Compounds and compositions for regulating ERK activity

Abstract

The present invention relates to compounds that modulate the activity of ERK. The present invention also relates to processes for preparing the above compounds, pharmaceutical compositions comprising the above compounds, and the use of the above compounds in the treatment of ERK-mediated pathologies, diseases, and disorders.

Description

[Technical Field]

[0001] The present invention relates to compounds that modulate the activity of ERK (extracellular signal-regulated kinase). The present invention also relates to processes for preparing the compounds, pharmaceutical compositions comprising the compounds, and the use of the compounds in the treatment of ERK-mediated pathologies, diseases, and disorders. [Background technology]

[0002] The MAPK (mitogen-activated protein kinase) pathway is a crucial signaling system that drives cell proliferation, differentiation, and survival. Numerous examples of tumorigenesis underlie abnormal regulation of this pathway. Abnormal signaling or inappropriate activation of the MAPK pathway has been shown in multiple tumor types and can occur through several different mechanisms, including activating mutations in RAS (rat sarcoma virus) and BRAF (B-Raf oncogene, serine / theonine kinase). The MAPK pathway frequently mutates in human cancers, particularly with KRAS (Karsten rat sarcoma virus) and BRAF mutations, which occur most frequently (approximately 30%). RAS mutations, especially gain-of-function mutations, have been detected in 9–30% of all cancers, with KRAS mutations having the highest prevalence (86%).

[0003] Extracellular signal-regulated kinases (ERKs) are a class of signaling kinases involved in transporting extracellular signals to cells and intracellular organelles. ERK1 and ERK2 are involved in regulating a wide range of activity, and dysregulation of the ERK1 / 2 cascade is known to cause various pathological conditions, including neurodegenerative diseases, developmental disorders, diabetes, and cancer. The role of ERK1 / 2 in cancer is particularly interesting because upstream activating mutations in its signaling cascade are thought to be involved in more than half of all cancers. Furthermore, excessive ERK1 / 2 activity has been found even in cancers without mutations in the upstream components, suggesting that ERK1 / 2 signaling plays a role in carcinogenesis even in cancers without mutational activation. The ERK pathway has also been shown to regulate tumor cell migration and invasion, and may therefore be associated with metastasis.

[0004] The prognosis for patients with certain cancers remains poor. Treatment resistance occurs frequently, and not all patients respond to available treatments. For example, the median survival time for patients with advanced colorectal cancer with BRAF mutations is less than 12 months. In normal cellular signaling, the MAPK pathway is tightly regulated by negative feedback at multiple levels. For example, in BRAF V600 mutant melanoma, upstream negative regulation of BRAF is lost, and these cells become more dependent on negative regulation at the ERK level.

[0005] While inhibition of the MAPK pathway can negatively impact melanoma cell proliferation, ERK hyperactivation can also be detrimental to cell survival. ERK hyperactivation via this mechanism leads to MAPK output, cell cycle arrest, unacceptable levels of cellular stress, and increased cell death. In vivo, MAPK hyperactivation results in severe and persistent tumor regression in BRAF mutant melanoma cell lines and patient-derived xenografts.

[0006] To achieve better clinical outcomes, it is crucial to develop new therapies for patients with cancer. Therapeutic options that are better tolerable and / or provide a sustained antitumor response are also desirable. [Overview of the project]

[0007] The compounds of the present invention are small molecule protein-protein interaction disruptors that can block the negative regulation of ERK, providing a novel therapeutic approach for the treatment of cancers such as MAPK-dysregulation cancer, BRAF and / or RAS-mutated cancer, melanoma, lung cancer, colorectal cancer, pancreatic cancer, and thyroid cancer.

[0008] Therefore, according to a first aspect of the present invention, formula (I): [ka] [In the formula, X is selected from N and CR6 (wherein R6 is selected from hydrogen and halo); R1 is selected from hydrogen and halo; R2 is -X1-R 2a and R 2a Selected from; X1 is selected from C1-C4 alkylenes and C2-C4 haloalkylenes; R 2a i) hydrogen, and ii) 0 to 3 substituents R 2b A ring is selected from those substituted with, where the ring is selected from a) a 3-6 member saturated or partially unsaturated carbon ring, b) a 5-6 member heteroaryl, c) phenyl, and d) a 4-6 member heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen; Each R 2b These are independently halo, hydroxyl, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, O-C1-C3 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, cyano, -CO2R 11 , -CO2N(R11 )2, -X2-CO2R 11 , and -X2-CO2N(R 11 )2; X2 is selected from C1-C5 alkylene and C3-C6 cycloalkylene; each R 11 is independently selected from hydrogen, C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 haloalkyl, and C3-C5 cyclohaloalkyl, or two R 11 groups are bonded together with the nitrogen atom to which they are connected to each other to form a 4- to 6-membered heterocyclic ring containing one heteroatom that is nitrogen; R3 is selected from hydrogen, C1-C3 alkyl and C1-C3 haloalkyl, and R4 is hydrogen, or R3 and R4 are bonded together with the piperidinyl ring of formula (I) to which R3 and R4 are connected to form a 7-membered or 8-membered bridged or fused heterocyclic ring; R5 is

Chemical

[0009] According to a second aspect of the present invention, the Specified herein provides compounds according to any one of the examples, or pharmaceutically acceptable salts thereof.

[0010] According to a third aspect of the present invention, a pharmaceutical composition comprising a compound according to a first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers is provided herein.

[0011] According to a fourth aspect of the present invention, the Specified herein provides combinations comprising a compound according to a first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, and one or more further therapeutically active agents.

[0012] A fifth aspect of the present invention is provided herein for a method of regulating ERK activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the present invention.

[0013] According to a sixth aspect of the present invention, the Specified herein provides a method for treating a patient having a disease associated with abnormal activity of the MAP kinase pathway, comprising administering to the patient a therapeutically effective amount of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the present invention.

[0014] According to a seventh aspect of the present invention, compounds according to a first or second aspect of the present invention or pharmaceutically acceptable salts thereof are provided for use as pharmaceuticals.

[0015] According to an eighth aspect of the present invention, the Specified herein provides compounds according to a first or second aspect of the present invention or pharmaceutically acceptable salts thereof for use in the treatment of cancer.

[0016] According to a ninth aspect of the present invention, the use of a compound according to a first or second aspect of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the treatment of cancer is provided herein. [Brief explanation of the drawing]

[0017] [Figure 1] The following shows (A) the change in tumor volume (mm3) and (B) the change in body weight (%) after administration of the compound of formula I (specifically, Example 13) to WM793 BRAFV600E tumor xenografts in nude mice. [Figure 2] The following shows (A) the change in tumor volume (mm3) and (B) the change in body weight (%) after administration of the compound of formula I (specifically, Example 4 or Example 5) to WM793 BRAFV600E tumor xenografts in nude rats. [Modes for carrying out the invention]

[0018] Accordingly, in a first embodiment, the present invention relates to formula (I): [ka] [In the formula, X is selected from N and CR6 (wherein R6 is selected from hydrogen and halo); R1 is selected from hydrogen and halo; R2 is -X1-R 2a and R 2a Selected from; X1 is selected from C1-C4 alkylenes and C2-C4 haloalkylenes; R 2a i) hydrogen, and ii) 0 to 3 substituents R 2b A ring is selected from those substituted with, where the ring is selected from a) a 3-6 member saturated or partially unsaturated carbon ring, b) a 5-6 member heteroaryl, c) phenyl, and d) a 4-6 member heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen; Each R 2b These are independently halo, hydroxyl, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, O-C1-C3 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, cyano, -CO2R 11 , -CO2N(R 11 )2, -X2-CO2R 11 , and -X2-CO2N(R 11 ) Selected from 2; X2 is selected from C1-C5 alkylenes and C3-C6 cycloalkylenes; Each R 11 These are independently selected from hydrogen, C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 haloalkyl, and C3-C5 cyclohaloalkyl, or two R 11 The groups bond together with the nitrogen atoms they are connected to, forming a 4- to 6-membered heterocycle containing one nitrogen heteroatom; R3 is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl, and R4 is hydrogen, or R3 and R4 are bonded together with the piperidinyl ring of formula (I) to which R3 and R4 are connected to form a 7-membered or 8-membered bridged or condensed heterocycle; R5 is [ka] (In the formula, R8 is selected from hydrogen, halo, C1-C6 alkyl, C3-C4 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 haloalkylene-O-C1-C4 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkylene-O-C1-C4 haloalkyl, C1-C6 alkylene-O-C1-C4 haloalkyl, C(=O)H, and cyano, and R9 is -X3-R 9a and R 9a Selected from; Alternatively, R8 and R9, together with the carbon atoms to which they are connected, form 0 to 3 R 9b A ring is formed by substitution with a group, where the ring is a) a 5-6 member saturated or partially unsaturated carbon ring, or b) a 5-6 member heterocycline containing one heteroatom which is O; X3 is selected from C1-C2 alkylenes and C3-C5 cycloalkylenes; R 9a i) hydrogen and ii) 0 to 3 R 9b A ring is selected from those substituted with a group, where the ring is a) phenyl, b) a 5-6 member heteroaryl, c) a C3-C7 cycloalkyl, d) a C7-C9 spiroalkyl, e) a 4-7 member heterocyclyl containing one or two heteroatoms that are each oxygen, or f) a 7-9 member spiroheterocyclyl containing one or two heteroatoms that are each oxygen; Each R 9b These are independently halo, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 alkyl, O-C1-C4 haloalkyl, C1-C4 alkylene-O-C1-C4 alkyl, C1-C4 haloalkylene-O-C1-C4 alkyl, C1-C4 alkylene-O-C1-C4 haloalkyl, C1-C4 haloalkylene-O-C1-C4 haloalkyl, and 0-2 R 9c C3-C7 cycloalkyl groups substituted with R groups, 0-2 R groups 9c C3-C7 cyclohaloalkyl groups substituted with R groups, 0-2 R groups 9c O-C3~C7 cycloalkyl groups substituted with R groups, 0~2 R groups 9c O-C3~C7 cyclohaloalkyl groups substituted with R groups, 0~2 R groups9c A 3- to 7-membered heterocycline containing one heteroatom, O, substituted with a group, and 0-2 R 9c O-3 to 7 membered heterocyclyl containing one heteroatom, O, substituted with a group, and 0 to 2 R 9c Phenyl groups substituted with R groups, 0-2 R groups 9c Pyridinyl substituted with a group, 0-2 R 9c O-C1~C3 alkylene-C3~C7 cycloalkyl groups substituted with R groups, 0~2 R groups 9c O-C1~C3 alkylene-C3~C7 cyclohaloalkyl groups substituted with R groups, and 0~2 R groups 9c Selected from O-C1~C3 alkylene-3~7 membered heterocyclines containing one heteroatom, which is oxygen, substituted with a group; or two R 9b The groups, in combination with the carbon atoms to which they are connected, have 0 to 2 R groups. 9c A ring is formed by substitution with a group, where the ring is a 4-6 membered heterocyclyl containing one heteroatom which is i) C3-C6 cycloalkyl or ii) oxygen; Each R 9c These are independently selected from halo (e.g., fluoro), CH3, and OCH3; Each R 10 It is a halo; m is selected from integers between 0 and 2. Compounds or pharmaceutically acceptable salts thereof are provided.

[0019] In one embodiment, the compound is given by formula (Ia): [ka] [In the formula, X is selected from N and CR6 (wherein R6 is selected from hydrogen and halo); R1 is selected from hydrogen and halo; R2 is -X1-R 2a and R 2a Selected from; X1 is selected from C1-C2 alkylenes and C2 haloalkylenes; R 2a i) hydrogen, and ii) 0 to 3 substituents R 2b A ring is selected from those substituted with, where the ring is selected from a) a 3-6 member saturated or partially unsaturated carbon ring, b) a 5-6 member heteroaryl, c) phenyl, and d) a 4-6 member heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen; Each R 2b These are independently: halo, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, O-C1-C3 alkyl, C1-C3 alkylene-O-C1-C3 alkyl, cyano, -CO2R 11 , -CO2N(R 11 )2, -X2-CO2R 11 , and -X2-CO2N(R 11 ) Selected from 2; X2 is selected from C1-C5 alkylenes and C3-C6 cycloalkylenes; Each R 11 These are independently selected from hydrogen, C1-C5 alkyl, and C3-C6 cycloalkyl. R3 is selected from hydrogen and methyl; R5 is [ka] (In the formula, R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2OCH2CH3, CH2CH2OCH3, C(=O)H, and cyano, and R9 is X3-R 9a and R 9a Selected from; Alternatively, R8 and R9, together with the carbon atoms to which they are connected, form 0 to 1 R 9b It forms a ring substituted with a group, where the ring is a 5-6 membered heterocyclyl containing one heteroatom which is oxygen; X3 is a C1-C2 alkylene; R 9a i) hydrogen, ii) 0-3 R 9bselected from a ring substituted with a group, wherein the ring is a) C4-C6 cycloalkyl, b) 6-membered heterocyclyl containing one heteroatom which is O, c) 7-9 membered spiroheterocyclyl containing one or two heteroatoms each of which is O; each R 9b is independently selected from halo, C1-C3 alkyl, O-C1-C3 alkyl, O-4-6 membered heterocyclyl containing one heteroatom which is O substituted with 0-2 R 9c groups, pyridinyl substituted with 0-2 R 9c groups, and O-C1-C3 alkylene-4-6 membered heterocyclyl containing one heteroatom which is O substituted with 0-2 R 9c groups; or or two R 9b groups, in combination with the carbon atoms to which they are connected to each other, form a ring substituted with 0-2 R 9c groups, wherein the ring is i) C3-C6 cycloalkyl, or ii) 4-6 membered heterocyclyl containing one heteroatom which is oxygen; each R 9c is independently selected from halo (e.g., fluoro), CH3 and OCH3; each R 10 is halo; m is an integer of 0 to 2)]] , which is a compound or a pharmaceutically acceptable salt thereof.

[0020] In one embodiment, X is CH or CF.

[0021] In one embodiment, X is CH.

[0022] In one embodiment, R2 is R 2a .

[0023] In one embodiment, R 2a is 0 to 3 substituents R 2ba ring substituted by , wherein the ring is selected from a) C4~C6 cycloalkyl, and b) 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen (e.g., fully saturated heterocyclyl).

[0024] In a preferred embodiment, R2 is R 2a and R 2a is a ring substituted with 0 to 3 substituents R 2b , wherein the ring is selected from a) C4~C6 cycloalkyl, and b) 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen (e.g., fully saturated heterocyclyl). In a particularly preferred embodiment, R 2a is a ring substituted with 1 to 3 substituents R 2b , wherein the ring is selected from a) C5~C6 cycloalkyl, and b) 4- to 6-membered heterocyclyl containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen (e.g., fully saturated heterocyclyl).

[0025] In an alternative embodiment, R2 is -X1-R 2a and X1 is selected from C1~C4 alkylene and C2~C4 haloalkylene, and R 2a is H.

[0026] In one embodiment, each R 2b is independently selected from halo, C1~C3 alkyl, and CO2H.

[0027] In one embodiment, each R 2b is independently selected from fluoro, chloro, methyl, and CO2H.

[0028] In one embodiment, R3 is H.

[0029] In one embodiment, R5 is

Chemical Structure

[0030] In one embodiment, R5 is [ka] Selected from.

[0031] One embodiment, each R 10 These are independently selected from fluoro, chloro, and bromo.

[0032] In one embodiment, R 2a is 1 to 3 substituents R 2b It is a C5-C6 cycloalkyl substituted with R. In one embodiment, R 2a is 1 to 3 substituents R 2b It is a C6 cycloalkyl substituted with R. In one embodiment, one R 2b It is CO2H, and the other 0-2 R 2b The groups are independently selected from methyl, fluoro, and chloro.

[0033] In one embodiment, R3 is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl, and R4 is hydrogen.

[0034] In one embodiment, R 9a teeth, [ka] [In the formula, R2 is, [ka] And two R 2a If a base exists, R has an undefined position. 2b The base has R at the defined position. 2b A ring carbon atom bonded to a group or a ring carbon atom bonded to a CO2H group (i.e., each [ka] [Can be located on any ring carbon atom that includes (but is not limited to) these.] It is selected from the group consisting of the following.

[0035] In one embodiment, the compound is of formula (Ib): [ka] [In the formula, X, R1, R3, R5, and each R 2b This is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention). In one embodiment, each R 2b These are independently selected from methyl, fluoro, and chloro.

[0036] In one embodiment, R 2a This has 0 to 3 substituents R 2b A 4-6 membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with R. In one embodiment, R 2a This has 0 to 2 substituents R 2b It is a 4-6 membered heterocycline (e.g., a fully saturated heterocycline) containing one heteroatom, which is nitrogen, substituted with R. In one embodiment, R 2a is one or two substituents R 2b A 4-6 membered heterocycline (e.g., a fully saturated heterocycline) containing one heteroatom, which is nitrogen, substituted with R, and each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro).

[0037] In one embodiment, R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano.

[0038] In one embodiment, R9 is X3-R 9a In one embodiment, X3 is CH2.

[0039] In one embodiment, R 9ais a ring substituted with 0 to 2 R 9b groups, wherein the ring is a) C5~C6 cycloalkyl, or b) 6-membered heterocyclyl containing one heteroatom which is O. In one embodiment, R 9a is a ring substituted with 0 or 1 R 9b groups, wherein the ring is a) C6 cycloalkyl, or b) 6-membered heterocyclyl containing one heteroatom which is O.

[0040] In one embodiment, each R 9b is independently selected from O-C1~C3 alkyl, and O-6-membered heterocyclyl containing one heteroatom which is O.

[0041] In one embodiment, R8 and R9, together with the carbon atom to which R8 and R9 are attached, form a ring substituted with 0 to 1 R 9b groups, wherein the ring is 5~6-membered heterocyclyl containing one heteroatom which is O.

[0042] In one embodiment, the compound is of formula (Ic) or (Id):

化

[0043] In one embodiment, the compound is of formula (Ic-1) or (Id-1):

化

[0044] In one embodiment, the compound is of formula (Ic-2) or (Id-2): [ka] [In the formula, R1, each R 2b These are R3, R6, and R 9b , and each R 10 R is defined independently above (for example, as defined in the most broad embodiment of the first aspect of the present invention). In one embodiment, R 9b This is selected from O-6 membered heterocyclyls and phenyl compounds, which contain one heteroatom that is oxygen.

[0045] In one embodiment, the compound is of formula (II): [ka] [In the formula, X, R1, R3, each R 2b These are independent, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 (e.g., 0 to 1) R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention) (for example, each R 9b(These are independently selected from a 6-membered heterocycline containing an O-C1~C3 alkyl group and one heteroatom which is O.)

[0046] In one embodiment, the compound is given by formula (III): [ka] [In the formula, X, R1, R3, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro); R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 (e.g., 0 to 1) R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention) (for example, each R 9b (These are independently selected from a 6-membered heterocycline containing an O-C1~C3 alkyl group and one heteroatom which is O.)

[0047] In one embodiment, the compound is given by formula (IV): [ka] [In the formula, X, R1, R3, each R 2b Each R is independent. 9b These are independent, and each R 10 This is independently defined as described above (for example, as defined in the most extensive embodiment of the first aspect of the present invention).

[0048] In one embodiment, the compound is given by formula (V): [ka] [In the formula, X, R1, R3, each R 9b These are independent, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro).

[0049] In one embodiment, the compound is given by formula (VI): [ka] [In the formula, X, R1, R3, each R 2b These are independent, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention) (for example, each R 9b (These are independently selected from a 6-membered heterocycline containing an O-C1~C3 alkyl group and one heteroatom which is O.)

[0050] In one embodiment, the compound is of formula (VII): [ka] [In the formula, X, R1, R3, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro); R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9bThis is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention) (for example, each R 9b (These are independently selected from a 6-membered heterocycline containing an O-C1~C3 alkyl group and one heteroatom which is O.)

[0051] In one embodiment, the compound is given by formula (VIII): [ka] [In the formula, X, R1, R3, each R 2b These are independent, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention) (for example, each R 9b (These are independently selected from a 6-membered heterocycline containing an O-C1~C3 alkyl group and one heteroatom which is O.)

[0052] In one embodiment, the compound is of formula (IX): [ka] [In the formula, X, R1, R3, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro); R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention) (for example, each R 9b (These are independently selected from a 6-membered heterocycline containing an O-C1~C3 alkyl group and one heteroatom which is O.)

[0053] In one embodiment, the compound is given by formula (X): [ka] [In the formula, X, R1, R3, each R 2b These are independent, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; R9 is R 9a Or X3-R 9a (especially R) 9a ) and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention) (for example, each R 9b (These are independently selected from a 6-membered heterocycline containing an O-C1~C3 alkyl group and one heteroatom which is O.)

[0054] In one embodiment, the compound is of formula (XI): [ka] [In the formula, X, R1, R3, and each R 10 This is independently defined as above (for example, as defined in the most extensive embodiment of the first aspect of the present invention), R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro); R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; R9 is R 9a Or X3-R 9a (especially R) 9a ) and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9bSelected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined above (for example, as defined in the most broad embodiment of the first aspect of the present invention) (for example, each R 9b (These are independently selected from a 6-membered heterocycline containing an O-C1~C3 alkyl group and one heteroatom which is O.)

