines such as methylamine, (C1-C4 alkyl)2 amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, C1-C4 alkoxy-C2-C4 alkylamines such as 2-methoxyethylamine, phenyl-C1-C4 alkylamines such as benzylamine, and amino acids or esters thereof such as glycine.

[0264] A preferred pharmaceutically acceptable prodrug of the compounds of this disclosure having an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C1-C12 acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 10 Examples of amides formed by alkanoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-(C1-C4 alkyl)piperazine-1-ylmethyl.

[0265] The in vivo effects of the compounds disclosed may be partially exerted by one or more metabolites formed in the human or animal body after administration of the compounds disclosed. As stated above, the in vivo effects of the compounds disclosed may also be exerted by the metabolism of a precursor compound (prodrug).

[0266] As used herein, the term “about” refers to a range that encompasses any normal variation recognized by those skilled in the art. In some embodiments, unless otherwise stated or evident from the context (except where such a number exceeds 100% of the possible values), the term “about” refers to a range of values ​​that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either the greater than or less than direction of the stated reference value.

[0267] As used herein, “alkyl,” “C1, C2, C3, C4, C5, or C6 alkyl,” or “C1-C6 alkyl” is intended to include a C1, C2, C3, C4, C5, or C6 linear saturated aliphatic hydrocarbon group and a C3, C4, C5, or C6 branched saturated aliphatic hydrocarbon group. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyls include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, or n-hexyl, and include moieties having 1 to 6 carbon atoms. In some embodiments, the linear or branched alkyl group has six or fewer carbon atoms (for example, C1-C6 for the linear group and C3-C6 for the branched group), and in other embodiments, the linear or branched alkyl group has four or fewer carbon atoms.

[0268] As used herein, the term “optionally substituted” is understood to mean that a given chemical moiety (e.g., an alkyl group) can (but is not required to) bond to other substituents (e.g., a heteroatom). For example, an optionally substituted alkyl group may be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group may have substituents other than hydrogen. For example, it may bond to a halogen atom, a hydroxyl group, or any other substituent described herein at any point along the chain. Thus, the term “optionally substituted” means that a given chemical moiety may contain other functional groups, but does not necessarily have any further functional groups. Substituents can themselves be optionally substituted.

[0269] As used herein, the term "cycloalkyl" refers to a group of atoms with 3 to 30 carbon atoms (e.g., C3-C3). 12 , C3~C 10This refers to saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., condensed, crosslinked, or spirocyclic) systems having C3-C8 rings. Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl, and adamantyl. In the case of polycyclic cycloalkyls, only one of the rings in the cycloalkyl must be non-aromatic.

[0270] As used herein, the term "heterocycloalkyl" means, unless otherwise specified, one or more heteroatoms (e.g., O, N, S, P, or Se) independently selected from the group consisting of nitrogen, oxygen, and sulfur, for example, one or one to two or one to three or one to four or one to five or one to six heteroatoms, or a saturated or partially unsaturated 3- to 8-membered monocyclic, 7- to 12-membered bicyclic (condensed, bridged, or spiro-ring) or 11- to 14-membered tricyclic ring system (condensed, bridged, or spiro-ring) having, for example, one, two, three, four, five, or six heteroatoms.Examples of heterocycloalkyl groups include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxyranyl, azetidinyl, oxetanyl, thietanyl, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl. 1,4-Oxazepanyl, 2-Oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-Oxa-6-azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-Dioxa-8-azaspiro[4.5]decanyl, 1,4-Dioxaspiro[4.5]decanyl, 1-Oxaspiro[4.5]decanyl, 1-azaspiro[4.5]decanyl, 3'H-Spiro[cyclohexane-1,1'-isobenzofuran]yl 7'H-spiro[cyclohexane-1,5'-fl[3,4-b]pyridine]-yl, 3'H-spiro[cyclohexane-1,1'-fl[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexane-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridinyl Examples include, but are not limited to, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2-azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2-methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl, 2-methyl-2-azaspiro[4.5]decanyl, 2-oxazaspiro[3.4]octanyl, and 2-oxazaspiro[3.4]octan-6-yl. In the case of polycyclic heterocycloalkyls, only one of the rings in the heterocycloalkyl must be non-aromatic (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0271] As used herein, the term "aryl" includes aromatic groups, including conjugated groups, or polycyclic systems having one or more aromatic rings, without any heteroatoms in the ring structure. The term "aryl" includes both monovalent and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, and naphthyl.

[0272] As used herein, the term "heteroaryl" is intended to include a carbon atom and one or more heteroatoms, for example, one, one to two, one to three, one to four, one to five, or one to six heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or a stable five-membered, six-membered, or seven-membered monocyclic or seven-membered, eight-membered, nine-membered, ten-membered, eleven-membered, or twelve-membered bicyclic aromatic heterocyclic ring consisting of, for example, one, two, three, four, five, or six heteroatoms. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or another substituent as defined). The nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., N → O and S(O) p (when p=1 or 2). Note that the total number of S and O atoms in the aromatic heterocyclic ring is 1 or less. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, and pyrimidine. Heteroaryl groups can be fused or bridged with non-aromatic, alicyclic or heterocyclic rings to form polycyclic systems (e.g., 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0273] Furthermore, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl groups, such as tricyclic and bicyclic groups, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, and indoridine.

[0274] As used herein, the terms "halo" or "halogen" refer to fluoro, chloro, bromo, and iodine.

[0275] As used herein, the terms “alkoxy” or “alkoxyl” include substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups.

[0276] As used herein, the term "cyano" refers to a substituent having a carbon atom bonded to a nitrogen atom by a triple bond, i.e.

[0277]

number

[0278] As used herein, the term "oxo" is understood to refer to a carbonyl group (i.e., C(O)).

[0279] Where used herein, the term “subject” is interchangeable with the term “subject in need of it,” both referring to a subject who has a disease or is at increased risk of developing a disease. “Subject” includes mammals. Mammals may be, for example, humans or appropriate non-human mammals, such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. A subject may also be a bird or poultry. In one embodiment, the mammal is a human. A subject in need of it may be a subject previously diagnosed or identified as having one of the diseases or disorders disclosed herein. A subject in need of it may also be a subject who has (e.g., is suffering from) one of the diseases or disorders disclosed herein. Alternatively, a subject in need of it may be a subject at higher risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject with a predisposition to developing such a disorder compared to the population as a whole). A subject in need of it may be refractory or resistant to one of the diseases or disorders disclosed herein (i.e., one that is not responding to treatment or has not yet responded to treatment). The subjects may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subjects requiring it have received and failed all known effective therapies for the disease or disorder disclosed herein. In some embodiments, the subjects requiring it have received at least one prior therapy.

[0280] As used herein, the terms “treatment,” “treating,” or “mitigating” are intended to refer to the entire process, which may include delaying, interrupting, preventing, controlling, or stopping an existing disorder and / or reducing its symptoms, but not necessarily indicating the complete elimination of all symptoms. As used herein, the term “effective dose” of the compound of formula (I) refers to the amount, i.e., the dosage, that is effective in inhibiting the AT2R-mediated response in a patient. The “effective dose” is determined as the amount that can treat or resolve the signs and symptoms of moderate to severe psoriasis in a subject compared to an untreated subject. In determining the effective dose or dosage of the compound of formula (I), several factors are taken into consideration, including but not limited to the compound being administered and its specific formulation: the patient’s size, age, and overall health; the degree of involvement or severity of the disorder; the individual subject’s response; the mode of administration; and other relevant circumstances.

[0281] The compounds of the present invention are AT2R antagonists, and when administered to subjects requiring them, they may provide therapeutic benefits while avoiding certain problems associated with other AT2R antagonists. Therefore, the compounds of the present invention are considered useful in treating conditions involving AT2R, such as pain. In some embodiments, this includes pain in neuropathic pain.

[0282] This disclosure provides a pharmaceutical composition comprising a compound of formula (I) and / or a salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, this disclosure provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, this disclosure provides a pharmaceutical composition comprising a salt of a compound of formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the pain is neuropathic pain, inflammatory pain, nociceptive pain, mixed nociceptive and neuropathic pain, visceral pain, postoperative pain, postherpetic pain, traumatic pain, phantom limb pain, fibromyalgia syndrome (FMS), back pain, cancer pain, chemotherapy-induced peripheral neuropathy (CIPN), or osteoarthritis (OA) pain. In some embodiments, neuropathic pain is diabetic peripheral neuropathic pain (DPNP). In some embodiments, back pain is chronic low back pain (CLBP). In some embodiments, visceral pain is pain associated with irritable bowel syndrome (IBS), bladder pain, prostate pain, or vulvovaginal pain.

[0283] This disclosure provides methods for treating diseases or disorders involving AT2R. In some embodiments, this disclosure provides a method for treating pain, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, this disclosure provides a method for treating neuropathic pain, inflammatory pain, nociceptive pain, mixed nociceptive and neuropathic pain, visceral pain, postoperative pain, postherpetic pain, traumatic pain, phantom limb pain, fibromyalgia syndrome (FMS), back pain, cancer pain, chemotherapy-induced peripheral neuropathy (CIPN), or osteoarthritis (OA) pain, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, this disclosure provides a method for treating neuropathic pain, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the Disclosure provides a method for treating fibromyalgia syndrome (FMS), comprising administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the Disclosure provides a method for treating osteoarthritis (OA) pain, comprising administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the Disclosure provides a method for treating diabetic peripheral neuropathic pain (DPNP), comprising administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the Disclosure provides a method for treating chronic low back pain (CLBP), comprising administering an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need. In some embodiments, the present disclosure provides a method for treating chemotherapy-induced peripheral neuropathy (CIPN), comprising administering an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.In some embodiments, the Disclosure provides a method for treating visceral pain (e.g., pain associated with irritable bowel syndrome (IBS), bladder pain, prostate pain, or vulvovaginal pain), comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need. The Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of pain. The Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of neuropathic pain, inflammatory pain, nociceptive pain, mixed nociceptive and neuropathic pain, visceral pain, postoperative pain, postherpetic pain, traumatic pain, phantom limb pain, fibromyalgia syndrome (FMS), back pain, cancer pain, chemotherapy-induced peripheral neuropathy (CIPN), or osteoarthritis (OA) pain. The Disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of neuropathic pain. In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of fibromyalgia syndrome (FMS). In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of osteoarthritis (OA) pain. In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of diabetic peripheral neuropathic pain (DPNP). In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of chronic low back pain (CLBP). In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of chemotherapy-induced peripheral neuropathy (CIPN). In some embodiments, the present disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof for use in the treatment of visceral pain (e.g., pain associated with irritable bowel syndrome (IBS), bladder pain, prostate pain, or vulvovaginal pain).

[0284] This disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of pain. This disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neuropathic pain, inflammatory pain, nociceptive pain, mixed nociceptive and neuropathic pain, visceral pain, postoperative pain, postherpetic pain, traumatic pain, phantom limb pain, fibromyalgia syndrome, back pain, cancer pain, chemotherapy-induced peripheral neuropathy (CIPN), or osteoarthritis (OA) pain. This disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of neuropathic pain. In some embodiments, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of fibromyalgia syndrome (FMS). In some embodiments, the Disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of osteoarthritis (OA) pain. In some embodiments, the Disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of diabetic peripheral neuropathic pain (DPNP). In some embodiments, the Disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of chronic low back pain (CLBP). In some embodiments, the Disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of chemotherapy-induced peripheral neuropathy (CIPN). In some embodiments, the Disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of visceral pain (e.g., pain associated with irritable bowel syndrome (IBS), bladder pain, prostate pain, or vulvovaginal pain).

[0285] Compositions of the compound of formula (I), or pharmaceutically acceptable salts thereof, may be formulated in unit dosage forms, each containing about 0.5 to about 1000 mg of the active ingredient. The term “unit dosage form” refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active material calculated to produce the desired therapeutic effect in association with at least one suitable pharmaceutically acceptable carrier, diluent, and / or excipient. It will be understood that the amount of compound actually administered will be determined by a physician in light of relevant circumstances, including the condition being treated, the route of administration selected, the actual compound administered, the age, weight, and response of the individual subject, and the severity of the subject’s symptoms. For example, in the pharmaceutical compositions of the present invention, the compounds of the present invention are intended to be used to treat pain (e.g., neuropathic pain) with long-term administration.

[0286] The compounds of this disclosure can be prepared by any suitable technique known in the art. Specific processes for the preparation of these compounds are further described in the appended examples.

[0287] In the descriptions of the synthesis methods described herein, and in any referenced synthesis methods used to prepare the starting materials, it should be understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and work-up procedure, can be selected by those skilled in the art.

[0288] Those skilled in organic synthesis will understand that the functional groups present in various parts of a molecule must be compatible with the reagents and reaction conditions used.

[0289] Furthermore, by utilizing the procedures described herein in conjunction with the conventional art in this field, further compounds of the Disclosure can be readily prepared. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can be used to prepare these compounds.

[0290] As will be understood by those skilled in the art of organic synthesis, the compounds of this disclosure are readily available through various synthetic routes, some of which are illustrated in the accompanying examples. Those skilled in the art will readily recognize what kinds of reagents and reaction conditions should be used to obtain the compounds of this disclosure, and how they should be applied and adapted in any particular case (where necessary or useful). Furthermore, some of the compounds of this disclosure can be readily synthesized by reacting them with other compounds of this disclosure under suitable conditions, by applying standard synthetic methods (which are well known to those skilled in the art), such as reduction, oxidation, addition, or substitution reactions, to convert one particular functional group present in the compound of this disclosure or its suitable precursor molecule to another. Similarly, those skilled in the art will readily apply synthetic protecting (or protecting) groups whenever necessary or useful, and suitable protecting groups, as well as methods for introducing and removing them, are well known to those skilled in the art of chemical synthesis, for example, in PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis," 4th edition (2006) (John Wiley & Sons).

[0291] The exemplified compounds were prepared as described below. Examples of other compounds of the present invention can be prepared according to schemes similar to those described herein.

[0292] A certain abbreviation is defined as follows:

[0293] [Table 2]

[0294] Example 1. Synthesis of Examples No. 1, 2, 4, 5, 13, 16, 19, 26, 33, 38, 40, 46, 56, 57, 58, 59, 61, 87, 98, 100, 101, 102, 107, 108, 109, 110, 111, and 112

[0295] [ka]

[0296] Step 1: 2-(1-benzyl-4-piperidylidene)-2-cyanoethyl acetate

[0297] [ka]

[0298] To a solution of 1-benzylpiperidine-4-one (3.45 kg, 18.2 mol) in toluene (10.0 L), 2-ethyl cyanoethyl (2.47 kg, 21.8 mol) and AcOH (875 g, 14.5 mol) were added in one step at 20°C to 25°C, and the reaction mixture was then heated to 110°C. After 4 hours, the reaction mixture was cooled to room temperature and concentrated directly under high vacuum. Water (10.0 L) was added to the mixture and stirred for 20 minutes. The mixture was extracted with ethyl acetate (10.0 L × 3). The combined organic phase was then washed with brine (10.0 L × 1), dried over anhydrous Na₂SO₄, and concentrated under high vacuum. The residue was purified by silica gel chromatography, eluted with 0-100% ethyl acetate / petroleum ether. Appropriate fractions were combined and concentrated to obtain the title compound (4.10 kg, yield 79.10%) as a pale yellow solid. 1 H NMR (399.91MHz, CDCl3):7.36-7.29(m,5H),4.29(q,J=7.2Hz,2H),3.57(s,2H),3.18(t,J=5.8Hz ,2H),2.82(t,J=5.7Hz,2H),2.67(t,J=5.7Hz,2H),2.60(t,J=5.8Hz,2H),1.37(t,J=7.2Hz,3H).

[0299] Step 2: Benzyl-4-(cyanomethyl)piperidine-4-carbonitrile

[0300] [ka]

[0301] To a solution of 2-(1-benzyl-4-piperidylidene)-2-cyanoethyl acetate (505 g, 1.78 mol) in EtOH (2.50 L) and H2O (500 mL), KCN (145.31 g, 2.23 mol) was added under a nitrogen atmosphere at 20-25°C. The reaction mixture was stirred at 80-85°C for 4 hours. Seven reaction products of the same scale were set up simultaneously. After cooling the reaction products to room temperature, all seven reaction products were combined and concentrated directly under high vacuum. Water (5.00 L) was added to the mixture, extracted with ethyl acetate (5.00 L x 3), the combined organic phase was washed with brine (5.00 L), dried over anhydrous Na2SO4, and concentrated under high vacuum. The crude product was ground with petroleum ether:tert-butyl methyl ether = 1:1 (5000 mL), filtered, and dried to obtain the title compound (2.38 kg, yield 80.0%) as a yellow solid. 1 H NMR (400.13MHz, CDCl3):7.35-7.29(m,5H),3.58(s,2H),2.96-2.93(m,2H),2.71(s,2H),2.42-2.36(m,2H),2.07-2.04(m,2H),1.82-1.79(m,2H).

