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] The present disclosure relates to compounds, pharmaceutical compositions, and methods comprising antagonists of angiotensin II receptor 2 (AT2R), and their use in the treatment of chronic pain, including nociceptive, neuropathic, and mixed pain, particularly in the treatment of osteoarthritis (OA) pain, or diabetic peripheral neuropathy pain (DPNP), or chronic low back pain (CLBP). Chronic pain can be classified into different categories of nociceptive, neuropathic, and mixed based on its mechanism. Nociceptive pain is caused by stimuli (including inflammation) that can potentially cause or actually cause damage to non-neural tissue, thereby activating 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, leading to sensory nervous system maladaptive hypersensitivity. Pain due to diabetic peripheral neuropathy is a typical example of peripheral neuropathic pain. Conditions that exhibit characteristics of both nociceptive and neuropathic pain are classified as mixed pain (for example, chronic low back pain can be a non-limiting example).

Background Art

[0002] Chronic pain is a very prevalent condition that has a major 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 or every day in the past six months, based on data from the National Health Interview Survey. An estimated 8% of the population had chronic pain that restricted their life or work activities on most or every day in the past six months. As a result, chronic pain is a major cause of healthcare costs, and the annual cost of chronic pain management in the United States in 2010 was estimated to be approximately $635 billion. Despite the high disease burden and social impact, the management of chronic pain is currently unsatisfactory. Non-pharmacological therapies alone are not sufficient to relieve pain or improve function, and the available pharmacological therapies are diverse, with only marginal benefits and significant safety risks. Currently, the drugs most frequently used to reduce the most common types of chronic pain are acetaminophen, non-steroidal anti-inflammatory drugs, and opioids. Gabapentinoids, other anti-seizure drugs (such as sodium valproate, carbamazepine, or lamotrigine), and some antidepressants (such as tricyclic drugs or duloxetine) can be used for specific pain disorders. Current pharmacological medical facilities typically provide low levels of effectiveness and give rise to tolerance problems and / or adverse side effects. Opioids are effective for acute pain but are associated with a high risk of abuse and the potential for severe adverse reactions, so treatment options for chronic pain are limited. The physical, emotional, and economic impact of chronic pain on patients and society, combined with the lack of effective and tolerable treatment options, represents a significant unmet medical need.

[0003] Existing treatments for neuropathic pain show moderate efficacy and unfavorable side effects. The renin-angiotensin system (RAS) is involved in neuropathic pain (see, for example, Pain Rep. 2021, 6, e869). The AT2R is associated with pain mechanisms in the nervous system and is expressed in damaged nerves and infiltrating immune cells (Proc. Natl. Acad. Sci. USA, 2018, 115, E8057-E8066). Damaged nerves and painful neuromas have higher AT2R expression than normal nerves. AT2R antagonists have been shown to be useful in relieving pain in animal experiments (Pain Medicine. 2013, 14, 1557; Pain Medicine. 2013, 14, 692) and clinical trials (Lancet. 2014, 383, 1637-1647). Relevant review articles 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 regulating blood pressure, body fluid balance, and pain perception. The angiotensin receptor is a G protein-coupled receptor, and Ang II activates the angiotensin II receptor 1 (AT1R) and the angiotensin II receptor 2 (AT2R).

[0004] The angiotensin type 2 receptor (AT2R) is associated with chronic neuropathic pain and inflammatory pain (see, for example, Behav Pharmacol, 2014, 25, 137, Pain Med, 2013, 14, 1557, Pain Med, 2013, 14, 692, International Publication No. 2007 / 106938, and International Publication No. 2006 / 066361), and there are no efficient treatment options for these. EMA401 (olodaterol), a highly selective AT2R antagonist, has been reported to have analgesic properties. EMA401 was studied for its high selectivity for AT2R and good oral bioavailability in phase 1 and phase 2 clinical trials (Lancet, 2014, 383, 1637), but was terminated due to preclinical toxicity findings. There are no other known AT2R antagonists approved for clinical trials for the treatment of pain. There remains an unmet need for AT2R antagonists with desired clinical properties to provide alternative therapies for treating pain disorders, such as osteoarthritis (OA) pain, or painful diabetic peripheral neuropathy (DPNP), chronic low back pain (CLBP), or other forms of chronic pain.

SUMMARY OF THE INVENTION

MEANS FOR SOLVING THE PROBLEM

[0005] The present disclosure provides compounds useful in the treatment of pain associated with AT2R activity, pharmaceutically acceptable salts thereof, and compositions thereof, including methods for preparing the compounds and compositions, and methods for using the compounds and compositions in the treatment of pain.

[0006] The present disclosure provides a compound of formula (I),

[0007]

CHEMICAL

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

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

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

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

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

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

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

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

[0016] In some embodiments, the present disclosure provides the use of a compound of the present disclosure or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of pain.

DETAILED DESCRIPTION OF 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]

Chemical formula

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

[0022]

Chemical formula

[0023]

Chemical formula

[0024] In another embodiment, the disclosure is a compound of formula (Ia), wherein

[0025]

Chemical formula

[0026]

Chemical formula

[0027]

[0028]

Chemical formula

[0029] is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C

[0030]

Chemical formula

[0031] In another embodiment, the disclosure is a compound of formula (Id), wherein

[0032]

Chemical formula

[0033] In another embodiment, the disclosure provides a compound of formula (Ie) wherein

[0034]

Chemical formula

[0035] In another embodiment, the disclosure is a compound of formula (If) wherein

[0036]

Chemical formula

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

[0038]

Chemical formula

[0039]

Chemical formula

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

[0041]

Chemical formula

[0042]

Chemical formula

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

[0044] [ka] During the ceremony, R 2 is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 Aryl is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 Aryl is one or more R 2a and optionally substituted with Each R 2a are independently halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl; X is C5~C 10 Heteroaryl, C6-C 10 Aryl,

[0045] [ka] And C5~C 10 Heteroaryl or C6-C 10Aryl is optionally substituted with one or more X a and each X is independently halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, a wherein R is H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 4 aryl, and C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 aryl is optionally substituted with one or more R 10 and each R 4a is independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, wherein R 4a is H, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C aryl, and C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 5 aryl is optionally substituted with one or more R 10 and each R 10 is independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, 5a wherein R is H or C1-C6 alkyl, 5a wherein R is C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 6 aryl, and C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C aryl is optionally substituted with one or more R 7 and each R 10 is independently halogen, cyano, or C3-C6 cycloalkyl, 10 wherein R 7a is H, halogen, or C1-C6 alkyl, wherein R 7a is H, halogen, or C1-C6 alkyl, or wherein R 8 is H, halogen, or C1-C6 alkyl, wherein R 9 is H, halogen, or C1-C6 alkyl, or wherein R8 and R 9 combine to form a C3-C6 cycloalkyl, R 10 and R 11 are each H, or R 10 and R 11 combine to form an oxo, R 12 is C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C1-C3-(phenyl), or C3-C 10 heterocycloalkyl, and C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C1-C3-(phenyl), or C3-C 10 heterocycloalkyl is optionally substituted with one or more R 12a s, each R 12a is independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl, a compound, or a pharmaceutically acceptable salt thereof is provided.

[0046] In another embodiment, the disclosure is a compound of formula (Ih-b), wherein

[0047]

Chemical formula

[0048] [Chemical formula] wherein, C5 - C 10 heteroaryl or C6 - C 10 aryl is optionally substituted with one or more X a ; each X is independently halogen, C1 - C6 alkyl, C1 - C6 alkoxyl, or C3 - C6 cycloalkyl; a R 4 is H, C1 - C6 alkyl, C3 - C6 cycloalkyl, or C6 - C 10 aryl; C1 - C6 alkyl, C3 - C6 cycloalkyl, or C6 - C 10 aryl is optionally substituted with one or more R 4a 4a ; each R is independently halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxyl, or C3 - C6 cycloalkyl; 4a R 5 is H, C1 - C6 alkyl, C3 - C6 cycloalkyl, or C6 - C 10 aryl; C1 - C6 alkyl, C3 - C6 cycloalkyl, or C6 - C 10 aryl is optionally substituted with one or more R 5a 5a ; each R is independently halogen, cyano, C1 - C6 alkyl, C1 - C6 alkoxyl, or C3 - C6 cycloalkyl; 5a R 6 is H or C1 - C6 alkyl; R 7 is C1 - C6 alkyl, C3 - C6 cycloalkyl, or C6 - C 10 aryl; C1 - C6 alkyl, C3 - C6 cycloalkyl, or C6 - C 10 aryl is optionally substituted with one or more R 7a ; Each R 7a is independently halogen, cyano, or C3-C6 cycloalkyl, R 8 is H, halogen, or C1-C6 alkyl, R 9 is H, halogen, or C1-C6 alkyl, or R 8 and R 9 combine to form C3-C6 cycloalkyl, R 10 and R 11 are each H, or R 10 and R 11 combine to form oxo, R 12 is C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C1-C3-(phenyl), or C3-C 10 heterocycloalkyl, where C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C1-C3-(phenyl), or C3-C 10 heterocycloalkyl is optionally substituted with one or more R 12a and provides a compound, or a pharmaceutically acceptable salt thereof. Each R 12a is independently halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0049] In another embodiment, the disclosure provides a compound of formula (Ii) wherein

[0050]

Chemical formula

[0051]

Chemical formula

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

[0053]

Chemical formula

[0054] In another embodiment, the disclosure is a compound of formula (Ik), wherein

[0055]

Chemical formula

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

[0057]

Chemical formula

[0058] In some embodiments, R 1 is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 aryl, and C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 aryl is optionally substituted with one or more R 1a .

[0059] In some embodiments, R 1 is C1-C6 alkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is C1 alkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is C2 alkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is C3 alkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is C4 alkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is C5 alkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is C6 alkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is methyl optionally substituted with one or more R 1a . In some embodiments, R 1 is ethyl optionally substituted with one or more R 1a . In some embodiments, R 1 is propyl optionally substituted with one or more R 1a . In some embodiments, R 1 is butyl optionally substituted with one or more R 1a . In some embodiments, R1 is pentyl optionally substituted with one or more R 1a . In some embodiments, R 1 is hexyl optionally substituted with one or more R 1a .

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

[0061] In some embodiments, R 1 is C3-C9 heterocycloalkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is C3 heterocycloalkyl optionally substituted with one or more R 1a . In some embodiments, R 1 is one or more R 1ais C4 heterocycloalkyl optionally substituted with one or more R 1 . In some embodiments, R 1a is C5 heterocycloalkyl optionally substituted with one or more R 1 . In some embodiments, R 1a is C6 heterocycloalkyl optionally substituted with one or more R 1 . In some embodiments, R 1a is C7 heterocycloalkyl optionally substituted with one or more R 1 . In some embodiments, R 1a is C8 heterocycloalkyl optionally substituted with one or more R 1 . In some embodiments, R 1a is C9 heterocycloalkyl optionally substituted with one or more R 1 . In some embodiments, R 1a is tetrahydropyranyl optionally substituted with one or more R

[0062] . In some embodiments, R 1 is C6-C 1a aryl optionally substituted with one or more R 10 . In some embodiments, R 1 is C6 aryl optionally substituted with one or more R 1a . In some embodiments, R 1 is C7 aryl optionally substituted with one or more R 1a . In some embodiments, R 1 is C8 aryl optionally substituted with one or more R 1a . In some embodiments, R 1 is C9 aryl optionally substituted with one or more R 1a . In some embodiments, R 1 is C 1a aryl optionally substituted with one or more R 10 . In some embodiments, R 1 is C6 aryl optionally substituted with one or more R 1ais phenyl optionally substituted.

[0063] In some embodiments, R 1a is halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0064] In some embodiments, R 1a is 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 is iodine.

[0065] In some embodiments, R 1a is C1-C6 alkyl. In some embodiments, R 1a is C1 alkyl. In some embodiments, R 1a is C2 alkyl. In some embodiments, R 1a is C3 alkyl. In some embodiments, R 1a is C4 alkyl. In some embodiments, R 1a is C5 alkyl. In some embodiments, R 1a is C6 alkyl. 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 pentyl. In some embodiments, R 1a is hexyl.

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

[0067] In some embodiments, R 1a is C3-C6 cycloalkyl. In some embodiments, R 1a is C3 cycloalkyl. In some embodiments, R 1a is C4 cycloalkyl. In some embodiments, R 1a is C5 cycloalkyl. In some embodiments, R 1a is C6 cycloalkyl. In some embodiments, R 1a is cyclopropyl. In some embodiments, R 1a When R is cycloalkyl, it is understood that the cycloalkyl may be bonded to R 1 via a covalent bond, or the ring atoms of the cycloalkyl may share the atoms of R 1 . In some embodiments, R 2 is C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 aryl, and C1-C6 alkyl, C3-C6 cycloalkyl, C3-C9 heterocycloalkyl, or C6-C 10 aryl is optionally substituted with one or more R 2a .

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

[0069] In some embodiments, R 2 is C3-C6 cycloalkyl optionally substituted with one or more R 2a In some embodiments, R 2 is C3 cycloalkyl optionally substituted with one or more R 2a In some embodiments, R 2 is C3 cycloalkyl optionally substituted with one or more R 2ais C4 cycloalkyl optionally substituted with. In some embodiments, R 2 is C5 cycloalkyl optionally substituted with one or more R 2a In some embodiments, R 2 is C6 cycloalkyl optionally substituted with one or more R 2a In some embodiments, R 2 is cyclopropyl optionally substituted with one or more R 2a In some embodiments, R 2 is cyclopentyl optionally substituted with one or more R 2a In some embodiments, R 2 is cyclohexyl optionally substituted with one or more R 2a In some embodiments, R

[0070] is C3-C9 heterocycloalkyl optionally substituted with one or more R 2 In some embodiments, R 2a is C3 heterocycloalkyl optionally substituted with one or more R 2 In some embodiments, R 2a is C4 heterocycloalkyl optionally substituted with one or more R 2 In some embodiments, R 2a is C5 heterocycloalkyl optionally substituted with one or more R 2 In some embodiments, R 2a is C6 heterocycloalkyl optionally substituted with one or more R 2 In some embodiments, R 2a is C7 heterocycloalkyl optionally substituted with one or more R 2 In some embodiments, R 2a is C8 heterocycloalkyl optionally substituted with one or more R 2 In some embodiments, R 2a is C9 heterocycloalkyl optionally substituted with one or more R 2 In some embodiments, R 2ais C9 heterocycloalkyl optionally substituted with. In some embodiments, R 2 is tetrahydropyranyl optionally substituted with one or more R 2a .

[0071] In some embodiments, R 2 is C6-C 2a aryl optionally substituted with one or more R 10 . In some embodiments, R 2 is C6 aryl optionally substituted with one or more R 2a . In some embodiments, R 2 is C7 aryl optionally substituted with one or more R 2a . In some embodiments, R 2 is C8 aryl optionally substituted with one or more R 2a . In some embodiments, R 2 is C9 aryl optionally substituted with one or more R 2a . In some embodiments, R 2 is C 2a aryl optionally substituted with one or more R 10 . In some embodiments, R 2 is phenyl optionally substituted with one or more R 2a .

[0072] In some embodiments, R 2a is halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0073] In some embodiments, R 2a is 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 is iodine.

[0074] In some embodiments, R 2a is C1-C6 alkyl. In some embodiments, R 2a is C1 alkyl. In some embodiments, R 2a is C2 alkyl. In some embodiments, R 2a is C3 alkyl. In some embodiments, R 2a is C4 alkyl. In some embodiments, R 2a is C5 alkyl. In some embodiments, R 2a is C6 alkyl. 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 pentyl. In some embodiments, R 2a is hexyl.

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

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

[0077] In some embodiments, when R 2a is cycloalkyl, the cycloalkyl may be bonded to R 2 via a covalent bond, or it is understood that the ring atoms of the cycloalkyl may share the atoms of R 2 .

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

[0079] In some embodiments, X is C5-C 10 heteroaryl, C6-C 10 aryl,

[0080] [Chemical formula] and C5-C 10 heteroaryl or C6-C 10 aryl is optionally substituted with one or more X a .

[0081] In some embodiments, X is C5-C 10 heteroaryl or C6-C 10 aryl, and C5-C 10 heteroaryl or C6-C 10 aryl is optionally substituted with one or more X a .