[0055] According to a second aspect of the present invention, as specified herein, [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound selected from or a pharmaceutically acceptable salt thereof is provided.

[0056] According to a third aspect of the present invention, a pharmaceutical composition comprising a compound according to a first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers is provided herein.

[0057] According to a fourth aspect of the present invention, the Specified herein provides combinations comprising a compound according to a first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, and one or more further therapeutically active agents.

[0058] A fifth aspect of the present invention is provided herein for a method of regulating ERK activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the present invention.

[0059] According to a sixth aspect of the present invention, the Specified herein provides a method for treating a patient having a disease associated with abnormal activity of the MAP kinase pathway, comprising administering to the patient a therapeutically effective amount of a compound according to the first or second aspect of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the third aspect of the present invention.

[0060] In one embodiment, the disease associated with abnormal activity of the MAP kinase pathway is cancer.

[0061] In one embodiment, the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0062] In one embodiment, the cancer contains BRAF and / or RAS mutations.

[0063] According to a seventh aspect of the present invention, compounds according to a first or second aspect of the present invention or pharmaceutically acceptable salts thereof are provided for use as pharmaceuticals.

[0064] According to an eighth aspect of the present invention, the Specified herein provides compounds according to a first or second aspect of the present invention or pharmaceutically acceptable salts thereof for use in the treatment of cancer.

[0065] In one embodiment, the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0066] In one embodiment, the cancer contains BRAF and / or RAS mutations.

[0067] According to a ninth aspect of the present invention, the use of a compound according to a first or second aspect of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a drug for the treatment of cancer is provided herein.

[0068] In one embodiment, the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0069] In one embodiment, the cancer contains BRAF and / or RAS mutations.

[0070] In one embodiment, the compound is administered parenterally. In another embodiment, the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonaryly, intrathecally, topically, or intranasally. In yet another embodiment, the compound is administered systemically.

[0071] In one embodiment, the patient is a mammal, such as a primate, such as a human.

[0072] Accordingly, the present invention provides the following numbered embodiments. It will be recognized that further embodiments of the present invention may be provided by combining the features specified in each embodiment with other specified features.

[0073] Embodiment 1. Formula (I): [ka] [In the formula, X is selected from N and CR6 (wherein R6 is selected from hydrogen and halo); R1 is selected from hydrogen and halo; R2 is -X1-R 2a and R 2a Selected from; X1 is selected from C1-C4 alkylenes and C2-C4 haloalkylenes; R 2a i) hydrogen, and ii) 0 to 3 substituents R 2bA ring is selected from those substituted with, where the ring is selected from a) a 3-6 member saturated or partially unsaturated carbon ring, b) a 5-6 member heteroaryl, c) phenyl, and d) a 4-6 member heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen; Each R 2b These are independently halo, hydroxyl, C1-C3 alkyl, C3-C4 cycloalkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, O-C1-C3 alkyl, C1-C3 alkyl-O-C1-C3 alkyl, cyano, -CO2R 11 , -CO2N(R 11 )2, -X2-CO2R 11 , and -X2-CO2N(R 11 ) Selected from 2; X2 is selected from C1-C5 alkylenes and C3-C6 cycloalkylenes; Each R 11 These are independently selected from hydrogen, C1-C5 alkyl, C3-C5 cycloalkyl, C1-C5 haloalkyl, and C3-C5 cyclohaloalkyl, or two R 11 The groups bond together with the nitrogen atoms they are connected to, forming a 4- to 6-membered heterocycle containing one nitrogen heteroatom; R3 is selected from hydrogen, C1-C3 alkyl, and C1-C3 haloalkyl, and R4 is hydrogen, or R3 and R4 are bonded together with the piperidinyl ring of formula (I) to which R3 and R4 are connected to form a 7-membered or 8-membered bridged or condensed heterocycle; R5 is [ka] (In the formula, R8 is selected from hydrogen, halo, C1-C6 alkyl, C3-C4 cycloalkyl, C1-C6 haloalkyl, C1-C6 alkylene-O-C1-C4 alkyl, C1-C6 haloalkylene-O-C1-C4 alkyl, C1-C6 hydroxyalkyl, C1-C6 haloalkylene-O-C1-C4 haloalkyl, C1-C6 alkylene-O-C1-C4 haloalkyl, C(=O)H, and cyano, and R9 is -X3-R 9a and R 9a Selected from; Alternatively, R8 and R9, together with the carbon atoms to which they are connected, form 0 to 3 R 9b A ring is formed by substitution with a group, where the ring is a) a 5-6 member saturated or partially unsaturated carbon ring, or b) a 5-6 member heterocycline containing one heteroatom which is O; X3 is selected from C1-C2 alkylenes and C3-C5 cycloalkylenes; R 9a i) hydrogen and ii) 0 to 3 R 9b A ring is selected from those substituted with a group, where the ring is a) phenyl, b) a 5-6 member heteroaryl, c) a C3-C7 cycloalkyl, d) a C7-C9 spiroalkyl, e) a 4-7 member heterocyclyl containing one or two heteroatoms that are each oxygen, or f) a 7-9 member spiroheterocyclyl containing one or two heteroatoms that are each oxygen; Each R 9b These are independently halo, hydroxy, C1-C4 alkyl, C1-C4 haloalkyl, O-C1-C4 alkyl, O-C1-C4 haloalkyl, C1-C4 alkylene-O-C1-C4 alkyl, C1-C4 haloalkylene-O-C1-C4 alkyl, C1-C4 alkylene-O-C1-C4 haloalkyl, C1-C4 haloalkylene-O-C1-C4 haloalkyl, and 0-2 R 9c C3-C7 cycloalkyl groups substituted with R groups, 0-2 R groups 9c C3-C7 cyclohaloalkyl groups substituted with R groups, 0-2 R groups 9c O-C3~C7 cycloalkyl groups substituted with R groups, 0~2 R groups 9c O-C3~C7 cyclohaloalkyl groups substituted with R groups, 0~2 R groups9c A 3- to 7-membered heterocycline containing one heteroatom, O, substituted with a group, and 0-2 R 9c O-3 to 7 membered heterocyclyl containing one heteroatom, O, substituted with a group, and 0 to 2 R 9c Phenyl groups substituted with R groups, 0-2 R groups 9c Pyridinyl substituted with a group, 0-2 R 9c O-C1~C3 alkylene-C3~C7 cycloalkyl groups substituted with R groups, 0~2 R groups 9c O-C1~C3 alkylene-C3~C7 cyclohaloalkyl groups substituted with R groups, and 0~2 R groups 9c Selected from O-C1~C3 alkylene-3~7 membered heterocyclines containing one heteroatom, which is oxygen, substituted with a group; or two R 9b The groups, in combination with the carbon atoms to which they are connected, have 0 to 2 R groups. 9c A ring is formed by substitution with a group, where the ring is a 4-6 membered heterocyclyl containing one heteroatom which is i) C3-C6 cycloalkyl or ii) oxygen; Each R 9c These are independently selected from halo (e.g., fluoro), CH3, and OCH3; Each R 10 It is a halo; m is selected from integers between 0 and 2. A compound of or a pharmaceutically acceptable salt thereof.

[0074] Embodiment 2. The compound is of formula (Ia): [ka] [In the formula, X is selected from N and CR6 (wherein R6 is selected from hydrogen and halo); R1 is selected from hydrogen and halo; R2 is -X1-R 2a and R 2a Selected from; X1 is selected from C1-C2 alkylenes and C2 haloalkylenes; R2a i) hydrogen, and ii) 0 to 3 substituents R 2b A ring is selected from those substituted with, where the ring is selected from a) a 3-6 member saturated or partially unsaturated carbon ring, b) a 5-6 member heteroaryl, c) phenyl, and d) a 4-6 member heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen; Each R 2b These are independently: halo, hydroxyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, O-C1-C3 alkyl, C1-C3 alkylene-O-C1-C3 alkyl, cyano, -CO2R 11 , -CO2N(R 11 )2, -X2-CO2R 11 , and -X2-CO2N(R 11 ) Selected from 2; X2 is selected from C1-C5 alkylenes and C3-C6 cycloalkylenes; Each R 11 These are independently selected from hydrogen, C1-C5 alkyl, and C3-C6 cycloalkyl. R3 is selected from hydrogen and methyl; R5 is [ka] (In the formula, R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2OCH2CH3, CH2CH2OCH3, C(=O)H, and cyano, and R9 is X3-R 9a and R 9a Selected from; Alternatively, R8 and R9, together with the carbon atoms to which they are connected, form 0 to 1 R 9b It forms a ring substituted with a group, where the ring is a 5-6 membered heterocyclyl containing one heteroatom which is oxygen; X3 is a C1-C2 alkylene; R 9a i) hydrogen, ii) 0-3 R 9bA ring is selected from those substituted with a group, where the ring is a) a C4-C6 cycloalkyl, b) a 6-membered heterocycline containing one heteroatom which is O, or c) a 7-9 membered spiroheterocycline containing one or two heteroatoms which are each O; Each R 9b These are independently halo, C1-C3 alkyl, O-C1-C3 alkyl, and 0-2 R 9c O-4 to 6 membered heterocyclyl containing one heteroatom, O, substituted with a group, 0 to 2 R 9c Pyridinyl substituted with a group, and 0-2 R groups 9c Selected from O-C1~C3 alkylene-4~6 membered heterocyclines containing one heteroatom, which is oxygen, substituted with a group; or two R 9b The groups, in combination with the carbon atoms to which they are connected, have 0 to 2 R groups. 9c A ring is formed by substitution with a group, where the ring is a 4-6 membered heterocyclyl containing one heteroatom which is i) C3-C6 cycloalkyl or ii) oxygen; Each R 9c These are independently selected from halo (e.g., fluoro), CH3, and OCH3; Each R 10 It is a halo; m is selected from integers between 0 and 2. The compound or a pharmaceutically acceptable salt thereof according to Embodiment 1.

[0075] Embodiment 3.X is CH or CF, the compound described in Embodiment 1 or Embodiment 2 or a pharmaceutically acceptable salt thereof.

[0076] Embodiment 4.X is CH, the compound described in Embodiment 3 or a pharmaceutically acceptable salt thereof.

[0077] Embodiment 5.R2 is R 2a The compound described in any one of Embodiments 1 to 4 or a pharmaceutically acceptable salt thereof.

[0078] Embodiment 6.R 2a However, 0 to 3 substituents R 2b A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 5, wherein the ring is selected from a 4-6 membered heterocyclil (e.g., a fully saturated heterocyclil) containing a) C4-C6 cycloalkyl and b) one or two heteroatoms independently selected from oxygen and nitrogen.

[0079] Embodiment 7.R 2a However, 1 to 3 substituents R 2b A compound according to Embodiment 6 or a pharmaceutically acceptable salt thereof, wherein the ring is substituted with a) a C5-C6 cycloalkyl and b) a 4-6 membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen.

[0080] Embodiment 8. Each R 2b However, independently selected from halo, C1-C3 alkyl, and CO2H, the compound described in any one of Embodiments 1-7 or a pharmaceutically acceptable salt thereof.

[0081] Embodiment 9. Each R 2b However, independently selected from fluoro, chloro, methyl, and CO2H, the compounds described in any one of Embodiments 1 to 8 or pharmaceutically acceptable salts thereof.

[0082] Embodiment 10. A compound according to any one of Embodiments 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R3 is H.

[0083] Embodiment 11.R5 is, [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of Embodiments 1 to 10.

[0084] Embodiment 12. A compound or pharmaceutically acceptable salt thereof according to Embodiment 11, wherein m is 1 or 2.

[0085] Embodiment 13.R5 is, [ka] A compound or a pharmaceutically acceptable salt thereof, selected from any one of Embodiments 1 to 12.

[0086] Embodiment 14. Each R 10 However, independently selected from fluoro, chloro, and bromo, the compounds described in any one of Embodiments 1 to 13 or pharmaceutically acceptable salts thereof.

[0087] Embodiment 15.R 2a However, 1 to 3 substituents R 2b A compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, which is a C5-C6 cycloalkyl substituted with .

[0088] Embodiment 16.R 2a However, 1 to 3 substituents R 2b A compound according to any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt thereof, which is a C6 cycloalkyl substituted with .

[0089] Embodiment 17.1 R 2b However, it is CO2H, and the other 0-2 R 2b A compound or pharmaceutically acceptable salt thereof according to Embodiment 15 or Embodiment 16, wherein each group is independently selected from methyl, fluoro, and chloro.

[0090] Embodiment 18. The compound is of formula (Ib): [ka] (In the formula, X, R1, R3, R5, and each R 2bA compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 16, wherein (is defined in any one of claims 1 to 16).

[0091] Embodiment 19. Each R 2b However, independently selected from methyl, fluoro, and chloro, the compounds described in Embodiment 18 or pharmaceutically acceptable salts thereof.

[0092] Embodiment 20.R 2a However, 0 to 3 substituents R 2b A compound according to any one of Embodiments 1 to 14 or a pharmaceutically acceptable salt thereof, which is a 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with .

[0093] Embodiment 21.R 2a However, 0 to 2 substituents R 2b The compound according to Embodiment 20 or a pharmaceutically acceptable salt thereof, which is a 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one heteroatom that is nitrogen, substituted with .

[0094] Embodiment 22.R 2a However, one or two substituents R 2b A 4-6 membered heterocycline (e.g., a fully saturated heterocycline) containing one heteroatom, which is nitrogen, substituted with R, and each R 2b A compound or pharmaceutically acceptable salt thereof according to Embodiment 20 or Embodiment 21, wherein the substituent is independently selected from methyl and halo (e.g., fluoro).

[0095] Embodiment 23. A compound or pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 22, wherein R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano.

[0096] Embodiment 24.R9 is X3-R 9aThe compound described in any one of Embodiments 1 to 23 or a pharmaceutically acceptable salt thereof.

[0097] Embodiment 25. The compound described in Embodiment 24 or a pharmaceutically acceptable salt thereof, wherein X3 is CH2.

[0098] Embodiment 26.R 9a However, 0 to 2 R 9b A compound according to any one of Embodiments 1 to 25 or a pharmaceutically acceptable salt thereof, wherein the ring is a ring substituted with a group, where the ring is a six-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O.

[0099] Embodiment 27.R 9a However, 0 or 1 R 9b A compound according to Embodiment 26 or a pharmaceutically acceptable salt thereof, wherein the ring is a ring substituted with a group, where the ring is a six-membered heterocycline containing one heteroatom which is a) C6 cycloalkyl or b) O.

[0100] Embodiment 28. Each R 9b However, the compounds described in any one of Embodiments 1 to 27 or pharmaceutically acceptable salts thereof are independently selected from O-C1 to C3 alkyl and O-6 membered heterocyclils containing one heteroatom which is O.

[0101] Embodiment 29. R8 and R9, together with the carbon atoms to which R8 and R9 are connected, form 0 to 1 R 9b A compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 22, wherein a ring is formed by substitution with a group, the ring being a 5- to 6-membered heterocycline containing one heteroatom which is oxygen.

[0102] Embodiment 30. R8 and R9, together with the carbon atoms to which R8 and R9 are connected, 9b A ring is formed by substitution with a group, where the ring is a 6-membered heterocyclyl containing one heteroatom which is O, and R 9b However, there are 0 to 2 (for example, 0) R9c O-4 to 6 membered heterocyclyl containing one heteroatom that is O, substituted with a group, and 0 to 2 (e.g., 0) R 9c A compound according to Embodiment 29 or a pharmaceutically acceptable salt thereof, selected from phenyls substituted with a group.

[0103] Embodiment 31. Formula (Ic) or (Id): [ka] (In the formula, X, R1, R2, R3, R 9b , and each R 10 A compound or a pharmaceutically acceptable salt thereof described in Embodiment 29 or Embodiment 30, which is independently defined in Embodiment 29 or Embodiment 30.

[0104] Embodiment 32. Formula (Ic-1) or (Id-1): [ka] (In the formula, X, R1, R2, R3, R 9b , and each R 10 A compound or a pharmaceutically acceptable salt thereof described in Embodiment 31, which is independently defined in Embodiment 31.

[0105] Embodiment 33. Formula (Ic-2) or (Id-2): [ka] (In the formula, R1, each R 2b These are R3, R6, and R 9b , and each R 10 The compound described in Embodiment 32 or a pharmaceutically acceptable salt thereof, which is independently defined in Embodiment 32.

[0106] Embodiment 34.R 9bHowever, the compounds described in Embodiment 32 or Embodiment 33 or pharmaceutically acceptable salts thereof, selected from O-6 membered heterocyclyls containing one heteroatom which is O, and phenyl.

[0107] Embodiment 35. The compound is of formula (II): [ka] [In the formula, X, R1, R3, each R 2b These are independent, and each R 10 This is independently defined as any one of Embodiments 1 to 14; R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 (e.g., 0 to 1) R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined in any one of Embodiments 1 to 16 (for example, each R 9b The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 14, wherein (is independently selected from a 6-membered heterocycline containing one heteroatom which is O-C1~C3 alkyl and O).

[0108] Embodiment 36. The compound is of formula (III): [ka] [In the formula, X, R1, R3, and each R 10 This is independently defined as any one of Embodiments 1 to 14; R2 is R 2a and; R 2a This has 0 to 3 substituents R 2bA 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro); R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 (e.g., 0 to 1) R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined in any one of Embodiments 1 to 16 (for example, each R 9b The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 14, wherein (is independently selected from a 6-membered heterocycline containing one heteroatom which is O-C1~C3 alkyl and O).

[0109] Embodiment 37. The compound is of formula (IV): [ka] (In the formula, X, R1, R3, each R 2b Each R is independent. 9b These are independent, and each R 10 A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 14, which is independently defined in any one of Embodiments 1 to 14.

[0110] Embodiment 38. The compound is of formula (V): [ka] [In the formula, X, R1, R3, each R 9b These are independent, and each R10 This is independently defined as any one of Embodiments 1 to 14; R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituent is independently selected from methyl and halo (e.g., fluoro), the compound according to any one of Embodiments 1 to 14 or a pharmaceutically acceptable salt thereof.

[0111] Embodiment 39. The compound is of formula (VI): [ka] [In the formula, X, R1, R3, each R 2b These are independent, and each R 10 This is independently defined as any one of Embodiments 1 to 14; R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined in any one of Embodiments 1 to 16 (for example, each R 9b The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 14, wherein (is independently selected from a 6-membered heterocycline containing one heteroatom which is O-C1~C3 alkyl and O).

[0112] Embodiment 40. The compound is of formula (VII): [ka] [In the formula, X, R1, R3, and each R 10 This is independently defined as any one of Embodiments 1 to 14; R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro); R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined in any one of Embodiments 1 to 16 (for example, each R 9b The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 14, wherein (is independently selected from a 6-membered heterocycline containing one heteroatom which is O-C1~C3 alkyl and O).

[0113] Embodiment 41. The compound is of formula (VIII): [ka] [In the formula, X, R1, R3, each R 2b These are independent, and each R 10This is independently defined as any one of Embodiments 1 to 14; R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined in any one of Embodiments 1 to 16 (for example, each R 9b The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 14, wherein (is independently selected from a 6-membered heterocycline containing one heteroatom which is O-C1~C3 alkyl and O).

[0114] Embodiment 42. The compound is of formula (IX): [ka] [In the formula, X, R1, R3, and each R 10 This is independently defined as any one of Embodiments 1 to 14; R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro); R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; The R9 is the X3-R 9a and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined in any one of Embodiments 1 to 16 (for example, each R 9b The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 14, wherein (is independently selected from a 6-membered heterocycline containing one heteroatom which is O-C1~C3 alkyl and O).

[0115] Embodiment 43. The compound is of formula (X): [ka] [In the formula, X, R1, R3, each R 2b These are independent, and each R 10 This is independently defined as any one of Embodiments 1 to 14; R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; R9 is R 9a Or X3-R 9a (especially R) 9a ) and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined in any one of Embodiments 1 to 16 (for example, each R 9b The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 14, wherein (is independently selected from a 6-membered heterocycline containing one heteroatom which is O-C1~C3 alkyl and O).

[0116] Embodiment 44. The compound is of formula (XI): [ka] [In the formula, X, R1, R3, and each R 10 This is independently defined as any one of Embodiments 1 to 14; R2 is R 2a and; R 2a This has 0 to 3 substituents R 2b A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R 2b The substituents are independently selected from methyl and halo (e.g., fluoro); R8 is selected from hydrogen, methyl, ethyl, CHF2, CH2CH2OCH3, C(=O)H, and cyano; R9 is R 9a Or X3-R 9a (especially R) 9a ) and; X3 is CH2; R 9a i) hydrogen and ii) 0 to 2 R 9b Selected from rings substituted with a group, where the ring is a 6-membered heterocycline containing one heteroatom which is a) C5-C6 cycloalkyl or b) O; each R 9b This is as defined in any one of Embodiments 1 to 16 (for example, each R 9b The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments 1 to 14, wherein (is independently selected from a 6-membered heterocycline containing one heteroatom which is O-C1~C3 alkyl and O).