[0302] Step 3: Benzyl-4-(carboxymethyl)piperidine-4-carboxylic acid

[0303] [ka]

[0304] 1-benzyl-4-(cyanomethyl)piperidine-4-carbonitrile (576 g, 2.41 mol) was added to a solution of KOH (540 g, 9.63 mol) in H2O (1700 mL). The reaction mixture was refluxed at 95°C to 100°C for 24 hours. Five reaction products of the same scale were set up simultaneously. The mixture was cooled to 20°C to 25°C, all five reaction products were combined, and the pH of the reaction mixture was adjusted to 5-6 with HCl (12.0 M, 3.00 L) at 20°C to 25°C. The mixture was filtered to obtain a filter cake, washed with H2O (6.00 L), and the cake was ground over MeCN (4.50 L) for 30 minutes at 25°C and filtered. The product was dried in a high-pressure oven for 15 hours to obtain the title product (2.04 kg, yield 61.1%) as a white solid. MS m / z 188.1 (M+H); 1 H NMR (400.13MHz, DMSO-d6): 7.39-7.31 (m, 5H), 3.72 (s, 2H), 2.68-2.55 (m, 4H), 2.44 (s, 2H), 2.03-1.99 (m, 2H), 1.62-1.56 (m, 2H).

[0305] Step 4: 8-benzyl-2-oxa-8-azaspiro[4.5]decane-1,3-dione

[0306] [ka]

[0307] In a 3 L flask, 1-benzyl-4-(carboxymethyl)piperidine-4-carboxylic acid (20 g, 72.12 mmol) was suspended in dichloromethane (400 mL) in N2 at 0°C, and trifluoroacetic anhydride (300 mL, 2134 mmol) was added dropwise to the suspension at 0°C. After the addition, the reaction mixture was heated to 45°C over 16 hours. The reaction mixture was concentrated under high vacuum to remove the solvent, the residue was dissolved in DCM (300 mL), and the solution was slowly added to 10% K2HPO4 aqueous solution (500 mL), maintaining the mixture at pH 8. The aqueous layer was extracted with DCM (300 mL x 3), the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under high vacuum to obtain the title product (10.5 g, 40.5 mmol, 100% by mass, yield 56.1%). 1 H NMR (400MHz, DMSO-d6)7.34-7.24(m,5H),3.46(s,2H),2.94(s,2H),2.74-2.70(m,2H),2.06-2.01(m,2H),1.83-1.81(m,4H).

[0308] 2-Fluoro-N-phenylaniline

[0309] [ka]

[0310] Under nitrogen, tris(dibenzylideneacetone)dipalladium(0) (162 mg, 0.17 mmol) and 1,1'-bis(diphenylphosphin)ferrocene (196 mg, 0.34 mmol) were added under nitrogen to a solution of 1-bromo-2-fluorobenzene (3.0 g, 16.97 mmol), aniline (1.76 g, 18.3 mmol), and sodium tert-butoxide (5.1 g, 50.9 mmol) in toluene (30.0 mL). The mixture was stirred at 100°C. After stirring overnight at 100°C, the reaction was cooled to room temperature, filtered, and concentrated to obtain the residue. Water (200 mL) was added to the residue, and it was extracted with EA (200 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by elution with 0-7% ethyl acetate / petroleum ether using silica gel flash chromatography to obtain the title compound (2.83 g, 95% by mass, yield 84.6%). 1 H NMR (400.14MHz, DMSO-d6):7.93(s,1H),7.31-7.22(m,4H),7.10-7.05(m,1H),7.00(d,J=8.3Hz,2H),6.94-6.91(m,1H),6.85-6.81(m,1H).

[0311] The compounds listed in the table below were prepared according to the procedure described above.

[0312] [Table 3]

[0313] Step 5: Benzyl-4-[2-(N-(2-fluorophenyl)anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid

[0314] [ka]

[0315] In a microwave tube, a mixture of 2-fluoro-N-phenylaniline (1.3 g, 6.7 mmol), 8-benzyl-2-oxa-8-azaspiro[4.5]decane-1,3-dione (1.0 g, 3.9 mmol), and trifluoroacetic acid (2.0 mL, 26.19 mmol) was dissolved in dichloromethane (5.0 mL), and the reaction mixture was heated in a microwave at 80°C. After 3 hours, the reaction mixture was cooled to room temperature and concentrated to obtain a crude residue. The residue was subjected to reverse-phase preparative HPLC: Xtimate C18 column (150 * 40mm * The compound was purified by elution at a rate of 30% to 70% B over several minutes using solvents A (water: NH4OH + NH4HCO3) and B (ACN) at a rate of 30% B to 70% B. Appropriate fractions were combined and freeze-dried to obtain the title compound (700 mg, yield 40.4%), MS m / z 447.1 (M+H).

[0316] 1-benzyl-4-[2-(2-fluoro-N-(2-fluorophenyl)anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid was prepared according to the procedure described above.

[0317] [Table 4]

[0318] Benzyl-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid; Formic acid

[0319] [ka]

[0320] To a solution of diphenylamine (6.65 g, 38.9 mmol) in tetrahydrofuran (30.0 mL), N-butyllithium (16 mL, 40 mmol, 2.5 mol / L) in hexane was added dropwise under N2 at -78°C, and the mixture was stirred for 15 minutes. Then, 8-benzyl-2-oxa-8-azaspiro[4.5]decane-1,3-dione (6.01 g, 19.7 mmol, 85% by mass) in tetrahydrofuran (30.0 mL) was added dropwise at -78°C. The reaction mixture was stirred at -78°C for 2 hours, then warmed to room temperature and stirred overnight. The reaction mixture was quenched by adding saturated NH4Cl (20 mL) and concentrated under high pressure to obtain a brown residue. Water (50 mL) and formic acid (10 mL) were added to the residue. The insoluble substance was collected by filtration, washed with ethyl acetate (60 mL x 4), and the solid was dried under high pressure to obtain the title compound (5.66 g, 97% by mass, yield 58.7%). MS m / z 429.0 (M+H-HCO2H).

[0321] Step 6: 4-[2-(N-(2-fluorophenyl)anilino)-2-oxo-ethyl]piperidine-4-carboxylate hydrochloride

[0322] [ka]

[0323] To a solution of 1-benzyl-4-[2-(N-(2-fluorophenyl)anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid (700 mg, 1.56 mmol) in tetrahydrofuran (20.0 mL), aqueous hydrochloric acid (1.0 mL, 36.5% by mass) was added all at once, followed by the addition of Pd / C (420 mg, 0.3962 mmol, 10% by mass) at room temperature. The mixture was stirred at 60 °C under H2 (50 psi) for 16 hours. The reaction mixture was filtered through a Celite pad and washed with MeOH and dichloromethane (1:1, 40 mL x 5). The filtrate was concentrated to obtain the crude title product (630 mg, 87.7% by mass, yield 90.3%). MS m / z 357.0 (M+H-HCl).

[0324] The compounds listed in the table below were prepared according to the procedure described above.

[0325] [Table 5]

[0326] 4-[2-(2-fluoro-N-(2-fluorophenyl)anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid; hydrochloride and 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid; hydrochloride were prepared according to the above procedure.

[0327] Indoline-1-carbonyl chloride

[0328] [ka]

[0329] A solution of indoline (10.01 g, 83.16 mmol) and triethylamine (17.5 mL, 125 mmol) in dichloromethane (50 mL) was added dropwise to a solution of triphosgene (12.98 g, 43.30 mmol) in dichloromethane (100 mL) at 0°C. The reaction mixture was slowly warmed to room temperature and stirred for 2 hours. The reaction mixture was quenched by carefully adding H2O (100 mL) and then extracted with dichloromethane (80 mL × 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under high pressure to obtain the title product (19.42 g, 75% by mass, yield 96.43%) as a brown solid. The crude product was used directly in the next step without purification. MS m / z 182.1 (M+H).

[0330] The compounds listed in the table below were prepared according to the procedure described above.

[0331] [Table 6-1]

[0332] [Table 6-2]

[0333] 2,2-difluoro-2-(2-fluorophenyl)acetyl chloride

[0334] [ka]

[0335] 2,2-Difluoro-2-(2-fluorophenyl)ethyl acetate

[0336] [ka]

[0337] To a stirred DMSO (20 mL) solution of bromodifluoroethyl acetate (5.00 g, 24.1 mmol), 1-fluoro-2-iodobenzene (4.5 g, 19 mmol) and copper (5.1 g, 79 mmol) were added, and the resulting solution was heated overnight at 50°C under N2. After completion, the reaction mixture was cooled to room temperature, and 60 mL of water was added to the mixture. The aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was then washed with brine (60 mL x 4), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluted with 0% to 10% ethyl acetate in petroleum ether, to obtain the title compound (3.31 g, 95% by mass, yield 59.7%) as a pale yellow oil. 1 H NMR(400.13MHz,CDCl3):7.66(dt,J=1.5,7.6Hz,1H),7.55-7.47(m,1H),7.27(t,J=7.6H z,1H),7.15(ddd,J=0.9,9.0,10.0Hz,1H),4.37(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).

[0338] 2,2-difluoro-2-(2-fluorophenyl)acetic acid

[0339] [ka]

[0340] To a stirred solution of 2,2-difluoro-2-(2-fluorophenyl)ethyl acetate (1.030 g, 4.485 mmol) in tetrahydrofuran (8.0 mL, 97 mmol) and water (0.8 mL), lithium hydroxide (385 mg, 8.708 mmol) was added, and the resulting solution was stirred under N2 at 60°C for 3 hours. After completion, the reaction mixture was cooled to room temperature, 1N HCl (8.0 mL) was added to adjust the pH to less than 2, water (30 mL) was added, and the residue was extracted with ethyl acetate (30 mL x 3). The combined organic phase was then washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the title compound (862 mg, 96% by mass, yield 97.05%) as a purple oil. 1 H NMR (400MHz, CDCl3): 11.36(d,J=4.0Hz,1H),7.72-7.64(m,1H),7.53(q,J=6.8Hz,1H),7.32-7.25(m,1H),7.21-7.12(m,1H).

[0341] 2,2-difluoro-2-(2-fluorophenyl)acetyl chloride

[0342] [ka]

[0343] To a solution of 2,2-difluoro-2-(2-fluorophenyl)acetic acid (100 mg, 0.5049 mmol, 96% by mass) in dichloromethane (1.0 mL), oxalyl chloride (90 μL, 1.017 mmol), followed by one drop of DMF, was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under high pressure to obtain the crude compound (92 mg, 90% by mass, yield 78.62%) as a pale yellow solid. The crude substance was used directly in the next step without purification.

[0344] 4-[2-(N-(2-fluorophenyl)anilino)-2-oxo-ethyl]-1-(indoline-1-carbonyl)piperidine-4-carboxylic acid (Example No. 56)

[0345] [ka]

[0346] To a solution of 4-[2-(N-(2-fluorophenyl)anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid hydrochloride (100.0 mg, 0.223 mmol, 87.7% by mass) in tetrahydrofuran (1.0 ml), N,O-bis(trimethylcisyl)acetamide (0.22 ml, 0.88 mmol) and N,N-diisopropylethylamine (0.12 ml, 0.69 mmol) were added. The mixture was stirred at room temperature for 1 hour, then indoline-1-carbonyl chloride (122.0 mg, 0.470 mmol, 75% by mass) was added to the reaction mixture, and it was then stirred at room temperature overnight. This reaction product was combined with the same reaction product from a smaller scale, 4-[2-(N-(2-fluorophenyl)anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid hydrochloride (30.0 mg, 0.223 mmol, 87.7% by mass). The reaction mixture was concentrated to obtain the residue, which was then subjected to reverse-phase preparative HPLC (Xtimate C18 100). * 30mm * The sample (10 μm) was purified by eluting from mobile phase A: water-formic acid and mobile phase B: ACN over 10 minutes to 50-70% B, and then to 100% B. Appropriate fractions were combined and freeze-dried to obtain the title product (42.6 mg, yield 38.0%). MS m / z 502.4(M+H); 1H NMR(400.21MHz,DMSO-d6):12.40(s,1H),7.53-7.46(m,10H),7.11(t,J=7.38Hz,1H),6.94(d,J=8.0Hz,1H),6.86(t,J=7.50 Hz,1H),3.79(t,J=8.3Hz,2H),3.35-3.17(m,4H),2.97(t,J=8.2Hz,2H),2.08(s,2H),2.01-1.97(m,2H),1.58-1.51(m,2H).

[0347] Examples 1, 2, 13, 16, 19, 26, 33, 38, 40, 46, 55, 57, 58, 59, 61, 87, 97, 98, 100, 101, 102, 107, and 108 were prepared according to the procedure described above.

[0348] [Table 7-1]

[0349] [Table 7-2]

[0350] [Table 7-3]

[0351] [Table 7-4]

[0352] [Table 7-5]

[0353] [Table 7-6]

[0354] 1-(5-bromo-4-pentyl-1,2,4-triazol-3-yl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (Example 4)

[0355] [ka]

[0356] Step 1: Methanol (50 mL) was added at 20°C to a solution of diethoxymethoxyethane (5 g, 33.7 mmol, 100% by mass) and formohydrazide (1.4 g, 23 mmol, 98% by mass). The mixture was stirred at 60°C for 3 hours. After cooling to 40°C, pentane-1-amine (2 g, 22.7 mmol) was added to the mixture and stirred overnight at 60°C. The mixture was cooled to room temperature and concentrated under reduced pressure. 20 mL of water was added to the reaction mixture, and then extracted with dichloromethane (20 mL x 4). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under high reduced pressure. The residue was purified by flash silica gel chromatography by elution with 0-3% methanol / dichloromethane to obtain 4-pentyl-1,2,4-triazole (2.55 g, 90% by mass, yield 72.6%) as a yellow oil. 1 H NMR(400.13MHz,DMSO-d6):8.52(s,2H),4.01(t,J=7.2Hz,2H),1.71(td,J=7 .4,14.8Hz,2H),1.34-1.22(m,2H),1.22-1.09(m,2H),0.84(t,J=7.3Hz,3H)

[0357] Step 2: N-bromosuccinimide (7 g, 38.5 mmol) was added at 20°C to a solution of 4-pentyl-1,2,4-triazole (2.5 g, 16.0 mmol, 90% by mass) in DMF (10 mL). The reaction mixture was stirred at 60°C for 3 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with brine (30 mL), dried on anhydrous Na2SO4, and concentrated under high vacuum. The residue was purified by flash silica gel chromatography, eluted with 0% to 33% ethyl acetate in petroleum ether, to obtain 3,5-dibromo-4-pentyl-4H-1,2,4-triazole (3.1 g, 95% by mass, yield 61%) as a colorless oil. 1 H NMR(400MHz,DMSO-d6):3.98(t,J=7.4Hz,2H),1.67(m,J=7.3Hz,2H),1.38-1.20(m,4H),0.87(t,J=7.1Hz,3H)

[0358] Step 3: To a solution of 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid hydrochloride (202 mg, 0.512 mmol, 95% by mass), 3,5-dibromo-4-pentyl-1,2,4-triazole (170 mg, 0.544 mmol), and cesium carbonate (470 mg, 1.44 mmol) in 2-methyl-2-butanol (4.0 mL), [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (43 mg, 0.05 mmol) was added. Nitrogen was passed through the flask. The resulting mixture was stirred overnight under nitrogen at 120°C. Once complete, the reaction mixture was cooled to room temperature, concentrated under high vacuum, pH adjusted to 7 with 1N HCl, and the solid was filtered off. The filtrate was concentrated under high vacuum. The residue was subjected to preparative HPLC (column: Xtimate C18 100). * 30mm *The solution was purified by eluting at 10 μm using mobile phase A: water-formic acid and mobile phase B: ACN over 10 minutes to 50-80% B, and then to 100% B. Appropriate fractions were combined and freeze-dried to obtain the title product (75.6 mg, yield 25.0%). MS m / z 554.2, 556.2 (M+H); 1 H NMR(400.13MHz,DMSO-d6):7.60-7.02(m,10H),3.75(t,J=7.4Hz,2H),3.03(d,J=8.9Hz,1H),2.98(d,J=5.5Hz,2H ),2.55(s,2H),2.14-2.00(m,2H),1.71-1.54(m,4H),1.34-1.23(m,2H),1.21-1.12(m,2H),0.83(t,J=7.3Hz,3H).