[0082] In some embodiments, X is a C5-C optionally substituted with one or more X a heteroaryl. In some embodiments, X is a C5 heteroaryl optionally substituted with one or more X 10 . In some embodiments, X is a C6 heteroaryl optionally substituted with one or more X a . In some embodiments, X is a C7 heteroaryl optionally substituted with one or more X a . In some embodiments, X is a C8 heteroaryl optionally substituted with one or more X a . In some embodiments, X is a C9 heteroaryl optionally substituted with one or more X a . In some embodiments, X is a C heteroaryl optionally substituted with one or more X a . In some embodiments, X is pyridyl, pyrimidyl, or 1,2,4-triazolyl, and pyridyl, pyrimidyl, or 1,2,4-triazolyl is optionally substituted with one or more X a . In some embodiments, X is pyridyl optionally substituted with one or more X 10 . In some embodiments, X is pyrimidyl optionally substituted with one or more X a . In some embodiments, X is triazolyl optionally substituted with one or more X a . In some embodiments, X is 1,2,4-triazolyl optionally substituted with one or more X a . In some embodiments, X is pyridyl a . In some embodiments, X is a C6-C aryl optionally substituted with one or more X a . In some embodiments, X is a C6 aryl optionally substituted with one or more X

[0083] In some embodiments, X is a C6-C aryl optionally substituted with one or more X a . In some embodiments, X is a C6 aryl optionally substituted with one or more X 10 . In some embodiments, X is a C7 aryl optionally substituted with one or more X a . In some embodiments, X is a C8 aryl optionally substituted with one or more X ais a C7 aryl optionally substituted with a . In some embodiments, X is one or more X a is a C8 aryl optionally substituted with a . In some embodiments, X is one or more X a is a C9 aryl optionally substituted with a . In some embodiments, X is one or more X a is a C 10 aryl optionally substituted with 10 . In some embodiments, X is phenyl.

[0084] In some embodiments, X a is halogen, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0085] In some embodiments, X a is 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 is iodine.

[0086] In some embodiments, X a is C1-C6 alkyl. In some embodiments, X a is C1 alkyl. In some embodiments, X a is C2 alkyl. In some embodiments, X a is C3 alkyl. In some embodiments, X a is C4 alkyl. In some embodiments, X a is C5 alkyl. In some embodiments, X a is C6 alkyl. 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 pentyl. In some embodiments, X a is hexyl.

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

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

[0089] In some embodiments, X is

[0090]

Chemical formula

[0091] In some embodiments, X is

[0092]

Chemical formula

[0093] In some embodiments, X is

[0094]

Chemical formula

[0095] In some embodiments, X is

[0096]

Chemical formula

[0097] In some embodiments, X is

[0098]

Chemical formula

[0099] In some embodiments, R 4 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 4a .

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

[0101] In some embodiments, R 4 is C1-C6 alkyl optionally substituted with one or more R 4a . In some embodiments, R 4 is C1 alkyl optionally substituted with one or more R 4a . In some embodiments, R 4 is one or more R4a is C2 alkyl optionally substituted with one or more R 4 . In some embodiments, R 4a is C3 alkyl optionally substituted with one or more R 4 . In some embodiments, R 4a is C4 alkyl optionally substituted with one or more R 4 . In some embodiments, R 4a is C5 alkyl optionally substituted with one or more R 4 . In some embodiments, R 4a is C6 alkyl optionally substituted with one or more R 4 . In some embodiments, R 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 hexyl.

[0102] In some embodiments, R 4 is C3-C6 cycloalkyl optionally substituted with one or more R 4a . In some embodiments, R 4 is C3 cycloalkyl optionally substituted with one or more R 4a . In some embodiments, R 4 is C4 cycloalkyl optionally substituted with one or more R 4a . In some embodiments, R 4 is C5 cycloalkyl optionally substituted with one or more R 4a . In some embodiments, R 4 is C6 cycloalkyl optionally substituted with one or more R 4a . In some embodiments, R 4 is one or more R 4ais cyclopropyl optionally substituted by one or more R 4 In some embodiments, R 4a is cyclobutyl optionally substituted by one or more R 4 In some embodiments, R 4a is cyclopentyl optionally substituted by one or more R 4 In some embodiments, R 4a is cyclohexyl optionally substituted by one or more R

[0103] In some embodiments, R 4 is C6-C 4a aryl optionally substituted by one or more R 10 In some embodiments, R 4 is C6 aryl optionally substituted by one or more R 4a In some embodiments, R 4 is C7 aryl optionally substituted by one or more R 4a In some embodiments, R 4 is C8 aryl optionally substituted by one or more R 4a In some embodiments, R 4 is C9 aryl optionally substituted by one or more R 4a In some embodiments, R 4 is C 4a aryl optionally substituted by one or more R 10 In some embodiments, R 4 is phenyl optionally substituted by one or more R 4a In some embodiments, R

[0104] In some embodiments, R 4a is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0105] In some embodiments, R 4a is 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 is iodine.

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

[0107] In some embodiments, R 4a is C1-C6 alkyl. In some embodiments, R 4a is C1 alkyl. In some embodiments, R 4a is C2 alkyl. In some embodiments, R 4a is C3 alkyl. In some embodiments, R 4a is C4 alkyl. In some embodiments, R 4a is C5 alkyl. In some embodiments, R 4a is C6 alkyl. 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 pentyl. In some embodiments, R 4a is hexyl.

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

[0109] In some embodiments, R 4a is a C3-C6 cycloalkyl. In some embodiments, R 4a is a C3 cycloalkyl. In some embodiments, R 4a is a C4 cycloalkyl. 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 is cyclohexyl.

[0110] In some embodiments, R 5 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 5a .

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

[0112] In some embodiments, R 5 is C1-C6 alkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C1 alkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C2 alkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C3 alkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C4 alkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C5 alkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C6 alkyl optionally substituted with one or more R 5a . In some embodiments, R 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 pentyl. In some embodiments, R 5 is hexyl.

[0113] In some embodiments, R 5 is C3-C6 cycloalkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C3 cycloalkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C4 cycloalkyl optionally substituted with one or more R 5a . In some embodiments, R 5 is C3-C6 cycloalkyl optionally substituted with 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 5ais halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0116] In some embodiments, R 5a is 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 is iodine.

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

[0118] In some embodiments, R 5a is C1-C6 alkyl. In some embodiments, R 5a is C1 alkyl. In some embodiments, R 5a is C2 alkyl. In some embodiments, R 5a is C3 alkyl. In some embodiments, R 5a is C4 alkyl. In some embodiments, R 5a is C5 alkyl. In some embodiments, R 5a is C6 alkyl. 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 pentyl. In some embodiments, R 5a is hexyl.

[0119] In some embodiments, R 5a is C1-C6 alkoxyl. In some embodiments, R 5a is C1 alkoxyl. In some embodiments, R5a is C2 alkoxyl. In some embodiments, R 5a is C3 alkoxyl. In some embodiments, R 5a is C4 alkoxyl. In some embodiments, R 5a is C5 alkoxyl. In some embodiments, R 5a is C6 alkoxyl. In some embodiments, R 5a is 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 is hexoxyl.

[0120] In some embodiments, R 5a is C3 - C6 cycloalkyl. In some embodiments, R 5a is C3 cycloalkyl. In some embodiments, R 5a is C4 cycloalkyl. In some embodiments, R 5a is C5 cycloalkyl. In some embodiments, R 5a is 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 is cyclohexyl.

[0121] In some embodiments, R 6 is H or C1 - C6 alkyl. In some embodiments, R 6 is H. In some embodiments, R 6 is C1 - C6 alkyl. 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 pentyl. In some embodiments, R 7 is hexyl.

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

[0125] In some embodiments, R 7 is C6-C 7a optionally substituted with one or more R 10It is aryl. In some embodiments, R 7 is C6 aryl optionally substituted with one or more R 7a . In some embodiments, R 7 is C7 aryl optionally substituted with one or more R 7a . In some embodiments, R 7 is C8 aryl optionally substituted with one or more R 7a . In some embodiments, R 7 is C9 aryl optionally substituted with one or more R 7a . In some embodiments, R 7 is C 7a aryl optionally substituted with one or more R 10 . In some embodiments, R 7 is phenyl optionally substituted with one or more R 7a .

[0126] In some embodiments, R 7a is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[0127] In some embodiments, R 7a is 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 is iodine.

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

[0129] In some embodiments, R 7a is C1-C6 alkyl. In some embodiments, R 7a is C1 alkyl. In some embodiments, R 7ais a C2 alkyl. In some embodiments, R 7a is a C3 alkyl. In some embodiments, R 7a is a C4 alkyl. In some embodiments, R 7a is a C5 alkyl. In some embodiments, R 7a is a C6 alkyl. 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 pentyl. In some embodiments, R 7a is hexyl.

[0130] In some embodiments, R 7a is a C1-C6 alkoxyl. In some embodiments, R 7a is a C1 alkoxyl. In some embodiments, R 7a is a C2 alkoxyl. In some embodiments, R 7a is a C3 alkoxyl. In some embodiments, R 7a is a C4 alkoxyl. In some embodiments, R 7a is a C5 alkoxyl. In some embodiments, R 7a is a C6 alkoxyl. In some embodiments, R 7a is 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 is hexoxyl.

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

[0132] In some embodiments, R 8 is H or C1-C6 alkyl. In some embodiments, R 8 is H. In some embodiments, R 8 is halogen. In some embodiments, R 8 is F. In some embodiments, R 8 is C1-C6 alkyl. In some embodiments, R 8 is C1 alkyl. In some embodiments, R 8 is C2 alkyl. In some embodiments, R 8 is C3 alkyl. In some embodiments, R 8 is C4 alkyl. In some embodiments, R 8 is C5 alkyl. In some embodiments, R 8 is C6 alkyl. 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 pentyl. In some embodiments, R 8is hexyl.

[0133] In some embodiments, R 9 is H or C1-C6 alkyl. In some embodiments, R 9 is H. In some embodiments, R 9 is halogen. In some embodiments, R 9 is F. In some embodiments, R 9 is C1-C6 alkyl. In some embodiments, R 9 is C1 alkyl. In some embodiments, R 9 is C2 alkyl. In some embodiments, R 9 is C3 alkyl. In some embodiments, R 9 is C4 alkyl. In some embodiments, R 9 is C5 alkyl. In some embodiments, R 9 is C6 alkyl. 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 pentyl. In some embodiments, R 9 is hexyl.

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

[0135] In some embodiments, R 10 and R 11 are each H, or R 10 and R 11 combine to form oxo. In some embodiments, R 10 and R 11 are each H. In some embodiments, R 10 and R 11 combine to form oxo.

[0136] In some embodiments, R 12 is C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C1-C3-(phenyl), or C3-C 10 heterocycloalkyl, and C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 aryl, C1-C3-(phenyl), or C3-C 10 heterocycloalkyl is optionally substituted with one or more R 12a .

[0137] In some embodiments, R 12 is C1-C6 alkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C1 alkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C2 alkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C3 alkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C3 alkyl optionally substituted with one or more R 12ais C4 alkyl optionally substituted by one or more R 12 . In some embodiments, R 12a is C5 alkyl optionally substituted by one or more R 12 . In some embodiments, R 12a is C6 alkyl optionally substituted by one or more R 12 . In some embodiments, R 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 pentyl. In some embodiments, R

[0138] . In some embodiments, R 12 is C3-C6 cycloalkyl optionally substituted by one or more R 12a . In some embodiments, R 12 is C3 cycloalkyl optionally substituted by one or more R 12a . In some embodiments, R 12 is C4 cycloalkyl optionally substituted by one or more R 12a . In some embodiments, R 12 is C5 cycloalkyl optionally substituted by one or more R 12a . In some embodiments, R 12 is C6 cycloalkyl optionally substituted by one or more R 12a . In some embodiments, R 12 is cyclopropyl optionally substituted by one or more R 12a . In some embodiments, R 12 is cyclobutyl optionally substituted by one or more R 12a . In some embodiments, R 12 is cyclopentyl optionally substituted by one or more R 12a . In some embodiments, R12 is cyclohexyl optionally substituted with one or more R 12a s.

[0139] In some embodiments, R 12 is C6-C 12a aryl optionally substituted with one or more R 10 s. In some embodiments, R 12 is C6 aryl optionally substituted with one or more R 12a s. In some embodiments, R 12 is C7 aryl optionally substituted with one or more R 12a s. In some embodiments, R 12 is C8 aryl optionally substituted with one or more R 12a s. In some embodiments, R 12 is C9 aryl optionally substituted with one or more R 12a s. In some embodiments, R 12 is C 12a aryl optionally substituted with one or more R 10 s. In some embodiments, R 12 is phenyl optionally substituted with one or more R 12a s.

[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 is isopropyl-phenyl.

[0141] In some embodiments, R 12 is C3-C 12a heterocycloalkyl optionally substituted with one or more R 10 s. In some embodiments, R12 is C3 heterocycloalkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C4 heterocycloalkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C5 heterocycloalkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C6 heterocycloalkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C7 heterocycloalkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C8 heterocycloalkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C9 heterocycloalkyl optionally substituted with one or more R 12a . In some embodiments, R 12 is C 12a heterocycloalkyl optionally substituted with one or more R 10 . In some embodiments, R 12 is cyclopropyl optionally substituted with one or more R 12a . In some embodiments, R 12 is indolinyl optionally substituted with one or more R 12a . In some embodiments, R 12 is tetrahydroquinolinyl optionally substituted with one or more R 12a .

[0142] In some embodiments, R 12a is halogen, cyano, C1-C6 alkyl, C1-C6 alkoxyl, or C3-C6 cycloalkyl.

[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 is iodine.

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

[0145] In some embodiments, R 12a is C1-C6 alkyl. In some embodiments, R 12a is C1 alkyl. In some embodiments, R 12a is C2 alkyl. In some embodiments, R 12a is C3 alkyl. In some embodiments, R 12a is C4 alkyl. In some embodiments, R 12a is C5 alkyl. In some embodiments, R 12a is C6 alkyl. 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 pentyl. In some embodiments, R 12a is hexyl.

[0146] In some embodiments, R 12a is C1-C6 alkoxyl. In some embodiments, R 12a is C1 alkoxyl. In some embodiments, R 12a is C2 alkoxyl. In some embodiments, R 12a is C3 alkoxyl. In some embodiments, R 12a is C4 alkoxyl. In some embodiments, R12a is a C5 alkoxyl. In some embodiments, R 12a is a C6 alkoxyl. In some embodiments, R 12a is 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 is hexoxyl.

[0147] In some embodiments, R 12a is C3-C6 cycloalkyl. In some embodiments, R 12a is C3 cycloalkyl. In some embodiments, R 12a is C4 cycloalkyl. In some embodiments, R 12a is C5 cycloalkyl. In some embodiments, R 12a is 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 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 is phenyl.

[0150] In some embodiments, X is

[0151]

Chem.

[0152] In some embodiments, X is

[0153]

Chem.

[0154] In some embodiments, X is

[0155]

Chem.

[0156]

Chem.

[0157] In some embodiments, X is

[0158]

Chem.

[0159]

Chem.

[0160] In some embodiments, R 1 and R 2 at least one of which is

[0161]

Chem.

[0162] The present disclosure provides the following compound

[0163]

Chem.

[0164] The present disclosure provides the following compound

[0165]

Chem.

[0166] The present disclosure provides the following compound

[0167]

Chem.

[0168] The present disclosure provides the following compound

[0169]

Chem.

[0170] The present disclosure provides the following compound

[0171]

Chem.

[0172] The present disclosure provides a compound as follows

[0173]

Chemical formula

[0174] The present disclosure provides a compound as follows

[0175]

Chemical formula

[0176] The present disclosure provides a compound as follows

[0177]

Chemical formula

[0178] The present disclosure provides a compound as follows

[0179]

Chemical formula

[0180] The present disclosure provides a compound as follows

[0181]

Chemical formula

[0182] The present disclosure provides a compound as follows

[0183] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0184] The present disclosure provides a compound as follows

[0185] [Chemical formula] or a pharmaceutically acceptable salt thereof.

[0186] In some embodiments, the compound is selected from the compounds described in Table I, and pharmaceutically acceptable salts and stereoisomers thereof.

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

[0188] In some embodiments, the compound is selected from the compounds described 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 a compound that is an isotope derivative (e.g., an isotope-labeled compound) of any one of the compounds disclosed herein.

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

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

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

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

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

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

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

[0230] It is understood that a deuterium-labeled compound contains deuterium atoms having a deuterium abundance that is substantially greater than the natural abundance of deuterium, which is about 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, using deuterium-labeled reagents instead of non-deuterium-labeled reagents.

[0232] The compound of the present invention containing the aforementioned deuterium atom or a pharmaceutically acceptable salt thereof is within the scope of the present invention. Furthermore, substitution with deuterium (i.e., 2 H) can provide certain therapeutic benefits resulting from higher 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 commonly understood by one of ordinary skill in the art to which this disclosure belongs. In this specification, the singular form also includes the plural form unless the context clearly indicates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are described below. References cited herein are not admitted to be prior art to the claimed invention. In case of conflict, the specification, including definitions, will control. The materials, methods, and examples are illustrative only and not intended to be limiting.