[0117] Embodiment 45. [ka] [ka] [ka] [ka] [ka] [ka] [ka] A compound selected from or a pharmaceutically acceptable salt thereof.

[0118] Embodiment 46. A pharmaceutical composition comprising a compound described in any one of Embodiments 1 to 45 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0119] Embodiment 47. A combination comprising a compound described in any one of Embodiments 1 to 45 or a pharmaceutically acceptable salt thereof, and one or more further therapeutically active agents.

[0120] Embodiment 48. A method for modulating ERK activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound described in any one of Embodiments 1 to 45 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 46.

[0121] Embodiment 49. A method for treating a patient having a disease associated with abnormal activity of the MAP kinase pathway, comprising administering to the patient a therapeutically effective amount of a compound described in any one of Embodiments 1 to 45 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 46.

[0122] Embodiment 50. The method according to Embodiment 49, wherein the disease associated with abnormal activity of the MAP kinase pathway is cancer.

[0123] Embodiment 51. The method according to Embodiment 50, wherein the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0124] Embodiment 52. The method according to Embodiment 50 or Embodiment 51, wherein the cancer contains BRAF and / or RAS mutations.

[0125] Embodiment 53. A compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 46 for use as a pharmaceutical.

[0126] Embodiment 54. A compound according to any one of Embodiments 1 to 46 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

[0127] Embodiment 55. The compound for use described in Embodiment 54 or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0128] Embodiment 56. A compound for use according to Embodiment 54 or Embodiment 55, or a pharmaceutically acceptable salt thereof, wherein the cancer contains BRAF and / or RAS mutations.

[0129] Embodiment 57. Use of a compound or a pharmaceutically acceptable salt thereof described in any one of Embodiments 1 to 46 in the manufacture of a pharmaceutical product for the treatment of cancer.

[0130] Embodiment 58. The use according to Embodiment 57, wherein the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0131] Embodiment 59. The use according to Embodiment 57 or Embodiment 58, wherein the cancer contains BRAF and / or RAS mutations.

[0132] definition For the purposes of interpreting this specification, unless otherwise specified, the following definitions shall apply as appropriate, and terms used in the singular form shall also include the plural form, and vice versa. It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural form unless otherwise explicitly indicated by the context. Thus, for example, "the compound" may include a reference to one or more compounds.

[0133] As used herein, the term "substituent" refers to a radical group that replaces a hydrogen atom in a given molecule.

[0134] As used herein, the term "alkyl" refers to a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, without unsaturation, and linked to the rest of the molecule by single bonds. For example, C1-C4 alkyl groups contain 1 to 4 carbon atoms. Examples of C1-C4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, 1-methylethyl (isopropyl), n-butyl, and t-butyl.

[0135] As used herein, the terms "halogen," "halo," and "hal" refer to fluorine, chlorine, bromine, or iodine. Halogen substituents and moieties, such as alkyls substituted with halogens (haloalkyls), may be monohalogenated, polyhalogenated, or perhalogenated.

[0136] As used herein, the term "haloalkyl" means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are replaced by halogen atoms. For example, C1-C4 haloalkyls contain 1-4 carbon atoms (and one or more halogen atoms).

[0137] As used herein, the term “hydroxyalkyl” means an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group are replaced by an -OH group. For example, C1-C4 hydroxyalkyls contain 1-4 carbon atoms (and one or more OH groups).

[0138] As used herein, the term "alkylene" refers to a linear or branched divalent group of an alkyl group. For example, "C1-C4 alkylene" contains 1 to 4 carbon atoms, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)2-, and -CH2CH(CH3)CH2-.

[0139] Similarly, as used herein, the term “haloalkylene” refers to the linear or branched divalent group of a haloalkyl group.

[0140] As used herein, the term "cycloalkyl" refers to a saturated carbocyclic ring group. For example, a C3-C6 cycloalkyl is any such ring group containing 3-6 carbon atoms, and in particular monocyclic rings, i.e., cyclobutyl, cyclopentyl, and cyclohexyl. However, cycloalkyls (e.g., C3-C6 cycloalkyls) can also be condensed (e.g., [ka] -5-membered condensed ring), or bridged (for example) [ka] -4-membered bridge ring) Possibly a biring ring system.

[0141] As used herein, the term “cyclohaloalkyl” means a cycloalkyl group as defined herein, wherein one or more hydrogen atoms of the cycloalkyl group are replaced by halogen atoms. In particular, if each of the one or more halogen atoms is a fluorine atom, then “cyclohaloalkyl” is “cyclofluoroalkyl.” Like cycloalkyls, halocycloalkyls may be condensed or cross-linked bicyclic ring systems.

[0142] As used herein, the terms “heterocyclyl,” “heterocycle,” “heterocyclic formula,” and “heterocyclic ring” refer to saturated or partially unsaturated, but non-aromatic heterocyclic groups, which can be monocyclic or polycyclic rings, including fused or bridging bicyclic ring systems. However, in particular, heterocyclyls are monocyclic rings. A heterocyclyl contains at least one non-carbon atom (typically N, O, or S unless otherwise specified) as a ring member, and so the remaining ring atoms are carbon. If a heterocyclyl (n-unsubstituted) contains S as a heteroatom, that S can be in the form of S, SO, or SO2 (in other words, an oxygen atom bonded to sulfur does not constitute a substitution). For example, the term "4- to 6-membered heterocyclyl containing one heteroatom selected from the group consisting of O, N, and S" refers to a ring group containing 4 to 6 ring atoms, each containing one heteroatom (either O, N, or S [the latter including S, SO, and SO2]), with the remaining ring atoms being carbon. An example of a 7-membered bridged heterocycle is: [ka] An example of a 7-membered condensed complex ring is: [ka] That is the case.

[0143] As used herein, the term “spirocycloalkyl” refers to a ring system comprising a first carbocyclic ring containing 3 to 6 ring carbon atoms, wherein two substituents on the carbocyclic atoms in the first carbocyclic ring collectively form a second carbocyclic ring containing 3 to 6 ring carbon atoms. In particular, spirocycloalkyls are saturated. As used herein, the term 6-8 membered spirocycloalkyl means that the total number of carbocyclic atoms in the first and second carbocyclic rings is 6 to 8. As those skilled in the art will understand, “spirocycloalkylene” is a diradical equivalent to “spirocycloalkyl.”

[0144] As used herein, the term “spiroheterocyclyl” refers to a ring system comprising a first carbocyclic or heterocyclic ring comprising 3 to 6 ring atoms, wherein two substituents on the carbocyclic atoms in the first carbocyclic or heterocyclic ring collectively form a second carbocyclic or heterocyclic ring comprising 3 to 6 ring atoms, wherein at least one of the first and second rings is a heterocyclic ring comprising one or more heteroatoms selected from the group consisting of O, N, and S (the latter of which may be in the form of S, SO, or SO2), particularly selected from the group consisting of O and N. In particular, spiroheterocyclyls are saturated. As used herein, the term 7-9 membered spiroheterocyclyl means that the total number of ring atoms in the first carbocyclic or heterocyclic ring and the second carbocyclic or heterocyclic ring is 7 to 9. For example, spiroheterocyclyl [ka] It is a seven-membered spiroheterocyclyl because it has seven ring atoms. As those skilled in the art will understand, a "spiroheterocyclyl" is a monoradical, while a "spiroheterocyclylene" is a diradical (similar to alkyls and alkylenes).

[0145] The term "heteroaryl," as used herein, refers, unless otherwise specified, to a monocyclic aromatic ring group containing one, two, three, or four heteroatoms individually selected from nitrogen, oxygen, and sulfur (in the form of S, SO, or SO2). Typical monocyclic heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 1-, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-, or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or 5-(1,2,4-triazolyl), 4- or 5-(1,2,3-triazolyl), 2-, 3-, or 4-pyridyl, 3- or 4-pyridazinyl, 2-pyridinyl, and 2-, 4-, or 5-pyrimidinyl. In particular, heteroaryls contain 1 to 3 heteroatoms individually selected from nitrogen, oxygen, and sulfur.

[0146] As used herein, the terms “3- to 6-membered saturated or partially unsaturated carbon rings” and “5- to 6-membered saturated or partially unsaturated carbon rings” refer to radical monocyclic rings that are saturated or partially unsaturated but not aromatic and do not have non-carbon atoms as ring members. Therefore, these terms include cycloalkyls such as cyclopentane, cyclo(mono)alkenes such as cyclopentene, and cyclodienes such as 1,3-cyclohexadiene. The former term includes 3, 4, 5, and 6-membered rings, while the latter is limited to 5 and 6-membered rings.

[0147] Depending on the selection of starting materials and procedures, compounds may exist in one of the possible stereoisomers, or as a mixture thereof, for example, as pure optical isomers, or as stereoisomer mixtures, such as racemic and diastereoisomer mixtures, depending on the number of chiral carbon atoms. The present invention intends to encompass all such possible stereoisomers, including racemic mixtures, diasteriomeric mixtures, and optically pure forms. Optically active (R)- and (S)-stereoisomers can be prepared using chiral synthons or chiral reagents, or they can be divided using conventional techniques. If the compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis configuration or a trans configuration. All tautomers are also intended to be included.

[0148] As used herein, the terms “salt” or “salts” refer to acid-addition or base-addition salts of the compounds of this disclosure. “Salt” more specifically includes “pharmaceutically acceptable salts.” “pharmaceutically acceptable salts” means salts that retain the biological efficacy and properties of the compounds of the present invention and are not typically biologically or otherwise undesirable. In many cases, the compounds of the present invention have the ability to form acidic and / or basic salts due to the presence of amino and / or carboxyl groups or similar groups. When both basic and acidic groups are present in the same molecule, the compounds of the present invention may also form internal salts, such as zwitterionic molecules. Pharmacologically acceptable acid addition salts can be formed from inorganic and organic acids.

[0149] Examples of inorganic acids that can induce salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids that can induce salt formation include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid.

[0150] pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Examples of inorganic bases that can derive salts include ammonium salts and metals of groups 1 through 12 of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly preferred salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples of organic bases that can derive salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, corinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0151] In another embodiment, the present invention relates to acetate, ascorbate, adipine, aspartate, benzoate, besilate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphor sulfonate, caprine, chloride / hydrochloride, chlortheophyllonate, citrate, ethane disulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutaric acid, glycolate, hippurate, hydroiodide / iodide, isethionate, lactate, lactate The present invention provides compounds in the form of bionates, lauryl sulfates, malates, maleates, malons, mandelates, mesilates, methyl sulfates, mucinates, naphthoates, napsylates, nicotinates, nitrates, octadecanoates, oleates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonates, propions, sebacinates, stearates, succinates, sulfosalicylates, sulfates, tartrates, tosylates, triphenylacetates, trifluoroacetates, or xinafoates.

[0152] In another aspect, the present invention provides compounds according to any one of Embodiments 1 to 45 in the form of sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, silver salts, zinc salts, copper salts, isopropylamine salts, benzathine salts, corinate salts, diethanolamine salts, diethylamine salts, lysine salts, meglumine salts, piperazine salts, or tromethamine salts.

[0153] All formulas provided herein are intended to represent compounds in both unlabeled and isotope-labeled forms. Isotope-labeled compounds have the structure depicted by the formulas provided herein, except in which one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen.

[0154] Furthermore, certain isotopes, in particular deuterium (i.e., 2The incorporation of H or D may result in certain therapeutic benefits derived from higher metabolic stability, e.g., increased in vivo half-life, reduced required dose, or improved therapeutic index or tolerance. In this context, deuterium is understood to be a substituent of the compound of the present invention. The concentration of deuterium may be defined by the isotopic enrichment factor. As used herein, the term “isotopic enrichment factor” means the ratio of the isotopic abundance to the natural abundance of a particular isotope. When a substituent in a compound of the present invention is indicated as deuterium, such a compound has an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation into each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom. It should be understood that the term “isotopic enrichment factor” can be applied to any isotope in the same way as the description for deuterium.

[0155] Other examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus (phosphorous), fluorine, and chlorine, respectively. 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 Examples include I. Therefore, the present invention is, for example, 3 H and 14 Radioactive isotopes such as C, or 2 H and 13It must be understood that this includes compounds that incorporate one or more of the aforementioned isotopes, including those that contain non-radioactive isotopes such as 13C. Such isotope-labeled compounds are used in metabolic studies. 14 (by C), reaction kinetic studies (for example) 2 H or 3 It is useful in detection or imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays (by H), or in radiotherapy for patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. The isotope-labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods similar to those described in the attached examples and preparations, using appropriate isotope-labeling reagents instead of conventionally used unlabeled reagents.

[0156] Pharmaceutical composition As used herein, the term “pharmaceutical composition” means the compound of the present invention or a pharmaceutically acceptable salt thereof, combined with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

[0157] As used herein, the term “pharmaceutically acceptable carrier” means a substance useful in the preparation or use of a pharmaceutical composition, and as will be known to those skilled in the art, examples include suitable diluents, solvents, dispersions, surfactants, antioxidants, preservatives, isotonic agents, buffers, emulsifiers, absorption retarders, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavorings, colorants, and combinations thereof (e.g., Remington, The Science and Practice of Pharmacy, 22 ndSee Ed. Pharmaceutical Press, 2013, pp. 1049-1070). The term “therapeutic dose” of the compound of the present invention means an amount of the compound of the present invention that is expected to elicit a biological or medical response in a subject, such as a reduction or inhibition of enzyme or protein activity, or to improve symptoms, alleviate a pathological condition, slow or delay the progression of a disease, or prevent a disease. In one non-limiting embodiment, the term “therapeutic dose” means an amount of the compound of the present invention that, when administered to a subject, is effective in at least partially alleviating, inhibiting, preventing, and / or improving a pathological condition, disorder, or disease that is mediated by ERK, or (ii) related to ERK activity, or (iii) characterized by (normal or abnormal) ERK activity; or (2) effective in reducing or inhibiting ERK activity; or (3) effective in reducing or inhibiting ERK expression. In another non-limiting embodiment, the term “therapeutic effective dose” means an amount of the compound of the present invention that, when administered to cells, or tissues, or noncellular biological materials, or culture media, is effective in at least partially reducing or inhibiting the activity of ERK; or is effective in at least partially reducing or inhibiting the expression of ERK.

[0158] As used herein, the term “subject” refers to primates (e.g., humans, males or females), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0159] As used herein, the terms “inhibit,” “inhibit,” or “to inhibit” mean the reduction or suppression of a given pathological condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0160] As used herein, the terms “to treat,” “to treat,” or “to cure” any disease or disorder mean reducing or relieving the disease or disorder (i.e., delaying or cessating the onset of the disease or at least one of its clinical symptoms); or reducing or relieving at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be identifiable to the patient.

[0161] As used herein, the terms “prevent,” “prevent,” or “prevention” of any disease or disorder mean preventive measures for a disease or disorder; or delaying the onset or progression of a disease or disorder.

[0162] When used herein, the terms “a,” “an,” “the,” and similar terms used in the context of the present invention (particularly in the context of the claims) should be interpreted as encompassing both singular and plural forms, unless otherwise specifically indicated herein or unless there is a particular contextual inconsistency.

[0163] All methods described herein may be carried out in any preferred order, unless otherwise specifically indicated herein or unless it is particularly evident in the context. Any examples or illustrative statements provided herein (e.g., "etc.") are intended solely to better illustrate the invention and do not impose any limitation on the scope of the invention as originally claimed.

[0164] Any chiral atom (e.g., carbon) of the compounds of the present invention may exist in a racemic state or enantio-enriched to exist in, for example, (R), (S), or (R,S) configurations. In certain embodiments, in the (R)- or (S)- configurations, each chiral atom has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. Substituents of atoms by unsaturated double bonds may exist in cis (Z) or trans (E) configurations, where possible.

[0165] Therefore, when used herein, the compounds of the present invention may be in one of the possible stereoisomers, rotational isomers, atropisomers, tautomers, or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antagonists), racemic compounds, or mixtures thereof.

[0166] Any resulting stereoisomer mixture can be separated, for example, by chromatography and / or fractional crystallization, into pure or substantially pure geometric or optical isomers, diastereomers, or racemates based on the physicochemical differences of their constituent components.

[0167] Any racemic mixture of the compound or intermediate of the present invention obtained can be resolved to its optical counterpart by known methods, for example, by separation of its diastereomer salt obtained with an optically active acid or base, and liberation of an optically active acidic or basic compound. More specifically, the compound of the present invention may be resolved to its optical counterpart by utilizing the basic moiety, for example, by fractional crystallization of a salt formed with an optically active acid, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. The racemic compound or racemic intermediate of the present invention can also be resolved by chiral chromatography, for example, by high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0168] Method for synthesizing the compound of the present invention Unless otherwise indicated herein or unless explicitly stated otherwise, all methods described herein may be performed in any preferred order. Any examples or illustrative statements provided herein (e.g., "etc.") are intended solely to better illustrate the invention and do not impose any limitation on the scope of the invention as originally claimed.

[0169] The compounds of this application can be prepared by a person skilled in the art of organic synthesis using commercially available starting materials, compounds known in the literature, or easily prepared intermediates, by utilizing standard synthetic methods and procedures that are either known to a person skilled in the art or would be apparent to a chemist skilled in the art in light of the teachings herein.

[0170] The compound of formula (I) can be prepared by the method shown in the following synthetic reaction scheme. In the scheme described below, it is well understood that protecting groups are used on sensitive or reactive groups if necessary, in accordance with general chemical principles. Protecting groups are handled according to standard organic synthesis methods, such as those described in Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 or Protecting Groups, 3rd edition, Thieme, Stuttgart, 2004. Protecting groups are removed at a stage that is convenient for the synthesis of the compound by methods readily apparent to those skilled in the art.

[0171] Those skilled in the art will recognize whether the compounds disclosed herein have stereocenters. The final product, intermediates, or starting materials may be affected by any suitable method known in the art. See, for example, “Stereochemistry of Organic Compounds” by ELEliel, S. Wilen, and LNMander (Wiley-Interscience, 1994).

[0172] The compounds of this disclosure can be synthesized by following the steps outlined in the reaction scheme. Starting materials are commercially available or prepared by known procedures as described in the reported literature.

[0173] The present invention further includes any modifications of the present method, in which the remaining steps are carried out using an intermediate product obtained at any stage as a starting material, or in which the starting material is formed in situ under reaction conditions, or in which the reactants are used in the form of their salts or optically pure materials. The compounds and intermediates of the present invention can also be converted to each other by methods generally known to those skilled in the art.

[0174] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition may be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also include inhalation or intranasal application. The pharmaceutical composition of the present invention may be in solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including, without limitation, solutions, suspensions, or emulsions). Tablets may be film-coated or enterically coated by methods known in the art. Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with one or more of the following: a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salt and / or polyethylene glycol; the tablets also contain c) Binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; if necessary d) Disintegrants, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and e) Absorbents, colorants, flavorings, and sweeteners.

[0175] Method of use of the present invention Compounds of formula (I), in free form or pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, such as ERK-modulating properties, as demonstrated, for example, in in vitro studies as provided in the following section, and are therefore suitable for therapeutic use or use as research chemicals, for example, as tool compounds.

[0176] The compounds of the present invention may be useful in the treatment of cancers selected from, for example, melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0177] Accordingly, in a further embodiment, the present invention provides the use of the compounds of the present invention as pharmaceutical agents. In a further embodiment, this therapy is selected from diseases that can be treated by modulation of ERK. In another embodiment, the disease is cancer, for example, selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0178] In another embodiment, the present invention provides a method for treating a patient having a disease associated with abnormal activity of the MAP kinase pathway, comprising administering to the patient a therapeutically effective amount of the compound according to the present invention or a pharmaceutically acceptable salt thereof. In another embodiment, the disease is a cancer, for example, selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

[0179] The pharmaceutical composition or combination of the present invention may, for example, be one or more active ingredients in a unit dose of about 1 to 1000 mg for a target weighing about 50 to 70 kg.

[0180] The compounds of the present invention may be administered simultaneously with, or before or after, one or more other therapeutic agents. The compounds of the present invention may be administered separately, by the same or different routes of administration, or together in the same pharmaceutical composition as the other agents. The therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid, which is therapeutically active or enhances therapeutic activity when administered to a patient in combination with the compounds of the present invention.

[0181] In one embodiment, the present invention provides a product comprising the compound of the present invention and at least one other therapeutic agent as a combination formulation for simultaneous, separate, or sequential use in a therapy. In one embodiment, the therapy is the treatment of a disease or condition mediated by ERK. The product provided as a combination formulation comprises a composition comprising the compound of the present invention and the other therapeutic agent combined in the same pharmaceutical composition, or a composition comprising the compound of the present invention and the other therapeutic agent in separate forms, for example, in the form of a kit.

[0182] In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharmaceutically acceptable carrier as described herein.