[0359] 1-(5-cyclopropylpyrimidine-4-yl)-4-(2-(diphenylamino)-2-oxoethyl)piperidine-4-carboxylic acid (Example No. 5)

[0360] [ka]

[0361] Step 1: Cyclopropylboronic acid (345 mg, 4.016 mmol), cesium carbonate (2.603 g, 7.988 mmol), 4-chloro-5-iodopyrimidine (1.011 g, 4.037 mmol), 1,4-dioxane (24 mL), and water (6.0 mL) were added to a flask under nitrogen. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (312 mg, 0.405 mmol) was added to the suspension. The reaction mixture was stirred under N2 at 95°C for 6 hours. After completion, the reaction mixture was cooled to room temperature, poured into water (50 mL), and extracted with DCM (40 mL x 3). The combined organic phase was then washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under high vacuum. The residue was purified by conventional silica gel chromatography (PE:SiO = 1:0-3:1) to 4-chloro-5-cyclopropylpyrimidine (284 mg, 91% by mass, yield 41.4%) as a colorless oil. MS m / z 154.9 (M+H);

[0362] Step 2: To a solution of 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid hydrochloride (151 mg, 0.362 mmol, 90% by mass) in N,N-dimethylacetamide (1.5 mL), 4-chloro-5-cyclopropylpyrimidine (105 mg, 0.618 mmol, 91% by mass) and potassium carbonate (245 mg, 1.77 mmol) were added. The mixture was stirred under nitrogen at 110°C for 5 hours. After completion, the reaction mixture was cooled to room temperature and combined with the pilot batch, and the pH was adjusted to 5 by adding 1N HCl. The mixture was then extracted with ethyl acetate (40 mL x 3). The combined organic phase was then dried over anhydrous Na2SO4 and concentrated under high vacuum. The residue was analyzed by preparative HPLC, column: Xtimate C18 100. * 30mm *The solution was purified by eluting at 10 μm, using mobile phase A: water-formic acid and mobile phase B: ACN, at 25-55% B over 14 minutes, and then up to 100% B. The appropriate fractions were combined and lyophilized to obtain 1-(5-cyclopropylpyrimidine-4-yl)-4-(2-(diphenylamino)-2-oxoethyl)piperidine-4-carboxylic acid (16.4 mg, yield 5.56%) as a yellow solid. MS m / z 457.4 (M+H); 1 H NMR(400MHz,DMSO-d6):12.48(br,1H),8.47(s,1H),8.04(s,1H),7.52-7.16(m,10H),3.88(d,J=14.4Hz,2H),3.59-3.50(m,1H) ),2.56(s,2H),2.47(s,1H),2.08(d,J=13.5Hz,2H),1.88-1.79(m,1H),1.67-1.57(m,2H),0.99-0.89(m,2H),0.74-0.67(m,2H)

[0363] 1-(3-chloropyrazine-2-yl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (Example No. 109)

[0364] [ka]

[0365] 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid hydrochloride (300 mg, 0.7202 mmol, 90% by mass) was dissolved in N,N-dimethylacetamide (4.0 mL), to which 2,3-dichloropyrazine (361 mg, 2.40 mmol) and potassium carbonate (332 mg, 2.40 mmol) were added. The mixture was stirred under N2 at 110°C for 5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to preparative HPLC (Instrument PREP-WI, column C18-6 100). * 30mm *The solution was purified using a 5 μm mobile phase (A: water-0.225% formic acid, B: ACN, elution of 45-75% of B over 15 minutes, followed by elution up to 100% B, at a flow rate of 25 mL / min). Appropriate fractions were combined and lyophilized to obtain the title product (45 mg, 99.3% by mass, yield 13.8%) as a white solid. MS m / z 451.0 (M+H); 1 H NMR(400.15MHz,DMSO-d6):12.37(br,1H),8.22(d,J=2.5Hz,1H),7.95(d,J=2.5Hz,1H),7 .68-7.06(m,10H),3.30-3.22(m,4H),2.56(s,2H),2.18-2.03(m,2H),1.73-1.58(m,2H).

[0366] 1-(1-cyclopropylimidazole-2-yl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid, formic acid (Example No. 110)

[0367] [ka]

[0368] Step 1: To a solution of 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid hydrochloride (400 mg, 1.1 mmol) in tetrahydrofuran (5.0 mL), N,O-bis(trimethylsilyl)acetamide (1.3 mL, 5.2 mmol) was added. The mixture was stirred at room temperature for 0.5 hours, then isothiocyanatocyclopropane (222 mg, 2.2 mmol) was added. The mixture was stirred at 50°C for 2 hours. After completion, the reaction product was concentrated. The residue was subjected to preparative HPLC (column: Phenomenex C18 75) * 30mm *The solution was purified by elution at 10-80% B and then up to 100% B using a 3 μm mobile phase with mobile phase A: water (10 mM NH4HCO3) and mobile phase B: ACN. Appropriate fractions were combined and lyophilized to obtain 1-(cyclopropyl carbamoti oil)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (250 mg, 90% by mass, yield 49.7%) as a white solid. MS m / z 438.1 (M+H).

[0369] Step 2: Iodomethane (60 μL, 0.94 mmol) was added to a solution of 1-(cyclopropyl carbamoti oil)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (250 mg, 0.54 mmol) in acetone (4.0 mL). The mixture was stirred under N2 at room temperature for 4 hours. The reaction product was concentrated to obtain 1-[(Z)-N-cyclopropyl-C-methylsulfanyl-carbonimidoyl]-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid; hydroiodide (300 mg, 90% by mass, yield 85.8%) as a white solid. The crude product was used directly in the next step.

[0370] Step 3: Pyridine (0.08 mL, 1 mmol) was added to a solution of 1-[(Z)-N-cyclopropyl-C-methylsulfanyl-carbonimidoyl]-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid, hydroiodide (300 mg, 0.46 mmol, 90% by mass) and 2,2-dimethoxyethane-1-amine (136 mg, 1.27 mmol) in acetonitrile (4 mL). The reaction mixture was stirred overnight at room temperature. 4.0 N HCl (4.0 mL) was added, and the mixture was stirred at room temperature for 16 hours. Once complete, the reaction mixture was neutralized with saturated Na2CO3 to pH 6, extracted with ethyl acetate (10 mL x 2), the organic layer was further washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to preparative HPLC (column: Xtimate C18 100). * 30mm *The solution was purified by elution at 10 μm, mobile phase A: water-0.225% formic acid, mobile phase B: ACN (elution at 15-45% B over 4 minutes, then up to 100% B). Appropriate fractions were combined and lyophilized to obtain the product 1-(1-cyclopropylimidazole-2-yl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid, formic acid (37.0 mg, 97.5% by mass, yield 15.8%). MS m / z 445.1 (M+H-HCO2H); 1 H NMR(400.13MHz,DMSO-d6):8.24(s,1H),7.52-7.17(m,10H),6.73(d,J=1.4Hz,1H),6.47(d,J=1.3Hz,1H),3.23- 3.17(m,1H),3.10-2.94(m,4H),2.55(s,2H),2.10-2.00(m,2H),1.63(dt,J=3.9,8.6Hz,2H),0.96-0.81(m,4H).

[0371] 4-[2-oxo-2-(N-phenylanilino)ethyl]-1-([1,2,4]triazolo[4,3-a]pyridine-3-yl)piperidine-4-carboxylic acid (Example No. 111)

[0372] [ka]

[0373] A mixture of 3-chloro-[1,2,4]triazolo[4,3-a]pyridine (96 mg, 0.61 mmol), 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid hydrochloride (85 mg, 0.20 mmol, 90% by mass) in 2-methyl-2-butanol (1.0 mL) was mixed with tBuXPhos Pd G3 (30 mg, 0.036 mmol) and cesium carbonate (200 mg, 0.61 mmol). The mixture was stirred overnight at 120°C under N2. After completion, the mixture was cooled to room temperature, and the crude product was subjected to preparative HPLC (Instrument NCX, column: Phenomenex Gemini-NX C18 100). * 30mm *The solution was purified using a 3 μm mobile phase (A: water-0.225% formic acid, B: ACN, elution to 10-70% B over 15 minutes, followed by elution to 100% B, flow rate: 25 mL / min). Appropriate fractions were combined and lyophilized to obtain the title product (44.2 mg, 99.6% by mass, yield 47.4%). MS m / z 456.4 (M+H); 1 H NMR(400MHz,DMSO-d6):8.10(d,J=7.0Hz,1H),7.59(d,J=9.3Hz,1H),7.55-7.08(m,11H),6 .85(t,J=6.7Hz,1H),3.19-3.09(m,4H),2.59(s,2H),2.23-2.08(m,2H),1.83-1.65(m,2H).

[0374] 1-(3-cyclopropyl-2-pyridyl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (Example No. 112)

[0375] [ka]

[0376] Step 1: Potassium carbonate (220 mg, 1.59 mmol) was added to a solution of tert-butanol (1.0 mL) containing 2-fluoro-3-iodopyridine (65 mg, 0.2915 mmol) and 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid hydrochloride (100 mg, 0.26 mmol). The mixture was stirred under N2 at 80°C for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was subjected to preparative HPLC (column: Phenomenex Gemini C18 250). * 50mm *The solution was purified by elution at 10 μm, mobile phase A: water-0.05% ammonium hydroxide (v / v), mobile phase B: ACN, at elution levels of 35-55%, 35-55%, and then 100% (elution up to 100% B) over 22 minutes. Appropriate fractions were combined and lyophilized to obtain 1-(3-iodo-2-pyridyl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (20.3 mg, 94% by mass, yield 13.6%) as a white solid.

[0377] Step 2: To a solution of 1-(3-iodo-2-pyridyl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (10.3 mg, 0.0179 mmol, 94% by mass), potassium cyclopropyltrifluoroborate (12 mg, 0.0803 mmol), and cesium carbonate (20 mg, 0.0614 mmol) in toluene (1.0 mL) and water (0.1 mL), tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.00856 mmol) and RuPhos (4 mg, 0.00814 mmol) were added. The mixture was stirred overnight at 100°C under N2. The mixture was cooled to room temperature and concentrated, combined with the pilot trial. The residue was subjected to preparative HPLC (column: Xtimate C18 100). * 30mm * The solution was purified by elution at 25-55% B and then up to 100% B using mobile phase A: water-0.225% formic acid and mobile phase B: CH3CN at 10 μm. Appropriate fractions were combined and freeze-dried to obtain the title product (3.5 mg, 95% by mass, 41% yield). MS m / z 456.4(M+H); 1 H NMR(400.13MHz,DMSO-d6):7.99(dd,J=1.6,4.8Hz,1H),7.49-7.18(m,10H),7.12(dd,J=1.5,7.6Hz,1H),6.85(dd,J=4.8,7.5Hz,1 H),3.15-3.09(m,4H),2.56(s,2H),2.15-2.03(m,2H),1.95-1.91(m,1H),1.73-1.56(m,2H),1.03-0.93(m,2H),0.72-0.62(m,2H).

[0378] Examples 35, 35A, 35B, 52, 60, 76, 77, 78, 80, 80A, 80B, 81, 82A, 82B, 83, 83A, 83B, 84, 85, 94, 99, 103, 104, 105, and 106 were prepared according to Scheme 2.

[0379] [ka]

[0380] Step 1: O1-tert-butyl O4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate

[0381] [ka]

[0382] To a solution of 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (15 g, 60.41 mmol) in tetrahydrofuran (150.0 ml), a solution of diisopropylaminolithium in THF / hexane (45.0 ml, 90.0 mmol, 2.0 mol / L) was added dropwise under N2 at -65°C. After stirring the mixture for 1 hour, bromoacetonitrile (6.4 ml, 91 mmol) was added dropwise at -65°C. The reaction mixture was then slowly warmed to room temperature and stirred overnight under N2. The reaction mixture was quenched by adding saturated NH4Cl (200.0 mL) and extracted with siRNA (200.0 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under high vacuum to obtain the residue. The residue was purified by elution with 0-27% ethyl acetate / petroleum ether using silica gel flash chromatography to obtain the title compound (8.2 g, 95% by mass, yield 45.9%). 1 H NMR(400.21MHz,DMSO-d6):3.77(s,3H),3.67(dt,J=14.1,4.6Hz,2H),2.96(s,2 H),2.57-2.56(m,1H),2.05-1.99(m,2H),1.61-1.52(m,2H),1.46-1.45(m,10H).

[0383] Step 2: 4-(carboxymethyl)piperidine-4-carboxylic acid; hydrochloride

[0384] [ka]

[0385] O1-tert-butyl O4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (8.25 g, 27.75 mmol, 95% by mass) was treated with hydrochloric acid (60 mL, 36%), and the reaction mixture was heated to 100°C and stirred overnight. The reaction mixture was cooled to room temperature and concentrated under high pressure to obtain the crude title compound (7.48 g, 80% by mass, yield 96.4%), which was used directly in the next step without purification. 1 H NMR (400.13MHz, DMSO-d6): 9.31 (br, 1H), 9.18 (br, 1H), 3.26-3.17 (m, 2H), 3.02-2.91 (m, 2H), 2.63 (s, 2H), 2.20-2.14 (m, 2H), 1.88-1.81 (m, 2H).

[0386] Step 3: 4-(carboxymethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylic acid

[0387] [ka]

[0388] To a solution of 4-(carboxymethyl)piperidine-4-carboxylic acid hydrochloride (9.6 g, 34 mmol, 80% by mass) in tetrahydrofuran (100.0 mL), N,O-bis(trimethylsilyl)acetamide (35 mL, 141 mmol, 99% by mass) was added. After stirring at room temperature for 30 minutes, the reaction mixture was cooled on an ice bath, and N,N-diisopropylethylamine (12 mL, 68.7 mmol) was added, followed by indoline-1-carbonyl chloride (12.01 g, 49.60 mmol, 75% by mass). The reaction mixture was warmed to room temperature and stirred overnight. Water was added to the reaction mixture (150 mL), the pH was adjusted to 4 with 1.0 saturated NH4Cl aqueous solution, and the mixture was extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under high pressure to obtain the residue. The residue was purified by silica gel flash chromatography, eluting from DCM to 10% MeOH / DCM, to obtain the title compound (8.4 g, 90% by mass, 66% yield). MS m / z 313.1 (M+H).

[0389] The compounds listed in the table below were prepared as described above.

[0390] [Table 8]

[0391] Step 4: 1-(indoline-1-carbonyl)-4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate methyl

[0392] [ka]

[0393] To a solution of 4-(carboxymethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylic acid (3.2 g, 8.7 mmol, 90% by mass) cooled on ice in methanol (6.0 mL) and acetonitrile (60.0 mL), (diazomethyl)trimethylsilane (2.0 mol / L) in hexane (17.0 mL, 34 mmol, 2.0 mol / L) was added dropwise, followed by the dropwise addition of N,N-diisopropylethylamine (3.0 mL, 17.17 mmol). The mixture was warmed to room temperature and stirred overnight. The mixture was quenched by adding water (80 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel flash chromatography, eluting with 0-56% ethyl acetate / petroleum ether to obtain the title compound (2.88 g, 90% by mass, 83% yield). MS m / z 361.0 (M+H).

[0394] The compounds listed in the table below were prepared as described above.