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

[0235] To avoid misunderstanding, it should be understood that when a group is modified by "described herein" in this specification, the group includes the broadest definition in which it first appears, as well as any and all specific definitions of that group.

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

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

[0238] As used herein, the term "isomer" means a compound having the same molecular formula but different in the order of bonding of atoms or the spatial arrangement of those atoms. Isomers that differ in the spatial arrangement of atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereoisomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers" or sometimes "optical isomers". A mixture containing equal amounts of the individual enantiomeric forms having opposite chirality 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 can exist as individual diastereomers or as a mixture of diastereomers called a "mixture of diastereomers". When one chiral center is present, the stereoisomers can be characterized by the absolute configuration (R or S) of that chiral center. The absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked according to the sequence rule of Cahn, Ingold and Prelog. (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 resulting from rotational hindrance centered on a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These arrangements are distinguished by their names with the prefixes cis and trans or Z and E, which indicate whether their groups are on the same or opposite sides of the double bond within the molecule according to the Cahn-Ingold-Prelog rules.

[0242] It should be understood that the compounds of the present disclosure can be represented as different chiral isomers or geometric isomers. When a compound has a chiral isomer or geometric isomer form, it is intended that all isomeric forms be included within the scope of the present disclosure, and it should also be understood that the naming of the compound does not exclude any isomeric form, and it should be understood that not all isomers have the same level of activity.

[0243] It should be understood that the structures and other compounds contemplated 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 "atropic isomer" refers to a type of stereoisomer in which the spatial arrangement of the atoms of two isomers is different. The existence of atropic isomers is due to the restriction of rotation caused by the rotational hindrance of large groups around the central bond. Such atropic isomers typically exist as mixtures, but as a result of recent advances in chromatography techniques, it has become possible to separate mixtures of two atropic isomers in selected cases.

[0245] As used herein, a "tautomer" is one of two or more structural isomers that exist in equilibrium and are readily convertible from one isomer to another. This conversion results in a formal shift of a hydrogen atom accompanied by a switch of adjacent conjugated double bonds. Tautomers exist as a mixture of a set of tautomers in solution. In a solution where tautomerization is possible, a chemical equilibrium of tautomers is reached. The exact ratio of tautomers depends on several factors including temperature, solvent, and pH. The concept of tautomers that are interconvertible by tautomerization is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, a simultaneous shift of electrons and a hydrogen atom occurs. Ring-chain tautomerism occurs as a result of the reaction of an aldehyde group (-CHO) in a sugar molecule with one of the hydroxy groups (-OH) in the same molecule, converting it to a cyclic (ring-shaped) form as shown by glucose.

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

[0247] Compounds that have the same molecular formula but differ in the nature or order of bonding of atoms or in the spatial arrangement of atoms are called "isomers". Isomers that differ in the spatial arrangement of atoms are called "stereoisomers". Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are mirror images that cannot be superimposed on each other are called "enantiomers". When a compound has an asymmetric center, for example, when the compound is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and are described by the R and S configurational rules of Cahn and Prelog or in a manner in which the molecule rotates the plane of polarization and is designated as dextrorotatory or levorotatory (i.e., as the (+) or (-)-isomer, respectively). A chiral compound can exist as either the individual enantiomers or a mixture thereof. A mixture containing enantiomers in the same proportion is called a "racemic mixture".

[0248] The compounds of the present disclosure may have one or more asymmetric centers. Accordingly, such compounds can be produced as individual (R) or (S) stereoisomers, or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in this specification and the claims is intended to include both the individual enantiomers and mixtures thereof, racemates, or other forms. Planar bonds in chemical structures are intended to include any isomers (e.g., enantiomers or diastereomers) and mixtures thereof. Methods for determining stereochemistry and methods for 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), and are, for example, by synthesis from optically active starting materials or by resolution of racemates. Some of the compounds of the present disclosure may have geometric isomeric centers (E isomers and Z isomers). It should be understood that the present disclosure encompasses all optical isomers, diastereoisomers, and geometric isomers, and mixtures thereof, that possess inflammasome inhibitory activity.

[0249] 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 characterization and determination of the absolute stereochemistry of the individual stereoisomers of the examples provided herein are within the skill of those in the art, and methods for such determination are well known in the pharmaceutical chemistry literature (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 diastereomeric derivatives containing a covalent bond between the chiral auxiliary and the enantiomeric substrate adopt a preferred conformation that can be predicted based on the differential shielding caused by the aromatic ring incorporated into the chiral discrimination reagent.

[0250] The present disclosure also encompasses compounds of the present disclosure as defined herein that include one or more isotope substitutions.

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

[0252] "Pharmaceutically acceptable salts" or "pharmaceutically acceptable salt" refers to one or more inorganic and organic salts of the compounds of the present invention that are relatively non-toxic. It will be understood by those skilled in the art that the compounds of the present invention are capable of forming salts. The compounds of the present invention contain basic heterocycles and thus 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 their preparation 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), S.M. Berge, et al., "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol 66, No.1, January 1977.

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

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

[0255] It should also be understood that certain compounds of the present disclosure may exhibit polymorphism and that the present 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 analysis, differential scanning calorimetry, thermogravimetric analysis, Diffuse Reflectance Infrared Fourier Transform (DRIFT) spectroscopy, Near Infrared (NIR) spectroscopy, solution and solid state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

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

[0257]

Chemical Structure

[0258] The compounds of the present disclosure containing an amine functional group can also form N-oxides. References herein to compounds disclosed herein containing an amine functional group include N-oxides. When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. N-oxides may be formed by treating the corresponding amine with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, the pages of Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (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 the present disclosure can be administered in the form of prodrugs that are decomposed in the human or animal body to release the compounds of the present disclosure. Prodrugs can be used to change the physical properties and / or pharmacokinetic properties of the compounds of the present disclosure. Prodrugs can be formed when the compounds of the present disclosure contain a suitable group or substituent to which a property-modifying group can be attached. Examples of prodrugs include derivatives containing an in vivo cleavable alkyl or acyl substituent at the sulfonylurea group in any one of the compounds of the formulas disclosed herein.

[0260] Accordingly, the present disclosure includes the compounds of the present 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 present disclosure includes compounds of the present disclosure produced by organic synthetic means and such compounds (i.e., compounds of the present disclosure) produced in the body of a human or animal by metabolism of a precursor compound can also be either synthetically produced compounds or metabolically produced compounds.

[0261] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure 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 references: 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", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987.

[0262] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a hydroxy group are, for example, in vivo cleavable esters or ethers. The in vivo cleavable esters or ethers of the compounds of the present disclosure containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the body of a human or animal to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramide cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C1-C 10 alkanoyl groups, such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-C 10 alkoxycarbonyl groups, such as ethoxycarbonyl, N,N-(C1-C6 alkyl)2 carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl group and the benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0263] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having a carboxy group are, for example, in vivo cleavable amides, for example, amides formed using 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 such as glycine or esters thereof.

[0264] Suitable pharmaceutically acceptable prodrugs of the compounds of the present disclosure having an amino group are, for example, amide derivatives cleavable in vivo. Suitable pharmaceutically acceptable amides derived from amino groups include, for example, acetyl, benzoyl, phenylacetyl, and C1-C 10 Amides formed with alkanoyl groups are included. Examples of ring substituents on the phenylacetyl group and benzoyl group include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C1-C4 alkyl)piperazin-1-ylmethyl.

[0265] The in vivo effect of the compound of the present disclosure can be partially exerted by one or more metabolites formed in the body of a human or animal after administration of the compound of the present disclosure. As described above, the in vivo effect of the compound of the present disclosure can also be exerted by the metabolism of the precursor compound (prodrug).

[0266] As used herein, the term "about" refers to a range that includes any normal variation recognized by those skilled in the art. In some embodiments, 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 (greater or lesser) direction of the recited reference value, unless otherwise stated or apparent from the context (except when such a number exceeds 100% of the possible value).

[0267] As used herein, "alkyl", "C1, C2, C3, C4, C5, or C6 alkyl" or "C1-C6 alkyl" is intended to include C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon groups, and C3, C4, C5, or C6 branched-chain saturated aliphatic hydrocarbon groups. For example, C1-C6 alkyl is intended to include C1, C2, C3, C4, C5, and C6 alkyl groups. Examples of alkyl 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 moieties having 1 to 6 carbon atoms. In some embodiments, the straight-chain or branched-chain alkyl has 6 or fewer carbon atoms (e.g., C1-C6 for straight-chain and C3-C6 for branched-chain), and in another embodiment, the straight-chain or branched-chain alkyl has 4 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 need not) be bonded to another substituent (e.g., a heteroatom). For example, an optionally substituted alkyl group can be a fully saturated alkyl chain (i.e., a pure hydrocarbon). Alternatively, the same optionally substituted alkyl group can have substituents different from hydrogen. For example, this can be bonded 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 has the possibility of containing other functional groups, but does not necessarily have any additional functional groups. Substituents can themselves be optionally substituted.

[0269] As used herein, the term "cycloalkyl" refers to 3 to 30 carbon atoms (e.g., C3-C 12 、C3-C 10Or, a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (e.g., fused, bridged, or spiro ring) system having (C3-C8). Examples of cycloalkyl 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 cycloalkyl, only one of the rings in the cycloalkyl needs to be non-aromatic.

[0270] As used herein, the term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic 3- to 8-membered, bicyclic 7- to 12-membered (fused, bridged or spirocyclic) or tricyclic 11- to 14-membered ring system (fused, bridged or spirocyclic) having one or more heteroatoms (e.g., O, N, S, P or Se) independently selected from the group consisting of nitrogen, oxygen and sulfur, e.g., 1 or 1 to 2 or 1 to 3 or 1 to 4 or 1 to 5 or 1 to 6 heteroatoms, or e.g., 1, 2, 3, 4, 5 or 6 heteroatoms, unless otherwise specified.Examples of the heterocycloalkyl group include piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, 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-azaspiro[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’-furo[3,4-b]pyridine]-yl, 3’H-spiro[cyclohexane-1,1’-furo[3,4-c]pyridine]-yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-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, 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-oxa-azaspiro[3.4]octanyl, 2-oxa-azaspiro[3.4]octan-6-yl, etc., but are not limited thereto. In the case of polycyclic heterocycloalkyl, only one of the rings in the heterocycloalkyl needs to be non-aromatic (for example, 4,5,6,7-tetrahydrobenzo[c]isoxazolyl).

[0271] As used herein, the term "aryl" includes groups having aromaticity including "conjugation", or polycyclic systems having one or more aromatic rings, and contains no arbitrary 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, naphthyl, etc.

[0272] As used herein, the term "heteroaryl" refers to one or from one to two or from one to three or from one to four or from one to five or from one to six heteroatoms independently selected from the group consisting of carbon atoms and one or more heteroatoms, such as nitrogen, oxygen and sulfur, or, for example, a stable 5-membered, 6-membered or 7-membered monocyclic or 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic aromatic heterocyclic ring consisting of 1, 2, 3, 4, 5 or 6 heteroatoms is intended to be included. The nitrogen atom may or may not be substituted (i.e., is N or NR, where R is, as defined, H or another substituent). Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O) p , where 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, pyrimidine, etc. The heteroaryl group may be fused or bridged with an alicyclic or heterocyclic ring that is not aromatic so as to form a polycyclic system (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, bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, deazapurine, indolizine.

[0274] As used herein, the term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0275] As used herein, the term "alkoxy" or "alkoxyl" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxyl radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentyloxy 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 describe a carbonyl group (i.e., C(O)).

[0279] As used herein, the term "subject" is interchangeable with the term "subject in need thereof", and both refer to a subject having a disease or an increased risk of developing a disease. "Subjects" include mammals. Mammals can be, for example, humans or suitable non-human mammals, such as primates, mice, rats, dogs, cats, cows, horses, goats, camels, sheep or pigs. The subject may also be a bird or poultry. In one embodiment, the mammal is a human. A subject in need thereof can be a subject previously diagnosed or identified as having a disease or disorder disclosed herein. A subject in need thereof may also be a subject having (e.g., suffering from) a disease or disorder disclosed herein. Alternatively, a subject in need thereof can be a subject at high risk of developing such a disease or disorder compared to the population as a whole (i.e., a subject having a predisposition to developing such a disorder more readily compared to the population as a whole). A subject in need thereof can be refractory or resistant to a disease or disorder disclosed herein (i.e., a disease or disorder disclosed herein that does not respond or has not yet responded to treatment). The subject can be resistant at the start of treatment or can become resistant during treatment. In some embodiments, a subject in need thereof has received and failed all known effective therapies for a disease or disorder disclosed herein. In some embodiments, a subject in need thereof has received at least one prior therapy.

[0280] As used herein, the terms "treatment", "treating", or "mitigating" are each intended to refer to all processes where there may be a delay, interruption, arrest, control, or halt of an existing disorder and / or a reduction in its symptoms, but not necessarily indicating complete elimination of all symptoms. As used herein, the term "effective amount" of a compound of formula (I) refers to an amount effective to inhibit an AT2R-mediated response in a patient, i.e., a dosage. An "effective amount" is determined as an amount capable of treating or eliminating the signs and symptoms of moderate to severe psoriasis in a subject as compared to the subject in an untreated state. In determining the effective amount or dosage of a compound of formula (I), several factors are considered, including but not limited to the compound administered and its particular formulation, the size, age, and general health of the patient; the degree of involvement or severity of the disorder; the response of the individual subject; the mode of administration; and other relevant circumstances.

[0281] The compounds of the present invention are AT2R antagonists and, when administered to a subject in need thereof, may provide a therapeutic benefit while avoiding certain problems associated with other AT2R antagonists. Accordingly, the compounds of the present invention are believed to be useful in the treatment of conditions where AT2R is involved, such as pain. In some embodiments, pain in neuropathic pain.

[0282] The present 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, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent, or excipient. In some embodiments, the present 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, a mixed type of 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, the neuropathic pain is diabetic peripheral neuropathic pain (DPNP). In some embodiments, the back pain is chronic low back pain (CLBP). In some embodiments, the visceral pain is pain associated with irritable bowel syndrome (IBS), bladder pain, prostatic pain, or vulvar pain.

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

[0284] The present 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. The present 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, a 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. The present 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, the present 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 present 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 present 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 present 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 present 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 present 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, prostatic pain, or vulvar pain).

[0285] The composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof may be formulated into unit dosage forms, and each dosage form contains from about 0.5 to about 1000 mg of the active ingredient. The term "unit dosage form" refers to physically discrete units suitable as unit dosages for human subjects and other mammals, and each unit is associated with at least one suitable pharmaceutically acceptable carrier, diluent, and / or excipient and contains a predetermined amount of the active material calculated to produce the desired therapeutic effect. It will be understood that the actual amount of the compound administered will be determined by the physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being 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 contemplated to be used for treating pain (e.g., neuropathic pain) by long-term administration.

[0286] The compounds of the present 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 accompanying examples.

[0287] In the description of the synthetic methods described herein and in any of the referenced synthetic 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 period, and work-up procedure, can be selected by those skilled in the art.

[0288] It is understood by those skilled in the art of organic synthesis that the functional groups present in the various parts of the molecule must be compatible with the reagents and reaction conditions utilized.

[0289] Furthermore, additional compounds of the present disclosure can be readily prepared by utilizing the procedures described herein in conjunction with ordinary techniques in the art. Those skilled in the art will readily understand that the conditions and known variations 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 the present disclosure are readily available by various synthetic routes, some of which are exemplified in the attached examples. Those skilled in the art will readily recognize which types of reagents and reaction conditions should be used to obtain the compounds of the present disclosure, and how they should be applied and adapted in any particular case (when necessary or useful). Further, some of the compounds of the present disclosure can be readily synthesized by reacting other compounds of the present disclosure under suitable conditions, for example, by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions (which methods are well known to those skilled in the art), or by converting one particular functional group present in the compounds of the present disclosure, or a suitable precursor molecule thereof, into another. Similarly, those skilled in the art can apply synthetic protecting (or protective) 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 and are described in detail, for example, in P.G.M. 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 invention can be made according to schemes similar to those described herein.

[0292] Certain abbreviations are defined as follows.