[0183] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which contains a compound of the present invention. In one embodiment, the kit comprises means for individually holding the compositions, such as a container, a partitioned bottle, or a partitioned foil pouch. An example of such a kit is a blister pack, as is commonly used for packaging tablets, capsules, and the like.

[0184] The kits of the present invention can be used to administer different dosage forms, such as orally and parenterally, to administer separate compositions at different dosing intervals, or to titrate separate compositions with each other. To assist with medication adherence, the kits of the present invention typically include instructions for administration.

[0185] In the combination therapy of the present invention, the compound of the present invention and other therapeutic agents may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and other therapeutic agents may be combined into a combination therapy (i) before the combination product is delivered to the physician (for example, in the case of a kit containing the compound of the present invention and other therapeutic agents); (ii) immediately before administration by the physician himself (or under the guidance of the physician); or (iii) by the patient himself, for example, while administering the compound of the present invention and other therapeutic agents sequentially.

[0186] Accordingly, the present invention provides a use of the compound of the present invention for treating ERK-mediated diseases or conditions, wherein the pharmacopoeia is prepared for administration together with another therapeutic agent. The present invention also provides a use of another therapeutic agent for treating ERK-mediated diseases or conditions, wherein the pharmacopoeia is administered together with the compound of the present invention.

[0187] The present invention also provides a compound of the present invention for use in a method of treating an ERK-mediated disease or condition, wherein the compound of the present invention is prepared for administration together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating an ERK-mediated disease or condition, wherein the other therapeutic agent is prepared for administration together with the compound of the present invention. The present invention also provides a compound of the present invention for use in a method of treating an ERK-mediated disease or condition, wherein the compound of the present invention is administered for administration together with another therapeutic agent. The present invention also provides another therapeutic agent for use in a method of treating an ERK-mediated disease or condition, wherein the other therapeutic agent is administered together with the compound of the present invention.

[0188] The present invention also provides the use of the compounds of the present invention for treating ERK-mediated diseases or conditions, wherein the patient has been previously treated (e.g., within 24 hours) with another therapeutic agent. The present invention also provides the use of another therapeutic agent for treating ERK-mediated diseases or conditions, wherein the patient has been previously treated (e.g., within 24 hours) with the compounds of the present invention.

[0189] General reaction scheme The compounds of the present invention can be prepared by proceeding according to the following general reaction scheme: Reaction Scheme I [ka] Reaction Scheme II [ka] Reaction Scheme III [ka] Reaction Scheme IV [ka] [Examples]

[0190] The following examples and synthesis schemes further illustrate this disclosure, but they should not be construed as limiting the scope or spirit of the specific procedures described herein. It should be understood that the examples are provided to illustrate specific embodiments and are not intended to limit the scope of this disclosure. Furthermore, it should be understood that various other embodiments, variations, and equivalents may be relied upon, which may be suggested to those skilled in the art without departing from the spirit of this disclosure and / or the appended claims.

[0191] The compounds of this disclosure can be prepared by methods known in the art of organic synthesis. It is understood that in all methods, protecting groups for sensitive or reactive groups may be used where necessary in accordance with general principles of chemistry. Protecting groups are handled according to standard methods of organic synthesis (TW. Green and PG. M. Wuts (1999), Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons). These groups are removed at a convenient stage in the synthesis of the compounds using methods readily apparent to those skilled in the art. Analytical methods, materials, and measurement means

[0192] Unless otherwise noted, reagents and solvents were used as received from the commercial suppliers. Proton nuclear magnetic resonance ( 1Unless otherwise noted, 1H NMR spectra were recorded using ICON-NMR under TopSpin program control on a Bruker AVANCE 400 MHz, 500 MHz, or 600 MHz NMR mass spectrometer. Spectra were measured at 298 K unless otherwise specified and referenced to solvent resonance. Tetramethylsilane (TMS) was used as an internal standard. Chemical shifts are reported in ppm against dimethyl sulfoxide (δ2.50), methanol (δ3.31), chloroform (δ7.26), or other solvents, as shown in the NMR spectral data. A small amount of dry sample (2-5 mg) was dissolved in a suitable deuterated solvent (1 mL). Chemical names were generated using CambridgeSoft's ChemBioDraw Ultra v19.

[0193] Mass spectra were acquired on LC-MS, SFC-MS, or GC-MS systems using electrospray, chemical, and electron impulse ionization methods from various instruments with the following configurations: Waters Acquity UPLC / SQD system with photodiode array detector and single quadrupole mass detector; Agilent 1200 system with G6110 series mass detector; Agilent 1290 Infinity II with DAD (photodiode array detector) and single quadrupole mass detector with ESI and APCI ionization (multimode); Waters AcQuity UPLC with PDA (photodiode array detector), ELSD, and single quadrupole mass detector with ESI ionization; Waters Auto Purification system with PDA (photodiode array detector) and single quadrupole mass detector with ESI ionization; [M+H] + This refers to the protonated molecular ion of a chemical species; [MH] - This refers to a molecular ion of a chemical species from which one proton has been lost; [M+Na] + This refers to a molecular ion of a chemical species to which one sodium ion has been added; [M-Boc+H] + This refers to a protonated molecular ion; [M-tBu+2H]+ This refers to the protonated molecular ion of a chemical species that does not have a tert-butyl group.

[0194] Abbreviation Some abbreviations used in the examples are as follows: 1,1-bis(diphenylphosphin)-ferrocenedichloropalladium(II)(PdCl2(dppf)); 1,1-carbonyldiimidazole(CDI); 1-hydroxy-7-azabenzotriazole(HOAt); 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HATU); 2,2'-bis-diphenylphosphanyl-[1,1']binaphthalenyl(BINAP); 4-dimethylaminopyridine(DMAP); 3-morpholinopropane-1-sulfonic acid(MOPS); acetic acid(AcOH); acetic anhydride(Ac2O); acetonitrile(CH3CN); aqueous solution(aq.); atmospheric pressure(atm.); back pressure regulator(BPR) ); broad (br); benzotriazole-1-yloxytris-(dimethylamino)-phosphonium hexafluorophosphate (BOP); doublet (d); dichloromethane (DCM); diethyl ether (Et2O); diisopropyl azodicarboxylate (DIAD); dimethyl sulfoxide (DMSO); diphenyl phosphoryl azide (DPPA); di-tert-butyl dicarbonate (Boc2O); equivalent (equiv.); ethanol (EtOH); ethyl acetate (Â); fetal bovine serum (FBS); Foster resonance energy transfer (FRET); gram (g); high-performance liquid chromatography (HPLC); high-resolution mass spectrum (HRMS); homogeneous time-resolved FRET (HTRF); time (h); hydrochloric acid (HCl); inner diameter (ID)); Isopropanol (iPrOH); Isopropylamine (iPr2NH); Liquid chromatography-mass spectrometry (LCMS); Liter (L); Lithium aluminum hydride (LAH); Lithium bis(trimethylsilyl)amide (LHMDS); Lithium diisopropylamide (LDA); Lithium hydroxide (LiOH); Luminescence (LUM); Magnesium sulfate (MgSO4); Mass spectrum (MS); Meta-chloroperbenzoic acid (mCPBA); Metabolism (MT); Methanol (MeOH); Methyl iodide (MeI); Methyl tert-butyl ether (MBTE); Microwave (MW); Microliter (μL); Micrometer (μm); Micromol (μmol); Milliliter (mL); Millimeter (mm); Millimole (mmol); Minute (min) ; Mole (mol); Multiple (m); N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC); n-butyllithium (n-BuLi); N-chlorosuccinimide (NCS); N-hydroxysuccinimide (NHS); N,N-diisopropyl-ethylamine (DIPEA); N,N-dimethylformamide (DMF); Isopropanol (iPrOH); Pentet (p); Potassium hydroxide (KOH); Potassium tert-butoxide (KOtBu); Palladium carbon (Pd / C); p-toluenesulfonic acid (PTSA); p-toluenesulfonyl chloride (TsCl); Phosphate-buffered saline (PBS); Quartet (q); Retention time (Rt); Roswell Park Memorial Laboratory medium (RPMI); Room temperature (RT); Saturation (sat.); Singlet(s); Sodium bicarbonate (NaHCO3); Sodium borohydride (NaBH4); Sodium carbonate (Na2CO3); Sodium hydride (NaH); Sodium hydroxide (NaOH); Sodium sulfate (Na2SO3); Sodium thiosulfate (Na2S2O3); Supercritical fluid chromatography (SFC); Tert-butoxycarbonyl (Boc); Tert-butyldimethylsilyl chloride (TBSCl); Tetrahydrofuran (THF); Toluene sulfonyl methyl isocyanide (TosMIC); Triethylamine (NEt3); Triethylsilane (Et3SiH); Trifluoroacetic acid (TFA); Trimethylaluminum (AlMe3); Trimethylsilyl trifluoromethanesulfonate (TMSOTf); Triplet(t); Tris(2-carboxyethyl)phosphine (TCEP); Tri-tert-butylphosphonium tetrafluoroborate (TTBP-HBF4); Thionyl chloride (SOCl2); Trimethylsilyl chloride (TMSCl); Weight (wt.). .

[0195] Intermediate 1 2-ethyl-6-fluoro-1H-indole [ka] Step a: At room temperature, 6-fluoro-1H-indole (62.5 g, 462 mmol) was added to dimethylacetamide (2.0 L) and H2O (200 mL), followed by bicyclo[2.2.1]hepta-2-ene (87.1 g, 925 mmol), and then K2CO3 (128 g, 927 mmol). The reaction mixture was sparged with N2 while stirring for 15 minutes. Bromoethane (150 g, 1.38 mol) was added, followed by bis(acetonitrile)palladium chloride (14.4 g, 55.0 mmol). A reflux condenser was attached to the flask, and the headspace was sparged with N2 for a further 45 minutes. The outlet was removed, and the reaction mixture was stirred at 70°C for a further 14 hours, then cooled to room temperature, diluted with MTBE (1.4 L), and filtered. The resulting mixture was poured into H2O (650 mL), and the organic layer was partitioned. The aqueous layer was extracted with MTBE (650 mL x 2), the combined organic extract was washed with H2O (500 mL x 2), dried on Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 1:10). The desired fractions were combined and concentrated under reduced pressure. This substance was further purified by recrystallization from hexane (200 mL) to obtain 2-ethyl-6-fluoro-1H-indole (95.0 g) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),7.36(dd,J=8.4,5.2Hz,1H),7.03(dd,J=10.0,2.4Hz,1H),6.79-6.74 (m,1H),6.12(dd,J=2.0,0.8Hz,1H),2.71(m,J=7.6Hz,2H),1.25(t,J=7.6Hz,3H).MS m / z 164.2 [M+H] + .

[0196] The compounds listed in Table 1 below were synthesized using the corresponding functionalized indoles and alkyl bromides, using the above procedure or a modification thereof.

[0197] [Table 1]

[0198] Intermediate 2 Ethyl(1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate [ka] Step a: 1.0 M LHMDS in 750 mL of THF was added to ethyl 4-oxocyclohexane-1-carboxylate (120 g, 705 mmol) in 600 mL of THF at -70°C. The reaction mixture was stirred for 1 hour. Next, MeI (211 g, 1.49 mol) was added, and the mixture was heated to 20°C while stirring for 3 hours. The reaction mixture was cooled to 0°C, quenched with saturated aqueous solution of NaHCO3 (1 L), and partially concentrated under reduced pressure to remove volatile organic compounds. The mixture was diluted with H2O and extracted with ethyl phosphate (500 mL x 3). The combined organic extract was dried and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl phosphate, 100:1 to 5:1). The desired fractions were combined and concentrated under reduced pressure to obtain racemic cis-ethyl-3-methyl-4-oxocyclohexane-1-carboxylate (30 g) as a pale yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.17-4.04(m,2H),2.82-2.70(m,1H),2.45-2.21(m,5H),1.89-1.71(m,1H),1.59-1.46(m,1H),1.25-1.16(m,3H),1.03-0.97(m,3H)

[0199] Step b: At room temperature under N2 conditions, tetraethoxytitanium (28.3 mL, 135 mmol) was added to racemic cis-ethyl-3-methyl-4-oxocyclohexane-1-carboxylate (8.3 g, 45.1 mmol) and (S)-2-methylpropane-2-sulfinamide (6.83 g, 56.3 mmol) in THF (100 mL). The reaction mixture was heated to 55 °C for 14 hours, then cooled to 0 °C and quenched with saturated aqueous NaHCO3 solution. The mixture was diluted with toluene, vigorously stirred, and filtered. The solid was washed with toluene (40 mL x 2), the combined organic extract was washed with saturated aqueous NaCl solution (50 mL), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (heptane:toluene, 100:0~40:60). The desired fractions were combined and concentrated under reduced pressure to obtain the separated diastereomer, ethyl(1S,3S,E)-4-(((S)-tert-butylsulfinyl)imino)-3-methylcyclohexane-1-carboxylate (peak 1, first to elute, 4.44 g), as a colorless liquid. 1 H NMR(400MHz,DMSO-d6)δ 4.06(q,J=7.1Hz,2H),3.50(dt,J=14.5,3.8Hz,1H),2.81(tt,J=12.3,3.8Hz,1H),2.60(dt,J=11.9,6.0Hz ,1H),2.28-2.08(m,3H),1.61-1.46(m,1H),1.40-1.27(m,1H),1.20-1.13(m,12H),0.98(d,J=6.4Hz,3H).

[0200] Step c: At 0°C, ethyl (1S,3S,E)-4-(((S)-tert-butylsulfinyl)imino)-3-methylcyclohexane-1-carboxylate (peak 1, 57 g, 198 mmol) was added to THF (570 mL), to which NaBH4 (7.5 g, 198 mmol) was added. The reaction mixture was stirred at 0°C for 1 hour, then quenched with saturated aqueous solution of NaHCO3 (300 mL), diluted with toluene (500 mL) and H2O (300 mL), and vigorously stirred for 1 hour. The resulting mixture was extracted with toluene (500 mL x 2). The combined organic extract was dried and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:toluene, 100:1~5:1). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl (1S,3S,4S)-4-(((S)-tert-butylsulfinyl)amino)-3-methylcyclohexane-1-carboxylate (35 g) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ 5.08-4.99(m,1H),4.10-3.95(m,2H),2.31-2.19(m,1H),1.97-1.77(m,3H),1.53-1.39 (m,1H),1.37-1.29(m,2H),1.21-1.14(m,4H),1.12-1.07(m,10H),1.03-0.96(m,3H).MS m / z 290.1 ​​[M+H] + .

[0201] Step d: At 0°C, 45.0 g, 456 mmol of ethyl (1S,3S,4S)-4-(((S)-tert-butylsulfinyl)amino)-3-methylcyclohexane-1-carboxylate was added to 270 mL, 1.08 mol of 1,4-dioxane. The reaction mixture was stirred at 20°C for 16 hours, and then concentrated under reduced pressure to obtain the crude product. This product was combined with another batch, triturated with 300 mL of petroleum ether, and filtered. The solid was recovered and dried under reduced pressure to obtain 82 g of ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate hydrochloride as a white solid.1 H NMR(400MHz,DMSO-d6)δ 8.23(s,3H),4.04(m,J=7.1Hz,2H),2.64(s,1H),2.38-2.21(m,1H),2.06(d,J=2.7Hz,1H),1.98-1 .82(m,2H),1.69-1.52(m,1H),1.36(t,J=10.5Hz,2H),1.27-1.08(m,4H),0.99(d,J=6.5Hz,3H).MS m / z 186.2 [M+H] + .

[0202] Intermediate 3 Methyl(2S,4S)-4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)-2-methylpiperidine-4-carboxylate [ka] Step a: TosMIC (366 g, 1.88 mol) was added to KOtBu (421 g, 3.75 mol) in 1,4-dioxane (2.8 L) at 0°C to approximately 10°C. The reaction mixture was stirred for 0.5 hours, after which EtOH (86.4 g, 1.88 mol) and tert-butyl(S)-2-methyl-4-oxopiperidine-1-carboxylate (200 g, 938 mmol) in 1,4-dioxane (1.2 L) were slowly added from a dropping funnel at 0°C to approximately 10°C. The mixture was stirred at 25°C for 16 hours. The mixture was poured into saturated aqueous solution of NH4Cl (4 L), extracted with MTBE (2 L x 2), the combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether: SiO, 10:1) to obtain tert-butyl(2S)-4-cyano-2-methylpiperidine-1-carboxylate (114g) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ 4.50(s,1H),4.03(d,J=13.9Hz,1H),2.88-2.69(m,2H),2.09-1.99(m,1H) ,1.92-1.86(m,2H),1.71-1.65(m,1H),1.45(s,9H),1.13(d,J=7.0Hz,3H).

[0203] Step b: At 25°C, tert-butyl(2S)-4-cyano-2-methylpiperidine-1-carboxylate (150 g, 704 mmol) was mixed with KOH (237 g, 4.22 mol) in EtOH / H2O (750 mL / 750 mL). The reaction mixture was stirred at 80°C for 2 hours, and then partially concentrated under reduced pressure to remove volatile organic compounds. The residue was extracted with MTBE (500 mL x 2), and the pH was lowered to 2-3 by adding citric acid (200 g). The mixture was diluted with H2O (500 mL) and extracted with ELISA (500 mL x 2). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (2S)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (120 g, crude) as a colorless oil.

[0204] Step c: (2S)-1-(tert-butoxycarbonyl)-2-methylpiperidine-4-carboxylic acid (120 g, 493 mmol) in DMF (1.2 L) at 25°C was mixed with K2CO3 (136 g, 986 mmol) and MeI (105 g, 740 mmol). The reaction mixture was stirred at 25°C for 6 hours. The mixture was poured into H2O (1 L) and extracted with MTBE (300 mL x 3). The combined organic extract was washed with saturated aqueous NaCl solution (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product as black oil. The crude product was purified by silica gel chromatography (petroleum ether: siRNA, 5:1). The desired fractions were combined and concentrated under reduced pressure to obtain 1-(tert-butyl)4-methyl(2S)-2-methylpiperidine-1,4-dicarboxylate (100g) as a yellow oil. 1H NMR(400MHz,CDCl3)δ 4.47(s,1H),4.00(d,J=12.0Hz,1H),3.66(s,3H),2.82(dt,J=2.5,13.4Hz,1H),2.68-2.52(m,1H),1. 91-1.83(m,1H),1.77-1.70(m,2H),1.50(dd,J=4.6,12.7Hz,1H),1.44(s,9H),1.12(d,J=7.0Hz,3H).

[0205] Step d: 1-(tert-butyl)4-methyl(2S)-2-methylpiperidine-1,4-dicarboxylate (100 g, 389 mmol) was added to a 1.0 M LDA solution in toluene (583 mL, 583 mmol) at -25°C. The reaction mixture was warmed to 25°C over 0.5 hours. 1-bromo-4-fluorobenzene (68 g, 389 mmol) was added, followed by Pd(dba)2 (8.94 g, 15.5 mmol) and TTBP-HBF4 (9.02 g, 31.1 mmol). The reaction mixture was stirred at 25°C for 16 hours, then poured into H2O (1 L) and extracted with RINKAN (300 mL x 2). The organic extract was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether: siRNA, 10:1), followed by preparative HPLC (column: Phenomenex luna C18 250mm x 100mm, 10μm; H2O and CH3CN (containing 0.1% formic acid), 55-75%), and then by spherical silica gel chromatography (petroleum ether: siRNA, 0-8%) to obtain 1-(tert-butyl)4-methyl(2S,4S)-4-(4-fluorophenyl)-2-methylpiperidine-1,4-dicarboxylate (35.5g) as a colorless oil. SFC method: Cellulose-2 50x4.6mm ID, 3μm; Mobile phase: Phase A for CO2, Phase B for CH3CN (0.05% DIPEA); Gradient elution of CH3CN (0.05% DIPEA) in CO2 5%~40%; Flow rate: 3mL / min; Detector: PDA column; Temperature: 35℃; Back pressure: 100bar; R t =1.279 minutes. 1H NMR(400MHz,CDCl3)δ 7.38-7.30(m,2H),7.08-6.95(m,2H),4.58-4.43(m,1H),4.03(d,J=12.6Hz,1H),3.64(s,3H),3.22-3.09(m,1H),2 .70-2.58(m,2H),2.06(dd,J=6.0,13.8Hz,1H),1.57(dt,J=5.0,13.3Hz,1H),1.45(s,9H),1.10(d,J=7.1Hz,3H).MS m / z 296.0 [M-tBu] + .

[0206] Step e: At 25°C, 120 g (341 mmol) of 1-(tert-butyl)4-methyl(2S,4S)-4-(4-fluorophenyl)-2-methylpiperidine-1,4-dicarboxylate was added to 1,4-dioxane (1.2 L) with a 4 M HCl solution in 1,4-dioxane (512 mL). The reaction mixture was stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure to obtain methyl(2S,4S)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate hydrochloride salt (98.3 g, crude). MS m / z 252.1 [M+H] + .