[0395] [Table 9]

[0396] 1-[(2-fluoro-4-isopropylphenyl)methyl]-4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate ethyl

[0397] [ka]

[0398] A mixture of methyl 4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate (1.0 g, 3.3 mmol, 90% by mass), trimethylamine (1.0 mL, 7.0 mmol), and 2-fluoro-4-isopropyl-benzaldehyde (700 mg, 4.00 mmol) in 1,2-dichloroethane (60.0 mL) was mixed with titanium(IV) isopropoxide (4.0 mL, 13 mmol). The mixture was stirred at 80°C for 2 hours. After the reaction mixture cooled to room temperature, sodium triacetoxyborohydride (2.1 g, 9.6 mmol) was added. The mixture was stirred at room temperature for 1 hour. Once complete, the mixture was quenched with water (5 mL), extracted with siRNA (10 ml x 3), the combined organic layer was dried over Na2SO4, filtered, concentrated, and the residue was collected. The residue was purified by preparative HPLC (YMC-Triart Prep C 18 250×50mm×10um, mobile phase A: water-0.225% formic acid, mobile phase B: ACN, elution to 10-50% B over 20 minutes, then to 100% B, flow rate: 110 mL / min). The eluent was concentrated, and the residue aqueous solution was basicized to a pH greater than 7 with NaHCO3. The mixture was extracted with DCM (30 mL × 3). The combined phases were dried over Na2SO4, filtered, and evaporated under high pressure to obtain the title compound (760 mg, 90% by mass, yield 57%). MS m / z 366.2(M+H);

[0399] Step 5: 2-[1-(indoline-1-carbonyl)-4-methoxycarbonyl-4-piperidyl]acetic acid

[0400] [ka]

[0401] A mixture of methyl 1-(indoline-1-carbonyl)-4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate (2.88 g, 7.19 mmol, 90% by mass) in methanol (8.0 mL), water (8.0 mL), and tetrahydrofuran (8.0 mL) was mixed with lithium hydroxide (0.36 g, 14.72 mmol) in one addition at room temperature, and the mixture was stirred overnight at room temperature. The reaction was monitored by LC-MS, and an additional lithium hydroxide (0.202 g, 8.27 mmol) was added, and the reaction was stirred overnight at room temperature. The reaction mixture was adjusted to pH 4 with 1.0 N HCl and extracted with ethyl acetate (18 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under high pressure to obtain the residue. The residue was purified by elution with 0-6% MeOH / DCM using silica gel flushing to obtain the title compound (1.52 g, 95% by mass, 58.0% yield). MS m / z 347 (M+H).

[0402] The compounds listed in the table below were prepared as described above.

[0403] [Table 10]

[0404] Step 6: rac-3-anilinocyclohexanone

[0405] [ka]

[0406] To a mixture of aniline (20.0 g, 208.3 mmol) in 2-cyclohexen-1-one (31.0 ml, 310 mmol), 4-dimethylaminopyridine (7.8 g, 62 mmol, 97% by mass) was added at room temperature. The mixture was stirred at room temperature for 3 days to obtain a red solution. The reaction mixture was purified by elution with 0-15% EA / petroleum by silica gel flash chromatography to obtain the title compound (31.7 g, yield 68.3%). 1A purity of 85% was obtained by 1H NMR. 1 H NMR(400.14MHz,CDCl3):7.15-7.11(m,2H),6.70(t,J=7.3Hz,1H),6.59(d,J=8.0Hz,2H),3.74-3.67( m,1H),2.79-2.74(m,1H),2.38-2.30(m,3H),2.19-2.12(m,1H),2.03-1.95(m,1H),1.72-1.65(m,2H).

[0407] [Table 11]

[0408] Step 7: 2,2,2-trifluoro-N-phenyl-N-[rac-3-oxocyclohexyl]acetamide

[0409] [ka]

[0410] To a solution of rac-3-anilinocyclohexanone (15.0 g, 67.3 mmol, 85% by mass) and triethylamine (19.0 ml, 134 mmol) in dichloromethane (150.0 ml), (2,2,2-trifluoroacetyl)2,2,2-trifluoroacetate (14.0 ml, 99.6 mmol) was added dropwise at 0°C. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to obtain the crude product (10.4 g, 90% by mass, yield 48.7%), which was used directly in the next step without further purification. 1 H NMR(400.21MHz,CDCl3):7.50-7.45(m,3H),7.25(d,J=6.3Hz,1H),7.15(d,J=6.8Hz,1H),4.84-4.76(m, 1H),2.67-2.62(m,1H),2.41-2.36(m,1H),2.27(t,J=13.3Hz,1H),2.18-2.07(m,3H),1.76-1.70(m,2H).

[0411] Step 8: 2,2,2-trifluoro-N-phenyl-N-[rac-3,3-difluorocyclohexyl]acetamide

[0412] [ka]

[0413] To a solution of 2,2,2-trifluoro-N-[(rac)-3-oxocyclohexyl]-N-phenyl-acetamide (10.4 g, 32.8 mmol, 90% by mass) in dichloromethane (100.0 ml), cooled on ice, diethylamino sulfur trifluoride (9.0 ml, 66.65 mmol) was added. The mixture was heated to room temperature, then stirred at room temperature for 2 hours. The reaction product was quenched by adding saturated NaHCO3 (100.0 ml), and the mixture was extracted with dichloromethane (150 ml x 2). The combined organic layers were washed with brine (100.0 ml), dried over Na2SO4, and concentrated under high vacuum to obtain the residue. The residue was purified by silica gel flash chromatography, eluted with 0-40% dichloromethane / petroleum ether, to obtain the title compound (6.5 g, 95% by mass, yield 61%). 1 H NMR(400.14MHz,CDCl3):7.41-7.35(m,3H),7.09(t,J=7.6Hz,2H),4.68-4.62(m,1H),2.30 -2.26(m,1H),2.02-1.96(m,2H),1.84-1.82(m,1H),1.62-1.52(m,3H),1.23-1.14(m,1H).

[0414] Step 9: N-[rac-3,3-difluorocyclohexyl]aniline

[0415] [ka]

[0416] Potassium carbonate (8.6 g, 61 mmol) was added dropwise to a solution of 2,2,2-trifluoro-n-phenyl-n-[rac-3,3-difluorocyclohexyl]acetamide (6.5 g, 20 mmol, 95% by mass) in methanol (100.0 ml) and water (10.0 ml) at room temperature. The reaction mixture was heated to 65 °C, and after 4 hours, the reaction mixture was cooled to room temperature and water was added (100.0 mL). The mixture was extracted with ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (20.0 ml), dried over Na₂SO₄, and concentrated under high vacuum to obtain the residue. The residue was purified by silica gel flash chromatography, eluted with 0-22% ethyl acetate / petroleum ether, to obtain the title compound (3.54 g, 90% by mass, yield 75%). MS m / z 212.2 (M+H). 1 H NMR (400.13MHz, CDCl3):7.14-7.09(m,2H),6.67(t,J=7.3Hz,1H),6.57(d,J=7.8Hz,2H),3. 60-3.53(m,1H),2.49-2.44(m,1H),2.03-1.95(m,2H),1.80-1.71(m,4H),1.28-1.15(m,1H).

[0417] The compounds listed in the table below were prepared as described above.

[0418] [Table 12]

[0419] N-cyclopentylaniline

[0420] [ka]

[0421] To a solution of cyclopentanone (3.05 g, 35.5 mmol) in dichloromethane (35 mL), aniline (3.35 g, 35.6 mmol) and sodium triacetoxyborohydride (9.4 g, 43.0 mmol) were added, and the mixture was stirred overnight at room temperature. Once complete, the reaction product was diluted with water (50 mL) and extracted with dichloromethane (30 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under high vacuum to obtain the residue. The residue was purified by flash silica gel chromatography, eluted with 0-8% ethyl acetate / petroleum ether, to obtain the title compound (5.1 g, 95% by mass, yield 85%). MS m / z = 162.0 (M + H).

[0422] N-phenyl-4-oxaspiro[2.5]octane-7-amine

[0423] [ka]

[0424] To a methanol (1.5 mL) solution of 4-oxaspiro[2.5]octan-7-one (116 mg, 0.83 mmol, 90% by mass) and aniline (83 mg, 0.87 mmol), acetic acid (0.03 mL, 0.5 mmol) and sodium borohydride cyanohydride (85 mg, 1.34 mmol) were added. The mixture was stirred overnight at room temperature. Once complete, the mixture was quenched with 1 N HCl (0.5 mL) and evaporated under high pressure. The residue was dissolved in  (10 mL × 2) and washed with brine (3 mL × 2). The organic layer was dried over Na₂SO₄, filtered, and evaporated under high pressure. The residue was purified by flash silica gel chromatography, eluted with 0-20% ethyl acetate in petroleum ether, to obtain the title compound (80 mg, 95% by mass, yield 45.17%). 1H NMR (400MHz, CDCl3):7.22-7.18(m,2H),6.79-6.76(m,1H),6.72-6.70(m,2H),3.92-3.88(m,1H),3.69-3.64(m,1H),3.62-3.59(m,1H) ,2.11-2.07(m,1H),1.92-1.87(m,1H),1.66-1.61(m,2H),0.89-0.87(m,1H),0.72-0.71(m,1H),0.52-0.51(m,1H),0.44-0.42(m,1H).

[0425] N-phenyltetrahydropyran-4-amine was prepared according to the procedure described above.

[0426] [Table 13]

[0427] Isolation of the isomer (2-fluoro-N-[3,3-difluorocyclohexyl]aniline)

[0428] [ka]

[0429] Dissolve N-[(racemic)-3,3-difluorocyclohexyl]-2-fluoroaniline (9.0 g) in the minimum amount of MeOH, and then pour the solution into SFC:DAICEL CHIRALPAK AD (250 mm). * (50 mm, 10 μm); Mobile phase A: CO2 B: 0.1% NH3H2O ​​Separation was performed by eluting with MEOH at a flow rate of 140 mL / min using 5% B.

[0430] The eluate from the first peak was collected and freeze-dried to obtain the title compound (2.99 g, yield 35%, ee: 98.5%). MS m / z 230.1 (M+H).

[0431] The eluate containing the primary second peak (80%) was collected and lyophilized. Then, SFC:DAICEL CHIRALCEL OD (250 mm) was used.* The compound was re-purified by (30 mm, 10 μm), mobile phase A: CO2, B: 0.1% NH3H2O ​​isopropanol, elution with 15% B, flow rate 60 mL / min) to obtain the title compound as a second enantiomer (1.2 g, yield 14%, ee: 99.9%). MS m / z 230.1 (M+H).

[0432] N-[(racemic)-2,2-difluorocyclopentyl]aniline

[0433] [ka]

[0434] Chlorobenzene (645 mg, 5.67 mmol), (racemic)-2,2-difluorocyclopentanamine hydrochloride (1.0 g, 6.28 mmol), BrettPhos Pd G3 (592 mg, 0.640 mmol), potassium tert-butoxide (1.456 g, 12.72 mmol), and 1,4-dioxane (18.0 mL) were added to a 50 mL flask, and the mixture was stirred under N2 at 60°C for 5 hours. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluted with 0-12% ethyl acetate in petroleum ether, to obtain the title compound (285 mg, 97% by mass, yield 22.3%). MS m / z 198.1 (M+H).

[0435] N-[(racemic)-3,3-difluorocyclopentyl]aniline

[0436] [ka]

[0437] To a solution of (racemic)-3-anilinocyclopentanone (1.015 g, 5.503 mmol, 95% by mass) in dichloromethane (10 mL), (diethylamino) sulfur trifluoride (1.9 mL, 14 mmol) was added at 0°C. The mixture was stirred overnight at room temperature. Once complete, the mixture was quenched with 1N NaHCO3 to a pH greater than 7, then water (50 mL) was added to the reaction mixture, and the residue was extracted with ethyl acetate (50 mL x 4). The combined organic phase was then washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by elution with 15% ethyl acetate in petroleum ether by conventional silica gel chromatography to obtain the title compound (256 mg, 90% by mass, yield 21.23%). MS m / z 198.2 (M+H).

[0438] Step 10: 4-[2-(N-[(rac)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(indoline-1-carbonyl)piperidine-4-carboxylate methyl

[0439] [ka]

[0440] To a solution of 2-[1-(indoline-1-carbonyl)-4-methoxycarbonyl-4-piperidyl]acetic acid (1.2 g, 3.3 mmol) and N-[rac-3,3-difluorocyclohexyl]aniline (770 mg, 3.2 mmol, 90% by mass) in pyridine (12.0 mL), phosphoryl chloride (460 μL, 4.90 mmol) was added under N2 at room temperature. The mixture was heated to 100 °C and heated for 5 hours. After heating, the reaction product was cooled to room temperature, 50 mL of water was carefully added to the reaction product, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (40 mL), dried over Na2SO4, and concentrated under high vacuum to obtain the residue. The residue was purified by silica gel flash chromatography and eluted with 0-43% ethyl acetate / petroleum ether to obtain the title compound (1.25 g, 98% by mass, yield 69%). MS m / z 540.4 (M+H).

[0441] The compounds listed in the table below were prepared as described above.

[0442] [Table 14-1]

[0443] [Table 14-2]

[0444] [Table 14-3]

[0445] [Table 14-4]

[0446] Step 11: Racemic mixture, 4-[2-(N-[-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(indoline-1-carbonyl)piperidine-4-carboxylic acid (Example No. 35)

[0447] [ka]

[0448] To a solution of 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(indoline-1-carbonyl)piperidine-4-carboxylate methyl (1.25 g, 2.27 mmol, 98% by mass) in 1,4-dioxane (10.0 mL), 1.0 M potassium hydroxide aqueous solution (4.5 mL, 4.5 mmol) was added at room temperature. The mixture was heated to 100 °C. After stirring for 5 hours, the reaction mixture was cooled to room temperature, 1.0 mL of formic acid was added, and the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was subjected to reverse-phase preparative HPLC (Xtimate C18 150).* 40mm * The compound was purified by eluting at 15% to 55% B over 10 minutes using a 10 μm (10 μm) mobile phase A: water (NH3H2O ​​+ NH4HCO3) and phase B: CH3CN. A suitable fraction was collected and lyophilized to obtain the title compound (0.7 g, 97% by mass, yield 60.0%). MS m / z 526.2 (M+H).

[0449] Examples 52, 60, 80, 81, 83, 94, 103, and 104 were prepared according to the procedure described above.

[0450] [Table 15-1]

[0451] [Table 15-2]

[0452] Isomer 2, 1-(6-fluoroindoline-1-carbonyl)-4-[2-(2-fluoro-N-[rel-(chiral)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid (Example No. 76)

[0453] [ka]

[0454] A mixture of the isomer 2-1-(6-fluoroindoline-1-carbonyl)-4-[2-(2-fluoro-N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl (109 mg, 0.1704 mmol, 90% by mass) in 2-propanol (3.0 mL, 39 mmol, 100% by mass) was mixed with sodium hydroxide (190 μL, 0.95 mmol, 5 mol / L in H2O), and the mixture was stirred overnight at 50°C. After completion, the mixture was cooled to room temperature and 3 mL of water was added. The mixture was then adjusted to pH approximately 4 with 1N HCl and extracted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under high pressure. The residue was subjected to preparative HPLC (column: Xtimate C18 100). * 30mm * The mixture was purified by eluting 65% to 95% and then 100% B over 2 minutes using mobile phase A: water-0.225% formic acid and mobile phase B: ACN at 10 μm. The product (34 mg, 100% by mass, yield 35.5%) was obtained as a yellow solid. MS m / z 562.5 (M+H). 1 H NMR(400MHz,DMSO-d6)12.27(br,1H),7.58-7.51(m,1H),7.48-7.39(m,2H),7.39-7.32(m,1H) ,7.15(dd,J=6.1,7.8Hz,1H),6.71(dd,J=2.2,10.6Hz,1H),6.67-6.60(m,1H),4.61(dt,J=3.1, 12.3Hz,1H),3.83(t,J=8.3Hz,2H),3.29-3.14(m,4H),2.93(t,J=8.1Hz,2H),2.35-2.24(m,1H) ),2.23-2.17(m,2H),1.91(s,3H),1.83-1.49(m,4H),1.43(d,J=8.8Hz,3H),1.18-0.91(m,1H).

[0455] Examples 77, 78, 82b, 82a, 84, 85, 99, 105, and 106 were prepared according to the procedure described above.

[0456] [Table 16-1]

[0457] [Table 16-2]

[0458] [Table 16-3]

[0459] Step 12: Isolation of isomers (Examples 35A and 35B)

[0460] [ka]

[0461] Dissolve the racemic mixture 4-[2-(N-[-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(indoline-1-carbonyl)piperidine-4-carboxylic acid (700.0 mg) in the minimum amount of MeOH, and then heat the solution in an SFC-80 column (DAICEL CHIRALPAK IE (250 mm)). * The sample was purified by eluting 60% of the sample (30 mm, 10 μm) with 0.1% NH4OH in mobile phase A: CO2 and B: EtOH at a flow rate of 80 mL / min.