[0293]

Table 2

[0294] Example 1. Synthesis of Example Numbers 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] [Chemical formula]

[0296] Step 1: Ethyl 2-(1-benzyl-4-piperidylidene)-2-cyanoacetate

[0297] [Chemical formula]

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

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

[0300] [Chemical formula]

[0301] To a solution of ethyl 2-(1-benzyl-4-piperidylidene)-2-cyanoacetate (505 g, 1.78 mol) in EtOH (2.50 L) and H2O (500 mL) was added KCN (145.31 g, 2.23 mol) at 20 - 25 °C under a nitrogen atmosphere. The reaction mixture was stirred at 80 - 85 °C for 4 h. Seven reactions of the same scale were set up simultaneously. After the reaction was cooled to room temperature, all seven reactions were combined and concentrated directly under high vacuum. Water (5.00 L) was added to the mixture, and the mixture was extracted with ethyl acetate (5.00 L × 3). The combined organic phases were washed with brine (5.00 L), dried over anhydrous Na2SO4, and concentrated under high vacuum. The crude product was triturated with petroleum ether:tert-butyl methyl ether = 1:1 (5000 mL), filtered, and dried to give the title compound (2.38 kg, yield 80.0%) as a yellow solid. 1 1H NMR (400.13 MHz, 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]

Chemical formula

[0304] To a solution of KOH (540 g, 9.63 mol) in H2O (1700 mL) was added 1-benzyl-4-(cyanomethyl)piperidine-4-carbonitrile (576 g, 2.41 mol). The reaction mixture was refluxed at 95 °C to 100 °C for 24 h. Five reactions of the same scale were set up simultaneously. The mixture was cooled to 20 °C to 25 °C, and all five reactions were combined. The reaction mixture was adjusted to pH 5 - 6 with HCl (12.0 M, 3.00 L) at 20 °C to 25 °C, and the mixture was filtered to obtain a filter cake. The filter cake was washed with H2O (6.00 L), and the cake was triturated with MeCN (4.50 L) at 25 °C for 30 min and filtered. The product was dried in a high vacuum oven for 15 h to give the title product (2.04 kg, yield 61.1%) as a white solid. MS m / z 188.1 (M+H); 1 H NMR (400.13 MHz, 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]

Chem.

[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) at 0 °C under N2, 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 h. The reaction was concentrated under high vacuum to remove the solvent, the residue was dissolved in DCM (300 mL), the solution was slowly added to 10% aqueous K2HPO4 solution (500 mL), and the mixture was maintained at pH 8. The aqueous layer was extracted with DCM (300 mL × 3), the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under high vacuum to give the title product (10.5 g, 40.5 mmol, 100 mass%, yield 56.1%). 1 H NMR (400 MHz, 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-phenyl-aniline

[0309] [Chemical formula]

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

[0311] The compounds in the following table were prepared according to the above procedure.

[0312] [Table 3]

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

[0314] [Chemical Structure]

[0315] In a microwave tube, a mixture of 2-fluoro-N-phenyl-aniline (1.3 g, 6.7 mmol), 8-benzyl-2-oxa-8-azaspiro[4.5]decan-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 purified by reverse-phase preparative-HPLC: Xtimate C18 column (150 * 40 mm * 10 μm), with solvent A: water (NH4OH + NH4HCO3) and solvent B: ACN, eluting in 30% B to 70% B in fraction units. Appropriate fractions were combined and lyophilized 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]

Chem.

[0320] To a solution of diphenylamine (6.65 g, 38.9 mmol) in tetrahydrofuran (30.0 mL) was added dropwise n-butyllithium (16 mL, 40 mmol, 2.5 mol / L) in hexane at -78 °C under N2, 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 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 vacuum to obtain a brown residue. Water (50 mL) and formic acid (10 mL) were added to the residue. The insoluble material was collected by filtration, washed with ethyl acetate (60 mL × 4), and the solid was dried under high vacuum to obtain the title compound (5.66 g, 97 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-carboxylic acid hydrochloride

[0322]

Chemical formula

[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) was added hydrochloric acid aqueous solution (1.0 ml, 36.5 mass%) all at once, and then Pd / C (420 mg, 0.3962 mmol, 10 mass%) was added 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 × 5). The filtrate was concentrated to obtain the crude title product (630 mg, 87.7 mass%, yield 90.3%). MS m / z 357.0 (M+H-HCl).

[0324] The compounds in the following table were prepared according to the above procedure.

[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]

Chemical formula

[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 layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under high vacuum to obtain the title product (19.42 g, 75 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 in the following table were prepared according to the above procedure.

[0331]

Table 6-1

[0332]

Table 6-2

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

[0334]

Chemical formula

[0335] Ethyl 2,2-difluoro-2-(2-fluorophenyl)acetate

[0336]

Chemical formula

[0337] To a stirred solution of ethyl bromodifluoroacetate (5.00 g, 24.1 mmol) in DMSO (20 mL), 1-fluoro-2-iodobenzene (4.5 g, 19 mmol) and copper (5.1 g, 79 mmol) were added, and the resulting solution was heated at 50 °C overnight under N2. After completion, the reaction mixture was cooled to room temperature, and then 60 mL of water was added to the mixture. The aqueous phase was extracted with ethyl acetate (50 mL × 3). Subsequently, the combined organic phases were washed with brine (60 mL × 4), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with 0% - 10% ethyl acetate in petroleum ether, to give 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=7.6Hz,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]

Chem.

[0340] To a stirred solution of ethyl 2,2-difluoro-2-(2-fluorophenyl)acetate (1.030 g, 4.485 mmol) in tetrahydrofuran (8.0 mL, 97 mmol) and water (0.8 mL) was added lithium hydroxide (385 mg, 8.708 mmol), and the resulting solution was stirred at 60 °C for 3 h under N2. When complete, the reaction 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 × 3). The combined organic phases were then washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the title compound (862 mg, 96% by mass, 97.05% yield) as a purple oil. 1 1H NMR (400 MHz, CDCl3): 11.36 (d, J = 4.0 Hz, 1H), 7.72 - 7.64 (m, 1H), 7.53 (q, J = 6.8 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.21 - 7.12 (m, 1H).

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

[0342]

Chem.

[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) was added oxalyl chloride (90 μL, 1.017 mmol), followed by 1 drop of DMF at 0 °C. The reaction mixture was stirred at room temperature for 1 h. When complete, the reaction mixture was concentrated under high vacuum to give the crude compound (92 mg, 90% by mass, 78.62% yield) as a pale yellow solid. The crude material 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]

Chemical formula

[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 mass %) in tetrahydrofuran (1.0 ml), N,O-bis(trimethylsilyl)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, and then indoline-1-carbonyl chloride (122.0 mg, 0.470 mmol, 75 mass %) was added to the reaction mixture, which was then stirred at room temperature overnight. This reaction was combined with the same reaction on a smaller scale of 4-[2-(N-(2-fluorophenyl)anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid; hydrochloride (30.0 mg, 0.223 mmol, 87.7 mass %). The reaction mixture was concentrated to obtain a residue, and purified by reverse-phase preparative HPLC (Xtimate C18 100 * 30 mm * 10 μm), mobile phase A: water - formic acid, mobile phase B: ACN, eluting with 50 - 70% B in 10 minutes and then to 100% B. The appropriate fractions were combined and lyophilized to obtain the title product (42.6 mg, yield 38.0%). MS m / z 502.4 (M+H); 11H NMR (400.21 MHz, DMSO-d6): 12.40 (s, 1H), 7.53 - 7.46 (m, 10H), 7.11 (t, J = 7.38 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 7.50 Hz, 1H), 3.79 (t, J = 8.3 Hz, 2H), 3.35 - 3.17 (m, 4H), 2.97 (t, J = 8.2 Hz, 2H), 2.08 (s, 2H), 2.01 - 1.97 (m, 2H), 1.58 - 1.51 (m, 2H).

[0347] Examples Nos. 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 above procedure.

[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]

Chem.

[0356] Step 1: Methanol (50 mL) was added to a solution of diethoxymethoxyethane (5 g, 33.7 mmol, 100% by mass) and formohydrazide (1.4 g, 23 mmol, 98% by mass) at 20 °C. The mixture was stirred at 60 °C for 3 hours. After cooling to 40 °C, pentan-1-amine (2 g, 22.7 mmol) was added to the mixture, and the mixture was stirred at 60 °C overnight. The mixture was cooled to room temperature and concentrated under reduced pressure. 20 mL of water was added to the reaction mixture, and then the mixture was extracted with dichloromethane (20 mL × 4). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under high vacuum. The residue was purified by flash silica gel chromatography, eluting 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 1H NMR (400.13 MHz, DMSO-d6): 8.52 (s, 2H), 4.01 (t, J = 7.2 Hz, 2H), 1.71 (td, J = 7.4, 14.8 Hz, 2H), 1.34 - 1.22 (m, 2H), 1.22 - 1.09 (m, 2H), 0.84 (t, J = 7.3 Hz, 3H)

[0357] Step 2: N-Bromosuccinimide (7 g, 38.5 mmol) was added to a solution of 4-pentyl-1,2,4-triazole (2.5 g, 16.0 mmol, 90% by mass) in DMF (10 mL) at 20 °C. 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 × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, and concentrated under high vacuum. The residue was purified by flash silica gel chromatography, eluting with 0% - 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 (400 MHz, DMSO-d6): 3.98 (t, J = 7.4 Hz, 2H), 1.67 (m, J = 7.3 Hz, 2H), 1.38 - 1.20 (m, 4H), 0.87 (t, J = 7.1 Hz, 3H)

[0358] Step 3: [(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 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). Nitrogen was passed through the flask. The resulting mixture was stirred under nitrogen at 120 °C overnight. When completed, the reaction mixture was cooled to room temperature, concentrated under high vacuum, the pH was 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 * 30 mm *Purification was performed by eluting with 10 μm, mobile phase A: water - formic acid, mobile phase B: ACN, from 50 - 80% B in 10 minutes and then up to 100% B. Appropriate fractions were combined and lyophilized to obtain the title product (75.6 mg, yield 25.0%). MS m / z 554.2, 556.2 (M + H); 1 H NMR (400.13 MHz, DMSO - d6): 7.60 - 7.02 (m, 10H), 3.75 (t, J = 7.4 Hz, 2H), 3.03 (d, J = 8.9 Hz, 1H), 2.98 (d, J = 5.5 Hz, 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 = 7.3 Hz, 3H).

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

[0360] [Chemical formula]

[0361] Step 1: A flask was charged under nitrogen with 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). Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (312 mg, 0.405 mmol) was added to the suspension. The reaction mixture was stirred at 95 °C for 6 h under N2. Upon completion, the reaction was cooled to room temperature, poured into water (50 mL) and extracted with DCM (40 mL × 3). The combined organic phases were then washed with brine (50 mL), dried over anhydrous Na2SO4 and concentrated in high vacuum. The residue was purified by normal silica gel chromatography (PE:EtOAc = 1:0~3:1) to give 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) were added 4-chloro-5-cyclopropyl-pyrimidine (105 mg, 0.618 mmol, 91% by mass) and potassium carbonate (245 mg, 1.77 mmol). The mixture was stirred at 110 °C for 5 h under nitrogen. Upon completion, the reaction mixture was cooled to room temperature, 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 × 3). The combined organic phases were then dried over anhydrous Na2SO4 and concentrated in high vacuum. The residue was purified by preparative HPLC, column: Xtimate C18 100 * 30 mm *Purification was carried out by eluting with 10 μm, mobile phase A: water - formic acid, mobile phase B: ACN, with 25 - 55% B for 14 minutes and then up to 100% B. The appropriate fractions were combined and lyophilized to obtain 1-(5-cyclopropylpyrimidin-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-chloropyrazin-2-yl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid (Example No. 109)

[0364]

Chemical formula

[0365] To a solution of 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid; hydrochloride (300 mg, 0.7202 mmol, 90% by mass) in N,N-dimethylacetamide (4.0 mL), 2,3-dichloropyrazine (361 mg, 2.40 mmol) and potassium carbonate (332 mg, 2.40 mmol) were added. The mixture was stirred at 110 °C for 5 hours under N2. 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 * 30 mm *Purified by HPLC (column: Phenomenex C18 75 × 30 mm, mobile phase A: water - 0.225% formic acid, mobile phase B: ACN, elution from 45 - 75% B in 15 minutes, then to 100% B, flow rate 25 mL / min). Appropriate fractions were combined and lyophilized to give the title product (45 mg, 99.3% by mass, yield 13.8%) as a white solid. MS m / z 451.0 (M + H); 1 1H NMR (400.15 MHz, DMSO - d6): 12.37 (br, 1H), 8.22 (d, J = 2.5 Hz, 1H), 7.95 (d, J = 2.5 Hz, 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 - cyclopropylimidazol - 2 - yl)-4-[2 - oxo - 2-(N - phenylanilino)ethyl]piperidine - 4 - carboxylic acid, formic acid (Example No. 110)

[0367]

Chemical Structure

[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) was added N,O - bis(trimethylsilyl)acetamide (1.3 mL, 5.2 mmol). The mixture was stirred at room temperature for 0.5 h, then isothiocyanatocyclopropane (222 mg, 2.2 mmol) was added. The mixture was stirred at 50 °C for 2 h. Upon completion, the reaction was concentrated. The residue was purified by preparative HPLC (column: Phenomenex C18 75 * 30 mm *Purification was carried out by eluting with 3 μm, mobile phase A: water (10 mM NH4HCO3), mobile phase B: ACN, from 10 - 80% B and then to 100% B. Appropriate fractions were combined and lyophilized to obtain 1-(cyclopropylcarbamothioyl)-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-(cyclopropylcarbamothioyl)-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 at room temperature for 4 hours under N2. The reaction 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-dimethoxyethan-1-amine (136 mg, 1.27 mmol) in acetonitrile (4 mL). The reaction was stirred at room temperature overnight. 4.0 N HCl (4.0 mL) was added and the mixture was stirred at room temperature for 16 hours. When completed, the reaction was neutralized with saturated Na2CO3 until the pH reached 6, extracted with ethyl acetate (10 mL × 2), the organic layer was further washed with brine (20 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Xtimate C18 100 * 30 mm *Purified by (10 µm, mobile phase A: water - 0.225% formic acid, mobile phase B: ACN, elution with 15 - 45% B in 4 minutes, then up to 100% B). The appropriate fractions were combined and lyophilized to obtain the product 1-(1-cyclopropylimidazol-2-yl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid, formic acid (37.0 mg, 97.5 mass%, yield 15.8%). MS m / z 445.1 (M + H - HCO2H); 1 H NMR (400.13 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.52 - 7.17 (m, 10H), 6.73 (d, J = 1.4 Hz, 1H), 6.47 (d, J = 1.3 Hz, 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, 8.6 Hz, 2H), 0.96 - 0.81 (m, 4H).

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

[0372]

Chemical Structure

[0373] To a mixture of 3-chloro-[1,2,4]triazolo[4,3-a]pyridine (96 mg, 0.61 mmol) and 4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylic acid, hydrochloride (85 mg, 0.20 mmol, 90 mass%) in 2-methyl-2-butanol (1.0 mL), tBuXPhos Pd G3 (30 mg, 0.036 mmol) and cesium carbonate (200 mg, 0.61 mmol) were added, and the mixture was stirred overnight at 120 °C under N2. When completed, the mixture was cooled to room temperature, and the crude material was separated by preparative HPLC (Instrument NCX, column: Phenomenex Gemini-NX C18 100 * 30 mm *Purified by HPLC (column: Phenomenex Gemini C18 250 × 5 mm, mobile phase A: water - 0.225% formic acid, mobile phase B: ACN, elution from 10 - 70% B in 15 min, then to 100% B, flow rate: 25 mL / min). Appropriate fractions were combined and lyophilized to give the title product (44.2 mg, 99.6% by mass, yield 47.4%). MS m / z 456.4 (M + H); 1 1H NMR (400 MHz, DMSO - d6): δ 8.10 (d, J = 7.0 Hz, 1H), 7.59 (d, J = 9.3 Hz, 1H), 7.55 - 7.08 (m, 11H), 6.85 (t, J = 6.7 Hz, 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]

Chemical Structure

[0376] Step 1: To a solution of 2 - fluoro - 3 - iodo - pyridine (65 mg, 0.2915 mmol) and 4-[2 - oxo - 2-(N - phenylanilino)ethyl]piperidine - 4 - carboxylic acid, hydrochloride (100 mg, 0.26 mmol) in tert - butanol (1.0 mL) was added potassium carbonate (220 mg, 1.59 mmol). The mixture was stirred at 80 °C for 3 h under N2. The mixture was cooled to room temperature and concentrated. The residue was purified by preparative HPLC (column: Phenomenex Gemini C18 250 * 50 mm *Purified by elution at 22 minutes with 35 - 55% (then to 100% B) of mobile phase A: water - 0.05% ammonia hydroxide (v / v) and mobile phase B: ACN. 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) were added tris(dibenzylideneacetone)dipalladium(0) (8 mg, 0.00856 mmol) and RuPhos (4 mg, 0.00814 mmol). The mixture was stirred at 100 °C overnight under N2. The mixture was cooled to room temperature, combined with a pilot run, and concentrated. The residue was purified by preparative HPLC (column: Xtimate C18 100 * 30 mm * Purified by elution with 25 - 55% B then to 100% B using mobile phase A: water - 0.225% formic acid and mobile phase B: CH3CN. Appropriate fractions were combined and lyophilized to obtain the title product (3.5 mg, 95% by mass, yield 41%). MS m / z 456.4 (M + H); 1 1H NMR (400.13 MHz, DMSO-d6): 7.99 (dd, J = 1.6, 4.8 Hz, 1H), 7.49 - 7.18 (m, 10H), 7.12 (dd, J = 1.5, 7.6 Hz, 1H), 6.85 (dd, J = 4.8, 7.5 Hz, 1H), 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 Nos. 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]

Chem.