[0207] Step f: At 0°C, methyl(2S,4S)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate hydrochloride salt (100 g, 348 mmol) was added to DCM (1 L), to which CDI (169 g, 1.04 mol) and DIPEA (270 g, 2.09 mol) were added. The reaction mixture was stirred at 25°C for 16 hours, then poured into cold H2O (1 L) and extracted with DCM (500 mL x 3). The combined organic extract was washed with saturated NaCl aqueous solution (300 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether: SiO, 1:4) to obtain methyl(2S,4S)-4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)-2-methylpiperidine-4-carboxylate (115g) as a colorless oil that partially solidifies over time.1 H NMR(400MHz,CDCl3)δ 7.83(s,1H),7.32(dd,J=5.2,7.5Hz,2H),7.16(s,1H),7.08(s,1H),7.02(t,J=8.2Hz,2H),4.64-4.53(m,1H),3.94(d,J=13.9Hz,1H),3.67( MS m / z 346.0 [M+H] + SFC method: Chiralpak AD-3 50x4.6mm ID3μm; Mobile phase: Phase A for CO2, Phase B for MeOH (0.05% DIPEA); Gradient elution of B in A 5%~40%; Flow rate: 3mL / min; Detector: DAD; Column temperature: 35℃; Back pressure: 100bar, R t =1.368 minutes.

[0208] Intermediate 4 2-Ethyl-6-fluoro-3-(((1r,4r)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-Z-indole [ka] Step a: Methyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (100 g, 632 mmol) in THF (1.0 L) at 0°C under N2 was dropwise mixed with NEt3 (116 mL, 834 mmol) and TMSCl (105 mL, 821 mmol). The reaction mixture was stirred at 0°C for 1 hour, then diluted with hexane (1.0 L) and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: SiO, 10:1). The desired fractions were combined and concentrated under reduced pressure to obtain methyl (1r,4r)-4-[(trimethylsilyl)oxy]cyclohexane-1-carboxylate (130 g) as a yellow oil.

[0209] Step b: Methyl(1r,4r)-4-[(trimethylsilyl)oxy]cyclohexane-1-carboxylate (130 g, 564 mmol) in DCM (1.0 L) was added dropwise to tetrahydro-4H-pyran-4-one (103 mL, 1.03 mol), Et3SiH (228 mL, 1.96 mol), and TMSOTf (145 mL, 652 mmol). The mixture was stirred at -78 °C for 5 minutes, then stirred at 0 °C for 1 hour. The reaction mixture was quenched with saturated aqueous solution of NaHCO3 (500 mL) and extracted with DCM (500 mL x 3). The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether: SiO, 2:1) to obtain methyl (1r,4r)-4-(oxan-4-yloxy)cyclohexane-1-carboxylate (135g) as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 3.85-3.70(m,2H),3.69-3.51(m,4H),3.45-3.35(m,2H),3.28-3.25(m,1H),2.32-2.2 0(m,1H),1.97-1.80(m,4H),1.79-1.71(m,2H),1.48-1.27(m,4H),1.27-1.10(m,2H).

[0210] Step c: Methyl (1r,4r)-4-(oxan-4-yloxy)cyclohexane-1-carboxylate (140 g, 577 mmol) in THF (1.5 L) was added dropwise to THF (318 mL, 636 mmol) solution of 2.0 M LAH. The reaction mixture was stirred at 0°C for 0.5 hours, then quenched with saturated aqueous solution of NaHCO3 (500 mL) and filtered. The filtrate was extracted with DCM (500 mL x 3). The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: siRNA, 1:1). The desired fractions were combined and concentrated under reduced pressure to obtain [(1r,4r)-4-(oxan-4-yloxy)cyclohexyl]methanol (110 g) as a yellow oil. 1H NMR(300MHz,DMSO-d6)δ 4.38(t,J=5.3Hz,1H),3.83-3.73(m,2H),3.64-3.53(m,1H),3.37-3.34(m,1H)3.31-3.24(m,2H),3.19(t,J =5.8Hz,2H),1.98-1.85(m,2H),1.83-1.66(m,4H),1.43-1.21(m,3H),1.18-1.02(m,2H),0.96-0.76(m,2H).

[0211] Step d: At 0°C under N2, [(1r,4r)-4-(oxan-4-yloxy)cyclohexyl]methanol (50.0 g, 233 mmol) was added to DIPEA (131 mL, 752 mmol) and sulfur trioxide pyridine complex (67.0 g, 421 mmol) in DMSO (300 mL). The reaction mixture was stirred for 1 hour, then quenched with 1 M citric acid aqueous solution (1.0 L) and extracted with DCM (500 mL x 3). The organic extract was washed with saturated NaCl aqueous solution, 1 M citric acid aqueous solution (1.0 L), and then again with saturated NaCl aqueous solution. The combined organic extract was dried over Na2SO4, filtered, concentrated under reduced pressure, and (1r,4r)-4-(oxan-4-yloxy)cyclohexane-1-carbaldehyde (49 g, crude) was obtained as a yellow oil. 1 H NMR(300MHz,DMSO-d6)δ 9.57(d,J=1.1Hz,1H),3.83-3.73(m,2H),3.64-3.53(m,1H),3.39-3.34(m,2H),3.30-3 .21(m,1H),2.29-2.16(m,1H),1.97-1.85(m,4H),1.82-1.72(m,2H),1.43-1.17(m,6H).

[0212] Step e: At 0°C, 2-ethyl-6-fluoro-1H-indole (31.5 g, 193 mmol), Et3SiH (156 mL, 966 mmol), and TFA (36.0 mL, 484 mmol) were added dropwise to (1r,4r)-4-(oxan-4-yloxy)cyclohexane-1-carbaldehyde (49 g, 231 mmol) in DCM (800 mL). The reaction mixture was stirred at 0°C for 1 hour, then quenched with saturated aqueous solution of NaHCO3 (500 mL) and extracted with DCM. The combined organic extract was washed with saturated aqueous solution of NaCl (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether: siRNA, 2:1). The desired fractions were combined and concentrated under reduced pressure. This substance was further purified by crystallization (petroleum ether: siRNA: DCM, 600:10:10) to obtain 2-ethyl-6-fluoro-3-{[(1r,4r)-4-(oxan-4-yloxy)cyclohexyl]methyl}-1H-indole (50.0 g) as a white solid. MS m / z 358 [MH] - . 1 H NMR(300MHz,DMSO-d6)δ 10.76(s,1H),7.32(dd,J=8.4,5.7Hz,1H),6.98(dd,J=10.2,2.1Hz,1H),6.79 6.81(m,1H),3.80-3.72(m,2H),3.57-3.52(m,1H),3.31-3.21(m,3H),2.63(dd,J=15.3,7.8Hz,2H) ,2.48-2.40(m,2H),1.91-1.60(m,6H),1.50-1.29(m,3H),1.20(t,J=7.8Hz,3H),1.12-0.96(m,4H).

[0213] The following compounds in Table 2 were synthesized using the corresponding functionalized indole and aldehyde / ketone intermediates, using the procedure described above or a modification thereof.

[0214] [Table 2-1]

[0215] [Table 2-2]

[0216] [Table 2-3]

[0217] Intermediate 5 Methyl 4-(4-fluorophenyl)piperidine-4-carboxylate [ka] Step a: At 0°C, 2-(4-fluorophenyl)acetonitrile (240 g, 1.78 mol) in DMF (1.2 L) was mixed with tert-butylbis(2-chloroethyl)carbamate (430 g, 1.78 mol) and NaH (156 g, 3.91 mol, 60 wt%) in batches over 10 minutes. The reaction mixture was then heated to 60°C and stirred for 4 hours. After cooling to room temperature, the mixture was poured into a mixed solution of H2O (3.6 L) and MTBE (3.6 L). The organic phase was separated, washed with saturated aqueous NaCl solution (1.5 L x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was triturated with heptane (2 L) and filtered to obtain tert-butyl 4-cyano-4-(4-fluorophenyl)piperidine-1-carboxylate (440 g) as a bright yellow solid. 1 H NMR(400MHz,DMSO)δ 7.60(m,2H),7.41-7.14(m,2H),4.13(d,J=12.6Hz,2H),3.01(s,2H),2.12(d,J=13.1Hz,2H),1.90(td,J=13.2,4.3Hz,2H),1.61-1.22(s,9H).

[0218] Step b: At room temperature, tert-butyl 4-cyano-4-(4-fluorophenyl)piperidine-1-carboxylate (638 g, 2.10 mol) was added to NaOH solution in H2O (3.2 L) (3.35 kg, 83.8 mol). Next, the reaction mixture was heated to 70°C and stirred for 16 hours. The mixture was cooled to 20°C, diluted with H2O (6.4 L), and the pH was adjusted to 6-7 with citric acid at 5-10°C. This mixture was extracted with MTBE (3 L x 2) and concentrated under reduced pressure to obtain 1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (620 g, crude) as a white solid. MS m / z 322.2 [MH] - .

[0219] Step c: 1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (620 g, 1.92 mol) in MeOH (6.2 L) at 10°C was joined dropwise with SOCl2 (684 g, 5.75 mol), and the reaction mixture was heated to 70°C with stirring for 16 hours. The mixture was cooled to 20°C, concentrated under reduced pressure, and diluted with H2O (3.1 L). The aqueous phase was extracted with MTBE (1 L) and neutralized to pH=7-8 with Na2CO3 at 5-10°C. The organic extract was filtered, washed with H2O (1 L), and concentrated under reduced pressure. The filtered cake was dissolved in DCM (1.5 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 4-(4-fluorophenyl)piperidine-4-carboxylate (260 g, crude) as an off-white solid. 1 H NMR(400MHz,CDCl3)δ MS m / z 238.1 [M+H] + .

[0220] The following compounds in Table 3 were synthesized using the corresponding phenylacetonitrile, either in the procedure described above or a modification thereof.

[0221] [Table 3]

[0222] Intermediate 6 ((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methanol [ka] Step a: Methyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (200 g, 1.26 mol) in DMF (1.0 L) at room temperature was mixed with imidazole (129 g, 1.90 mol), followed by TBSCl (166 g, 1.1 mol). The reaction mixture was stirred at room temperature for 1.5 hours, and then diluted with H2O (2.0 L) and SiO (2.0 L). The layers were separated, the organic layer was washed with H2O (500 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:SiO, 10:0~20:1) to obtain methyl (1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate (295 g) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ 3.47-3.72(m,4H),2.15-2.33(m,1H),1.23-1.41(m,4H),1.16-1.46(m,4H),0.85(s,9H),0.04(s,6H).

[0223] Step b: At 0°C under N2, 180 g, 660 mmol of methyl (1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexane-1-carboxylate in 1.5 L of THF was gradually added with 25.1 g, 660 mmol of LAH, and the reaction mixture was stirred for 1 hour. At 0°C under N2, the reaction mixture was quenched with 25 mL of H2O, followed by 25 mL of 10 wt% aqueous NaOH solution, and then 50 mL of H2O. Next, 100 g of Na2SO4 was added, and the mixture was filtered. The filtered cake was washed with 500 mL x 2 of ELISA, and the filtrate was concentrated under reduced pressure to obtain ((1r,4r)-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)methanol (121 g, crude) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 4.34(t,J=5.3Hz,1H),3.59-3.43(m,1H),3.23-3.12(m,2H),1.82-1.72(m,2H) ,1.71-1.61(m,2H),1.30-1.07(m,3H),0.95-0.79(m,11H),0.06--0.03(m,6H).

[0224] Intermediate 7a and intermediate 7b (S)-3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline and (R)-3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline [ka] Step a: 6-fluoro-1H-indole (150 g, 1.11 mol) in DCM (2.1 L) at room temperature was mixed with 4-(benzyloxy)cyclohexane-1-one (317 g, 1.55 mol). Next, Et3SiH (516 g, 4.44 mol) was added, followed by TFA (506 g, 4.44 mol). The reaction mixture was stirred at room temperature for 2 hours, and then quenched with H2O (1.1 L) and saturated aqueous solution of NaHCO3 (500 mL). The layers were separated, and the aqueous layer was extracted with DCM (600 mL x 3). The combined organic extract was washed with saturated aqueous solution of NaCl (1 L), passed through a phase separator, and concentrated to obtain the crude product. The crude product was stirred overnight in petroleum ether (500 mL) and MeOH (175 mL). The solid was filtered and washed with MeOH until the filtrate was clear and colorless to obtain 3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoro-1H-indole (614 g, four batches in parallel) as a white solid.

[0225] Step b: To 3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoro-1H-indole (167 g, 518 mmol) at room temperature, TFA (1.18 kg, 10.3 mol), followed by Et3SiH (580 g, 4.99 mol), was added. The reaction mixture was heated to 40°C for 25 minutes, then cooled and concentrated under reduced pressure to remove the TFA. The resulting solution was diluted with DCM (1.0 L). The mixture was poured into a saturated aqueous solution of NaHCO3 (1.0 L) to neutralize the remaining TFA. The neutralized solution was passed through a phase separator and concentrated under reduced pressure to obtain the crude product. The crude product was triturated with MTBE (200 mL), and the filtered cake was washed with further MTBE (200 mL) and MeOH (800 mL) to obtain 3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline (266 g in four parallel batches) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 7.20-7.39(m,5H),6.83-7.04(m,1H),6.08-6.35(m,2H),5.55-5.87(m,1H),4.40-4.55(m,2H),3.42-3.51(m,1H),3 .18-3.29(m,2H),2.99-3.08(m,1H),1.96-2.10(m,2H),1.66-1.80(m,1H),1.42-1.59(m,2H),0.93-1.27(m,4H).MS m / z 326.2 [M+H] + .

[0226] Step c: 3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline (350 g, 1.08 mol) was separated by chiral SFC to obtain (S)-3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline and (R)-3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline. SFC method: DAIEL CHIRALPAK AD 250 mm x 50 mm 10 μm; mobile phase: Phase A: 0.1% NH3 in H2O, and Phase B (A:B, 70:30) with iPrOH obtained peak 1 (first elution, intermediate 7a) and peak 2 (second elution, intermediate 7b).

[0227] Peak 1 (110g) was obtained as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.14-7.44(m,5H),6.84-7.04(m,1H),6.11-6.33(m,2H),5.59-5.79(m,1H),4.42-4.55(m,2H),3.40-3.53(m,1H),3 .17-3.31(m,2H),2.98-3.10(m,1H),1.94-2.12(m,2H),1.65-1.81(m,1H),1.42-1.59(m,2H),0.94-1.22(m,4H).MS m / z 326.5 [M+H] + .

[0228] Peak 2 (110g) was obtained as an off-white solid. 1H NMR(400MHz,DMSO-d6)δ 7.18-7.41(m,5H),6.85-7.00(m,1H),6.11-6.31(m,2H),5.61-5.78(m,1H),4.36-4.61(m,2H),3.40-3.51(m,1H),3 .17-3.31(m,2H),2.97-3.11(m,1H),1.96-2.12(m,2H),1.66-1.80(m,1H),1.42-1.59(m,2H),0.98-1.20(m,4H).MS m / z 326.2 [M+H] + Note: The absolute stereochemical configuration was not determined.

[0229] Intermediate 8a and intermediate 8b ((2R,5S)-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol and ((2S,5R)-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol [ka] Step a: Imidazole (298 g, 4.38 mol) was added to (3,4-dihydro-2H-pyran-2-yl)methanol (200 g, 1.75 mol) in DMF (10 L) at 0°C. Tert-butylchlorodiphenylsilane (530 g, 1.93 mol) was added, and the reaction mixture was stirred at room temperature for 1.5 hours. Then, it was quenched with saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate:heptane, 0:100~20:80). The desired fractions were combined and concentrated under reduced pressure to obtain tert-butyl((3,4-dihydro-2H-pyran-2-yl)methoxy)diphenylsilane (560 g) as a colorless oil. MS m / z353[M+H] + .

[0230] Step b: Borane dimethyl sulfide complex (780 mL, 7.8 mol) was added dropwise to tert-butyl((3,4-dihydro-2H-pyran-2-yl)methoxy)diphenylsilane (550 g, 1.56 mol) in anhydrous THF (6 L) under N2 at 0°C. The reaction mixture was warmed to room temperature and stirred at room temperature for 3 hours. Next, 5N aqueous NaOH (1.87 L, 9.35 mol) was slowly added to the reaction mixture at room temperature over 2 hours, followed by the dropwise addition of 30% aqueous H2O2 (1.38 L, 12.5 mol) over 1.5 hours. The reaction mixture was stirred at 55°C for 2 hours. Then, it was quenched with saturated aqueous NaHCO3, stirred at room temperature for 0.5 hours, and extracted with ethyl acetate. The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate, 5:1). The desired fractions were combined and concentrated under reduced pressure to obtain 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol (450 g) as a colorless oil. MS m / z 393.2[M+Na] + .

[0231] Step c: 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol (430 g, 1.16 mol) in anhydrous THF (7 L) at 0°C was gradually mixed with NaH (278 g, 6.96 mol, 60 wt%), and the resulting mixture was stirred at room temperature for 1 hour. Next, (bromomethyl)benzene was added, and the reaction mixture was stirred at room temperature for 5 hours. Then, it was quenched with saturated aqueous NH4Cl solution and diluted with ethyl acetate. The layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:ethyl acetate, 200:1). The desired fractions were combined and concentrated under reduced pressure to obtain a racemic mixture of trans((5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)(tert-butyl)diphenylsilane (200 g) as a colorless oil. 1H NMR(300MHz,CDCl3)δ 7.73-7.56(m,4H),7.41-7.14(m,11H),4.60-4.38(m,2H),4.12-3.94(m,1H),3.64(dd,J=9.0,3.0Hz,1H),3.53 -3.22(m,3H),3.10(t,J=10.5Hz,1H),2.22-2.06(m,1H),1.90-1.76(m,1H),1.49-1.13(m,2H),0.99(s,9H).MS m / z 483.2 [M+Na] + .

[0232] Step d: At 0°C, 12M HCl (452 ​​mL, 5.42 mol) was added to a racemic mixture of trans((5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methoxy)(tert-butyl)diphenylsilane (500 g, 1.08 mol) in MeOH (5 L). The reaction mixture was stirred at room temperature for 5 hours, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase C18 chromatography (CH3CN and H2O, 35:65) to obtain a racemic mixture of trans5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol.

[0233] Step e: Separating a single enantiomer of a racemic mixture of trans-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol by preparative-SFC [chiral ART amylose-C NEO, 5cm x 25cm 5μm; mobile phase A: CO2, mobile phase B: iPrOH:hexane = 2:1 (0.1% 2M NH3-MeOH); flow rate: 200 mL / min; gradient: isocratic 18% B; column temperature: 35℃; back pressure: 100 bar; wavelength: 220 nm; sample solvent: EtOH; injection volume: 1.2 mL; number of operations: 250], and separating to peak 1 (intermediate 8a, R t =8.33 mins) and peak 2 (intermediate 8b, R t (=9.80 minutes) was obtained.

[0234] Peak 1: ((2S,5R)-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol or ((2R,5S)-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol as a colorless oil (56.7g). 1 H NMR(300MHz,CDCl3)δ 7.43-7.15(m,5H),4.66-4.41(m,2H),4.18-4.01(m,1H),3.56(dd,J=11.4,3.3Hz,1H),3.51-3.30(m, 3H),3.20(t,J=10.5Hz,1H),2.51(s,1H),2.28-2.15(m,1H),1.68-1.56(m,1H),1.55-1.25(m,2H).MS m / z 223.2 [M+H] + .

[0235] Peak 2: ((2S,5R)-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol or ((2R,5S)-5-(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol as a colorless oil (54.4g). 1 H NMR(300MHz,CDCl3)δ 7.44-7.14(m,5H),4.65-4.43(m,2H),4.18-4.01(m,1H),3.55(dd,J=11.4,3.0Hz,1H),3.50-3.29(m, 3H),3.20(t,J=10.4Hz,1H),2.64(s,1H),2.27-2.13(m,1H),1.69-1.55(m,1H),1.55-1.26(m,2H).MS m / z 223.2 [M+H] + Note: The absolute stereochemical configuration was not determined.

[0236] Intermediate 9 Methyl 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate [ka] Step a: At room temperature, CDI (70.7 g, 436 mmol) was added to methyl 4-(4-fluorophenyl)piperidine-4-carboxylate (69.0 g, 291 mmol) in DCM (500 mL), and the reaction mixture was stirred for 2 hours. The resulting mixture was quenched with H2O and extracted with DCM. The organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated to obtain methyl 4-(4-fluorophenyl)-1-(imidazole-1-carbonyl)piperidine-4-carboxylate (100 g, crude) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ 8.02(t,J=1.1Hz,1H),7.51-7.34(m,3H),7.28-7.14(m,2H),7.06-6.99(m,1H),3.84(d, J=13.8Hz,2H),3.64(s,3H),3.30-3.21(m,2H),2.49-2.41(m,2H),2.20-1.95(m,2H).MS m / z 332 [M+H] + .