[0462] The eluate from the first peak was collected and lyophilized to obtain the title compound (275.3 mg, yield 40.5%, ee: 100%). MS m / z 526.2 (M+H). 1H NMR(400.14MHz,DMSO-d6):12.12(br,OH),7.59-7.51(m,3H),7.32(d,J=6.0Hz,2H ),7.27-7.22(m,1H),7.15(t,J=7.6Hz,1H),6.98-6.88(m,2H),4.68(t,J=12.4Hz, 1H),3.82(t,J=8.2Hz,2H),3.33-3.20(m,4H),3.01(t,J=8.1Hz,2H),2.28-2.25(m ,3H),2.04-1.94(m,3H),1.82-1.78(m,2H),1.69-1.43(m,5H),1.16-1.05(m,1H).

[0463] The eluate from the second peak was collected and lyophilized to obtain the title compound (284.7 mg, yield 41.9%, ee: 98.6%) as the second enantiomer. MS m / z 526.2 (M+H). 1 H NMR(400.14MHz,DMSO-d6):12.11(br,OH),7.53-7.45(m,3H),7.26(d,J=6.4Hz,2H),7.17 (d,J=7.3Hz,1H),7.09(t,J=7.6Hz,1H),6.91(d,J=7.9Hz,1H),6.84(t,J=7.3Hz,1H),4.6 2(t,J=12.4Hz,1H),3.76(t,J=8.2Hz,2H),3.24-3.14(m,4H),2.95(t,J=8.1Hz,2H),2.23 -2.18(m,3H),1.92-1.88(m,3H),1.75-1.73(m,2H),1.63-1.46(m,5H),1.10-0.99(m,1H).

[0464] Examples 80b and 80a were prepared according to the procedure described above.

[0465] Racemic mixture, SFC-80 (Column: Daicel ChiralPak IG (250) * Separation was performed using a 30mm, 10um mobile phase (A: CO2 B: 0.1% NH3H2O ​​EtOH, 40% elution, flow rate: 80 mL / min) to obtain 80b and 80a.

[0466] Racemic mixture, SFC-80, Column: DAIEL CHIRALPAK AD (250mm) * Separation was performed using a 30 mm, 10 μm mobile phase (A: CO2; B: 0.1% NH3H2O ​​IPA; B%: 35%, flow rate: 80 mL / min) to obtain 3b and 83a.

[0467] [Table 17]

[0468] Examples 6, 8, 9, 10, 11, 12, 14, 15, 17, 18, 34, 36, 37, 39, 41, 41A, 41B, 43, 43A, 43B, 45, 45A, 45B, 47, 53, 54, 86, 95, and 96 were prepared according to the above procedure.

[0469] [ka]

[0470] Examples 44, 44A, and 44B were prepared according to Scheme 3.

[0471] Step 1: 4-(carboxymethyl)-1-[(4-fluorophenyl)-methylcarbamoyl]piperidine-4-carboxylic acid

[0472] [ka]

[0473] A mixture of N-(4-fluorophenyl)-N-methyl-carbamoyl chloride (5.91 g, 25.2 mmol, 80% by mass) and 4-(carboxymethyl)piperidine-4-carboxylic acid hydrochloride (6.98 g, 25.0 mmol, 80% by mass) in tetrahydrofuran (100 mL) was to be mixed dropwise with N,O-bis(trimethylsilyl)acetamide (25 mL, 100 mmol), followed by the dropwise addition of N,N-diisopropylethylamine (13.5 mL, 77.3 mmol) at 0°C. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched by adding water (50 mL), the pH was adjusted to 3 with 1.0 N HCl, and the mixture was extracted with RINKAN (60 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated under high vacuum to obtain the residue. The residue was purified by elution using silica gel flushing with petroleum ether and 0-100% ethyl acetate (0.1% formic acid) / petroleum ether to obtain the title compound (6.11 g, 95% by mass, yield 68.7%). MS m / z 339.3 (M+H).

[0474] [Table 18]

[0475] Step 2: N-(4-fluorophenyl)-N-methyl-1,3-dioxo-2-oxa-8-azaspiro[4.5]decane-8-carboxamide; 2,2,2-trifluoroacetic acid

[0476] [ka]

[0477] To a solution of 4-(carboxymethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylic acid (0.5 g, 1 mmol, 95% by mass) in DCM (5.0 mL), 2,2,2-trifluoroacetic anhydride (0.5 mL, 4 mmol, 99% by mass) was added at room temperature, and the reaction mixture was stirred overnight. The reaction mixture was concentrated under high vacuum, toluene (5 mL) was added to the residue, and the mixture was concentrated under high vacuum again (repeated 3 times) to obtain the crude title product (600 mg, 90% by mass, 90% yield), which was used directly in the next step.

[0478] [Table 19]

[0479] Step 3: Racemic mixture 4-[2-(N-[-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylic acid (Example No. 44)

[0480] [ka]

[0481] A mixture of racemic N-[3,3-difluorocyclohexyl]aniline (0.5 g, 2.0 mmol, 90% by mass), N-(4-fluorophenyl)-N-methyl-1,3-dioxo-2-oxa-8-azaspiro[4.5]decane-8-carboxamide; and 2,2,2-trifluoroacetic acid (0.6 g, 2.0 mmol, 90% by mass) in dichloromethane (5 mL, 99.5% by mass) was placed in a microwave tube, and the reaction was heated in a microwave at 80°C for 4 hours. The mixture was concentrated to obtain the residue. The crude product was analyzed by reverse-phase preparative HPLC using Welch Xtimate C18 100. * 30mm *The compound was purified by elution from 45%B to 75%B using a 5 μm column, mobile phase A: water (0.225% formic acid), and mobile phase B: CH3CN. Appropriate fractions were collected and lyophilized to obtain the title compound (170 mg, 99% by mass, 20% yield). MS m / z 532.4 (M+H). 1 H NMR(400.14MHz,DMSO-d6):12.16(br,1H),7.52-7.43(m,3H),7.20-7.08(m,6H),4.61-4.55(m,1H),3.18-3.05(m,2H),3.01(s,3H),2.96-2 .90(m,2H),2.35-2.26(m,1H),2.05(s,2H),1.97-1.92(m,1H),1.73- 1.61(m,4H),1.59-1.53(m,3H),1.18-1.13(m,2H),1.08-0.99(m,1H).

[0482] Examples 10, 14, 15, 17, 18, 34, 36, 37, 39, 41, 45, 53, 54, 86, 95, and 96 were prepared according to the procedure described above.

[0483] [Table 20-1]

[0484] [Table 20-2]

[0485] [Table 20-3]

[0486] [Table 20-4]

[0487] [Table 20-5]

[0488] 4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]-1-(indoline-1-carbonyl)piperidine-4-carboxylic acid (Example No. 6)

[0489] [ka]

[0490] To a solution of N-cyclohexylaniline (115 mg, 0.643 mmol) in tetrahydrofuran (2 mL), n-butyllithium (0.3 mL, 0.80 mmol, 2.5 M in hexane) was added under nitrogen at -78°C and stirred for 15 minutes at -78°C. Then, a solution of 8-(indoline-1-carbonyl)-2-oxa-8-azaspiro[4.5]decane-1,3-dione (170 mg, 0.433 mmol, 80% by mass) in tetrahydrofuran (2 mL) was added under N2 at -78°C. The reaction mixture was then stirred under N2 at -78°C and slowly warmed to room temperature over 1 hour. The reaction mixture was quenched with saturated NH4Cl (3.0 ml) and concentrated. The residue was analyzed by reverse-phase preparative HPLC. * 30mm * Using a 10 μm atmosphere, mobile phase A: water-0.225% formic acid, and mobile phase B: ACN, the product was purified by elution at 58–88% B and then up to 100% B over 10 minutes. Appropriate fractions were combined and freeze-dried to obtain the title product (31.7 mg, 97.4% by mass, yield 14.6%) as a white solid. MS m / z 490.4(M+H); 1H NMR(400.13MHz,DMSO-d6):12.18(br,1H),7.54-7.39(m,3H),7.22-7.13(m,3H),7.09(t,J=7 .5Hz,1H),6.90(d,J=8.0Hz,1H),6.87-6.80(m,1H),4.37(t,J=11.9Hz,1H),3.76(t,J=8.1Hz ,2H),3.26-3.10(m,4H),2.95(t,J=8.1Hz,2H),2.16(s,2H),1.89(d,J=13.8Hz,2H),1.77-1. 61(m,4H),1.51(d,J=12.6Hz,1H),1.41(t,J=9.1Hz,2H),1.34-1.19(m,2H),1.00-0.75(m,3H)

[0491] Examples 8, 9, 11, and 12 were prepared according to the procedure described above.

[0492] [Table 21]

[0493] Step 4: Isolation of isomers (Examples 44A and 44B)

[0494] [ka]

[0495] Racemic 4-[2-(N-[-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylic acid 485 mg, SFC-80, Daicel ChiralPak IG (250 * The samples were purified by eluting 40% of B (30 mm, 10 μm) with 0.1% NH4OH in mobile phase A: CO2 and B: EtOH at a flow rate of 80 mL / min.

[0496] The eluate from the first peak was collected and lyophilized to obtain the title compound (225.3 mg, 0.4153 mmol, yield 45.98%, ee: 98.7%). MS m / z 532.4 (M+H). 1 H NMR(400.13MHz,DMSO-d6):12.08(br,1H),7.58-7.49(m,3H),7.26-7.14(m,6H),4.64(t,J=12.4Hz,1H),3.15-3.11(m,2H),3.07(s,3H),3.0 2-2.96(m,2H),2.30-2.22(m,1H),2.11(s,2H),1.99-1.92(m,1H),1.7 91.71(m,4H)1.64-1.42(m,3H),1.24-1.19(m,2H),1.13-1.02(m,1H).

[0497] The eluate from the second peak was collected and lyophilized to obtain the title compound (223.0 mg, 0.4153 mmol, yield 45.98%, ee: 99.4%). MS m / z 532.5 (m+1). 1 H NMR(400.13MHz,DMSO-d6):12.08(br,1H),7.57-7.49(m,3H),7.26-7.16(m,6H),4.64(t,J=12.1Hz,1H),3.15-3.09(m,2H),3.07(s,3H),3.02 -2.97(m,2H),2.35-2.26(m,1H),2.11(s,2H),2.04-1.88(m,1H),1.79 -1.68(m,4H),1.64-1.40(m,3H),1.29-1.19(m,2H),1.13-1.02(m,1H).

[0498] Examples 41a, 41b, 43a, 43b, 45a, and 45b were prepared according to the procedure described above.

[0499] [Table 22-1]

[0500] [Table 22-2]

[0501] Example No. 3 was prepared according to Scheme 4.

[0502] [ka]

[0503] Step 1: O1-tert-butyl O4-ethyl 4-(2-ethoxy-2-oxo-ethyl)piperidine-1,4-dicarboxylate

[0504] [ka]

[0505] O1-tert-butyl O4-ethylpiperidine-1,4-dicarboxylate (11.0 g, 41.4 mmol) in tetrahydrofuran (60 mL) was added dropwise to a solution of LDA (41 mL, 82.0 mmol) in tetrahydrofuran (138 mL) under nitrogen at -78°C. The addition was completed after 45 minutes, and the mixture was stirred below -70°C. After 65 minutes, 2-ethyl bromo (8 mL, 72.1 mmol) in tetrahydrofuran (60 mL) was added below -68°C, and the mixture was stirred. After 1 hour, the reaction mixture was gradually warmed to 0°C. After 1 hour, saturated ammonium chloride was added, and the mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by elution with hexane:methyl tert-butyl ether (60:40) using silica gel flash chromatography to obtain the title compound (8.90 g, 57% yield). MS m / z 244.2 (M+H-BOC).

[0506] Step 2: 4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylate ethyl hydrochloride

[0507] [ka]

[0508] Hydrochloric acid (68 mL, 274 mmol, 4.0 M in dioxane) was added at 0°C to a solution of O1-tert-butyl O4-ethyl 4-(2-ethoxy-2-oxo-ethyl)piperidine-1,4-dicarboxylate (8.62 g, 25.1 mmol) in 1,4-dioxane (40 mL), and the mixture was stirred. The reaction mixture was gradually warmed to ambient temperature. After 30 minutes, the solvent was concentrated under reduced pressure to obtain the title compound (7.02 g, 99% yield). MS m / z 244.0 (M+H).

[0509] 4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate methyl acetate

[0510] [ka]

[0511] To a solution of methyl 1-benzyl-4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate (2.0 g, 6.2 mmol, 95% by mass) in tetrahydrofuran (30.0 mL), acetic acid (0.72 mL, 13 mmol) was added all at once, followed by the addition of Pd / C (1.55 g, 1.46 mmol, 10% by mass) at room temperature. The mixture was stirred at 60°C for 16 hours under hydrogen (50 psi). The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with methanol and dichloromethane (1:1, 100 mL x 6). The filtrate was concentrated under reduced pressure to obtain the title compound (1.9 g).

[0512] Steps 3 and 4: 4-(2-ethoxy-2-oxo-ethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylate ethyl

[0513] [ka]

[0514] Pyridine (17 mL) was added at 0°C to 4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylic acid hydrochloride (5.91 g, 21.1 mmol) in dichloromethane (100 mL) and stirred. While maintaining the temperature at 0°C, triphosgene (3.84 g, 12.7 mmol) was added in small amounts. The reaction mixture was gradually heated to 40°C and stirred. After 1 hour, the reaction mixture was concentrated under reduced pressure. Brine was added to the mixture and extracted with dichloromethane. The organic layers were combined, extracted with saturated sodium bicarbonate and brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 1-chlorocarbonyl-4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylic acid ethyl (5.75 g, 18.8 mmol).

[0515] 5.75 g, 18.8 mmol of ethyl 1-chlorocarbonyl-4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylate (5.75 g, 18.8 mmol) was added to 62 mL of acetonitrile at 0°C, and 3.16 mL, 28.2 mmol of indoline (50 mL) was added to 50 mL of acetonitrile at 0°C. Potassium carbonate (17.5 g, 126.8 mmol) was added, and the mixture was stirred at 76°C. After 18 hours, the solvent was concentrated under reduced pressure, and the mixture was extracted by DCM. The organic layers were combined, extracted with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography, eluted with 1-80% toluene / hexane, to obtain the title compound (3.75 g, yield 51%). MS m / z 389.0 (M+H).

[0516] Step 5: 2-[4-ethoxycarbonyl-1-(indoline-1-carbonyl)-4-piperidyl]acetic acid

[0517] [ka]

[0518] Potassium carbonate (1.97 g, 14.3 mmol) was added to ethyl 4-(2-ethoxy-2-oxo-ethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylate (3.25 g, 8.37 mmol) in methanol (35 mL) and water (3 mL), and the mixture was stirred at 50°C. After 18 hours, the reaction mixture was cooled, and 5N aqueous HCl was added until the pH reached 3.0. The mixture was extracted with dichloromethane (DCM). The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography by elution with 60% (MeOH:DCM(10:90)) from dichloromethane to obtain the title compound (2.71 g, 78% yield). MS m / z 361.0 (M+H).

[0519] [Table 23]

[0520] Steps 6 and 7: 1-(indoline-1-carbonyl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylate ethyl

[0521] [ka]

[0522] Thionyl chloride (17.90 mL, 35.8 mmol, 2.00 M in dichloromethane) was added to a solution of 2-[4-ethoxycarbonyl-1-(indoline-1-carbonyl)-4-piperidyl]acetic acid (2.58 g, 7.12 mmol) in dichloromethane (172 m) and tetrahydrofuran (42 mL), and the mixture was stirred at ambient temperature. After 15 minutes, the mixture was concentrated under reduced pressure to obtain ethyl 4-(2-chloro-2-oxo-ethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylate (2.71 g, 99% yield).

[0523] N-phenylaniline (17.0 mL, 7.00 mmol, 4.0 M in dichloromethane) in pyridine (0.20 mL, 2.47 mmol) was added to a solution of 4-(2-chloro-2-oxo-ethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylate ethyl (2.71 g, 7.16 mmol) in dichloromethane (170 mL), and the mixture was stirred at ambient temperature. After 3 hours, the reaction mixture was extracted with dichloromethane. The organic layers were combined, extracted with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography, eluted with siRNA:hexane (50:50), to obtain the title compound (2.46 g, 67% yield). MS m / z 512.2 (M+H).