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

[0381]

Chem.

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

Chem.

[0385] O1-tert-Butyl O4-methyl 4-(cyanomethyl)piperidine-1,4-dicarboxylate (8.25 g, 27.75 mmol, 95 mass %) was treated with hydrochloric acid (60 mL, 36%), and the reaction mixture was heated to 100 °C and stirred overnight. The reaction was cooled to room temperature and concentrated under high vacuum to give the crude title compound (7.48 g, 80 mass %, yield 96.4%), which was used directly in the next step without purification. 1 1H NMR (400.13 MHz, 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]

Chem.

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

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

[0390]

Table 8

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

[0392]

Chemical formula

[0393] A solution of 4-(carboxymethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylic acid (3.2 g, 8.7 mmol, 90% by mass) in methanol (6.0 mL) and acetonitrile (60.0 mL), cooled on ice, was added dropwise with (diazomethyl)trimethylsilane (2.0 mol / L) in hexane (17.0 mL, 34 mmol, 2.0 mol / L), and then N,N-diisopropylethylamine (3.0 mL, 17.17 mmol) was added dropwise. 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 × 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated to obtain a 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, yield 83%). MS m / z 361.0 (M+H).

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

[0395]

Table 9

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

[0397]

Chemical formula

[0398] Methyl 4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate: To a mixture of acetic acid (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 added titanium(IV) isopropoxide (4.0 mL, 13 mmol). The mixture was stirred at 80 °C for 2 h. After the reaction mixture was cooled to room temperature, sodium triacetoxyborohydride (2.1 g, 9.6 mmol) was added. The mixture was stirred at room temperature for 1 h. Upon completion, the mixture was quenched with water (5 mL) and extracted with EtOAc (10 ml × 3). The combined organic layers were dried over Na2SO4, filtered and concentrated to collect the residue. The residue was purified by preparative HPLC (YMC-Triart Prep C18 250×50 mm×10 um, mobile phase A: water - 0.225% formic acid, mobile phase B: ACN, elution from 10 - 50% B in 20 min and then to 100% B, flow rate: 110 mL / min). The eluate was concentrated and the residue aqueous solution was basified 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 vacuum to give the title compound (760 mg, 90% by mass, 57% yield). MS m / z 366.2 (M+H);

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

[0400]

Chemical Structure

[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 added lithium hydroxide (0.36 g, 14.72 mmol) at room temperature all at once, and the mixture was stirred at room temperature overnight. Monitoring the reaction by LCMS, additional lithium hydroxide (0.202 g, 8.27 mmol) was added and the reaction was stirred at room temperature overnight. 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 vacuum to obtain a residue. The residue was purified by silica gel flash eluting with 0 - 6% MeOH / DCM to obtain the title compound (1.52 g, 95% by mass, yield 58.0%). MS m / z 347 (M + H).

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

[0403]

Table 10

[0404] Step 6: rac-3-anilinocyclohexanone

[0405]

Chemical formula

[0406] To a mixture of aniline (20.0 g, 208.3 mmol) in 2-cyclohexen-1-one (31.0 ml, 310 mmol) was added 4-dimethylaminopyridine (7.8 g, 62 mmol, 97% by mass) at room temperature. The mixture was stirred at room temperature for 3 days to obtain a red solution. The reaction mixture was purified by silica gel flash chromatography eluting with 0 - 15% EA / petroleum to obtain the title compound (31.7 g, yield 68.3%, 1A purity of 85% was obtained by \(^1\)H NMR. 1 \(^1\)H NMR (400.14 MHz, CDCl\(_3\)): δ 7.15 - 7.11 (m, 2H), 6.70 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 8.0 Hz, 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]

Chemical formula

[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) was added dropwise (2,2,2-trifluoroacetyl) 2,2,2-trifluoroacetate (14.0 ml, 99.6 mmol) at 0 °C. The mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure to give the crude product (10.4 g, 90% by mass, yield 48.7%), which was used directly in the next step without further purification. 1 \(^1\)H NMR (400.21 MHz, CDCl\(_3\)): δ 7.50 - 7.45 (m, 3H), 7.25 (d, J = 6.3 Hz, 1H), 7.15 (d, J = 6.8 Hz, 1H), 4.84 - 4.76 (m, 1H), 2.67 - 2.62 (m, 1H), 2.41 - 2.36 (m, 1H), 2.27 (t, J = 13.3 Hz, 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]

Chem.

[0413] To a solution of 2,2,2-trifluoro-N-[(rac)-3-oxocyclohexyl]-N-phenyl-acetamide (10.4 g, 32.8 mmol, 90 wt%) in dichloromethane (100.0 mL) cooled on ice was added diethylaminosulfur trifluoride (9.0 mL, 66.65 mmol). The mixture was warmed to room temperature and then stirred at room temperature for 2 hours. The reaction was quenched by adding saturated NaHCO3 (100.0 mL), and the mixture was extracted with dichloromethane (150 mL×2). The combined organic layers were washed with brine (100.0 mL), dried over Na2SO4, and concentrated under high vacuum to give a residue. The residue was purified by silica gel flash chromatography, eluting with 0 - 40% dichloromethane / petroleum ether, to give the title compound (6.5 g, 95 wt%, yield 61%). 1 1H NMR (400.14 MHz, CDCl3): 7.41 - 7.35 (m, 3H), 7.09 (t, J = 7.6 Hz, 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]

Chem.

[0416] A solution of 2,2,2-trifluoro-N-phenyl-N-[(3R,3S)-3,3-difluorocyclohexyl]acetamide (6.5 g, 20 mmol, 95% by mass) in methanol (100.0 mL) and water (10.0 mL) was added dropwise with potassium carbonate (8.6 g, 61 mmol) at room temperature. The reaction mixture was heated to 65 °C and after 4 hours, the reaction was cooled to room temperature and water was added (100.0 mL). The mixture was extracted with ethyl acetate (200 mL × 3). The combined organic layers were washed with brine (20.0 mL), dried over Na2SO4 and concentrated in high vacuum to give a residue. The residue was purified by silica gel flash chromatography eluting with 0 - 22% ethyl acetate / petroleum ether to give the title compound (3.54 g, 90% by mass, 75% yield). MS m / z 212.2 (M+H). 1 1H NMR (400.13 MHz, CDCl3): 7.14 - 7.09 (m, 2H), 6.67 (t, J = 7.3 Hz, 1H), 6.57 (d, J = 7.8 Hz, 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 in the following table were prepared as described above.

[0418] [Table 12]

[0419] N-Cyclopentylaniline

[0420] [Chemical formula]

[0421] To a solution of cyclopentanone (3.05 g, 35.5 mmol) in dichloromethane (35 mL) were added aniline (3.35 g, 35.6 mmol) and sodium triacetoxyborohydride (9.4 g, 43.0 mmol), and then the mixture was stirred at room temperature overnight. Upon completion, the reaction was diluted with water (50 mL) and extracted with dichloromethane (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated under high vacuum to give a residue. The residue was purified by flash silica gel chromatography eluting with 0 - 8% ethyl acetate / petroleum ether to give 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]octan - 7 - amine

[0423]

Chem.

[0424] To a solution of 4 - oxaspiro[2.5]octan - 7 - one (116 mg, 0.83 mmol, 90% by mass) and aniline (83 mg, 0.87 mmol) in methanol (1.5 mL) were added acetic acid (0.03 mL, 0.5 mmol) and sodium cyanoborohydride (85 mg, 1.34 mmol). The mixture was stirred at room temperature overnight. Upon completion, the mixture was quenched with 1N HCl (0.5 mL) and evaporated under high vacuum. The residue was dissolved in EtOAc (10 mL×2) and washed with brine (3 mL×2). The organic layer was dried over Na2SO4, filtered, and evaporated under high vacuum. The residue was purified by flash silica gel chromatography eluting with 0 - 20% ethyl acetate in petroleum ether to give the title compound (80 mg, 95% by mass, yield 45.17%). 11H NMR (400 MHz, CDCl3): δ 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 above procedure.

[0426]

Table 13

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

[0428]

Chemical Structure

[0429] N-[(racemic)-3,3-difluorocyclohexyl]-2-fluoro-aniline (9.0 g) was dissolved in the minimum amount of MeOH, and the solution was separated by elution with SFC: DAICEL CHIRALPAK AD (250 mm * × 50 mm, 10 μm); mobile phase A: CO2 B: 0.1% NH3·H2O in MeOH with 5% B, flow rate: 140 mL / min.

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

[0431] The eluate having the major second peak (80%) was collected and lyophilized. Then, SFC: DAICEL CHIRALCEL OD (250 mm* Repurified by (column dimensions: 30 mm, 10 μm; mobile phase A: CO2, B: 0.1% NH3·H2O in isopropanol, elution at 15% B, flow rate 60 mL / min), and the title compound was obtained as the 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]

Chemical formula

[0434] Into a 50 mL flask were charged 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). The mixture was stirred at 60 °C for 5 h under N2. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography, eluting with 0 - 12% ethyl acetate in petroleum ether, to give 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]

Chemical formula

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

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

[0439]

Chemical Structure

[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) was added phosphoryl chloride (460 μL, 4.90 mmol) under N2 at room temperature. The mixture was heated to 100 °C and heated for 5 hours, then the reaction was cooled to room temperature, 50 mL of water was carefully added to the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (40 mL), dried over Na2SO4, and concentrated in high vacuum to give a residue. The residue was purified by silica gel flash chromatography eluting with 0 - 43% ethyl acetate / petroleum ether to give the title compound (1.25 g, 98% by mass, yield 69%). MS m / z 540.4 (M+H).

[0441] The compounds in the following table 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 4-[2-(N-[-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(indoline-1-carbonyl)piperidine-4-carboxylic acid (Example No. 35)

[0447]

Chemical formula

[0448] To a solution of methyl 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(indoline-1-carbonyl)piperidine-4-carboxylate (1.25 g, 2.27 mmol, 98% by mass) in 1,4-dioxane (10.0 mL) was added 1.0 M aqueous potassium hydroxide solution (4.5 mL, 4.5 mmol) at room temperature. The mixture was heated to 100 °C. After stirring for 5 hours, the reaction 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* 40 mm * (10 μm), mobile phase A: water (NH₃·H₂O + NH₄HCO₃), phase B: CH₃CN, eluted and purified with 15% - 55% B in 10 minutes. Appropriate fractions were 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] Example numbers 52, 60, 80, 81, 83, 94, 103 and 104 were prepared according to the above procedure.

[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 number 76)

[0453]

Chemical formula

[0454] Methyl 2-1-(6-fluoroindoline-1-carbonyl)-4-[2-(2-fluoro-N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate (109 mg, 0.1704 mmol, 90 mass %) in 2-propanol (3.0 mL, 39 mmol, 100 mass %) was added sodium hydroxide (190 μL, 0.95 mmol, 5 mol / L in H2O), and then the mixture was stirred at 50 °C overnight. When completed, the mixture was cooled to room temperature and 3 mL of water was added. Then the mixture was adjusted to pH about 4 with 1N HCl and extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under high vacuum. The residue was purified by preparative HPLC (column: Xtimate C18 100 * 30 mm * 10 um, mobile phase A: water - 0.225% formic acid, mobile phase B: ACN, eluted from 65% to 95% in 2 minutes and then to 100% B for purification, and the product (34 mg, 100 mass %, yield 35.5%) was obtained as a yellow solid. MS m / z 562.5 (M+H), 1 H NMR (400 MHz, 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, 7.8 Hz, 1H), 6.71 (dd, J = 2.2, 10.6 Hz, 1H), 6.67 - 6.60 (m, 1H), 4.61 (dt, J = 3.1, 12.3 Hz, 1H), 3.83 (t, J = 8.3 Hz, 2H), 3.29 - 3.14 (m, 4H), 2.93 (t, J = 8.1 Hz, 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 = 8.8 Hz, 3H), 1.18 - 0.91 (m, 1H).

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

[0456]

Table 16-1

[0457]

Table 16-2

[0458]

Table 16-3

[0459] Step 12: Isolation of Isomers (Example Nos. 35A and 35B)

[0460]

Chemical Structure

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

[0462] The eluate of the first peak was collected and lyophilized to give the title compound (275.3 mg, yield 40.5%, ee: 100%). MS m / z 526.2 (M+H). 11H NMR (400.14 MHz, DMSO-d6): 12.12 (br, OH), 7.59 - 7.51 (m, 3H), 7.32 (d, J = 6.0 Hz, 2H), 7.27 - 7.22 (m, 1H), 7.15 (t, J = 7.6 Hz, 1H), 6.98 - 6.88 (m, 2H), 4.68 (t, J = 12.4 Hz, 1H), 3.82 (t, J = 8.2 Hz, 2H), 3.33 - 3.20 (m, 4H), 3.01 (t, J = 8.1 Hz, 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 of the second peak was collected and freeze-dried 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 1H NMR (400.14 MHz, DMSO-d6): 12.11 (br, OH), 7.53 - 7.45 (m, 3H), 7.26 (d, J = 6.4 Hz, 2H), 7.17 (d, J = 7.3 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 6.91 (d, J = 7.9 Hz, 1H), 6.84 (t, J = 7.3 Hz, 1H), 4.62 (t, J = 12.4 Hz, 1H), 3.76 (t, J = 8.2 Hz, 2H), 3.24 - 3.14 (m, 4H), 2.95 (t, J = 8.1 Hz, 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] Example Nos. 80b and 80a were prepared according to the above procedure.

[0465] The racemate was separated by SFC-80 (column: Daicel ChiralPak IG (250 * × 30 mm, 10 μm); mobile phase: A: CO2 B: 0.1% NH3·H2O in EtOH, eluted at 40%, flow rate: 80 mL / min) to obtain 80b and 80a.

[0466] The racemate was separated by SFC-80, column: DAICEL CHIRALPAK AD (250mm * × 30mm, 10um), mobile phase: A: CO2; B: 0.1% NH3·H2O IPA; B%: 35%, flow rate: 80 mL / min) to obtain 3b and 83a.

[0467]

Table 17

[0468] Example Nos. 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]

Chemical formula

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

[0471] Step 1: 4-(Carboxymethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylic acid

[0472]

Chemical formula

[0473] 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) were added dropwise with N,O-bis(trimethylsilyl)acetamide (25 mL, 100 mmol), and then N,N-diisopropylethylamine (13.5 mL, 77.3 mmol) was added dropwise 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 extracted with EtOAc (60 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under high vacuum to obtain a residue. The residue was purified by silica gel flash eluting from petroleum ether to 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]

Chemical formula

[0477] 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) was added with trifluoroacetic anhydride (0.5 mL, 4 mmol, 99% by mass) 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 it was concentrated under high vacuum (repeated 3 times) to obtain the crude title product (600 mg, 90% by mass, yield 90%), which was used directly in the next step.

[0478]

Table 19

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

[0480]

Chemical formula

[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; 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 a residue. The crude product was separated by reversed-phase preparative HPLC using Welch Xtimate C18 100 * 30 mm *Purification was carried out using a 5 μm column, mobile phase A: water (0.225% formic acid), B: CH3CN, eluting from 45% B to 75% B. Appropriate fractions were collected and lyophilized to obtain the title compound (170 mg, 99% by mass, yield 20%). MS m / z 532.4 (M+H). 1 H NMR (400.14 MHz, 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] Example numbers 10, 14, 15, 17, 18, 34, 36, 37, 39, 41, 45, 53, 54, 86, 95 and 96 were prepared according to the above procedure.