[0237] Step b: 2-{2-[(tert-butyldimethylsilyl)oxy]ethyl}-6-fluoro-1H-indole (70.1 g, 239 mmol) in THF (800 mL) was added dropwise to 1.0 M LHMDS in THF (319 mL, 319 mmol), followed by 2.0 M AlMe3 solution in toluene (146 mL, 252 mmol). The mixture was stirred for a further 30 minutes at -25°C. Next, methyl 4-(4-fluorophenyl)-1-(imidazole-1-carbonyl)piperidine-4-carboxylate (88.0 g, 266 mmol) was added at -25°C. The mixture was heated to 60°C and stirred for 2 hours, then cooled to 0°C and quenched at 0°C by adding saturated aqueous solution of NH4Cl. The resulting mixture was diluted with H2O and extracted by DCM. The combined organic extracts were washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether:DCM:siRNA, 10:1:1). The desired fractions were combined and concentrated under reduced pressure to obtain the crude substance (102 g) as a yellow oil. The reaction was repeated with further methyl 4-(4-fluorophenyl)-1-(imidazole-1-carbonyl)piperidine-4-carboxylate (35 g) to obtain an additional 52.7 g of crude product. The combined lot (155 g) was dried to obtain methyl 1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (152 g) as a yellow solid. 1 H NMR(300MHz,CDCl3)δ 7.46-7.42(m,1H),7.40-7.30(m,2H),7.15-6.84(m,4H),6.40(s,1H),4.07-3.45(m,7H),3.36-3.21(m,2H),3.0 3(m,J=7.3Hz,2H),2.63(t,J=16.9Hz,2H),2.11-1.75(m,2H),0.88(d,J=21.2Hz,9H),0.04(d,J=24.3Hz,6H).MS m / z 557 [M+H] + .

[0238] The compounds listed in Table 4 below were synthesized using the corresponding functionalized piperidine and indole intermediates, using the procedure described above or a modification thereof.

[0239] [Table 4]

[0240] Intermediate 10 (3S,4R)-4-fluoro-1-methylpyrrolidine-3-amine [ka] Step a: At 0°C, formaldehyde (1.27 g, 42.5 mol) and NaBH4 (2.20 g, 58.0 mmol) were added in small amounts to tert-butyl(3S,4R)-4-fluoropyrrolidine-3-yl carbamate (7.9 g, 38.6 mmol) in MeOH (79 mL). The resulting reaction mixture was warmed to room temperature and stirred for 14 hours. The resulting reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The combined organic extract was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (MeOH:DCM, 3:97~5:95). The desired fractions were combined and concentrated under reduced pressure to obtain tert-butyl((3S,4R)-4-fluoro-1-petylpyrrolidine-3-yl) carbamate (7.5 g) as a yellow liquid. 1 H NMR(400MHz,DMSO-d6)δ 6.92(s,1H),4.99-4.83(m,1H),3.98-3.92(m,1H),3.12-3.01(m,1H),2.77-2.7 3(t,J=8Hz,1H),2.54-2.53(m,1H),2.49-2.37(m,1H),2.23(s,3H),1.38(s,9H).

[0241] Step b: At 0°C, tert-butyl((3S,4R)-4-fluoro-1-methylpyrrolidine-3-yl)carbamate (9.20 g, 0.0422 mol) was added dropwise to 1,4-dioxane (92.0 mL) in 4 M HCl solution. The reaction mixture was warmed to room temperature and stirred for 3 hours, then concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in MeOH and stirred at room temperature for 1 hour, during which time the solid precipitated. The mixture was filtered to obtain (3S,4R)-4-fluoro-1-methylpyrrolidine-3-amine hydrochloride salt (6.24 g) as an off-white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.26(s,4H),5.55-5.4(d,J=52.8Hz,1H),4.18(s,1H),3.73-3.39(m,4H),2.89(s,3H).

[0242] Intermediate 11 5-Bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid [ka] Step a: At 15°C, 10.0 g, 86.1 mmol, NET3 (17.4 g, 172 mmol), DMAP (1.05 g, 8.61 mmol), and 4-methylbenzenesulfonyl chloride (19.7 g, 103 mmol) were added to 60 mL of DCM. The reaction mixture was stirred at 15°C for 16 hours, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:petroleum ether, 0:100~40:60). The desired fractions were combined and concentrated under reduced pressure to obtain tetrahydropyran-4-ylmethyl 4-methylbenzenesulfonate (22.0 g) as a white solid.

[0243] Step b: Methyl 5-bromo-1H-indole-3-carboxylate (4.50 g, 17.7 mmol) in DMF (60 mL) at 15°C was mixed with tetrahydropyran-4-ylmethyl 4-methylbenzenesulfonate (14.4 g, 53.1 mmol) and K2CO3 (9.79 g, 70.8 mmol). The reaction mixture was stirred at 95°C for 3 hours, then added to saturated NaCl aqueous solution (500 mL), and subsequently extracted with ethyl acetate (400 mL x 2). The combined organic extract was washed with saturated NaCl aqueous solution (400 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate: petroleum ether, 0:100~35:65). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 5-bromo-1-(tetrahydropyran-4-ylmethyl)indole-3-carboxylate (6.00 g) as a white solid. MS m / z 351.9 [M+H] + .

[0244] Step c: At 15°C, methyl 5-bromo-1-(tetrahydropyran-4-ylmethyl)indole-3-carboxylate (5.50 g, 15.6 mmol) was added to MeOH (30 mL), H2O (15 mL), and THF (60 mL). NaOH (1.25 g, 31.2 mmol) was added. The reaction mixture was stirred at 50°C for 20 hours. The solvent was concentrated under reduced pressure, THF (100 mL) was added, and the reaction mixture was concentrated again under reduced pressure. Next, a 4 M HCl solution in 1,4-dioxane (30 mL) was added to the residue, and the resulting mixture was concentrated to obtain 5-bromo-1-(tetrahydropyran-4-ylmethyl)indole-3-carboxylic acid (7.5 g, crude) as a bright red solid. MS m / z 339.9 [M+H] + .

[0245] Intermediate 12 5-Chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid [ka] Step a: At room temperature under N2 conditions, 4-chloro-2-iodoaniline (4.00 g, 15.8 mmol) was added to DMSO (59 mL) and H2O (20 mL), to which Cs2CO3 (5.14 g, 15.8 mmol) and copper(I) oxide (0.226 g, 1.58 mmol) were added. Next, methyl 3-oxobutanoate (2.04 mL, 18.9 mmol) was added, and the reaction mixture was stirred at 100 °C for 7 hours. The reaction mixture was cooled to room temperature, diluted with SiO2 (300 mL), and washed with saturated aqueous solution of NaCl (150 mL) and H2O (150 mL). The single aqueous layer was extracted with SiO2 (150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product as a dark brown oil. The crude product was purified by silica gel chromatography (Â1:heptane, 0:100-30:70). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 5-chloro-2-methyl-1H-indole-3-carboxylate (860 mg) as a brown solid. MS m / z 224.1 [M+H] + .

[0246] Step b: At room temperature under N2 conditions, (tetrahydro-2H-pyran-4-yl)methyl 4-methyl tosylate (1.38 g, 5.10 mmol) and K2CO3 (1.88 g, 13.6 mmol) were added to methyl 5-chloro-2-methyl-1H-indole-3-carboxylate (0.760 g, 3.40 mmol) in DMF (17.9 mL). The reaction mixture was stirred at 95 °C for 12 hours, then cooled to room temperature, and a mixture of saturated NaCl aqueous solution and H2O (1:1, 75 mL) was added. The resulting mixture was extracted with toluene (150 mL and 75 mL). The combined organic extract was washed with saturated NaCl aqueous solution (75 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (toluene:heptane, 0:100~30:70). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (952 mg). MS m / z 322.1[M+H] + .

[0247] Step c: Methyl 5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (2.73 g, 8.48 mmol) was added to methyl 5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (8.48 mL, 25.5 mmol) in aqueous 3N NaOH (8.48 mL, 25.5 mmol) at room temperature. The reaction mixture was stirred at 50°C for 2 days, then aqueous 3N NaOH (5.65 mL, 17.0 mmol) was added, and the mixture was stirred for a further 2 days. The reaction mixture was extracted with Et2O to remove unreacted starting material. The aqueous phase was acidified to approximately pH 1 with aqueous 1N HCl, which produced a concentrated suspension. This suspension was extracted with ELISA (120 mL and 60 mL x 2). The combined organic extracts were washed with a saturated aqueous solution of NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid (2.13 g, crude) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 12.23(s,1H),7.95(d,J=2.1Hz,1H),7.63(d,J=8.7Hz,1H),7.18(dd,J=8.7,2.2Hz,1H),4.12(d,J=7.5Hz, 2H),3.85-3.74(m,2H),3.18(td,J=11.2,3.3Hz,2H),2.73(s,3H),2.07-1.99(m,1H),1.41-1.32(m,4H).MS m / z 308.1 [M+H] + .

[0248] Intermediate 13 5-Chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid [ka] Step a: At 0°C under N2, pyridine (248 g, 3.13 mol) was added to 5-chloro-1H-indole (190 g, 1.25 mol) in anhydrous THF (950 mL). Next, a solution of 2,2,2-trichloroacetyl chloride (570 g, 3.13 mol) in anhydrous THF (400 mL) was added dropwise over 2 hours. The reaction mixture was heated to 25°C and stirred for 14 hours, then diluted with toluene (5.0 L) and washed with H2O (5.0 L x 2). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was treated with petroleum ether:toluene (5:1, 600 mL) and filtered. The filtered cake was dried to obtain 2,2,2-trichloro-1-(5-chloro-1H-indole-3-yl)ethane-1-one (302g) as an off-white solid. 1 H NMR(400MHz,CDCl3)δ 8.92(br s,1H),8.45(d,J=2.0Hz,1H),8.37(d,J=3.0Hz,1H),7.40(d,J=4.4Hz,1H),7.32(dd,J=2.0,4.4Hz,1H).MS m / z 295.9 [M+H] + .

[0249] Step b: At room temperature, 2,2,2-trichloro-1-(5-chloro-1H-indole-3-yl)ethane-1-one (252 g, 849 mmol) was added to 1.25 L of MeOH with 47.6 g of KOH (849 mmol) in 48 mL of H2O until the pH reached 11. The reaction mixture was stirred at 80°C for 5 hours. The mixture was cooled to 25°C, neutralized with 4 M aqueous HCl, and concentrated under reduced pressure. The resulting residue was dissolved in 2 L of siRNA and washed with 2 L of H2O. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was treated with petroleum ether:siRNA (8:1, 200 mL) and filtered. The filtered cake was collected and dried to obtain methyl 5-chloro-1H-indole-3-carboxylate (131 g) as an off-white powder. MS m / z210.0[M+H] + .

[0250] Step c: Methyl 5-chloro-1H-indole-3-carboxylate (50 g, 238 mmol) in CH3CN (250 mL) at room temperature was mixed with K2CO3 (65.0 g, 470 mmol) and 4-(bromomethyl)tetrahydro-2H-pyran (65.0 g, 363 mmol). The reaction mixture was stirred at 80°C for 48 hours, then cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in RINKAN (1.0 L), washed with H2O (1.0 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl 5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (73 g, crude) as a bright yellow solid. 1 H NMR(400MHz,CDCl3)δ 8.17(d,J=1.6Hz,1H),7.80(s,1H),7.24-7.30(m,2H),4.02(d,J=7.2Hz,2H),3.94-4 .00(m,2H),3.93(s,3H),3.30-3.33(m,2H),2.06-2.12(m,1H),1.39-1.51(m,4H).MS m / z 308.0 [M+H] + .

[0251] Step d: At -40°C, n-BuLi (2.5M, 119mL) was added dropwise to iPr2NH (36.0g, 356mmol) in anhydrous THF (200mL). The reaction mixture was heated to 0°C with stirring for 0.5 hours, and then added dropwise to a mixture of methyl 5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (73g, 237mmol) in anhydrous THF (700mL) at -70°C. The reaction mixture was stirred at -70°C for 0.5 hours. Then DMF (34.7g, 474mmol) was added. The reaction mixture was stirred for a further 0.5 hours at -70°C, and then poured into saturated aqueous solution of NH4Cl (2L) and extracted with  (1.5L). The organic extract was washed with H2O (1.5 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was treated with petroleum ether:siRNA (5:1, 400 mL) and filtered. The filtered cake was collected and dried to obtain methyl 5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (46 g) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 10.63(s,1H),8.13(s,1H),7.90(d,J=8.8Hz,1H),7.50(d,J=2.0,8.8Hz,1H),4.50(d,J=7.6Hz,2H),3.94( s,3H),3.76(dd,J=2.8,11.6Hz,2H),3.76(td,J=2.4,11.2Hz,2H),1.90-2.10(m,1H),1.24-1.35(m,4H).MS m / z 336.1 [M+H] + .

[0252] Step e: Methyl 5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (20 g, 59.6 mmol) was added to methyl 5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (20 g, 59.6 mmol) in THF (200 mL) and MeOH (100 mL) at room temperature using a dropping funnel over 30 minutes. The reaction mixture was stirred at room temperature over the weekend. The reaction mixture was partially concentrated under reduced pressure to remove volatile organic compounds. The resulting residue was diluted with H2O and treated with 1N HCl aqueous solution until pH reached 1. The yellow suspension was filtered, washed with H2O, and dried under a stream of N2. The resulting substance was resuspended in DCM and concentrated several times under reduced pressure to obtain a free-flowing yellow solid. The aqueous phase from the filtration was partitioned between siRNA and H2O to separate the organic phase. The organic layer was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain an orange solid. The solid obtained from filtration was combined with the solid obtained from extraction and triturated in heptane. The resulting suspension was filtered, and the solid was further dried to obtain 5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid (22.2 g) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 11.01(s,1H),8.42(d,J=2.2Hz,1H),7.69(d,J=8.9Hz,1H),7.35(dd,J=8.9,2.3Hz,1H),4.43 (d,J=7.2Hz,2H),3.81-3.73(m,2H),3.19-3.09(m,2H),2.04-1.86(m,1H),1.42-1.17(m,4H).

[0253] The following compounds in Table 5 were synthesized using the corresponding indole and alkyl tosylate, employing the above procedure or a modification thereof.

[0254] [Table 5]

[0255] Intermediate 14 Methyl 4-(6-chloropyridine-3-yl)piperidine-4-carboxylate [ka] Step a: 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (3.00 g, 12.3 mmol) in toluene (15 mL) at 0°C was added dropwise over 0.25 hours using a 0.6 M NaHMDS solution in toluene (25 mL, 15.0 mmol). Next, a 1.9 M ZnCl2 solution in 2-Me-THF (10 mL, 19.0 mmol) was added, and the reaction mixture was stirred at 0°C for 1 hour. To the mixture, 2-chloro-5-iodopyridine (2.95 g, 12.3 mmol) was added, followed by [Pd(mu-Br)t-Bu3P]2 (CAS#185812-86-6, 0.9 g, 1.16 mmol). The reaction mixture was stirred at room temperature for 17 hours, then quenched with H2O (10 mL), diluted with DCM, and celite® was added. Next, the mixture was filtered through a celite® plug and rinsed with DCM. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 25:75~40:60). The desired fractions were combined and concentrated under reduced pressure to obtain 1-(tert-butyl)4-methyl4-(6-chloropyridine-3-yl)piperidine-1,4-dicarboxylate (0.9 g) as a powder. 1 H NMR(400MHz,MeOD-d4)δ 8.39(d,J=2.7Hz,1H),7.86(dd,J=2.7,8.5Hz,1H),7.45(dd,J=0.6,8.5Hz,1H),3.89-3.98(m, 2H),3.70(s,3H),2.96-3.17(m,2H),2.53(d,J=13.5Hz,2H),1.82-1.94(m,2H),1.45(s,9H).MS m / z 299.0 [M-tBu+2H] + .

[0256] Step b: 1-(tert-butyl)4-methyl4-(6-chloropyridine-3-yl)piperidine-1,4-dicarboxylate (630 mg, 1.78 mmol) in MeOH (3 mL) at room temperature was dropwise added to a 4 M HCl solution in 1,4-dioxane (1.00 mL, 4.00 mmol). The reaction mixture was heated to 40°C for 3.5 hours, and then directly concentrated under reduced pressure to obtain methyl4-(6-chloropyridine-3-yl)piperidine-4-carboxylate (519 mg, crude) as an off-white solid. MS m / z 255.1 [M+H] + .

[0257] The following compounds in Table 6 were synthesized using appropriately substituted halogenated aromatics, employing the above procedure or a modification thereof.

[0258] [Table 6]

[0259] Intermediate 15 Methyl(2S,4S)-4-(3,4-difluorophenyl)-1-(1H-imidazole-1-carbonyl)-2-methylpiperidine-4-carboxylate [ka] Step a: At room temperature, 2-(4-fluorophenyl)acetonitrile (2.73 g, 17.8 mmol) was added to THF (25 mL), and the reaction mixture was stirred for 2 minutes. Next, (S)-2-((4-methyl-N-(1-(tosyloxy)propan-2-yl)phenyl)sulfonamide)ethyl 4-methylbenzenesulfonate (4.00 g, 6.87 mmol) solution was slowly added to THF (15 mL) at room temperature. The reaction mixture was stirred at 40°C for 1 hour, and then cooled to room temperature while stirring for a further 12 hours. The reaction mixture was quenched with H2O (100 mL) and extracted with siRNA (100 mL). The combined organic extracts were washed with H2O (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude substance was purified by silica gel chromatography (siRNA:hexane, 10:90~15:85) to obtain (2S)-4-(3,4-difluorophenyl)-2-methyl-1-tosylpiperidine-4-carbonitrile (4.0 g). MS m / z 392.1[M+H] + .

[0260] Step b: At room temperature, (2S)-4-(3,4-difluorophenyl)-2-methyl-1-tosylpiperidine-4-carbonitrile (4.00 g, 10.2 mmol) was mixed with (2S)-4-(3,4-difluorophenyl)-2-methyl-1-tosylpiperidine-4-carboxylic acid (4.00 g, 10.2 mmol) in EtOH and H2O (1:1, 30 mL) and KOH (11.4 g, 205 mmol). The reaction mixture was stirred at 110 °C for 4 days, cooled to room temperature, acidified with concentrated HCl (15 mL), and extracted with ELISA (50 mL x 2). The organic extract was washed with saturated aqueous NaCl solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (2S)-4-(3,4-difluorophenyl)-2-methyl-1-tosylpiperidine-4-carboxylic acid (4.5 g, crude). MS m / z 409.8 [M+H] + .

[0261] Step c: (2S)-4-(3,4-difluorophenyl)-2-methyl-1-tosylpiperidine-4-carboxylic acid (4.5 g, 10.9 mmol) in DMF (45 mL) at room temperature was mixed with K2CO3 (14.9 g, 108 mmol) and MeI (4.7 mL, 74.8 mmol). The reaction mixture was stirred at 40°C for 12 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with ELISA (100 mL x 2). The combined organic extract was washed with saturated aqueous NaCl solution (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl(2S)-4-(3,4-difluorophenyl)-2-methyl-1-tosylpiperidine-4-carboxylate (1.65 g, crude). MS m / z 423.9 [M+H] + .

[0262] Step d: At room temperature, methyl(2S)-4-(3,4-difluorophenyl)-2-methyl-1-tosylpiperidine-4-carboxylate (1.45 g, 3.42 mmol) was added to MeOH (30 mL), to which metallic magnesium (5.8 g) was added. The reaction mixture was sonicated for 5 hours, quenched with saturated NH4Cl aqueous solution (50 mL), and extracted with ELISA (50 mL x 2). The organic extract was washed with saturated NaCl aqueous solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl(2S,4S)-4-(3,4-difluorophenyl)-2-methylpiperidine-4-carboxylate (450 mg, crude). MS m / z 270.1 [M+H] + .

[0263] Step e: At 0°C, methyl(2S)-4-(3,4-difluorophenyl)-2-methylpiperidine-4-carboxylate (450 mg, 1.67 mmol) was added to DCM (10 mL), to which (Boc)2O (0.806 mL, 3.51 mmol) and DIPEA (0.87 mL, 5.01 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours, then quenched with H2O (10 mL), extracted with DCM (10 mL x 2), and washed with saturated aqueous NaCl solution (10 mL). The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(tert-butyl)4-methyl(2S,4S)-4-(3,4-difluorophenyl)-2-methylpiperidine-1,4-dicarboxylate (150 mg, crude).

[0264] Step f: At 0°C, 150 mg (0.406 mmol) of 1-(tert-butyl)4-methyl(2S,4S)-4-(3,4-difluorophenyl)-2-methylpiperidine-1,4-dicarboxylate was added to 5 mL of MeOH, to which a 4 M HCl solution in 1,4-dioxane (0.32 mL, 1.29 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain methyl(2S,4S)-4-(3,4-difluorophenyl)-2-methylpiperidine-4-carboxylate hydrochloride salt (110 mg, crude). MS m / z 270.5 [M+H] + .

[0265] Step g: At 0°C, methyl(2S)-4-(3,4-difluorophenyl)-2-methylpiperidine-4-carboxylate hydrochloride salt (110 mg, 0.408 mmol) was added to DIPEA (0.43 mL, 2.45 mmol) and CDI (205 mg, 1.27 mmol). The reaction mixture was stirred at room temperature for 4 hours, then diluted with DCM and washed with saturated aqueous solutions of H2O and NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:hexane, 0:100~100:0) to obtain methyl(2S,4S)-4-(3,4-difluorophenyl)-1-(1H-imidazole-1-carbonyl)-2-methylpiperidine-4-carboxylate (120 mg). MS m / z364.1[M+H] + .