[0524] Step 8: 1-(indoline-1-carbonyl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (Example No. 3)

[0525] [ka]

[0526] A 5N sodium hydroxide aqueous solution (4.8 mL, 24.1 mmol) was added at ambient temperature to a 30 mL solution of 1-(indoline-1-carbonyl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylate ethyl (2.46 g, 4.81 mmol) in ethanol, and the mixture was stirred at 50°C. After 18 hours, the reaction mixture was concentrated under reduced pressure to obtain a residue. A 5N HCl aqueous solution was added, and the mixture was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography using DCM:[MeOH:DCM(10:90)] to obtain the title compound (1.97 g, yield 84%). MS m / z 484.4(M+H); 1H NMR(DMSO-d6)d12.38(s,1H),7.40-7.29(m,11H),7.11(t,J=7.7Hz,1H),6.94(d,J=8.0Hz,1H),6.86(t,J=7.4Hz,1H) ,3.79(t,J=8.2Hz,2H),3.35-3.18(m,4H),2.97(t,J=8.2Hz,2H),2.56(s,2H),2.00-1.96(m,2H),1.59-1.52(m,2H).

[0527] Examples 48, 49, 50, 51, 62, 63, 64, 65, 66, 67, 68, 68A, 68B, 69, 70, 71, 72, 72A, 72B, 73, 74, 74A, 74B, 75, 75A, 75B, 79, 88, 89, 90, 91, 92, and 93 were prepared according to Scheme 5.

[0528] [ka]

[0529] Step 1: 1-Benzyl-4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate methyl

[0530] [ka]

[0531] 24.00 mL, 329.4 mmol of thionyl chloride (2.0 M solution in DCM) was added dropwise to a methanol (400 mL) solution of 1-benzyl-4-(carboxymethyl)piperidine-4-carboxylic acid (10.00 g, 36.06 mmol), and the mixture was stirred at 60°C. After 18 hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layers were combined, dried over MgSO4, filtered, and evaporated. The residue was dissolved in DCM, packed onto silica gel, and purified by 120 g silica column with 1%-10% methanol in dichloromethane. The fractions were combined and evaporated. The residue was then dried under high reduced pressure to obtain the title compound (9.46 g, yield 85.9%). MS m / z 306.0 (M+H).

[0532] Step 2: 2-(1-benzyl-4-methoxycarbonyl-4-piperidyl)acetic acid

[0533] [ka]

[0534] Potassium carbonate (8.50 g, 61.5 mmol) was added to methyl 1-benzyl-4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate (11.06 g, 36.21 mmol) in methanol (120 mL) and water (5.50 mL), and the mixture was stirred at 60°C. After 18 hours, the reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with ice-cold water, washed with methyl tert-butyl ether, and the organic layer was discarded. The aqueous layer was cooled to 0°C and acidified with 1.0 M HCl to a pH of approximately 7.0 while maintaining the temperature below 10°C. A white precipitate formed, which was stirred at room temperature for 1 hour, filtered, and the precipitate was collected and dried to obtain the title compound (8.48 g, yield 80.4%). MS m / z 292.1 (M+H).

[0535] Steps 3 and 4: 1-Benzyl-4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl

[0536] [ka]

[0537] Thionyl chloride (29.0 mL, 398.7 mmol) was added to a solution of 2-(1-benzyl-4-methoxycarbonyl-4-piperidyl)acetic acid (8.46 g, 29.0 mmol) in chloroform (100 mL) and tetrahydrofuran (100 mL), and the mixture was stirred at ambient temperature. After 15 minutes, the mixture was concentrated under reduced pressure to obtain methyl 1-benzyl-4-(2-chloro-2-oxo-ethyl)piperidine-4-carboxylate (9.0 g, 99% yield).

[0538] N-cyclohexylaniline (4.50 mL, 26.09 mmol) in DCM (100.0 mL) and pyridine (10.00 mL, 124.0 mmol) was added to a solution of 1-benzyl-4-(2-chloro-2-oxo-ethyl)piperidine-4-carboxylate methyl (7.40 g, 23.90 mmol) in DCM (100 mL), toluene (50 mL), and 4-dimethylaminopyrirdine (0.150 g, 1.21 mmol), and the mixture was stirred at 70°C. After 18 hours, the reaction mixture was quenched with brine and extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography, eluted with toluene:hexane (90:10), to obtain the title compound (8.00 g, 74.7% yield). MS m / z 449.4 (M+H).

[0539] 1-Benzyl-4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl

[0540] [ka]

[0541] Under N2 conditions, phosphoryl chloride (4.6 mL, 49 mmol, 99 mg) was added dropwise to a solution of 2-(1-benzyl-4-methoxycarbonyl-4-piperidyl)acetic acid (7.5 g, 24 mmol, 95% by mass) and N-[(racemic)-3,3-difluorocyclohexyl]aniline (6.5 g, 28 mmol, 90% by mass) in pyridine (70.0 mL) at room temperature. After addition, the mixture was heated to 100 °C, stirred for 5 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (400 mL) and extracted with ethyl acetate (400 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under high pressure to obtain the crude product. This was purified by flash silica gel chromatography, eluted with 0-8% MeOH / DCM, to obtain the title product (8.1 g, 90% by mass, yield 62%). MS m / z 485.2 (M+H).

[0542] The compounds listed in the table below were prepared in the same manner as described above.

[0543] [Table 24]

[0544] Step 5: 4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl

[0545] [ka]

[0546] 10% Pd / C (3.201 g, 29.74 mmol) in methanol (50.0 mL) was added to a solution of 1-benzyl-4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl (7.98 g, 17.80 mmol) in methanol (325 mL). The mixture was sealed, purged with nitrogen and hydrogen, pressurized with hydrogen, and shaken on a shaker at 50°C and 10 PSI. After 10 hours, the reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain the title compound (5.53 g, yield 86.7%). MS m / z 359.0 (M+H).

[0547] The compounds listed in the table below were prepared according to the procedure described above.

[0548] [Table 25]

[0549] Step 6: 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(2-pyridyl)piperidine-4-carboxylate methyl

[0550] [ka]

[0551] Under N2 conditions, a mixture of methyl 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate (3.0 g, 6.5 mmol, 85% by mass) and 2-bromopyridine (3.2 g, 19 mmol, 95% by mass) in toluene (30.0 mL) was mixed with tris(dibenzylideneacetone)dipalladium(0) (310 mg, 0.3 mmol, 95% by mass), RuPhos (640 mg, 1.3 mmol, 95% by mass), and sodium tert-butoxide (1.3 g, 13 mmol, 97% by mass). The mixture was stirred at 100 °C for 4 hours. The reaction product was cooled to room temperature, the solvent was removed under high reduced pressure, the residue was dissolved in DCM (50 mL), washed with water (20 mL), the organic layer was dried over Na2SO4, filtered, and concentrated under high reduced pressure. The residue was purified by flash silica gel chromatography, eluting with 0% to 40% siRNA / petroleum ether to obtain the title product (1.38 g, 2.63 mmol, 90% by mass, 41% yield). MS m / z 472.3 (M+H).

[0552] 4-[2-(N-(3,3-difluorocyclohexyl)-2-fluoroanilino)-2-oxo-ethyl]-1-(2-pyridyl)piperidine-4-carboxylate methyl was prepared according to the above procedure.

[0553] [Table 26]

[0554] Racemic mixture, 4-[2-(N-[(racemic mixture)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-[(4-isopropylphenyl)methyl]piperidine-4-carboxylate methyl

[0555] [ka]

[0556] A mixture of racemic 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl (200 mg, 0.46 mmol, 90% by mass) and 4-isopropylbenzaldehyde (140 mg, 0.93 mmol) in 1,2-dichloroethane (5.0 mL) was mixed with titanium(IV) isopropoxide (0.46 mL, 1.3 mmol, 85% by mass). The mixture was stirred at 80°C for 1 hour, then sodium triacetoxyborohydride (300 mg, 1.373 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was quenched with water (5 mL) and concentrated. The residue was dissolved in MeOH (5.0 mL), and the solid was filtered off. The filtrate was concentrated and subjected to preparative HPLC (Phenomenex C18 100). * 30mm * The solution was purified by elution at 10 μm, mobile phase A: water-formic acid, mobile phase B: acetonitrile (elution at 22-52% B, then up to 100% B). Appropriate fractions were combined and lyophilized to obtain the title product as formate, 60 mg, 95% by mass, yield 23.7%). 1 H NMR(400MHz,DMSO-d6):8.15(s,2H),7.60-7.42(m,3H),7.34-7.06(m,6H),4.58(t,J =12.5Hz,1H),3.58(s,3H),2.84(td,J=6.9,13.8Hz,1H),2.35-2.15(m,6H),1.87(br d,J=4.5Hz,3H),1.73(d,J=10.0Hz,2H),1.65-1.26(m,6H),1.17(d,J=6.9Hz,6H),1.09-0.92(m,1H).

[0557] The intermediates listed in the table below were prepared according to the procedure described above.

[0558] [Table 27]

[0559] Racemic mixture, 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-[2-(4-fluorophenyl)propanoyl]piperidine-4-carboxylate methyl

[0560] [ka]

[0561] To a solution of racemic 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl (201 mg, 0.48 mmol, 94% by mass) and racemic 2-(4-fluorophenyl)propanoic acid (97 mg, 0.57 mmol) in DCM (3.0 mL), N,N-diisopropylethylamine (0.165 mL, 0.94 mmol) and HATU (270 mg, 0.69 mmol) were added, and the mixture was stirred overnight at room temperature. The mixture was quenched with water (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated under high vacuum. The residue was purified by flash silica gel chromatography (elution with 0-7% MeOH / DCM) to obtain the title compound (305 mg, 68% by mass, 79.5% yield) as a brown oily substance. MS m / z 545.3 (M+H).

[0562] [Table 28]

[0563] Racemic mixture, 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-[2-(2-fluorophenyl)propanoyl]piperidine-4-carboxylate methyl

[0564] [ka]

[0565] To a solution of (racemic)-2-(2-fluorophenyl)propanoic acid (200 mg, 1.07 mmol, 90% by mass) in DCM (3.0 mL), oxalyl chloride (0.190 mL, 2.15 mmol) was added, followed by the addition of one drop of DMF at 0°C. The reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was concentrated under high pressure to obtain (racemic)-2-(2-fluorophenyl)propanoyl chloride (230 mg, 85% by mass).

[0566] Next, the prepared acid chloride (207 mg, 0.943 mmol, 85% by mass) was added to a solution of racemic 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl (200 mg, 0.47 mmol, 93% by mass) and triethylamine (0.17 mL, 1.2 mmol) in DCM (4.0 mL). The mixture was stirred overnight at 40°C. The reaction mixture was cooled to room temperature and filtered. The residue was purified by elution with 50-58% Â (petroleum ether) by conventional silica gel chromatography to obtain the title compound (140 mg, 90% by mass, yield 49.07%). MS m / z 545.2 (M+H).

[0567] [Table 29]

[0568] Racemic mixture, 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(4-fluoroindoline-1-carbonyl)piperidine-4-carboxylate methyl

[0569] [ka]

[0570] To a solution of racemic 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl (220 mg, 0.45 mmol, 80% by mass) and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) in DCM (4.0 mL), 4-fluoroindoline-1-carbonyl chloride (130 mg, 0.55 mmol, 85% by mass) was added at room temperature. The mixture was stirred at room temperature for 2 hours to obtain a colorless solution. After completion, water (10 mL) was added to the reaction product and extracted with siRNA (10 mL × 2). The combined organic layer was washed with brine (20 mL × 2), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (elution with 0-65% siRNA / petroleum ether) to obtain the title compound (120 mg, 95% by mass, yield 45.8%). MS m / z 558.2 (M+H).

[0571] [Table 30]

[0572] 1-[Cyclopropyl(phenyl)carbamoyl]-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylate methyl

[0573] [ka]

[0574] At 0°C, N-cyclopropyl-N-phenyl-carbamoyl chloride (0.261 g, 1.33 mmol) was added to a mixture of methyl 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylate (380 mg, 1.08 mmol) and potassium carbonate (448 mg, 3.24 mmol) in acetonitrile (50 mL). The resulting mixture was heated to room temperature and stirred under nitrogen for 90 minutes. The reaction product was diluted with RINKAN and water and extracted twice with RINKAN. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified over 40 g of silica gel using a gradient of 0% to 100% RINKAN in hexane for 20 minutes to obtain 476 mg (86%) of the title product. MS m / z 512 [M+H].

[0575] Step 7 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(2-pyridyl)piperidine-4-carboxylic acid (Example No. 74)

[0576] [ka]

[0577] To a solution of 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(2-pyridyl)piperidine-4-carboxylate methyl (1.38 g, 2.63 mmol, 90% by mass) in 2-propanol (16.0 mL, 98% by mass), 2.6 mL of NaOH aqueous solution (13 mmol, 5 mol / L) was added, and the mixture was heated to 50°C and stirred overnight. After cooling to room temperature, the mixture was acidified with KHSO4 aqueous solution to a pH of less than 4, and the mixture was extracted with RINKAN (20 mL x 3). The combined organic phase was washed with 10 mL of brine, dried over Na2SO4, filtered, and concentrated under high pressure. The residue was purified by preparative HPLC (Welch Xtimate Prep C 18 250×50mm×10um, conditions: water (10mM NH4HCO3) / MeCN 5%~35%) to obtain the title product (0.89g, 97% by mass, yield 71.6%), MS m / z 458.3 (M+H).

[0578] Example No. 75 was prepared according to the procedure described above.

[0579] [Table 31]

[0580] Racemic mixture, 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-[(4-isopropylphenyl)methyl]piperidine-4-carboxylic acid (Example No. 51)

[0581] [ka]

[0582] A solution of racemic 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-[(4-isopropylphenyl)methyl]piperidine-4-carboxylate methyl (50 mg, 0.090 mmol, 95% by mass) in 1,4-dioxane (1.0 mL) and water (0.5 mL) was prepared by adding potassium hydroxide (24 mg, 0.428 mmol) at room temperature. The mixture was stirred at 100 °C for 5 hours. The mixture was cooled to room temperature, combined, and the pH was adjusted to approximately 7 by adding formic acid, and the mixture was concentrated. The residue was subjected to preparative HPLC (Phenomenex C18 150). * 30mm * The solution was purified by eluting at 20-60% B and then 100% B over 12 minutes using a 5 μm mobile phase (A: water (0.04% NH3H2O ​​+ 10 mM NH4HCO3) and mobile phase (B: ACN). Appropriate fractions were combined and freeze-dried to obtain the title product (13.4 mg, 100% by mass, yield 29.0%) as a white solid. MS m / z 513.5(M+H); 1 H NMR(400.13MHz,DMSO-d6):12.10(br,1H),7.57-7.40(m,3H),7.25-7.23(m,2H),7.17-7.10(m,4H),4.66-4.56(m,1H),3.28(s,2H),2.87-2.84 (m,1H),2.25-2.15(m,4H),2.13(s,2H),1.94-1.80(m,3H),1.73(d,J=1 0.9Hz,2H),1.64-1.29(m,6H),1.17(d,J=7.0Hz,6H),1.09-0.95(m,1H)

[0583] Examples 50, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 79, and 88 were prepared according to the procedure described above.

[0584] [Table 32-1]

[0585] [Table 32-2]

[0586] [Table 32-3]

[0587] [Table 32-4]

[0588] Example 97 1-[Cyclopropyl(phenyl)carbamoyl]-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid

[0589] [ka]

[0590] A solution of lithium hydroxide (131 mg, 5.47 mmol) in water (2 mL) was added at room temperature to a solution of 1-[cyclopropyl(phenyl)carbamoyl]-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylate methyl (475 mg, 0.928 mmol) in ethanol (2 mL) and THF (2 mL). The reaction mixture was stirred overnight at 50°C. The reaction mixture was cooled, diluted with water and dichloromethane, and acidified to approximately 2.0 pH with 5.0 M aqueous HCl solution (approximately 1 mL). The mixture was extracted three times with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified over 30 minutes using 40 g of silica gel with a gradient of 0.5% to 10% MeOH in DCM to obtain 355 mg (77%) of the title product. MS (m / z): 498 [M+H]. 1H NMR(400.13MHz,CDCl3):7.54-7.46(m,3H),7.31(dd,J=1.6,6.9Hz,3H),7.24(m,6H),7.13-7.09(m,3H),3.50(dt,J=14.0,4.2 Hz,2H),3.21-3.14(m,2H),2.74-2.69(m,1H),2.54(s,2H),2.02(dd,J=3.3,10.6Hz,2H),0.92-0.84(m,4H),0.70-0.66(m,2H).