[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]

Chemical formula

[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 the mixture was stirred at -78 °C for 15 minutes. Then, a solution of 8-(indoline-1-carbonyl)-2-oxa-8-azaspiro[4.5]decane-1,3-dione (170 mg, 0.433 mmol, 80 wt%) in tetrahydrofuran (2 mL) was added under N2 at -78 °C. Subsequently, the reaction mixture was stirred under N2 at -78 °C and slowly warmed to room temperature over 1 hour. The reaction was quenched with saturated NH4Cl (3.0 ml) and concentrated. The residue was purified by reverse-phase preparative HPLC using Xtimate C18 100 * 30 mm * 10 µm, mobile phase A: water - 0.225% formic acid, mobile phase B: ACN, eluting with 58 - 88% B in 10 minutes and then to 100% B over 10 minutes for purification. The appropriate fractions were combined and lyophilized to obtain the title product (31.7 mg, 97.4 wt%, yield 14.6%) as a white solid. MS m / z 490.4 (M+H); 11H NMR (400.13 MHz, DMSO-d6): 12.18 (br, 1H), 7.54 - 7.39 (m, 3H), 7.22 - 7.13 (m, 3H), 7.09 (t, J = 7.5 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 6.87 - 6.80 (m, 1H), 4.37 (t, J = 11.9 Hz, 1H), 3.76 (t, J = 8.1 Hz, 2H), 3.26 - 3.10 (m, 4H), 2.95 (t, J = 8.1 Hz, 2H), 2.16 (s, 2H), 1.89 (d, J = 13.8 Hz, 2H), 1.77 - 1.61 (m, 4H), 1.51 (d, J = 12.6 Hz, 1H), 1.41 (t, J = 9.1 Hz, 2H), 1.34 - 1.19 (m, 2H), 1.00 - 0.75 (m, 3H)

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

[0492]

Table 21

[0493] Step 4: Isolation of Isomers (Examples Nos. 44A and 44B)

[0494]

Chem.

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

[0496] The eluate of 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 (400.13 MHz, DMSO-d6): 12.08 (br, 1H), 7.58 - 7.49 (m, 3H), 7.26 - 7.14 (m, 6H), 4.64 (t, J = 12.4 Hz, 1H), 3.15 - 3.11 (m, 2H), 3.07 (s, 3H), 3.02 - 2.96 (m, 2H), 2.30 - 2.22 (m, 1H), 2.11 (s, 2H), 1.99 - 1.92 (m, 1H), 1.79 1.71 (m, 4H) 1.64 - 1.42 (m, 3H), 1.24 - 1.19 (m, 2H), 1.13 - 1.02 (m, 1H).

[0497] The eluate of 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 (400.13 MHz, DMSO-d6): 12.08 (br, 1H), 7.57 - 7.49 (m, 3H), 7.26 - 7.16 (m, 6H), 4.64 (t, J = 12.1 Hz, 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] Example Nos. 41a, 41b, 43a, 43b, 45a and 45b were prepared according to the above procedure.

[0499]

Table 22-1

[0500]

Table 22-2

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

[0502]

Chemical Structure

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

[0504]

Chemical Structure

[0505] O1-tert-butyl O4-ethyl piperidine-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) at -78 °C under nitrogen. The addition was completed after 45 minutes and the mixture was stirred below -70 °C. After 65 minutes, ethyl 2-bromoacetate (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 give a residue. The residue was purified by silica gel flash chromatography eluting with hexane:methyl tert-butyl ether (60:40) to give the title compound (8.90 g, 57% yield). MS m / z 244.2 (M+H-BOC).

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

[0507]

Chemical Structure

[0508] Hydrochloric acid (68 mL, 274 mmol, 4.0 M in dioxane) was added 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) at 0 °C and stirred. The reaction mixture was gradually warmed to ambient temperature. After 30 minutes, the solvent was concentrated under reduced pressure to give the title compound (7.02 g, 99% yield). MS m / z 244.0 (M+H).

[0509] Methyl 4-(2-methoxy-2-oxo-ethyl)piperidine-4-carboxylate, acetic acid

[0510]

Chem.

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

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

[0513]

Chem.

[0514] Pyridine (17 mL) was added to 4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylic acid; hydrochloride (5.91 g, 21.1 mmol) in dichloromethane (100 mL) at 0 °C and stirred. While maintaining the temperature at 0 °C, triphosgene (3.84 g, 12.7 mmol) was added portionwise. The reaction mixture was gradually warmed 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, brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain ethyl 1-chlorocarbonyl-4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylate (5.75 g, 18.8 mmol).

[0515] Ethyl 1-chlorocarbonyl-4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylate (5.75 g, 18.8 mmol) in acetonitrile (62 mL) was added to indoline (3.16 mL, 28.2 mmol) in acetonitrile (50 mL) 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 with DCM. The organic layers were combined, extracted with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel flash chromatography, eluting with 1 - 80% EtOAc / hexane to obtain the title compound (3.75 g, 51% yield). MS m / z 389.0 (M+H).

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

[0517]

Chemical formula

[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 h, the reaction was cooled, 5N aqueous HCl was added until pH 3.0 was reached, and the mixture was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography, eluting with 60% (MeOH:DCM (10:90)) from dichloromethane to give the title compound (2.71 g, 78% yield). MS m / z 361.0 (M+H).

[0519]

Table 23

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

[0521]

Chem.

[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 mL) and tetrahydrofuran (42 mL), and the mixture was stirred at ambient temperature. After 15 min, it was concentrated under reduced pressure to give 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 ethyl 4-(2-chloro-2-oxo-ethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylate (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 give a residue. The residue was purified by silica gel flash chromatography, eluting with EtOAc:hexane (50:50) to give 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]

Chemical Structure

[0526] 5N aqueous sodium hydroxide solution (4.8 mL, 24.1 mmol) was added to a solution of ethyl 1-(indoline-1-carbonyl)-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylate (2.46 g, 4.81 mmol) in ethanol (30 mL) at ambient temperature, and the mixture was stirred at 50 °C. After 18 hours, the reaction mixture was concentrated under reduced pressure to give a residue. 5N aqueous HCl 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 give a residue. The residue was purified by silica gel flash chromatography, eluting with DCM:[MeOH:DCM (10:90)] to give the title compound (1.97 g, 84% yield). MS m / z 484.4 (M+H); 11H NMR (DMSO-d6) δ 12.38 (s, 1H), 7.40 - 7.29 (m, 11H), 7.11 (t, J = 7.7 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.86 (t, J = 7.4 Hz, 1H), 3.79 (t, J = 8.2 Hz, 2H), 3.35 - 3.18 (m, 4H), 2.97 (t, J = 8.2 Hz, 2H), 2.56 (s, 2H), 2.00 - 1.96 (m, 2H), 1.59 - 1.52 (m, 2H).

[0527] Example Nos. 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]

Chemical Structure

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

[0530]

Chemical Structure

[0531] Thionyl chloride (2.0 M solution in DCM) (24.00 mL, 329.4 mmol) was added dropwise to a solution of 1-benzyl-4-(carboxymethyl)piperidine-4-carboxylic acid (10.00 g, 36.06 mmol) in methanol (400 mL), 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, loaded onto silica gel, and purified on a 120 g silica column using 1% - 10% methanol in dichloromethane. The fractions were combined and evaporated. Then, the residue was dried under high vacuum 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]

Chemical formula

[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 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 about 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: Methyl 1-benzyl-4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]piperidine-4-carboxylate

[0536]

Chem.

[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, it was concentrated under reduced pressure to give 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 methyl 1-benzyl-4-(2-chloro-2-oxo-ethyl)piperidine-4-carboxylate (7.40 g, 23.90 mmol) in DCM (100 mL), toluene (50 mL) and 4-dimethylaminopyridine (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 give a residue. The residue was purified by silica gel flash chromatography eluting with EtOAc:hexane (90:10) to give the title compound (8.00 g, 74.7% yield). MS m / z 449.4 (M+H).

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

[0540]

Chem.

[0541] Under N2, to a solution of 2-(1-benzyl-4-methoxycarbonyl-4-piperidyl)acetic acid (7.5 g, 24 mmol, 95% by mass) and N-[(rac)-3,3-difluorocyclohexyl]aniline (6.5 g, 28 mmol, 90% by mass) in pyridine (70.0 mL), phosphoryl chloride (4.6 mL, 49 mmol, 99% by mass) was added dropwise at room temperature. After the addition, the mixture was heated to 100 °C and 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 × 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under high vacuum to obtain a crude product, which was purified by flash silica gel chromatography eluting with 0 - 8% MeOH / DCM to give the title product (8.1 g, 90% by mass, yield 62%). MS m / z 485.2 (M + H).

[0542] The compounds in the following table were prepared in the same manner as the above procedure.

[0543]

Table 24

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

[0545]

Chem.

[0546] 10% Pd / C (3.201 g, 29.74 mmol) in methanol (50.0 mL) was added to a solution of methyl 1-benzyl-4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]piperidine-4-carboxylate (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 for 10 hours. 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, 86.7% yield). MS m / z 359.0 (M+H).

[0547] The compounds in the following table were prepared according to the above procedure.

[0548]

Table 25

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

[0550]

Chem.

[0551] Under N2, to 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) were added 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 was cooled to room temperature, the solvent was removed under high vacuum, 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 vacuum. The residue was purified by flash silica gel chromatography, eluting with 0% - 40% EtOAc / petroleum ether to give the title product (1.38 g, 2.63 mmol, 90% by mass, 41% yield). MS m / z 472.3 (M+H).

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

[0553]

Table 26

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

[0555]

Chemical formula

[0556] A mixture of racemic methyl 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate (200 mg, 0.46 mmol, 90% by mass) and 4-isopropylbenzaldehyde (140 mg, 0.93 mmol) in 1,2-dichloroethane (5.0 mL) was added 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 purified by preparative HPLC (Phenomenex C18 100 * 30 mm * 10 um, mobile phase A: water-formic acid, mobile phase B: acetonitrile, elution with 22 - 52% B and then up to 100% B). The appropriate fractions were combined and lyophilized to obtain the title product as the formate salt, 60 mg, 95% by mass, yield 23.7%). 1 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 2H), 7.60 - 7.42 (m, 3H), 7.34 - 7.06 (m, 6H), 4.58 (t, J = 12.5 Hz, 1H), 3.58 (s, 3H), 2.84 (td, J = 6.9, 13.8 Hz, 1H), 2.35 - 2.15 (m, 6H), 1.87 (br d, J = 4.5 Hz, 3H), 1.73 (d, J = 10.0 Hz, 2H), 1.65 - 1.26 (m, 6H), 1.17 (d, J = 6.9 Hz, 6H), 1.09 - 0.92 (m, 1H).

[0557] The intermediates in the following table were prepared according to the above procedure.

[0558]

Table 27

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

[0560]

Chemical Structure

[0561] To a solution of racemic methyl 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate (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) were added N,N-diisopropylethylamine (0.165 mL, 0.94 mmol) and HATU (270 mg, 0.69 mmol), and then the mixture was stirred at room temperature overnight. The mixture was quenched with water (10 mL) and extracted with DCM (5 mL × 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, eluting with 0 - 7% MeOH / DCM, to give the title compound (305 mg, 68% by mass, 79.5% yield) as a brown oil. MS m / z 545.3. (M+H).

[0562]

Table 28

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

[0564]

Chemical Structure

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

[0566] Next, to a solution of racemic 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylic acid methyl (200 mg, 0.47 mmol, 93% by mass) and triethylamine (0.17 mL, 1.2 mmol) in DCM (4.0 mL) was added the prepared acid chloride (207 mg, 0.943 mmol, 85% by mass). The mixture was stirred at 40 °C overnight. The reaction mixture was cooled to room temperature and filtered. The residue was purified by normal silica gel chromatography, eluting with 50 - 58% EtOAc:petroleum ether, 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 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(4-fluoroindoline-1-carbonyl)piperidine-4-carboxylic acid methyl

[0569]

Chem.

[0570] A solution of racemic methyl 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]piperidine-4-carboxylate (220 mg, 0.45 mmol, 80% by mass) and N,N-diisopropylethylamine (0.16 mL, 0.92 mmol) in DCM (4.0 mL) was added 4-fluoroindoline-1-carbonyl chloride (130 mg, 0.55 mmol, 85% by mass) at room temperature. The mixture was stirred at room temperature for 2 hours to obtain a colorless solution. Upon completion, water (10 mL) was added to the reaction and extracted with EtOAc (10 mL × 2). The combined organic layers were 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% EtOAc / petroleum ether) to give the title compound (120 mg, 95% by mass, yield 45.8%). MS m / z 558.2 (M+H).

[0571]

Table 30

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

[0573]

Chem.

[0574] At 0 °C, 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) was added N-cyclopropyl-N-phenyl-carbamoyl chloride (0.261 g, 1.33 mmol). The resulting mixture was warmed to room temperature and stirred under nitrogen for 90 minutes. The reaction was diluted with EtOAc and water and extracted twice with EtOAc. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel (40 g) using a gradient of 0% to 100% EtOAc in hexane over 20 minutes to give the title product 476 mg (86%). 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]

Chemical Structure

[0577] A solution of methyl 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(2-pyridyl)piperidine-4-carboxylate (1.38 g, 2.63 mmol, 90% by mass) in 2-propanol (16.0 mL, 98% by mass) was added with an aqueous NaOH solution (2.6 mL, 13 mmol, 5 mol / L). The mixture was heated to 50 °C and stirred overnight. After cooling to room temperature, the mixture was acidified with an aqueous KHSO4 solution to a pH of less than 4, and the mixture was extracted with EtOAc (20 mL × 3). The combined organic phases were washed with 10 mL of brine, dried over Na2SO4, filtered, and concentrated under high vacuum. The residue was purified by preparative HPLC (Welch Xtimate Prep C18 250×50 mm×10 um, condition: water (10 mM NH4HCO3) / MeCN from 5% to 35%) to obtain the title product (0.89 g, 97% by mass, yield 71.6%), MS m / z 458.3 (M+H).

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

[0579]

Table 31

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

[0581]

Chem.

[0582] A solution of racemic methyl 4-[2-(N-[3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-[(4-isopropylphenyl)methyl]piperidine-4-carboxylate (50 mg, 0.090 mmol, 95% by mass) in 1,4-dioxane (1.0 mL) and water (0.5 mL) was added with 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, adjusted to about pH 7 by adding formic acid, and concentrated. The residue was purified by preparative HPLC (Phenomenex C18 150 * 30 mm * 5 μm, mobile phase A: water (0.04% NH₃H₂O + 10 mM NH₄HCO₃), mobile phase B: ACN, eluting with 20 - 60% B in 12 minutes and then to 100% B. The appropriate fractions were combined and lyophilized 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 ¹H NMR (400.13 MHz, 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 = 10.9 Hz, 2H), 1.64 - 1.29 (m, 6H), 1.17 (d, J = 7.0 Hz, 6H), 1.09 - 0.95 (m, 1H)

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

[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]

Chemical formula

[0590] A solution of lithium hydroxide (131 mg, 5.47 mmol) in water (2 mL) was added at room temperature to a solution of methyl 1-[cyclopropyl(phenyl)carbamoyl]-4-[2-oxo-2-(N-phenylanilino)ethyl]piperidine-4-carboxylate (475 mg, 0.928 mmol) in ethanol (2 mL) and THF (2 mL), and the reaction mixture was stirred at 50 °C overnight. The reaction mixture was cooled, diluted with water and dichloromethane, and acidified to pH ca. 2.0 with 5.0 M aqueous HCl (ca. 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 give the crude product, which was purified on 40 g of silica gel using a gradient of 0.5% - 10% MeOH in DCM over 30 min to give 355 mg (77%) of the title product. MS (m / z): 498 [M+H]. 11H NMR (400.13 MHz, CDCl3): δ 7.54 - 7.46 (m, 3H), 7.31 (dd, J = 1.6, 6.9 Hz, 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, 10.6 Hz, 2H), 0.92 - 0.84 (m, 4H), 0.70 - 0.66 (m, 2H).

[0591] Isolation of Isomers (Example Nos. 74A and 74B)

[0592]

Chemical Structure

[0593] 1.62 g of racemic 4-[2-(N-[(racemic)-3,3-difluorocyclohexyl]anilino)-2-oxo-ethyl]-1-(2-pyridyl)piperidine-4-carboxylic acid was purified by eluting with SFC-80, Daicel ChiralCel IG (250 mm * × 50 mm, 10 μm), mobile phase: A: CO2, B: 0.1% NH3·H2O in EtOH, at 40% and a flow rate of 80 mL / min.

[0594] The eluate of the first peak was collected and lyophilized to obtain Isomer 1 of the title compound (546.5 mg, yield 33.9%, ee: 100%). MS m / z 458.4 (M + H). 1 1H NMR (400.13 MHz, DMSO-d6): δ 12.0 (brs, 1H), 8.03 (dd, J = 1.2, 4.8 Hz, 1H), 7.49 - 7.45 (m, 4H), 7.24 - 7.22 (m, 2H), 6.73 (d, J = 8.8 Hz, 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 of the second peak was collected and lyophilized 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 (400.13 MHz, DMSO-d6): 12.18 (brs, 1H), 8.06 (dd, J = 1.4, 4.9 Hz, 1H), 7.51 - 7.45 (m, 4H), 7.25 - 7.24 (m, 2H), 6.74 (d, J = 8.7 Hz, 1H), 6.57 (dd, J = 5.1, 6.9 Hz, 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] Example Nos. 72a, 72b, 75b, 75a, 68b and 68a were prepared according to the above procedure.