[0266] The following compounds in Table 7 were synthesized using the corresponding substituted phenylacetonitriles, with the above procedure or a modification thereof.

[0267] [Table 7]

[0268] Intermediate 16 Ethyl(1S,3S,4S)-4-amino-3-chlorocyclohexane-1-carboxylate [ka] Step a: At room temperature, 4.68 mL, 29.4 mmol of ethyl 4-oxocyclohexane-1-carboxylate (4.68 mL) was added to 30 mL of DMF, to which 16.4 mL, 118 mmol of NET3 and 7.51 mL, 58.8 mmol of TMSCl were added. A reflux condenser was attached to a flask equipped with an N2 inlet and a needle outlet, and the reaction mixture was heated to 120 °C for 5 hours. The reaction mixture was cooled to 0 °C in an ice bath and diluted with H2 O and siRNA until all solids were dissolved. The siRNA layer was washed with saturated aqueous solution of NaCl (50 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 4-((trimethylsilyl)oxy)cyclohexa-3-ene-1-carboxylate (7.13 g, crude) as an orange oil.

[0269] Step b: Sodium acetate (6.03 g, 73.5 mmol) was added to ethyl 4-((trimethylsilyl)oxy)cyclohexa-3-ene-1-carboxylate (7.13 g) in acetone (50 mL) and H2O (12.5 mL) at 0°C. Next, NCS (5.89 g, 44.1 mmol) was added all at once, and the reaction mixture was stirred while warming to room temperature for 72 hours. The reaction mixture was diluted with siRNA and H2O and stirred vigorously. The organic layer was partitioned, washed with saturated aqueous NaCl solution (40 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (iPrOH:heptane, 0:100~50:50). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl (1S,3S)-3-chloro-4-oxocyclohexane-1-carboxylate (1.4 g).

[0270] Step c: (1.4 g, 6.84 mmol) of (1S,3S)-3-chloro-4-oxocyclohexane-1-carboxylate in THF (34.2 mL) at room temperature under N2 was mixed with (S)-2-methylpropane-2-sulfinamide (1.66 g, 13.7 mmol). Next, tetraethoxytetraethoxytitanium (4.30 mL, 20.5 mmol) was rapidly added, and the reaction mixture was heated to 55°C for 3 hours. The reaction mixture was cooled to 0°C and carefully diluted with saturated aqueous solution of NaHCO3, which produced a white precipitate. This substance was extracted with ethyl acetate, and the organic extract was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:heptane, 0:100~100:0), which yielded two peaks: peak 1 (first to elute) and peak 2 (second to elute). The desired fractions corresponding to peak 1 were combined and concentrated under reduced pressure to obtain ethyl (1S,3S,E)-4-(((S)-tert-butylsulfinyl)imino)-3-chlorocyclohexane-1-carboxylate (450 mg) as a colorless liquid. 1 H NMR(400MHz,DMSO)δ 5.03(dd,J=11.7,5.1Hz,1H),4.11(m,J=7.1Hz,2H),3.81-3.57(m,1H),3.07-2.88(m,1H),2.66(d,J=13.5Hz,1H),2.39( td,J=13.3,4.8Hz,1H),2.16(d,J=13.4Hz,1H),2.06-1.89(m,1H),1.62(qd,J=12.8,4.0Hz,1H),1.21(d,J=4.3Hz,12H).

[0271] Step d: NaBH4 (270 mg, 7.15 mmol) was added to ethyl (1S,3S,E)-4-(((S)-tert-butylsulfinyl)imino)-3-chlorocyclohexane-1-carboxylate in THF (15.4 mL) and EtOH (5 mL) under N2 at 0°C. The reaction mixture was stirred for 1 hour, then quenched with saturated aqueous NaHCO3 and diluted with DCM and H2O while vigorously stirring for 30 minutes. The organic layer was passed through a phase separator and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (HCl:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl (1S,3S,4S)-4-(((S)-tert-butylsulfinyl)amino)-3-chlorocyclohexane-1-carboxylate (301 mg) as a colorless oil. 1 H NMR(400MHz,DMSO)δ 5.26(d,J=6.1Hz,1H),4.18-3.91(m,3H),3.06(td,J=10.7,5.6Hz,1H),2.51-2.36(m,2H),2.03(d,J=14.9 Hz,1H),1.96-1.88(m,1H),1.78(m,J=12.3Hz,1H),1.54-1.39(m,2H),1.20(t,J=7.1Hz,3H),1.13(s,9H).

[0272] Step e: At room temperature, ethyl (1S,3S,4S)-4-(((S)-tert-butylsulfinyl)amino)-3-chlorocyclohexane-1-carboxylate was added to ethyl (1S,3S,4S)-4-(((S)-tert-butylsulfinyl)amino)-3-chlorocyclohexane-1-carboxylate in 5 mL of DCM. The reaction mixture was stirred for 1 hour, during which time a white precipitate formed. The reaction mixture was concentrated under reduced pressure, and the resulting substance was triturated (2x) with heptane to obtain ethyl (1S,3S,4S)-4-amino-3-chlorocyclohexane-1-carboxylate hydrochloride salt (180 mg) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.38(s,3H),4.17(ddd,J=12.0,10.3,4.3Hz,1H),4.09(m,J=7.1Hz,2H),3.24(s,1H),2.60-2.53(m,1H),2.47-2.37(m,1 H),2.16(dt,J=9.4,4.0Hz,1H),1.96(d,J=8.1Hz,1H),1.81(m,J=12.4Hz,1H),1.55-1.45(m,2H),1.20(t,J=7.1Hz,3H).

[0273] Intermediate 17 tert-butyl(1R,3S,4S)-3-amino-4-methylcyclopentane-1-carboxylate [ka] Step a: Oxalyl chloride (4.78 mL, 54.6 mmol) was added dropwise to cyclopenta-3-ene-1-carboxylic acid (5.1 g, 45.5 mmol) in DCM (55 mL) and DMF (0.5 mL) at 0°C, and the reaction mixture was warmed overnight to room temperature. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in DCM (50 mL), and then cooled back to 0°C. Tert-butanol (13.1 mL, 136 mmol) and NEt3 (12.7 mL, 91 mmol) solution in DCM (20 mL) were added dropwise. The reaction mixture was warmed overnight to room temperature with stirring, and then quenched with saturated aqueous NaHCO3 solution. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic extract was washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over Na2SO4, and passed through a phase separator. The filtrate was concentrated under reduced pressure to obtain tert-butylcyclopenta-3-ene-1-carboxylate (4.75 g, crude) as oil.

[0274] Step b: At 0°C, mCPBA (8.23 g, 36.7 mmol) was added to tert-butylcyclopenta-3-ene-1-carboxylate (4.75 g, 28.2 mmol) in DCM (100 mL). The reaction mixture was stirred overnight at room temperature. The precipitate was filtered, and the filtrate was washed with saturated aqueous solution of NaHCO3 (100 mL x 2), followed by saturated aqueous solution of NaCl (100 mL). The resulting organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure (incubator temperature 35°C) to obtain the crude product. The crude product was purified by silica gel chromatography ( Depositphotos:heptane, 0:100~100:0). The desired fraction was concentrated under reduced pressure to obtain tert-butyl(1R,3s,5S)-6-oxabicyclo[3.1.0]hexane-3-carboxylate (3.6 g). 1 H NMR(400MHz,DMSO-d6)δ 5.67(s,2H),3.03(tt,J=9.4,6.6Hz,1H),2.58-2.50(m,4H),1.43(s,9H).

[0275] Step c: At room temperature under N2 conditions, CuI (0.154 g, 0.809 mmol) was added to tert-butyl(1R,3s,5S)-6-oxabicyclo[3.1.0]hexane-3-carboxylate in THF (28 mL), and the reaction mixture was cooled to -40°C. Next, a 3.0 M methylmagnesium chloride solution in THF (5.39 mL, 16.2 mmol) was added dropwise, and the reaction mixture was stirred overnight at room temperature. Then it was cooled to 0°C, quenched with a saturated NH4Cl solution, and stirred for 10 minutes. The stirred mixture was diluted with RINKAN and transferred to a separatory funnel. The layers were separated, and the aqueous layer was extracted with RINKAN (2x). The combined organic extracts were washed with a saturated NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (RINKAN:heptane, 0:100~50:50). The desired fractions were combined and concentrated under reduced pressure to obtain tert-butyl(1R,3S,4S)-3-hydroxy-4-methylcyclopentane-1-carboxylate (1.12 g) as a clear oil. 1H NMR(400MHz,DMSO-d6)δ 4.66(s,1H),3.56(m,J=6.2Hz,1H),2.79(qd,J=8.9,6.7Hz,1H),2.17-2.03(m,1H),1.96(dt,J=13.4,6.8Hz,1 H),1.68(dddd,J=28.6,13.2,9.4,6.3Hz,2H),1.41(d,J=2.0Hz,9H),1.25-1.19(m,1H),0.95(d,J=6.8Hz,3H).

[0276] Step d: Under N2 at -25°C, DIPEA (2.93 mL, 16.8 mmol) was added to tert-butyl (1R,3S,4S)-3-hydroxy-4-methylcyclopentane-1-carboxylate (1.12 g, 5.59 mmol) in DCM (14.0 mL). The temperature of the reaction mixture was maintained at -20 to -30°C, and a solution of sulfur trioxide pyridine complex (1.16 g, 7.27 mmol) in DMSO (4.66 mL) was added dropwise. The reaction mixture was then placed in an ice / H2O bath with stirring for 2 hours. The reaction mixture was quenched with 1.0 M aqueous citric acid solution, the organic layer was passed through a phase separator, and the aqueous layer was extracted with DCM (5 mL x 3). The combined organic extracts were washed with 1 M aqueous citric acid solution, saturated aqueous NaCl solution, and then H2O. The organic substance was passed through a phase separator and concentrated under reduced pressure to obtain tert-butyl(1R,3S)-3-methyl-4-oxocyclopentane-1-carboxylate (1.03 g, crude) as a yellow crystalline solid.

[0277] Step e: At room temperature under N2 conditions, tert-butyl(1R,3S)-3-methyl-4-oxocyclopentane-1-carboxylate (1.03 g, 5.17 mmol) was added in one step to (S)-2-methylpropane-2-sulfinamide (0.783 g, 6.46 mmol) in THF (17 mL). Next, tetraethoxytetraethoxytitanium (3.54 g, 15.5 mmol) was added, and the reaction mixture was heated to 55 °C for 18 hours. The reaction mixture was cooled to 0 °C and quenched with saturated aqueous solution of NaHCO3, which produced a white precipitate. The reaction mixture was diluted with toluene and H2O and stirred vigorously. The solid precipitate was partitioned and washed with toluene (40 mL x 2). The combined organic extract was washed with saturated aqueous solution of NaCl (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (SiO:heptane, 0:100-60:40). The desired fraction corresponding to peak 1 (first elution) was combined and concentrated under reduced pressure to obtain tert-butyl(1R,4S,Z)-3-(((S)-tert-butylsulfinyl)imino)-4-methylcyclopentane-1-carboxylate (270 mg) as an off-white solid. Note: Absolute steric dynamics were assigned based on peak retention time compared to the product of step b in the intermediate to intermediate 2. 1 H NMR(400MHz,DMSO-d6)δ 3.03-2.81(m,3H),2.67(dt,J=13.1,6.9Hz,1H),2.27(dt,J=12.4,7.2Hz ,1H),1.43(s,9H),1.41-1.33(m,1H),1.18(s,9H),1.11(d,J=6.8Hz,3H).

[0278] Step f: At 0°C under N2, tert-butyl(1R,4S,Z)-3-(((S)-tert-butylsulfinyl)imino)-4-methylcyclopentane-1-carboxylate (270 mg, 0.896 mmol) was added all at once to THF (6 mL) with NaBH4 (42.4 mg, 1.12 mmol). The reaction mixture was stirred at 0°C for 1 hour, then quenched with saturated aqueous solution of NaHCO3, diluted with ethyl acetate, then with H2O, and vigorously stirred for 1 hour. The resulting mixture was extracted with ethyl acetate (50 mL x 2), the combined organic extract was washed with saturated aqueous solution of NaCl (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:heptane, 5:95~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain tert-butyl(1R,3S,4S)-3-(((S)-tert-butylsulfinyl)amino)-4-methylcyclopentane-1-carboxylate (89 mg) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 5.17(d,J=7.0Hz,1H),3.08(p,J=7.7Hz,1H),2.77(qd,J=8.8,5.8Hz,1H),2.21-1.99(m,2H),1.97 -1.73(m,2H),1.40(s,9H),1.29(ddd,J=12.7,9.9,8.5Hz,1H),1.12(s,9H),1.04(d,J=6.7Hz,3H).

[0279] Step g: At room temperature, tert-butyl(1R,3S,4S)-3-(((S)-tert-butylsulfinyl)amino)-4-methylcyclopentane-1-carboxylate (90 mg, 0.297 mmol) was added to 1,4-dioxane (185 μL, 0.741 mmol) in 4 M HCl solution. The reaction mixture was stirred for 1 hour, and then concentrated directly to obtain a white solid. This substance was triturated with Et2O (20 mL), and the residual solvent was removed under reduced pressure to obtain tert-butyl(1R,3S,4S)-3-amino-4-methylcyclopentane-1-carboxylate hydrochloride salt (52 mg) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 8.08(s,3H),3.08(s,1H),2.92(p,J=8.6Hz,1H),2.18(ddd,J=13.0,8.0,6.6Hz,2H),1.98(dq,J=9. 8,7.0Hz,1H),1.93-1.70(m,1H),1.42(s,9H),1.34(dt,J=12.8,9.7Hz,1H),1.07(d,J=6.6Hz,3H).

[0280] Intermediate 18 (2S,3S)-1,2-dimethylazetidine-3-amine [ka] Step a: Bromine (7.14 mL, 139 mmol) was slowly added to (E)-buta-2-en-1-ol (11.8 mL, 139 mmol) in DCM (350 mL) at room temperature. The reaction mixture was stirred for 2 hours, and then treated with a saturated aqueous solution of Na2S2O3. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2,3-dibromobutan-1-ol (crude) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 4.39(dq,J=9.3,6.6Hz,1H),4.26(ddd,J=9.2,4.8,3.6Hz,1H),4.11-4.07(m,2H),2.41-2.35(m,1H),1.91(d,J=6.6Hz,3H).

[0281] Step b: At room temperature, 2,3-dibromobutan-1-ol (33 g, 142 mmol) in Et2O (100 mL) was mixed with a solution of KOH (7.98 g, 142 mmol) in H2O (100 mL), and the reaction mixture was stirred at room temperature for 18 hours. The layers were separated, the organic layer was washed with saturated aqueous NaCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2-(1-bromoethyl)oxirane (crude). 1H NMR(400MHz,CDCl3)δ 3.87(p,J=6.9Hz,1H),3.24(ddd,J=6.8,3.8,2.5Hz,1H),2.96(dd,J=4.8,3.8Hz,1H),2.75(dd,J=4.8,2.5Hz,1H),1.72(d,J=6.9Hz,3H).

[0282] Step c: Diphenylmethaneamine (25.1 mL, 146 mmol) was added to 2-(1-bromoethyl)oxirane (22 g, 146 mmol) in MeOH at room temperature. The reaction mixture was stirred for 18 hours, then heated under reflux for 24 hours. The mixture was concentrated under reduced pressure, the crude product was extracted with Et2O, the organic layer was washed with saturated aqueous NaHCO3 solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. To confirm the structure, a small amount of the substance was purified by silica gel chromatography (siRNA:heptane, 30:70). The desired fractions were combined and concentrated under reduced pressure to obtain trans-1-benzhydryl-2-methylazetidine-3-ol as oil. 1 H NMR(400MHz,DMSO)δ 7.40(dt,J=8.1,1.7Hz,4H),7.26(ddd,J=10.3,8.5,6.8Hz,4H),7.17(td,J=7.2,1.8Hz,2H),5.28(d,J=6.4Hz,1H),4.35 (s,1H),3.66(p,J=6.5Hz,1H),3.43(t,J=6.7Hz,1H),2.91(p,J=6.1Hz,1H),2.42(t,J=7.0Hz,1H),0.61(d,J=6.1Hz,3H).

[0283] Step d: At 0°C, trans-1-benzhydryl-2-methylazetidine-3-ol (8.43 g, 29.9 mmol) was added to DCM (200 mL) with DMSO (21.3 mL, 299 mmol) and NEt3 (16.7 mL, 120 mmol). Next, sulfur trioxide pyridine complex (19.1 g, 120 mmol) was added, and the reaction mixture was stirred for 2 hours, then warmed to room temperature. The reaction mixture was diluted with saturated aqueous NaCl solution, and the crude product was extracted with siRNA. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 20:80). The desired fractions were combined and concentrated under reduced pressure to obtain 1-benzhydryl-2-methylazetidine-3-one (4.9 g) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.50(ddd,J=7.9,4.1,1.3Hz,4H),7.31(td,J=7.6,5.9Hz,4H),7.25-7.18(m,2H ),4.82(s,1H),4.26-4.01(m,2H),3.82(d,J=15.9Hz,1H),0.76(d,J=6.8Hz,3H).

[0284] Step e: At -78°C, 1-benzhydryl-2-methylazetidine-3-one (4.9 g, 19.5 mmol) was added to THF (29.2 mL, 29.2 mmol) with a 1.0 M L-selectlide solution. The reaction mixture was stirred for 30 minutes, then the condenser was removed and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was cooled to -78°C and H2O (5 mL), EtOH (5 mL), 30% H2O2 aqueous solution (5 mL), and 1N NaOH aqueous solution (5 mL) were added. The condenser was removed and the mixture was stirred at room temperature for 1 hour. Solid Na2S2O3 was added and the crude product was extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:heptane, 50:50). The desired fractions were combined and concentrated under reduced pressure to obtain cis-1-benzhydryl-2-methylazetidine-3-ol (4.9 g) as a white solid.1 H NMR(400MHz,DMSO-d6)δ 7.40(m,4H),7.26(m,4H),7.16(m,2H),5.03(d,J=5.6Hz,1H),4.46(s,1H), 4.21(m,1H),3.38(m,1H),3.02(m,1H),2.95(m,1H),0.67(d,J=6.5Hz,3H).

[0285] Step f: At 0°C, 7.28 mL (52.2 mL) of NEt3 and 2.04 mL (26.1 mmol) of methanesulfonyl chloride were added to 100 mL of DCM containing cis-1-benzhydryl-2-methylazetidine-3-ol. The condenser was removed, the reaction mixture was stirred at room temperature for 3 hours, then diluted with DCM and washed with H2O (200 mL x 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane (containing 1% NEt3), 0:100~50:50). The desired fractions were combined and concentrated under reduced pressure to obtain cis-1-benzhydryl-2-methylazetidine-3-ylmethanesulfonate (3.65 g). 1 H NMR(400MHz,CDCl3)δ 7.50-7.39(m,4H),7.35-7.19(m,6H),5.18(td,J=6.1,2.2Hz,1H),4.43(s,1H),3.69(td,J=6.4,1.4H z,1H),3.57(dt,J=10.1,1.9Hz,1H),3.19(dd,J=10.1,6.1Hz,1H),3.06(s,3H),0.86(d,J=6.4Hz,3H).

[0286] Step g: At room temperature, cis-1-benzhydryl-2-methylazetidine-3-ylmethanesulfonate (5.36 g, 16.2 mmol) was added to iPrOH (100 mL) with 30% NH4OH aqueous solution (21.0 mL, 162 mmol). The reaction mixture was heated under reflux at 60°C for 2 hours, then cooled to room temperature and concentrated under reduced pressure. The residue was extracted with DCM and washed with saturated aqueous solution of NaHCO3 and saturated aqueous solution of NaCl. The organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain trans-1-benzhydryl-2-methylazetidine-3-amine (crude). 1 H NMR(400MHz,DMSO-d6)δ 7.40(td,J=7.7,1.3Hz,4H),7.26(dt,J=12.2,7.5Hz,4H),7.20-7.13(m,2H),4.43(s,1H),3 .42-3.29(m,2H),2.95(t,J=7.3Hz,1H),2.85(dd,J=7.7,3.1Hz,1H),0.61(d,J=6.2Hz,3H).

[0287] Step h: At room temperature, trans-1-benzhydryl-2-methylazetidine-3-amine (3.2 g, 12.7 mmol) was added to DCM (100 mL), to which Boc2O (4.42 mL, 19.0 mmol) and DIPEA (6.64 mL, 38.0 mmol) were added. The reaction mixture was stirred for 2 hours, and then concentrated under reduced pressure. The residue was diluted with siRNA and washed with saturated aqueous solution of NaHCO3, followed by saturated aqueous solution of NaCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 20:80). The desired fractions were combined and concentrated under reduced pressure to obtain racemic tert-butyl((2S,3S)-1-benzhydryl-2-methylazetidine-3-yl)carbamate (3.5 g). 1H NMR(400MHz,DMSO)δ 7.44-7.37(m,4H),7.32-7.22(m,5H),7.19-7.13(m,2H),4.10-3.99(m,1H),3.43(t,J=6.5Hz,1H), 3.32(s,1H),3.12(dd,J=8.0,3.6Hz,1H),2.98(t,J=7.9Hz,1H),1.36(s,9H),0.57(d,J=6.5Hz,3H).