[0591] Isolation of isomers (Examples 74A and 74B)

[0592] [ka]

[0593] 1.62 g of racemic 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(2-pyridyl)piperidine-4-carboxylic acid, SFC-80, Daicel ChiralCel IG (250 mm * The sample was purified by eluting 40% of the sample with 0.1% NH3H2O ​​in mobile phases A:CO2 and B:EtOH (50 mm, 10 μm) at a flow rate of 80 mL / min.

[0594] The eluate from the first peak was collected and freeze-dried to obtain isomer 1 of the title compound (546.5 mg, yield 33.9%, ee: 100%). MS m / z 458.4 (M+H). 1 H NMR(400.13MHz,DMSO-d6):12.0(brs,1H),8.03(dd,J=1.2,4.8Hz,1H),7.49-7.45(m,4H),7.24-7.22(m,2H),6.73(d,J=8.8Hz,1H),6.57(m ,1H),4.65-4.59(m,1H),3.53-3.31(m,4H),2.23-2.19(m,3H),1.90- 1.87(m,3H),1.76-1.73(m,2H),1.62-1.39(m,5H),1.04-1.01(m,1H).

[0595] The eluate from the second peak was collected and freeze-dried to obtain isomer 2 of the title compound (586.6 mg, yield 36.5%, ee: 99.8%). MS m / z 458.5 (M+H). 1 H NMR(400.13MHz,DMSO-d6):12.18(brs,1H),8.06(dd,J=1.4,4.9Hz,1H),7.51- 7.45(m,4H),7.25-7.24(m,2H),6.74(d,J=8.7Hz,1H),6.57(dd,J=5.1,6.9Hz, 1H),4.66-4.60(m,1H),3.51-3.47(m,2H),3.37-3.35(m,2H),2.25-2.23(m,3H ),1.95-1.90(m,3H),1.77-1.74(m,2H),1.62-1.57(m,5H),1.11-1.06(m,1H).

[0596] Examples 72a, 72b, 75b, 75a, 68b, and 68a were prepared according to the procedure described above.

[0597] Racemic 72, SFC, Daicel ChiralPak IG (250 * (30 mm, 10 μm); Mobile phase: A: CO2; B: EtOH with 0.1% NH3H2O. 40% of B was eluted and separated at a flow rate of 80 mL / min to obtain 72a and 72b.

[0598] Racemic mixture 75, SFC, column: DAIEL CHIRALCEL IG (250mm) * (50 mm, 10 μm); Mobile phase: A: CO2; B: EtOH with 0.1% NH3H2O. 35% of B was eluted and separated at a flow rate of 140 mL / min to obtain 75a and 75b.

[0599] Racemic mixture 68, SFC (column: DAIEL CHIRALCEL IG (250mm) * (30 mm, 10 μm); Mobile phase: A: CO2; B: EtOH with 0.1% NH3H2O. Separation was performed by eluting 30% of B at a flow rate of 70 mL / min to obtain 68a and 68b.

[0600] [Table 33-1]

[0601] [Table 33-2]

[0602] Steps 6 and 7: 4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]-1-(2-pyridyl)piperidine-4-carboxylic acid (Example No. 49)

[0603] [ka]

[0604] 2-chloropyridine (0.032 mL, 0.033 mmol) was sealed in a 1.40 mL solution of dioxane containing 4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]piperidine-4-carboxylate methyl (0.10 g, 0.28 mmol), sodium tert butoxide (0.110 mg, 1.14 mmol), chloro-(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II)-methyl-t-butyl ether adduct and RuPhos paradacycle (0.035 mg, 0.041 mmol), and stirred at 100°C. After 24 hours, the reaction mixture was cooled, packed into an SCX-2, and eluted with 2.0 M ammonia in acetonitrile and methanol. The filtrate is concentrated under reduced pressure to obtain the residue, which is then analyzed by reverse-phase preparative HPLC using XBridge C18 150. * 19mm * The compound was purified by elution from 30% to 60% B using a 5 μm column with mobile phase A: 20 mM NH4CO3 pH 9 and B: CH3CN. A suitable fraction was collected and lyophilized to obtain the title compound (63 mg, 54% yield). MS m / z 422.2 (M+H). 1H NMR(DMSO-d6)d12.04(s,1H),8.05(dd,J=1.3,4.8Hz,1H),7.49-7.43(m,4H),7.18-7.16(m,2H),6.73(d,J=8.8Hz,1H),6.56(dd,J=4.9,6.6Hz,1H ),4.41-4.34(m,1H),3.50-3.22(m,4H),2.15(s,2H),1.89(ddd,J=13.1, 6.1,3.2Hz,2H),1.75-1.66(m,4H),1.53-1.37(m,5H),0.97-0.85(m,3H)

[0605] The compounds listed in the table below were prepared according to the procedure described above.

[0606] [Table 34-1]

[0607] [Table 34-2]

[0608] Examples 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, and 32 were prepared according to Scheme 6.

[0609] [ka]

[0610] Steps 1 and 2 were combined according to Scheme 4. Step 3: 4-(2-ethoxy-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate ethyl

[0611] [ka]

[0612] N-(4-fluorophenyl)-N-methyl-carbamoyl chloride (9.65 g, 51.4 mmol) in acetonitrile (100 mL) was added at 0°C to 4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylate ethyl hydrochloride (6.00 g, 21.4 mmol) in DCM (20 mL) at 0°C. Potassium carbonate (8.9 g, 64.3 mmol) was added and the mixture was stirred at 76°C. After 18 hours, the solvent was concentrated under reduced pressure and the mixture was extracted with DCM. The organic layers were combined, extracted with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography by elution with 1-80% toluene / hexane to obtain the title compound (4.03 g, yield 47%). MS m / z 395.0

[0613] Step 4: 2-[4-ethoxycarbonyl-1-[(4-fluorophenyl)-methyl-carbamoyl]-4-piperidyl]acetic acid

[0614] [ka]

[0615] Potassium carbonate (2.40 g, 17.4 mmol) was added to 4-(2-ethoxy-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate ethyl (4.03 g, 10.20 mmol) in methanol (50 mL) and water (2 mL), and the mixture was stirred at 50°C. After 18 hours, the reaction mixture was cooled, and 5N hydrochloric acid aqueous solution was added until the pH reached 3.0. The mixture was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography, eluting from DCM with 40% (MeOH:DCM(20:80)) to obtain the title compound (3.00 g, yield 80%). MS m / z 367.0 (M+H).

[0616] Steps 5 and 6: 1-[(4-fluorophenyl)-methyl-carbamoyl]-4-[2-[N-(m-tolyl)anilino]-2-oxo-ethyl]piperidine-4-carboxylate ethyl

[0617] [ka]

[0618] Thionyl chloride (0.12 mL, 1.6 mmol) in chloroform (0.60 mL) was added to a solution of (2-[4-ethoxycarbonyl-1-[(4-fluorophenyl)-methyl-carbamoyl]-4-piperidyl]acetic acid (0.10 g, 0.27 mmol) in tetrahydrofuran (0.19 mL) and stirred at 60°C. After 2 hours, the mixture was concentrated under reduced pressure to obtain 4-(2-chloro-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate ethyl (0.13 g, 99% yield).

[0619] 3-methyl-N-phenylaniline (0.06 g, 0.30 mmol) in pyridine (0.16 mL, 1.98 mmol) was added to a solution of 4-(2-chloro-2-oxo-ethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylate ethyl (0.13 g, 0.35 mmol) in DCM (0.97 mL) and stirred at 40°C. After 16 hours, the reaction mixture was quenched with MeOH (0.5 mL) and concentrated under a nitrogen stream. The residue was extracted with DCM (2.5 mL) and saturated sodium bicarbonate (1.0 mL). The organic layer was separated, dried on diatomaceous earth, and concentrated under a nitrogen stream. The crude product was analyzed by reverse-phase preparative HPLC using XBridge C18 150. * 19mm * The compound was purified by elution from 60%B to 90%B using a 5 μm column, mobile phase A: 20 mM NH4CO3 pH 9, and mobile phase B: CH3CN. A suitable fraction was collected and lyophilized to obtain the title compound (55 mg, 98% by mass, 29% yield). MS m / z 332.2 (M+H).

[0620] Step 7: 1-[(4-fluorophenyl)-methyl-carbamoyl]-4-[2-[N-(m-tolyl)anilino]-2-oxo-ethyl]piperidine-4-carboxylic acid (Example No. 23)

[0621] [ka]

[0622] 0.20 mL, 1.0 mmol of 5N sodium hydroxide aqueous solution was added to a solution of 1-[(4-fluorophenyl)-methyl-carbamoyl]-4-[2-[N-(m-tolyl)anilino]-2-oxo-ethyl]piperidine-4-carboxylate (0.05 g, 0.17 mmol) in ethanol (1.50 mL), and the mixture was stirred at 80°C. After 18 hours, the reaction mixture was concentrated under a nitrogen stream. 0.50 mL of water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated and discarded. The aqueous layer was acidified to approximately pH 2 with HCl (4.0 M, 0.045 mL), extracted with ethyl acetate (1.0 mL x 2), and the combined organic layers were dried on diatomaceous earth and concentrated under a nitrogen stream to obtain the residue. The crude product was analyzed by reverse-phase preparative HPLC using XBridge C18 150. * 19mm * The compound was purified by elution from 60% to 90% B using a 5 μm column, mobile phase A: 20 mM NH4CO3 pH 9, and mobile phase B: CH3CN. A suitable fraction was collected and lyophilized to obtain the title compound (15 mg, 100% by mass, 23% yield). MS m / z 504.2 (M+H). 1 H NMR(DMSO-d6)d 12.49(s,1H),7.360-7.17(m,13H),3.20-3.11(m,2H),3.00(s,3H),3.00-2 .92(m,2H),2.41(s,2H),2.29(s,3H),1.77-1.73(m,2H),1.32-1.24(m,2H).

[0623] Examples 21, 22, 24, 25, 27, 28, 29, 30, 31, and 32 were prepared according to the procedure described above.

[0624] [Table 35-1]

[0625] [Table 35-2]

[0626] Example No. 20 was prepared according to Scheme 7.

[0627] [ka]

[0628] Step 1 was prepared according to Step 3 of Scheme 5.

[0629] Step 2: 2-[1-[(4-fluorophenyl)-methyl-carbamoyl]-4-methoxycarbonyl-4-piperidyl]acetic acid

[0630] [ka]

[0631] Potassium carbonate (3.00 g, 21.7 mmol) was added to ethyl 4-(2-ethoxy-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate (5.03 g, 12.68 mmol) in methanol (20 mL) and water (2 mL), and the mixture was stirred at 60°C. After 18 hours, the reaction mixture was cooled, and 5N hydrochloric acid aqueous solution was added until the pH became 3.0. The mixture was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography, eluting from DCM with 40% (MeOH:DCM(20:80)) to obtain the title compound (0.80 g, yield 20%). MS m / z 353.2 (M+H).

[0632] Step 3: N-(1-cyclopropylcyclopropyl)aniline

[0633] [ka]

[0634] In a glove box, 1-cyclopropylcyclopropanamine hydrochloride (0.30 g, 2.25 mmol), sodium tert butoxide (0.48 g, 4.9 mmol), and [BrettPhos Pd(crotyl)]OTf (0.83 g, 0.098 mmol) were added as solids to a 25 mL Biotage tube containing a stirring rod. Then, 1,4-dioxane (4.5 mL) and chlorobenzene (0.27 g, 2.41 mmol) were added. The tube was capped and removed from the glove box. It was heated at 85°C using a Biotage Initiator microwave. After 10 minutes of heating, it was stable at 85°C and 0 bar. After 12 hours, the reaction mixture was cooled and filtered through a small Celite plug. The Celite was rinsed with DCM. The filtrate was diluted with DCM to 45 mL. The solution was washed with 20 mL of saturated ammonium chloride. The organic matter was dried over Na2SO4 and evaporated. The residue was dissolved in dichloromethane, packed into silica gel, and purified by 40 g silica column with 5%-20% siRNA in hexane. The fractions were combined and evaporated. The residue was then dried under high pressure to obtain the title compound (0.240 g, 61% yield). MS m / z 174.2 (M+H). 1 H NMR(CD2Cl2)d:7.19-7.14(m,2H),6.84-6.81(m,2H),6.71-6.67(m,1H),4.39-4.28(m,1H),1 .41-1.34(m,1H),0.73-0.69(m,2H),0.66-0.63(m,2H),0.45-0.40(m,2H),0.19-0.15(m,2H).

[0635] Steps 4 and 5: 4-[2-(N-(1-cyclopropylcyclopropyl)anilino)-2-oxo-ethyl]-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate methyl

[0636] [ka]

[0637] Thionyl chloride (1.0 mL, 13.7 mmol) was added to a solution of (2-[4-methoxycarbonyl-1-[(4-fluorophenyl)-methyl-carbamoyl]-4-piperidyl]acetic acid (0.47 g, 1.33 mmol) in chloroform (20 mL) and tetrahydrofuran (10 mL), and the mixture was stirred at 60°C. After 1 hour, the mixture was concentrated under reduced pressure to obtain 4-(2-chloro-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate methyl (0.49 g, 99% yield).

[0638] N-(1-cyclopropylcyclopropyl)aniline (0.23 g, 0.30 mmol) in DCM (10.0 mL) and pyridine (0.600 mL, 7.42 mmol) was added to a solution of 4-(2-chloro-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate methyl (0.49 g, 1.33 mmol) in DCM (10 mL) and stirred at 60°C. After 2 hours, the reaction mixture was quenched with brine and extracted with ethyl acetate. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash chromatography, eluted with toluene:hexane (90:10), to obtain the title compound (0.10 g, yield 14%). MS m / z 508.4 (M+H).

[0639] Step 6: 4-[2-(N-(1-cyclopropylcyclopropyl)anilino)-2-oxo-ethyl]-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylic acid (Example No. 20)

[0640] [ka]

[0641] A 5N sodium hydroxide aqueous solution (4.81 mL, 24.0 mmol) was added to a methanol (5 mL) solution of 4-[2-(N-(1-cyclopropylcyclopropyl)anilino)-2-oxo-ethyl]-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate methyl (0.10 g, 1.00 mmol) and stirred at 80°C. After 18 hours, the reaction mixture was concentrated under reduced pressure. The aqueous layer was acidified with HCl to approximately pH 2 and extracted with dichloromethane. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by reverse-phase preparative HPLC using a 15×30mm BEH HILIC guard column, a water BEH HILIC 100×30mm 5u, 110A column, and a Phenomenex Kinetex EVO C18 100×30mm 5u, 100A column with a 15×30mm EVO guard column, using an in-line heater at 50°C and eluting at 14% to 48% B over 10 minutes with a high pH of 10 mM ammonium bicarbonate aqueous solution (pH 10 / 5% MeOH (solvent A)) and ACN (solvent B). Appropriate fractions were collected and lyophilized to obtain the title compound (0.021 g, yield 21.6%). MS m / z 494.2 (M+H). 1 H NMR(DMSO-d6)d 7.58-7.01(m,9H),3.63-2.83(m,7H),2.12-1.63(m,7H),1.29-1.13(m,2H),0.65-0.31(m,6H).

[0642] Example No. 42 was prepared according to Scheme 8.

[0643] [ka]

[0644] Step 1 2-(1-tert-butoxycarbonyl-4-ethoxycarbonyl-4-piperidyl)acetic acid

[0645] [ka]

[0646] In a 1 L round-bottom flask, potassium carbonate (8.6 g, 62 mmol) was added in a solution of 1-tert-butyl 4-ethyl 4-(2-ethoxy-2-oxo-ethyl)piperidine-1,4-dicarboxylate (10.4 g, 30.3 mmol) in methanol (100 mL) and water (5 mL). The reaction mixture was stirred at 60 °C. After 14 hours, the reaction mixture was concentrated under reduced pressure, then diluted with ethyl acetate, and concentrated again. The reaction mixture was diluted with ethyl acetate and water, and the pH was adjusted to approximately pH 3 using 5N HCl. The reaction mixture was extracted with ethyl acetate, the combined organic solution was washed with brine, dried over Na₂SO₄, filtered, and concentrated to obtain the title product, which was used directly in the next step. MS (m / z): 216.0 (M + H - Boc).