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

[0598] Racemate 75 was separated by SFC on a column: DAICEL CHIRALCEL IG (250 mm * 50 mm, 10 μm); mobile phase: A: CO2; B: 0.1% NH3H2O in EtOH, eluting with 35% B at a flow rate of 140 mL / min to obtain 75a and 75b.

[0599] Racemate 68 was separated by SFC (column: DAICEL CHIRALCEL IG (250 mm * 30 mm, 10 μm); mobile phase: A: CO2; B: 0.1% NH3H2O in EtOH, eluting with 30% 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]

Chemical formula

[0604] 2-Chloropyridine (0.032 mL, 0.033 mmol) was sealed in a solution of methyl 4-[2-(N-cyclohexylanilino)-2-oxo-ethyl]piperidine-4-carboxylate (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, RuPhos paracyclic (0.035 mg, 0.041 mmol) in dioxane (1.40 mL) and stirred at 100 °C. After 24 h, the reaction mixture was cooled, filled onto SCX-2, and eluted with 2.0 M ammonia in acetonitrile and methanol. The filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative reverse-phase HPLC using an XBridge C18 150 * 19 mm * 5 μm column, mobile phase A: 20 mM NH4CO3 pH 9, B: CH3CN, eluting from 30% B to 60% B. Appropriate fractions were collected and lyophilized to give the title compound (63 mg, 54% yield). MS m / z 422.2 (M+H). 11H NMR (DMSO-d6) δ 12.04 (s, 1H), 8.05 (dd, J = 1.3, 4.8 Hz, 1H), 7.49 - 7.43 (m, 4H), 7.18 - 7.16 (m, 2H), 6.73 (d, J = 8.8 Hz, 1H), 6.56 (dd, J = 4.9, 6.6 Hz, 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, 3.2 Hz, 2H), 1.75 - 1.66 (m, 4H), 1.53 - 1.37 (m, 5H), 0.97 - 0.85 (m, 3H)

[0605] The compounds in the following table were prepared according to the above procedure.

[0606]

Table 34-1

[0607]

Table 34-2

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

[0609]

Chemical Structure

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

[0611]

Chemical Structure

[0612] N-(4-Fluorophenyl)-N-methyl-carbamoyl chloride (9.65 g, 51.4 mmol) in acetonitrile (100 mL) was added at 0 °C to ethyl 4-(2-ethoxy-2-oxo-ethyl)piperidine-4-carboxylate; 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 h, 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 give a residue. The residue was purified by silica gel flash chromatography eluting with 1 - 80% EtOAc / hexane to give the title compound (4.03 g, 47% yield). MS m / z 395.0

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

[0614]

Chemical formula

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

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

[0617]

Chem.

[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 the mixture was stirred at 60 °C. After 2 hours, the mixture was concentrated under reduced pressure to obtain ethyl 4-(2-chloro-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate (0.13 g, yield 99%).

[0619] 3-Methyl-N-phenyl-aniline (0.06 g, 0.30 mmol) in pyridine (0.16 mL, 1.98 mmol) was added to a solution of ethyl 4-(2-chloro-2-oxo-ethyl)-1-(indoline-1-carbonyl)piperidine-4-carboxylate (0.13 g, 0.35 mmol) in DCM (0.97 mL), and the mixture was 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 over diatomaceous earth, and concentrated under a nitrogen stream. The crude product was purified by preparative reverse-phase HPLC using an XBridge C18 150 * 19 mm * 5 μm column, mobile phase A: 20 mM NH4CO3 pH 9, B: CH3CN, eluting from 60% B to 90% B. The appropriate fractions were collected and lyophilized to obtain the title compound (55 mg, 98% by mass, yield 29%). 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]

Chem.

[0622] 5N aqueous sodium hydroxide solution (0.20 mL, 1.0 mmol) 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. Water (0.50 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was separated and discarded. The aqueous layer was acidified to about pH 2 with HCl (4.0 M, 0.45 mL), extracted with ethyl acetate (1.0 mL × 2), and the combined organic layers were dried over diatomaceous earth and concentrated under a nitrogen stream to obtain a residue. The crude product was purified by preparative reverse-phase HPLC using an XBridge C18 150 * 19 mm * 5 μm column, mobile phase A: 20 mM NH4CO3 pH 9, B: CH3CN, and eluting with a gradient from 60% B to 90% B. Appropriate fractions were collected and lyophilized to obtain the title compound (15 mg, 100% by mass, yield 23%). MS m / z 504.2 (M + H). 1 1H NMR (DMSO-d6) δ 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] Example Nos. 21, 22, 24, 25, 27, 28, 29, 30, 31, and 32 were prepared according to the above procedure.

[0624]

Table 35-1

[0625]

Table 35-2

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

[0627]

Chemical formula

[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]

Chemical formula

[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 was cooled, 5N aqueous hydrochloric acid was added until pH 3.0 was reached, and the mixture was extracted with DCM. The organic layers were combined, dried over MgSO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel flash chromatography, eluting with 40% (MeOH:DCM (20:80)) from DCM to give the title compound (0.80 g, 20% yield). MS m / z 353.2 (M+H).

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

[0633]

Chemical formula

[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 stir bar. 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 with a Biotage Initiator microwave. After 10 minutes of heating, it was stable at a temperature of 85 °C and a pressure of 0 bar. After 12 hours, the reaction mixture was cooled and filtered through a small plug of celite. 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, loaded onto silica gel and purified on a 40 g silica column using 5% - 20% EtOAc in hexane. The fractions were combined and evaporated. Then, the residue was dried under high vacuum to obtain the title compound (0.240 g, yield 61%). MS m / z 174.2 (M+H). 1 H NMR (CD2Cl2) δ: 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: Methyl 4-[2-(N-(1-cyclopropylcyclopropyl)anilino)-2-oxo-ethyl]-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate

[0636]

Chem.

[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, it was concentrated under reduced pressure to obtain methyl 4-(2-chloro-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate (0.49 g, yield 99%).

[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 methyl 4-(2-chloro-2-oxo-ethyl)-1-[(4-fluorophenyl)-methyl-carbamoyl]piperidine-4-carboxylate (0.49 g, 1.33 mmol) in DCM (10 mL), and the mixture was 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 a residue. The residue was purified by silica gel flash chromatography, eluting with EtOAc: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]

Chem.

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

Chem.

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

[0645]

Chem.

[0646] Potassium carbonate (8.6 g, 62 mmol) was added to a 1 L round-bottom flask 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 h, the reaction mixture was concentrated under reduced pressure, then diluted with EtOAc and concentrated again. The reaction mixture was diluted with EtOAc and water, and then the pH was adjusted to about pH 3 using 5N HCl. The reaction mixture was extracted with EtOAc, the combined organic solutions were washed with brine, dried over Na2SO4, filtered, and concentrated to give 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]

Chem.

[0649] Step 2: Thionyl chloride (10 mL, 137.3 mmol, 100 mass %) was added to a chloroform (100 mL) solution of 2-(1-tert-butoxycarbonyl-4-ethoxycarbonyl-4-piperidyl)acetic acid (8.9 g, 28 mmol), 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-vacuum 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 mass %) in CAN (150 mL, 2850 mmol, 99.8 mass %) was combined with N-(3,3-difluorocyclohexyl)aniline (Scheme 2 / Step 9, 6.2 g, 29 mmol, 100 mass %), and then pyridine (12 mL, 151.7 mmol, 100 mass %), and heated to 60 °C under nitrogen. The reaction was held at this temperature for 1 hour, then concentrated to give a residue, which was loaded onto a 25 g silica column and flash chromatographed on a 300 g silica gel column, eluting with 0 - 100% EtOAc / hexane. The fractions containing the product were combined and concentrated to give a mixture. This mixture was dissolved in a 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 EtOAc × 2 (2 × 100 mL), washed with brine, dried over Na2SO4, filtered, and concentrated to give the title product. MS m / z 509.0 (M + H - Boc). ES / MS (m / z) (M + H) 509.0.

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

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

[0653] The eluate of the second peak was collected and lyophilized 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]

Chemical formula

[0656] 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 wt%), which is isomer 2, in tetrahydrofuran (2 mL) was added with an aqueous sodium hydroxide solution (10 mol / L, 1 mL) containing methanol (1 mL). 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 while heating under a nitrogen stream. The mixture was diluted with EtOAc (about 15 mL) and about 5 mL of water, and then hydrochloric acid (1 mol / L) in diethyl ether (1 mL, 5 mmol, 5 mol / L) was added to neutralize the pH. The organic matter was extracted twice with EtOAc, the combined organic solvents were washed with brine, dried over Na2SO4, filtered, concentrated, and dried in a high vacuum oven at 50 °C over the weekend to obtain the title product. MS (m / z): 479.4 (M-H). 1H NMR (400.13 MHz, 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 for in vitro binding affinity Solubilization of the compound The test compound and the reference compound were received as dry powder reagents, weighed, solubilized in 100% DMSO to generate a working stock concentration of 10 mM.

[0658] Membrane preparation protocol (hAT2R / HEK293 and rAT2R / HEK293) The hAT2R membrane was prepared from human embryonic kidney (HEK293) cells stably transfected with the recombinant human angiotensin-II receptor subtype 2 (hAT2R). Cells from the stable cell line were grown in tissue culture flasks to generate a large cell population. Cell pellets (greater than 1 gm) and these cell pellets were cryopreserved prior to initiating this membrane isolation procedure for each receptor isoform. The frozen cell pellets were thawed in ice-cold homogenization / resuspension buffer (50 mM Tris-HCl, pH 7.5) containing one EDTA per 50 mL of buffer and a Complete® protease inhibitor tablet (Roche Diagnostics), and the cell pellets were resuspended at a ratio of 10 mL of homogenization buffer per 1 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, the pellet was homogenized as before, and centrifuged at 1100×g for 10 minutes at 4°C. Both supernatants were combined and subsequently centrifuged at 35,000×g for 60 minutes at 4°C. The final centrifugation pellet containing the isolated membrane (pellet 2) was resuspended in buffer containing protease inhibitor (4 - 5 mL / g of starting cell paste), flash frozen in liquid nitrogen, and stored at -80°C. Protein concentration was determined using a BCA kit (Thermo Scientific, Inc.) with bovine serum albumin (BSA) as a standard.

[0659] 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 ) was determined using a human recombinant 125Determined from a competitive radioligand binding assay using [125I]-Tyr4)-angiotensin-II (2200 Ci / mmol). Assays were performed by a scintillation proximity assay (SPA) method using polyvinyltoluene (PVT) wheat germ agglutinin-conjugated SPA beads (Perkin Elmer catalog number RPNQ0001). 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 controls and test compounds were diluted and 10-point concentration-response curves were obtained using a 4-fold serial dilution protocol onto the assay plate and acoustically dispensed from DMSO stocks using an automated ECHO instrument technology (Labcyte, Inc.). Concentration-response curves were generated in the usual manner 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, a direct count of this stock was measured by taking 20 μL aliquots of this radioligand after dilution on the test day (2.5-fold working stock) and counted on a Wizard2 Gamma Counter (PerkinElmer). hAT2R membranes were 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. Also, the hAT1R membrane PVT-WGA SPA bead final concentration was 0.5 μg / well hAT1R membrane + 0.1 mg / well PVT-WGA SPA beads. All binding assays were initiated by directly dispensing the 2.5-fold 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 beads mixture, i.e., hAT2R membrane-SPA beads mixture (30 μL), rAT2R membrane-SPA beads mixture, or AT1R membrane-SPA beads mixture (30 μL) was added to the assay plate. All dispensing steps were performed using a Multiflo FX (Biotek, Inc.) bulk dispensing instrument. After the reagent addition step, the assay plate was sealed and the plate contents were mixed on a bench-top microplate shaker for 1 minute. 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). Unlabeled angiotensin-II controls were included in each plate as experimental assay references. Results for experimental test compounds were confirmed in duplicate experiments. Separate experiments were performed to obtain n = 2 or more.

[0661] Data analysis procedure Using each plate containing the positive control angiotensin-II positive reference compound and the experimental compound, the compound was tested in a 10-point concentration response curve (CRC) format. The maximum binding response (Max) was determined in 32 control wells per plate using assay buffer treatment only, and the minimum binding control or non-specific 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 percentage of the maximum response after correcting for non-specific binding as shown below. % Specific inhibition = 100 - [(CPM - Min) / (Max - Min) × 100]

[0662] The percentage of specific binding (y-axis) was plotted against the log concentration of the compound (x-axis). The concentration that produces 50% inhibition of binding (IC50 ) was determined from a 4-parameter logistic non-linear regression analysis (Analyzer, version 17, GeneData Screener). The affinity constant (K i ) was calculated from the IC 50 in the following equation. K i = IC 50 / (1 + L / K d ) Wherein, L is the radioactive ligand concentration used in the experiment (determined for each experiment by counting an aliquot of the radioactive ligand mixture), and K d is the equilibrium binding affinity constant of the radioactive ligand determined from saturation binding analysis. The K d of hAT2R = 0.066 nM, and the K d of hAT1R = 0.178 nM.

[0663] The binding affinity for the compounds of the present disclosure was determined according to the assays described herein.

[0664]

Table 36-1

[0665]

Table 36-2

[0666] Example 3. Comparative data on ex vivo human binding affinity of AT2R and AT1R. The binding affinity for the compounds of the present disclosure was determined according to the assays described above.

[0667]

Table 37

[0668] The selected compounds of the present disclosure are up to 10,000-fold selective for AT2R compared to AT1R. Compounds that are selective for AT2R compared to AT1R may provide a more potent 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 of the compound. Ex vivo autoradiography assays were performed as described herein.

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

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

[0672] [Table 38]

[0673] Furthermore, the amount of test compound present in each plasma sample was determined and plotted against the % receptor occupancy values to calculate the IC50 / IC80 values 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 a 12-hour light cycle and free access to food and water. On the day of the test, rats were administered the test compound or the corresponding vehicle (p.o. or s.c.). At a predetermined time after administration of the test compound, anesthesia was induced with 5% isoflurane. Once anesthetized, the abdomen was shaved and the animals were placed in a custom-built 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 body temperature of the rats during the procedure. A lower dose of isoflurane (1 - 3%) was utilized to maintain anesthesia throughout the experiment. Once the 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). The AT2R agonist C21 or vehicle was injected intradermally (30 uL), and skin blood flow was monitored for 25 minutes. Data were analyzed using Moor version 6.0 software in the region of interest, and the inhibition of the increase in skin blood flow was calculated. Inhibition of C21-induced skin blood flow indicates that the compound is acting as an AT2R antagonist. It is understood that the compounds of the present disclosure can act as AT2R antagonists, as exemplified by Example No. 3 acting as an antagonist.

[0676]

Table 40

[0677] Example 6. X-ray Crystallographic Analysis of Example 44B X-ray crystallographic analysis was performed to determine the absolute configuration of Example No. 44B as described below.

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

[0679] A total of 46940 reflections were collected in the 2θ range of 7.622 - 133.178. The limiting indices were -9 ≤ h ≤ 10, -15 ≤ k ≤ 15, -27 ≤ l ≤ 27. As a result, 9241 unique reflections (Rint = 0.0489) were obtained. The structure was analyzed using SHELXT (Sheldrick, G.M. 2015. Acta Cryst. A71, 3 - 8) and refined using SHELXL (Sheldrick, G.M. 2015. Acta Cryst. C71, 3 - 8) against (F 2 The total number of refined parameters was 835 compared to 9241 data. All reflections were included in the refinement. The goodness-of-fit of F 2 was 1.073, and the final R values were R1 = 0.0412 and wR2 = 0.1114 for [I > 2σ(I)]. The maximum difference peak and hole were 0.57 and -0.38 Å-3, respectively.

[0680] Description of crystal preparation 48 mg of the amorphous compound was dissolved in 480 μL of methanol and stored in a half-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 is 0.20 × 0.20 × 0.10 mm 3It was a colorless block with the dimensions of. The symmetry of the crystal structure was assigned 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) Å3, Z = 4, Dc = 1.345 g / cm3, F(000) = 1120.0, μ(CuKα) = 0.878 mm-1, and T = 150.00(10) K. The absolute configuration structure is as follows.

[0682] [Chemical formula]

Claims

1. A compound of formula (I), 【Chemical 1】 wherein, R １ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R １ａ and, Each R １ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ -C ６ alkyl, C １ -C ６ alkoxyl, or C ３ -C ６ cycloalkyl, and R ３ is H or C １ to C ６ alkyl, X is C ５ to C １０ heteroaryl, C ６ to C １０ aryl, [Chemical Formula 2] and the C ５ ~C １０ heteroaryl or C ６ ~C １０ aryl is optionally substituted with one or more X ａ and is optionally substituted with one or more X Each X ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ４ is H, C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl, and the C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl is optionally substituted with one or more R ４ａ s, Each R ４ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ５ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ５ａ and, Each R ５ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ６ is H or C １ to C ６ alkyl, R ７ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ７ａ 's, Each R ７ａ is independently halogen, cyano, or C ３ to C ６ cycloalkyl, R ８ is H, halogen, or C １ to C ６ alkyl, R ９ is H, halogen, or C １ to C ６ alkyl, or alternatively, R ８ and R ９ combine to form C ３ to C ６ cycloalkyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form oxo, R １２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ s, Each R １２ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, a compound, or a pharmaceutically acceptable salt thereof.

2. The compound is a compound of the following formula [Chemical Formula 3] wherein, wherein, R １ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R １ａ and, Each R １ａ is, independently, halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and X is C ５ to C １０ heteroaryl, C ６ to C １０ aryl, [Chemical Formula 4] and the C ５ - C １０ heteroaryl or C ６ - C １０ aryl is optionally substituted with one or more X ａ and Each X ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ４ is H, C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl, and the C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl is optionally substituted with one or more R ４ａ 's, Each R ４ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ５ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ５ａ and, Each R ５ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ６ is H or C １ -C ６ alkyl, R ７ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ７ａ and Each R ７ａ is independently halogen, cyano, or C ３ to C ６ cycloalkyl, R ８ is H, halogen, or C １ to C ６ alkyl, R ９ is H, halogen, or C １ to C ６ alkyl, or R ８ and R ９ combine to form C ３ -C ６ cycloalkyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form oxo, R １２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ ; Each R １２ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound is a compound of the following formula 【Chemical Formula 5】 wherein, wherein, R １ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ３ -C ９ heterocycloalkyl, or C ６ -C １０ aryl, and the C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ３ -C ９ heterocycloalkyl, or C ６ -C １０ aryl is optionally substituted with one or more R １ａ ; Each R １ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ３ is H or C １ ~C ６ alkyl, and R ４ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ４ａ and, Each R ４ａ is, independently, halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ５ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ５ａ s, Each R ５ａ is independently halogen, cyano, C １ -C ６ alkyl, C １ -C ６ alkoxyl, or C ３ -C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound is a compound of the following formula 【Chemical Formula 6】 wherein, wherein, R １ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R １ａ and, Each R １ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ ~C ６ alkyl, C １ ~C ６ alkoxyl, or C ３ ~C ６ cycloalkyl, and R ３ is H or C １ -C ６ alkyl, R ６ is H or C １ ~C ６ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. The compound is a compound of the following formula 【Chemical Formula 7】 wherein, wherein, R １ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R １ａ and, Each R １ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ s, Each R ２ａ is independently halogen, C １ ~C ６ alkyl, C １ ~C ６ alkoxyl, or C ３ ~C ６ cycloalkyl, and R ３ is H or C １ -C ６ alkyl, R ７ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ７ａ s, Each R ７ａ is independently halogen, cyano, or C ３ to C ６ cycloalkyl, R ８ is H, halogen, or C １ ~C ６ alkyl, and R ９ is H, halogen, or C １ to C ６ alkyl, or R ８ and R ９ are combined to form C ３ -C ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which forms cycloalkyl.

6. The compound is a compound of the following formula 【Chemical Formula 8】 wherein, wherein, R １ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R １ａ and, Each R １ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ s, Each R ２ａ is independently halogen, C １ ~C ６ alkyl, C １ ~C ６ alkoxyl, or C ３ ~C ６ cycloalkyl, and R ３ is H or C １ -C ６ alkyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form oxo, R １２ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ６ -C １０ aryl, C １ -C ３ -(phenyl), or C ３ -C １０ heterocycloalkyl, wherein the C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ６ -C １０ aryl, C １ -C ３ -(phenyl), or C ３ -C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ 's, Each R １２ａ is independently halogen, cyano, C １ ~C ６ alkyl, C １ ~C ６ alkoxyl, or C ３ ~C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. The compound is a compound of the following formula 【Chemical Formula 9】 wherein, wherein, R １ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R １ａ s, Each R １ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ３ is H or C １ ~C ６ alkyl, and R １２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ s, Each R １２ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. The compound is a compound of the following formula 【Chemical Formula 10】 wherein, wherein, R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and X is C ５ ~C １０ heteroaryl, C ６ ~C １０ aryl, 【Chemical 11】 and the C ５ - C １０ heteroaryl or C ６ - C １０ aryl is optionally substituted with one or more X ａ and, Each X ａ is, independently, halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ４ is H, C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl, and the C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl is optionally substituted with one or more R ４ａ 's, Each R ４ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ５ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ５ａ and, Each R ５ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ６ is H or C １ ~C ６ alkyl, and R ７ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ７ａ ; Each R ７ａ is independently halogen, cyano, or C ３ to C ６ cycloalkyl, R ８ is H, halogen, or C １ ~C ６ alkyl, and R ９ is H, halogen, or C １ to C ６ alkyl, or R ８ and R ９ combine to form C ３ to C ６ cycloalkyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form oxo, R １２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ ; Each R １２ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. The compound is a compound of the following formula 【Chemical Formula 12】 wherein, wherein, R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ -C ６ alkyl, C １ -C ６ alkoxyl, or C ３ -C ６ cycloalkyl, and X is C ５ ~C １０ heteroaryl, C ６ ~C １０ aryl, 【Chemical 13】 and the C ５ to C １０ heteroaryl or C ６ to C １０ aryl is optionally substituted with one or more X ａ and is optionally substituted with one or more X Each X ａ is, independently, halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ４ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ４ａ and Each R ４ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ５ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ５ａ and, Each R ５ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ６ is H or C １ ~C ６ alkyl, and R ７ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C ６ -C １０ aryl, and the C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, or C ６ -C １０ aryl is optionally substituted with one or more R ７ａ 's, Each R ７ａ is independently halogen, cyano, or C ３ to C ６ cycloalkyl, and R ８ is H, halogen, or C １ ~C ６ alkyl, and R ９ is H, halogen, or C １ ~C ６ alkyl, or R ８ and R ９ combine to form C ３ to C ６ cycloalkyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form oxo, R １２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ s, Each R １２ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. The compound is a compound of the following formula 【Chemical 14】 wherein, wherein, R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and X is C ５ ~C １０ heteroaryl, C ６ ~C １０ aryl, 【Chemical Formula 15】 and the C ５ to C １０ heteroaryl or C ６ to C １０ aryl is optionally substituted with one or more X ａ and is Each X ａ is independently a halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ４ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ４ａ and, Each R ４ａ is, independently, halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ５ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ５ａ and Each R ５ａ is, independently, halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ６ is H or C １ ~C ６ alkyl, and R ７ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ７ａ 's, Each R ７ａ is, independently, halogen, cyano, or C ３ to C ６ cycloalkyl, R ８ is H, halogen, or C １ ~C ６ alkyl, and R ９ is H, halogen, or C １ to C ６ alkyl, or R ８ and R ９ combine to form C ３ ~C ６ to form a cycloalkyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form oxo, R １２ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ６ -C １０ aryl, C １ -C ３ -(phenyl), or C ３ -C １０ heterocycloalkyl, and said C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ６ -C １０ aryl, C １ -C ３ -(phenyl), or C ３ -C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ 's, Each R １２ａ independently is halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. The compound is a compound of the following formula 【Chemical Formula 16】 wherein, R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and X is C ５ ~C １０ heteroaryl, C ６ ~C １０ aryl, 【Chemical 17】 and said C ５ ~C １０ heteroaryl or C ６ ~C １０ aryl is optionally substituted with one or more X ａ and is optionally substituted with one or more X Each X ａ is, independently, halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ４ is H, C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl, and the C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl is optionally substituted with one or more R ４ａ 's, Each R ４ａ is, independently, halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ５ is H, C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl, and the C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl is optionally substituted with one or more R ５ａ s, Each R ５ａ is, independently, halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ６ is H or C １ -C ６ alkyl, R ７ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ７ａ s, Each R ７ａ is independently halogen, cyano, or C ３ to C ６ cycloalkyl, R ８ is H, halogen, or C １ ~C ６ alkyl, and R ９ is H, halogen, or C １ ~C ６ alkyl, or R ８ and R ９ combine to form C ３ -C ６ cycloalkyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form an oxo, R １２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ６ to C １０ aryl, C １ to C ３ -(phenyl), or C ３ to C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ s, Each R １２ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. The compound is a compound of the following formula 【Chemical Formula 18】 wherein, wherein, X is C ５ ~C １０ heteroaryl, C ６ ~C １０ aryl, 【Chemical Formula 19】 and said C ５ ~C １０ heteroaryl or C ６ ~C １０ aryl is optionally substituted with one or more X ａ and is Each X ａ is, independently, halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ４ is H, C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ４ａ s, Each R ４ａ is, independently, halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ５ is H, C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl, and the C １ ~C ６ alkyl, C ３ ~C ６ cycloalkyl, or C ６ ~C １０ aryl is optionally substituted with one or more R ５ａ 's, Each R ５ａ is, independently, halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ６ is H or C １ -C ６ alkyl, R ７ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ７ａ s, Each R ７ａ is, independently, halogen, cyano, or C ３ to C ６ cycloalkyl, R ８ is H, halogen, or C １ ~C ６ alkyl, and R ９ is H, halogen, or C １ to C ６ alkyl, or R ８ and R ９ combine to form C ３ -C ６ to form cycloalkyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form oxo, R １２ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ６ -C １０ aryl, C １ -C ３ -(phenyl), or C ３ -C １０ heterocycloalkyl, and the C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ６ -C １０ aryl, C １ -C ３ -(phenyl), or C ３ -C １０ heterocycloalkyl is optionally substituted with one or more R １２ａ 's, Each R １２ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. The compound is a compound of the following formula 【Chemical 20】 wherein, wherein, n is 0, 1, or 2, R １ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R １ａ s, Each R １ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and Each R １２ａ is independently halogen, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

14. The compound is a compound of the following formula 【Chemical 21】 wherein, wherein, R １ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R １ａ and, Each R １ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and said C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is, independently, halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. The compound is a compound of the following formula 【Chemical 22】 wherein, R １ is C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ３ -C ９ heterocycloalkyl, or C ６ -C １０ aryl, and said C １ -C ６ alkyl, C ３ -C ６ cycloalkyl, C ３ -C ９ heterocycloalkyl, or C ６ -C １０ aryl is optionally substituted with one or more R １ａ and, Each R １ａ is independently halogen, C １ -C ６ -alkyl, C １ -C ６ -alkoxyl, or C ３ -C ６ -cycloalkyl, and R ２ is C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl, and the C １ to C ６ alkyl, C ３ to C ６ cycloalkyl, C ３ to C ９ heterocycloalkyl, or C ６ to C １０ aryl is optionally substituted with one or more R ２ａ and, Each R ２ａ is independently halogen, C １ to C ６ alkyl, C １ to C ６ alkoxyl, or C ３ to C ６ cycloalkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. wherein, R １ is methyl, ethyl, propyl, butan-2-yl, pentyl, 3-methylbutan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or phenyl, and the methyl, ethyl, propyl, butan-2-yl, pentyl, 3-methylbutan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or phenyl is optionally substituted with one or more R １ａ groups, Each R １ａ is independently fluorine, chlorine, methyl, isopropyl, methoxyl, or cyclopropyl, and R ２ is methyl, ethyl, propyl, butan-2-yl, pentyl, 3-methylbutan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or phenyl, and the methyl, ethyl, propyl, butan-2-yl, pentyl, 3-methylbutan-2-yl, cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, or phenyl is optionally substituted with one or more R ２ａ groups, Each R ２ａ is independently fluorine, chlorine, methyl, isopropyl, methoxyl, or cyclopropyl, and

16. 【Chemical 23】 wherein the triazolyl, pyrimidinyl, pyridinyl, and phenyl are optionally substituted with one or more X ａ and are optionally substituted with Each X ａ is independently bromine, pentyl, or cyclopropyl, and R ４ is methyl, ethyl, isopropyl, pentyl, cyclopentyl, or phenyl, and the methyl, ethyl, isopropyl, pentyl, cyclopentyl, or phenyl is optionally substituted with one or more R ４ａ groups, Each R ４ａ is independently fluorine, methyl, methoxyl, or cyclopropyl, and R ５ is methyl, ethyl, isopropyl, pentyl, cyclopentyl, or phenyl, and the methyl, ethyl, isopropyl, pentyl, cyclopentyl, or phenyl is optionally substituted with one or more R ５ａ groups, Each R ５ａ is independently fluorine, methyl, methoxyl, or cyclopropyl, R ６ is tert-butyl, and R ７ is phenyl optionally substituted with one or more R ７ａ groups, and Each R ７ａ is independently fluorine, R ８ is H, F, or methyl, R ９ is H, F, or methyl, or R ８ and R ９ combine to form cyclopropyl, R １０ and R １１ are each H, or R １０ and R １１ combine to form oxo, R １２ is pyridyl, indolinyl, tetrahydroquinolinyl, phenyl, or isopropyl-phenyl, and the pyridyl, indolinyl, tetrahydroquinolinyl, phenyl, or isopropyl-phenyl is optionally substituted with one or more R １２ａ groups Each R １２ａ which is independently fluorine, cyano, isopropyl, methoxyl, or cyclopropyl, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. X is triazolyl, pyrimidinyl, pyridinyl, phenyl, R １ is phenyl, and R ２ is phenyl, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

17.

18. 【Chemical 24】 and R ４ is phenyl and R ５ is methyl, a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

19. X is 【Chemical 25】 and R １０ and R １１ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R and R combine to form an oxo group.

20. X is 【Chemical 26】 and R １２ is 【Chemical 27】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is

21. X is ​ and R １０ and R １１ combine to form an oxo group, and R １２ is 【Chemical 29】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is

22. R １ and R ２ at least one of which is 【Chemical Formula 30】 The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein X is

23. The compound is 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 The compound according to claim 1, wherein or a pharmaceutically acceptable salt thereof.

24. The compound is 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 【Table 2-5】 【Table 2-6】 【Table 2-7】 【Table 2-8】 【Table 2-9】 【Table 2-10】 【Table 2-11】 【Table 2-12】 【Table 2-13】 【Table 2-14】 【Table 2-15】 【Table 2-16】 【Table 2-17】 【Table 2-18】 【Table 2-19】 【Table 2-20】 【Table 2-21】 The compound according to claim 1, wherein or a pharmaceutically acceptable salt thereof.

25. The compound is 【Table 3-1】 【Table 3-2】 【Table 3-3】 The compound according to claim 1, wherein or a pharmaceutically acceptable salt thereof.

26. A pharmaceutical composition comprising the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers, diluents, or excipients.

27. A method for treating pain, comprising administering to a subject in need thereof a therapeutically effective amount of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof.

28. The method according to claim 27, wherein the pain is neuropathic pain, inflammatory pain, nociceptive pain, a mixed type of nociceptive and neuropathic pain, visceral pain, postoperative pain, postherpetic pain, traumatic pain, phantom limb pain, fibromyalgia syndrome, back pain, cancer pain, chemotherapy-induced neuropathic pain (CINP), or osteoarthritis (OA) pain.

29. The method according to claim 27, wherein the pain is neuropathic pain.

30. The method according to claim 29, wherein the neuropathic pain is diabetic peripheral neuropathic pain.

31. The method according to claim 27, wherein the pain is chronic low back pain.

32. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use in the treatment of pain.

33. A compound for use according to claim 32, wherein the pain is neuropathic pain, inflammatory pain, nociceptive pain, a mixed type of nociceptive and neuropathic pain, visceral pain, postoperative pain, postherpetic pain, traumatic pain, phantom limb pain, fibromyalgia syndrome, syndrome, back pain, cancer pain, chemotherapy-induced neuropathic pain (CINP), or osteoarthritis (OA) pain.

34. A compound for use according to claim 32, wherein the pain is neuropathic pain.

35. A compound for use according to claim 34, wherein the neuropathic pain is diabetic peripheral neuropathic pain.

36. A compound for use according to claim 32, wherein the pain is chronic low back pain.

37. Use of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of pain.

38. The use according to claim 37, wherein the pain is neuropathic pain, inflammatory pain, nociceptive pain, a mixed type of nociceptive and neuropathic pain, visceral pain, postoperative pain, postherpetic pain, traumatic pain, phantom limb pain, fibromyalgia syndrome, back pain, cancer pain, chemotherapy-induced neuropathic pain (CINP), or osteoarthritis (OA) pain.

39. The use according to claim 37, wherein the pain is neuropathic pain.

40. The use according to claim 37, wherein the neuropathic pain is diabetic peripheral neuropathic pain.

41. The use according to claim 37, wherein the pain is chronic low back pain.

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