[0647] Steps 2 and 3 Racemic 1-tert-butyl 4-ethyl 4-[2-(N-(3,3-difluorocyclohexyl)anilino)-2-oxo-ethyl]piperidine-1,4-dicarboxylate

[0648] [ka]

[0649] Step 2: Thionyl chloride (10 mL, 137.3 mmol, 100% by mass) was added to a solution of 2-(1-tert-butoxycarbonyl-4-ethoxycarbonyl-4-piperidyl)acetic acid (8.9 g, 28 mmol) in chloroform (100 mL), and the reaction mixture was heated at 60°C for 30 minutes. The reaction solvent was evaporated, treated with toluene, and concentrated (repeated twice) to remove excess thionyl chloride. The crude product was dried in a high-pressure oven at 50°C for 1 hour and used directly in the next step.

[0650] Step 3: 1-tert-butyl 4-ethyl 4-(2-chloro-2-oxo-ethyl)piperidine-1,4-dicarboxylate (13.76 g, 29.27 mmol, 71 mg) in CAN (150 mL, 2850 mmol, 99.8 mg) was combined with N-(3,3-difluorocyclohexyl)aniline (Scheme 2 / Step 9, 6.2 g, 29 mmol, 100 mg) and then pyridine (12 mL, 151.7 mmol, 100 mg), and the mixture was heated to 60°C under nitrogen. The reaction mixture was held at this temperature for 1 hour, then concentrated to obtain a residue, which was packed into a 25 g silica column and flash-chromatographed on a 300 g silica gel column. Elution was performed with 0-100% siRNA / hexane, and the fractions containing the product were combined and concentrated to obtain a mixture. This mixture was dissolved in the minimum volume of DMSO and purified by reverse-phase chromatography using a C18 column. The product-containing fractions were combined, CH3CN was removed, then extracted with Â×2 (2×100 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to obtain the title product. MS m / z 509.0 (M+H-Boc). ES / MS(m / z)(M+H)509.0.

[0651] Chiral separation of racemic 1-tert-butyl 4-ethyl 4-[2-(N-(3,3-difluorocyclohexyl)anilino)-2-oxo-ethyl]piperidine-1,4-dicarboxylate 1.6 g of the racemic 1-tert-butyl 4-ethyl 4-[2-(N-(3,3-difluorocyclohexyl)anilino)-2-oxo-ethyl]piperidine-1,4-dicarboxylate was purified by eluting 10% B at a flow rate of 70 mL / min using SFC-80, Chiralpak IG (30 × 250 mm), mobile phase A: CO2, B: EtOH.

[0652] The eluate from the first peak was collected and freeze-dried to obtain isomer 1 of the title compound (583.7 mg, yield 48.6%, ee: >99%). MS (m / z) 509.2 (M+H).

[0653] The eluate from the second peak was collected and freeze-dried to obtain isomer 2 of the title compound (567.2 mg, yield 47.2%, ee: 98.4%). MS (m / z) 509.2 (M+H).

[0654] Step 4 Isomer 2: 1-tert-butyl 4-ethyl 4-[2-oxo-2-(N-3,3-difluorocyclohexyl]anilino)ethyl]piperidine-1,4-dicarboxylate (Example No. 42)

[0655] [ka]

[0656] To a solution of isomer 2, 1-tert-butyl 4-ethyl 4-[2-oxo-2-(N-3,3-difluorocyclohexyl]anilino)ethyl]piperidine-1,4-dicarboxylate (50 mg, 0.098 mmol, 100 mass%), in tetrahydrofuran (2 mL), an aqueous sodium hydroxide solution (10 mol / L, 1 mL) containing methanol (1 mL) was added. The reaction mixture was heated to 80°C. After heating overnight, the reaction mixture was cooled to room temperature, and then all volatile substances were evaporated by heating under a nitrogen stream. The mixture was diluted with ethyl (approximately 15 mL) and approximately 5 mL of water, and then the pH was neutralized by adding hydrochloric acid (1 mol / L) in diethyl ether (1 mL, 5 mmol, 5 mol / L). The organic matter was extracted twice with ethyl, the combined organic solvent was washed with brine, dried over Na₂SO₄, filtered, concentrated, and dried over the weekend in a high-pressure oven at 50°C to obtain the title product. MS(m / z):479.4(MH). 1H NMR (400.13MHz, CDCl3):7.53-7.49(m,3H),7.11(br s,2H),4.86-4.80(m,1H),3.62-3.53(m,2H),3.31-3.23(m,2H),2.33-2.24(m,3H),2.11-2.01(m,3H),1. 96-1.89(m,1H),1.85-1.73(m,1H),1.71-1.57(m,2H),1.45(s,9H),1.35-1.28(m,3H),1.25-1.18(m,1H).

[0657] Example 2. Assay on in vitro binding affinity Solubilization of compounds The test compound and reference compound were received as dry powder reagents, weighed, and solubilized in 100% DMSO to produce a 10 mM working stock concentration.

[0658] Membrane preparation protocols (hAT2R / HEK293 and rAT2R / HEK293) The hAT2R membrane was prepared from human embryonic kidney (HEK293) cells stably transfected with recombinant human angiotensin-II receptor subtype 2 (hAT2R). Cells derived from stable cell lines were grown in tissue culture flasks to generate large cell populations. Cell pellets (over 1 gm) and these cell pellets were cryopreserved for each receptor isoform before initiating this membrane isolation procedure. The frozen cell pellets were thawed in ice-cold homogenization / resuscitation buffer (50 mM Tris-HCl, pH 7.5) containing one Complete® protease inhibitor tablet (Roche Diagnostics) per 50 mL of buffer, and the cell pellets were resuspended at a ratio of 10 mL of homogenization buffer per gram of starting cell pellet. The cell suspension was homogenized using a Teflon glass homogenizer driven by an overhead motor for 15-20 strokes, and then centrifuged at 1100×g for 10 minutes at 4°C. The supernatant was stored on ice, and the pellet was homogenized in the same manner and centrifuged at 1100×g for 10 minutes at 4°C. Both supernatants were combined and then centrifuged at 35,000×g for 60 minutes at 4°C. The final centrifuged pellet containing the isolated membranes (pellet 2) was resuspended in a buffer containing a protease inhibitor (4-5 mL / g of starting cell paste), rapidly frozen in liquid nitrogen, and then stored at -80°C. Protein concentrations were determined using a BCA kit (ThermoScientific, Inc.) with bovine serum albumin (BSA) as the standard.

[0659] The membrane hAT1R / CHO was purchased from PerkinElmer, Inc. Cell membranes prepared from Chinese hamster ovary (CHO) cells expressing recombinant human angiotensin-II receptor subtype I (hAT1R) were purchased from PerkinElmer (catalog number ES-072-M400UA).

[0660] Receptor binding protocol Receptor binding affinity (K i ) is a human recombinant ([ 125The results were determined by a competitive radioligand binding assay using [I]-Tyr4)-angiotensin-II (2200 Ci / mmol). The assay was performed using a scintillation proximity assay (SPA) with polyvinyltoluene (PVT) wheat germ agglutinin-conjugated SPA beads (Perkin Elmer catalog number RPNQ0001). The radioligand, membrane, and SPA bead reagents were diluted to working stock concentrations using assay buffer containing BSA (50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 0.1% w / v fatty acid-free BSA). Reference control and test compounds were diluted, and a 10-point concentration-response curve was obtained using a 4-fold serial dilution protocol on assay plates, and acoustically dispensed from DMSO stock using automated ECHO instrument technology (Labcyte, Inc.). Concentration response curves were routinely constructed using the highest final assay concentration for the reference angiotensin-II control at 50 nM and the highest final assay concentration for the test compound at 50 μM. To quantify the concentration of [125I]-tyr4 angiotensin-II used in each assay, the radioligand was diluted on the day of the test (2.5-fold working stock), and the direct count of this stock was measured by taking four 20 μL aliquots and counted using a Wizard2 Gamma Counter (PerkinElmer). The hAT2R membrane was combined with PVT-WGA SPA beads to obtain a final assay concentration of 0.25 μg / well of hAT2R membrane + 0.1 mg / well of PVT-WGA SPA beads. The final concentration of the hAT1R membrane PVT-WGA SPA beads was 0.5 μg / well of hAT1R membrane + 0.1 mg / well of PVT-WGA SPA beads. All binding assays were initiated by directly dispensing a 2.5x radioligand stock into a 384-well assay plate (Greiner bio-one, catalog number 781095, white clear bottom) and adding 20 μL of this radioligand stock to a calculated final assay concentration of 66 pM.For all assays, following the addition of the radioligand, a membrane-SPA bead mixture, i.e., hAT2R membrane-SPA bead mixture (30 μL), rAT2R membrane-SPA bead mixture, or AT1R membrane-SPA bead mixture (30 μL), was added to the assay plate. All dispensing steps were performed using a Multiflo FX (Biotek, Inc.) bulk dispenser. After the reagent addition step, the assay plate was sealed and the plate contents were mixed for 1 minute on a benchtop microplate shaker. After a 10-hour incubation at room temperature to allow bead sedimentation and radioligand binding, the bound radioactivity was quantified using a Microbeta Trilux scintillation counter (Perkin Elmer) and expressed as counts per minute (CPM). An unlabeled angiotensin-II control was included in each plate as an experimental assay reference. Results for the experimental test compounds were confirmed by duplication experiments. Separate experiments were performed to obtain n=2 or more.

[0661] Data Analysis Procedure Compounds were tested in a 10-point concentration response curve (CRC) format using plates containing a positive control angiotensin-II positive reference compound and the experimental compound. The maximum binding response (Max) was determined in 32 control wells per plate using assay buffer treatment only, and the minimum binding control or nonspecific binding response (Min) was also determined in 32 wells per plate by treatment with 50 nM angiotensin-II. All test sample concentration responses were normalized against this control response and calculated as the maximum response percentage after correcting for nonspecific binding, as shown below. Specific inhibition % = 100 - [(CPM-Min) / (Max-Min) × 100]

[0662] The specific binding percentage (y-axis) was plotted against the logarithmic concentration of the compound (x-axis). The concentration that results in 50% inhibition of binding (IC) is shown.50 The affinity constant (K) was determined using 4-parameter logistic nonlinear regression analysis (Analyzer, version 17, GeneData Screener). i ) is derived from the following formula IC 50 It was calculated from that. K i =IC 50 / (1+L / K d ) In the formula, L is the concentration of the radioactive ligand used in the experiment (determined for each experiment by counting aliquots of the radioactive ligand mixture), and K d This was the equilibrium binding affinity constant of the radioactive ligand determined from saturated binding analysis. K of hAT2R d =0.066nM, and K of hAT1R d = 0.178 nM.

[0663] The binding affinity of the compounds disclosed herein was determined according to the assay described herein.

[0664] [Table 36-1]

[0665] [Table 36-2]

[0666] Example 3. Comparative data of ex vivo human binding affinity between AT2R and AT1R. The binding affinity of the compounds disclosed herein was determined according to the assay described above.

[0667] [Table 37]

[0668] The selected compounds of this disclosure are up to 10,000 times more selective to AT2R than to AT1R. Compounds that are more selective to AT2R than to AT1R may provide a stronger analgesic effect.

[0669] Example 4. AT2R ex vivo autoradiography and rat binding affinity The ability of a compound to engage its target can be measured by determining the receptor occupancy rate of the compound. An ex vivo autoradiography assay was performed as described herein.

[0670] Twenty male Sprague Dawley rats (140–150 grams, Envigo) were kept under controlled laboratory conditions with free access to food and water during a 12-hour light cycle. On the morning of the experiment, the rats were orally administered either a vehicle (1% (w / v) hydroxyethylcellulose, 0.25% (w / v) polysorbate 80, 0.05% (v / v) antifoaming agent 1510-US) or an appropriate dose of the test compound (5 mL / kg, n=4 rats / group) using the same vehicle. After a predetermined survival time, plasma and adrenal glands were collected and frozen at -80°C until analysis. Frozen 20 μm sections of the adrenal glands from each animal were collected on gelatin-coated slides and stored at -80°C. Autoradiography to detect AT2R occupancy (RO) was performed under low-temperature conditions using a modified method from FMJ Heemskerk, et al, Brain Research 677 (1995) 29-38. Full coupling was detected at 0.3 nM. 125 The binding was defined by I-CGP42112 (a selective AT2R agonist, Perkin Elmer, Inc.), and 10 μM of unlabeled AngII was added to define nonspecific binding. After exposure to a phosphoimager plate (BAS TR2025, GE Healthcare), the bound radioactivity was measured using MCID software (Imaging Research, Inc.) and calibrated... 125The calculations are performed using the I standard (American Radiolabeled Chemicals, Inc.). Specific ligand binding for each animal is calculated by subtracting nonspecific binding from total binding.

[0671] Following the procedure described above, the RO of the selected compounds was determined as shown below. The compounds of this disclosure exhibited high levels of RO.

[0672] [Table 38]

[0673] Furthermore, the amount of the test compound present in each plasma sample was determined and plotted against the % receptor occupancy value, and the IC50 / IC80 values ​​were calculated as shown below (GraphPad Prism).

[0674] [Table 39]

[0675] Example 5. Inhibition of C21-induced increase in skin blood flow. Male Sprague Dawley rats (n=6–8 rats / group, 250–350 grams, Envigo) were maintained under controlled laboratory conditions with free access to food and water during a 12-hour light cycle. On the day of the experiment, the rats were administered the test compound or the corresponding vehicle (po or sc). Anesthesia was induced with 5% isoflurane at a predetermined time after administration of the test compound. Once anesthetized, the abdomen was shaved and the animals were placed in a custom-made dark box equipped with a heater (WPI Air Therm) to maintain the temperature inside the box at 29–30°C. A rectal temperature probe, heating pad, and temperature controller (Harvard Apparatus) were also used to maintain the rats' body temperature during the procedure. Lower doses of isoflurane (1–3%) were used to maintain anesthesia throughout the experiment. Once body temperature stabilized at approximately 36.5°C, two baseline skin blood flow scans were performed at 2.5-minute intervals using a Moor Laser Doppler Imager (Model LDI2-IR). AT2R agonist C21 or vehicle was intradermally injected (30 μL), and skin blood flow was monitored for 25 minutes. Data were analyzed in the area of ​​interest using Moor version 6.0 software to calculate the inhibition of increased skin blood flow. Inhibition of C21-induced skin blood flow indicates that the compound acts as an AT2R antagonist. It is understood that the compounds of this disclosure may act as AT2R antagonists, as exemplified by Example No. 3, which acts as an antagonist.

[0676] [Table 40]

[0677] Example 6. X-ray crystallography of Example 44B X-ray crystallography was performed to determine the absolute configuration of Example No. 44B, as described below.

[0678] Description of the equipment and data acquisition Equipment: Rigaku Oxford Diffraction XtaLAB Synergy four-axis diffractometer equipped with HyPix-6000HE area detector. Cryogenic system: Oxford Cryostream 800 A microfocus source (μ-CMF) with Cu:λ=1.54184Å, 50W, and multilayer mirrors. Distance from crystal to CCD detector: d = 35 mm Tube voltage: 50kV Tube current: 1mA

[0679] A total of 46,940 reflections were collected in the 2θ range of 7.622 to 133.178. The limiting exponents were -9 ≤ h ≤ 10, -15 ≤ k ≤ 15, and -27 ≤ l ≤ 27. This yielded 9,241 intrinsic reflections (Rint = 0.0489). The structure was analyzed using SHELXT (Sheldrick, GM2015. Acta Cryst. A71, 3-8), and SHELXL was used (F 2 (compared to) refined (Sheldrick, GM2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 835 compared to 9241 data points. All reflections were included in the refinement. F 2 The goodness of fit was 1.073, and the final R values ​​for [I>2σ(I)] were R1=0.0412 and wR2=0.1114. The maximum differential peak and Hall were 0.57 and -0.38 Å-3, respectively.

[0680] Explanation of crystal preparation 48 mg of amorphous compound was dissolved in 480 μL of methanol and stored in a partially sealed 4 mL vial. The solution was slowly evaporated at room temperature. Crystals were observed on the second day.

[0681] Summary of results The crystal measures 0.20 × 0.20 × 0.10 mm. 3It was a colorless block with the following dimensions. The symmetry of the crystal structure was attributed to the monoclinic space group P21 with the following parameters: a=8.92190(10)Å, b=12.6874(2)Å, c=23.2348(3)Å, α=90°, β=93.1960(10)°, γ=90°, V=2625.99(6)ų, Z=4, Dc=1.345g / cm³, F(000)=1120.0, μ(CuKα)=0.878mm⁻¹, and T=150.00(10)K. The absolute configuration structure is as follows:

[0682] [ka]

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