[0288] Step i: A single enantiomer was separated using a chiral SFC: ChiralPak IG21 x 250 mm, 80 g / min, 15% MeOH, and 10 mM ammonia to obtain tert-butyl((2S,3S)-1-benzhydryl-2-methylazetidine-3-yl)carbamate (1.77 g, peak 1, first elution) and tert-butyl((2R,3R)-1-benzhydryl-2-methylazetidine-3-yl)carbamate (1.7 g, peak 2, second elution).

[0289] Step j: Palladium hydroxide (1.09 g, 1.56 mmol) was added to tert-butyl((2S,3S)-1-benzhydryl-2-methylazetidine-3-yl)carbamate (5.49 g, 15.6 mmol) in EtOH (75 mL) at room temperature under N2. The reaction mixture was stirred under H2 (1 atm, balloon) for 2 hours, then purged with N2 and filtered. The filtrate was concentrated under reduced pressure to obtain tert-butyl((2S,3S)-2-methylazetidine-3-yl)carbamate (crude). 1 H NMR(400MHz,DMSO-d6)δ 4.35-4.22(m,1H),3.83-3.70(m,1H),3.53-3.43(m,1H),3.40-3.34(m,1H),1.37(s,9H),1.04(d,J=6.6Hz,3H).

[0290] Step k: At room temperature, tert-butyl((2S,3S)-2-methylazetidine-3-yl)carbamate (2.9 g, 15.6 mmol) was added to DCM (100 mL), to which formaldehyde (8.58 mL, 31.1 mmol) and sodium triacetoxyborohydride (6.60 g, 31.1 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, and then diluted with DCM. The organic layer was washed with saturated aqueous NaHCO3 and saturated aqueous NaCl. The resulting organic material was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (MeOH:DCM (containing 1% NH4OH), 20:80). The desired fractions were combined and concentrated under reduced pressure to obtain tert-butyl((2S,3S)-1,2-dimethylazetidine-3-yl)carbamate (2.67 g) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 7.26(d,J=7.8Hz,1H),3.98(qd,J=7.5,3.0Hz,1H),3.21-3.05(m,2H),3.01(t,J=7.5Hz,1H),2.13(s,3H),1.37(s,9H),0.91(d,J=6.4Hz,3H).

[0291] Step 1: At room temperature, tert-butyl((2S,3S)-1,2-dimethylazetidine-3-yl)carbamate (2.67 g, 13.3 mmol) was added to 1,4-dioxane (33.3 mL, 133 mmol) in a 4 M HCl solution. The reaction mixture was stirred for 2 hours, and then concentrated under reduced pressure to obtain (2S,3S)-1,2-dimethylazetidine-3-amine hydrochloride salt (2.4 g, crude) as an oil that solidified over time.

[0292] Intermediate 19 ((1r,4r)-4-isopropoxycyclohexyl)methyl 4-methylbenzenesulfonate [ka] Step a: Methyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (31.9 g, 202 mmol) in THF (400 mL) was added dropwise to N2 at 0°C, to which NEt3 (30.9 mL, 222 mmol) and TMSCl (26.0 mL, 204 mmol) were added dropwise. The reaction mixture was stirred at 0°C for 30 minutes, then diluted with 25 mL of heptane, stirred vigorously, and filtered. The resulting clear filtrate was concentrated under reduced pressure to obtain a crude silyl ether intermediate as a colorless oil. The crude silyl ether was dissolved in anhydrous DCM (400 mL) at room temperature under N2. The resulting solution was treated with acetone (17.8 mL, 242 mmol), and the reaction mixture was cooled to -78°C. Next, Et3SiH (38.6 mL, 242 mmol), followed by TMSOTf (14.6 mL, 81 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 5 minutes, then warmed to 0°C. The reaction mixture was stirred further at 0°C for 1 hour, then neutralized with saturated aqueous solution of NaHCO3 (20 mL), and vigorously stirred for 5 minutes. The resulting mixture was extracted with DCM (40 mL), the organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 0:100~80:20). The desired fractions were combined and concentrated under reduced pressure to obtain methyl(1r,4r)-4-isopropoxycyclohexane-1-carboxylate (37.7 g) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 3.80-3.66(m,4H),3.29(tt,J=10.6,3.9Hz,1H),2.37-2.22(m,1H),2.12- 1.96(m,4H),1.57-1.42(m,2H),1.34-1.27(m,2H),1.16(d,J=6.1Hz,6H).

[0293] Step b: Methyl (1r,4r)-4-isopropoxycyclohexane-1-carboxylate (14.2 g, 70.9 mmol) in THF (250 mL) was added dropwise to 1.0 M LAH in THF (78 mL, 78 mmol) at 0°C under N2. The reaction mixture was stirred at 0°C for 10 minutes, and then carefully quenched with saturated aqueous NaHCO3 at 0°C under N2. The mixture was diluted with ELISA (100 mL) and filtered. The separated organic phase of the filtrate was concentrated under reduced pressure to obtain ((1r,4r)-4-isopropoxycyclohexyl)methanol (11.9 g, crude) as a colorless oil. 1 H NMR(400MHz,DMSO-d6)δ 4.38(t,J=5.3Hz,1H),3.69(hept,J=6.1Hz,1H),3.26-3.14(m,3H),1.96-1.82(m,2H),1.81-1.63(m, 2H),1.36-1.21(m,1H),1.16-1.09(m,1H),1.06(d,J=6.1Hz,7H),0.90(tdd,J=13.3,11.7,3.3Hz,2H).

[0294] Step c: At 0°C, NET3 (8.05 mL, 58.0 mmol) and TsCl (6.6 g, 34.8 mmol) were added to ((1r,4r)-4-isopropoxycyclohexyl)methanol (5.00 g, 29.0 mmol) in DCM (145 mL). The reaction mixture was heated to room temperature with stirring for 72 hours. The reaction mixture was diluted with H2O and DCM, and the organic layer was passed through a phase separator. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 0:100~80:20). The desired fractions were combined and concentrated under reduced pressure to obtain ((1r,4r)-4-isopropoxycyclohexyl)methyl 4-methylbenzenesulfonate (7.45 g) as a colorless oil that solidified over time. MS m / z 327.3 [M+H] + .

[0295] Intermediate 20 (1r,4r)-4-isopropoxycyclohexane-1-carbaldehyde [ka] Step a: Under N2 at -19°C, DIPEA (19.7 mL, 113 mmol) was added to ((1r,4r)-4-isopropoxycyclohexyl)methanol (6.49 g, 37.7 mmol) in DCM (77 mL). Next, sulfur trioxide pyridine complex (7.79 g, 49.0 mmol) in DMSO (48.3 mL) was added dropwise at a rate that maintained the temperature below -9°C. The reaction mixture was heated to 0°C, stirred for 30 minutes, and then poured into a separatory funnel containing H2O (150 mL) and DCM (150 mL). The organic layer was partitioned and separated. The aqueous layer was extracted with DCM (50 mL x 2). The combined organic extracts were washed with saturated aqueous NaCl solution, passed through a phase separator, and concentrated under reduced pressure to obtain the crude product. The crude product was concentrated by silica gel chromatography (siRNA:heptane, 10:90-50:50). The desired fractions were combined and concentrated under reduced pressure. This substance was purified by silica gel chromatography (siRNA:heptane, 0:100-20:100). The desired fractions were combined and concentrated under reduced pressure to obtain (1r,4r)-4-(benzyloxy)cyclohexane-1-carbaldehyde (4.21 g) as a clear yellow oil. 1 H NMR(400MHz,CDCl3)δ 9.66(d,J=1.5Hz,1H),4.01-3.47(m,1H),3.47-3.11(m,1H),2.36-2.14(m,1H),2.14-1.80(m,4H),1.42-1.24(m,4H),1.23-1.08(m,6H).

[0296] Intermediate 21 5-Chloro-2-formyl-1-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid [ka] Step a: AlCl3 (395 g, 2.96 mol) was added to 5-chloro-1H-pyrrolo[2,3-b]pyridine (90 g, 592 mmol) in DCM (900 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes, and then 2,2,2-trichloroacetyl chloride (162 g, 888 mmol) was added dropwise over 20 minutes. The reaction mixture was stirred for a further 3 hours, and then quenched by adding H2O (1 L) at 0°C and extracted with siRNA (1 L x 3). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by trituration with MeOH to obtain 2,2,2-trichloro-1-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)ethane-1-one (160 g) as a yellow solid. MS m / z297[M+H] + .

[0297] Step b: At room temperature, 2,2,2-trichloro-1-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-yl)ethane-1-one (160 g, 541 mmol) was mixed with KOH (33.3 g, 595 mmol). The reaction mixture was stirred at room temperature for 2.5 hours, after which the pH was adjusted to 7 with 1N HCl aqueous solution. The resulting precipitate was collected by filtration. The filtered cake was washed with H2O (500 mL) and MeOH (300 mL x 3), dried under reduced pressure, and methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (80 g, crude) was obtained as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 12.78(s,1H),8.34-8.28(m,3H),3.84(m,3H).

[0298] Step c: Methyl 5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (80 g, 381 mmol) was mixed with ethyl orthoformate (320 mL) at room temperature. The reaction mixture was stirred at 180 °C for 3 hours, then cooled to 0 °C, and heptane (300 mL) was added. The resulting mixture was stirred for 30 minutes, and the precipitate was collected by filtration. The filtered cake was dried under reduced pressure to obtain methyl 5-chloro-1-(diethoxymethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (70 g, crude) as a yellow solid. 1 H NMR(400MHz,DMSO-d6)δ 8.44(d,J=2.4Hz,1H),8.26(d,J=2.4Hz,1H),8.14-8.12(s,1H),6.80(s,1H) ),3.86(s,3H),3.72-3.68(m,2H),3.66-3.62(m,2H),1.15(t,J=7.0Hz,6H).

[0299] Step d: At -78°C, LDA (48.1 g, 449 mmol) was added dropwise to methyl 5-chloro-1-(diethoxymethyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (70 g, 224 mmol) in THF (700 mL). The reaction mixture was stirred for 1 hour, and then methyl formate (53.8 g, 897 mmol) was added dropwise. The reaction mixture was slowly warmed at room temperature for about 1 hour, and the reaction mixture was quenched by adding saturated aqueous solution of NH4Cl (800 mL) at 0°C and extracted with siRNA (800 mL x 3). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by trituration with THF (300 mL) to obtain methyl 5-chloro-2-formyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (11 g) as a brown solid. MS m / z 239[M+H] + .

[0300] Step e: Methyl 5-chloro-2-formyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (300 mg, 1.26 mmol) in DMF (6.29 mL) at room temperature was mixed with ((1r,4r)-4-isopropoxycyclohexyl)methyl 4-methylbenzenesulfonate (410 mg, 1.26 mmol) and K2CO3 (695 mg, 5.03 mmol). The reaction mixture was heated to 100°C for 3 hours, then diluted with ethyl and washed with H2O (20 mL x 3) and saturated aqueous NaCl solution. The resulting organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was diluted with DCM, adsorbed onto celite®, evaporated to dryness, and purified by silica gel chromatography (ethyl:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 5-chloro-2-formyl-1-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (402 mg). 1 H NMR(400MHz,CDCl3)δ 10.87(s,1H),8.52(d,J=2.4Hz,1H),8.49(d,J=2.4Hz,1H),4.63(d,J=7.4Hz,2H),4.03(s,3H),3.75-3.60(m,1H),3.31-3.15(m, MS m / z393.1[M+H] + .

[0301] Step f: Methyl 5-chloro-2-formyl-1-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (402 mg, 1.023 mmol) was added to methyl 5-chloro-2-formyl-1-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (5.12 mL, 10.2 mmol) in THF (5.12 mL) and MeOH (5.12 mL) at room temperature. The reaction mixture was heated to 50°C for 1.5 hours, then cooled to room temperature, diluted with 1M Na2S2O3 aqueous solution, and extracted with DCM (10 mL x 3). The combined organic extract was passed through a phase separator and concentrated under reduced pressure to obtain 5-chloro-2-formyl-1-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid (crude). MS m / z379.2[M+H] + .

[0302] Intermediate 22 5-Chloro-2-(difluoromethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid [ka] Step a: At 0°C, methyl 5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (49 mg, 0.146 mmol) was added to DCM (0.75 mL) with deoxofluor (0.135 mL, 0.730 mmol). The reaction mixture was stirred for 5 minutes, and then warmed to room temperature while stirring for 2 hours. Further deoxofluor (0.135 mL, 0.730 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C, quenched by adding ice-cold saturated NaHCO3 aqueous solution, and partitioned between DCM and H2O. The aqueous phase was washed with DCM, and the combined organic substances were washed with saturated NaHCO3 aqueous solution and saturated NaCl aqueous solution. The combined organic substances were dried on MgSO4, filtered, and concentrated under reduced pressure to obtain methyl 5-chloro-2-(difluoromethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (88.4 mg, crude) as a yellowish-brown solid.

[0303] Step b: Methyl 5-chloro-2-(difluoromethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (52.2 mg, 0.146 mmol) was added to methyl 5-chloro-2-(difluoromethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (0.729 mL, 0.729 mmol) in THF (0.50 mL) and MeOH (0.25 mL) at room temperature. The reaction mixture was heated to 50°C for 1.5 hours, and then concentrated under reduced pressure to remove the organic solvent. The residue was diluted with H2O and then treated with 1N HCl aqueous solution until pH reached 1. The resulting suspension was diluted with ELISA and the layers were separated. The aqueous layer was extracted with toluene, the combined organic substances were washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 5-chloro-2-(difluoromethyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid (35.1 mg, crude) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ 13.28(s,1H),8.09(d,J=2.2Hz,1H),7.87(d,J=9.0Hz,1H),7.42(dd,J=9.0,2.2Hz,1H),4.33(d,J=7 MS m / z 342.3 [MH] - .

[0304] Intermediate 23 5-Chloro-2-cyano-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid [ka] Step a: Methyl 5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (110 mg, 0.329 mmol) in EtOH (1.65 mL) at room temperature was mixed with pyridine (0.053 mL, 0.658 mmol) and hydroxylamine hydrochloride salt (27.4 mg, 0.395 mmol). The reaction mixture was heated overnight at 80°C, then cooled to room temperature and concentrated under reduced pressure. The resulting substance was dissolved in H2O / Â, and the layers were separated. The organic phase was washed with a saturated aqueous solution of NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain methyl(E)-5-chloro-2-((hydroxyimino)methyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (110 mg, crude) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 12.03(s,1H),8.97(s,1H),8.02(d,J=2.0Hz,1H),7.78(d,J=9.0Hz,1H),7.35(dd,J=8.9,2.2Hz,1H),4.52( d,J=7.2Hz,2H),3.88(s,3H),3.83-3.74(m,2H),3.21-3.10(m,2H),2.13-1.98(m,1H),1.43-1.22(m,4H).MS m / z 351.3 [M+H] + .

[0305] Step b: Methyl(E)-5-chloro-2-((hydroxyimino)methyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (109 mg, 0.311 mmol) in NEt3 (1.5 mL) at room temperature was mixed with Ac2O (0.059 mL, 0.621 mmol). The reaction mixture was heated to 90°C for 2 hours, then cooled to room temperature and partitioned between ethyl acetate and H2O. The aqueous phase was washed with ethyl acetate. The combined organic extracts were washed with saturated aqueous NaCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:heptane, 0:100-80:20). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 5-chloro-2-cyano-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (85 mg) as a yellowish-brown solid. 1 H NMR(400MHz,DMSO-d6)δ 8.08(dd,J=2.1,0.6Hz,1H),7.95(dd,J=9.0,0.7Hz,1H),7.55(dd,J=9.0,2.1Hz,1H),4.36(d,J=7.5 Hz,2H),3.93(s,3H),3.87-3.77(m,2H),3.24-3.15(m,2H),2.18-2.04(m,1H),1.41-1.29(m,4H).MS m / z 333.4 [M+H] + .

[0306] Step c: Methyl 5-chloro-2-cyano-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (83.7 mg, 0.252 mmol) was added to 1N NaOH aqueous solution (528 μL, 0.528 mmol) in THF (958 μL) and MeOH (479 μL) at room temperature. The reaction mixture was stirred overnight at room temperature, then concentrated under reduced pressure to remove the organic solvent. The residue was diluted with H2O and treated with 1N HCl aqueous solution until pH reached 1. The resulting suspension was diluted with ELISA and the layers were separated. The aqueous layer was extracted with ELISA, the combined organic matter was washed with saturated NaCl aqueous solution, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 5-chloro-2-cyano-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid (71 mg, crude) as a solid. 1 H NMR(400MHz,DMSO-d6)δ 13.45(s,1H),8.11(d,J=2.1Hz,1H),7.91(d,J=9.0Hz,1H),7.51(dd,J=9.0,2.2Hz,1H),4.33( d,J=7.4Hz,2H),3.86-3.77(m,2H),3.27-3.13(m,2H),2.17-2.03(m,1H),1.44-1.31(m,4H).MS m / z 317.5 [M+H] + .

[0307] Intermediate 24 Methyl 4-phenylpiperidine-4-carboxylate [ka] Step a: Bromobenzene (1.21 mL, 11.5 mmol) was added to 1-tert-butyl 4-methylpiperidine-1,4-dicarboxylate (3.63 g, 14.9 mmol) in toluene (38.2 mL) at room temperature under N2. The mixture was purged with N2 for approximately 10 minutes, and then bis(tri-tert-butylphosphine)palladium(0) (CAS# 53199-31-8, 0.246 g, 0.481 mmol) was added, followed by a 1.0 M LHMDS solution in toluene (20.6 mL, 20.6 mmol). The reaction mixture was stirred at room temperature for 24 hours, then quenched with 2 mL AcOH, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 0:100~40:60). The desired fractions were combined and concentrated under reduced pressure to obtain 1-(tert-butyl)4-methyl4-phenylpiperidine-1,4-dicarboxylate (2.09 g) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ 7.47-7.33(m,4H),7.31-7.23(m,1H),3.95(dtd,J=13.7,4.5,1.3Hz,2H),3.68(s,3H),3.0 5(s,2H),2.53(dp,J=13.6,2.2Hz,2H),1.86(ddd,J=13.4,11.4,4.2Hz,2H),1.48(s,9H).MS m / z 342.2 [M+Na] + .

[0308] Step b: 1-(tert-butyl)4-methyl4-phenylpiperidine-1,4-dicarboxylate (2.15 g, 6.73 mmol) in MeOH (16.8 mL) exposed to air at room temperature was added dropwise to a 4 M HCl solution in 1,4-dioxane (3.37 mL, 13.5 mmol). The reaction mixture was stirred for 8 hours, then poured into a saturated aqueous solution of NaHCO3 (50 mL). The substance was extracted with ELISA (20 mL x 3), the combined organic matter was washed with saturated aqueous solution of NaCl (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain methyl4-phenylpiperidine-4-carboxylate (crude) as a white solid. MS m / z 220.4 [M+H] +.

[0309] Intermediate 25a and intermediate 25b 3-(((2S,5R)-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole and 3-(((2R,5S)-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole [ka] Step a: At 0°C, 6-(((tert-butyldiphenylsilyl)oxy)methyl)tetrahydro-2H-pyran-3-ol (intermediate 8b, 16.0 g, 43.18 mmol) was added to THF (200 mL) with NaH (3.4 g, 86.4 mmol) and ethyl iodide (10.4 mL, 130 mmol). The reaction mixture was stirred at room temperature for 2 hours, then cooled to 0°C, quenched with cold H2O, and extracted with ethyl iodide. The organic extract was washed with saturated aqueous solutions of H2O and NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl iodine:hexane, 2:98~5:95). The desired fractions were combined and concentrated under reduced pressure to obtain racemic trans tert-butyl((5-ethoxytetrahydro-2H-pyran-2-yl)methoxy)diphenylsilane (6.8 g, first eluted) as a colorless oil. 1 H NMR(400MHz,CDCl3)δ 7.69-7.63(m,4H),7.42-7.32(m,6H),4.10-4.05(m,1H),3.74-3.68(m,1H),3.60-3.48(m,3H),3.37-3.30(m,2H) ,3.15-3.08(m,1H),2.20-2.15(m,1H),1.84-1.80(m,1H),1.40-1.30(m,2H),1.20(t,J=7.2Hz,3H),1.05(s,9H).

[0310] Step b: At 0°C, 1.0 M TBAF solution in THF (34.1 mL, 34.1 mmol) was added to racemic trans tert-butyl((5-ethoxytetrahydro-2H-pyran-2-yl)methoxy)diphenylsilane (6.8 g, 17.1 mmol) in THF (100 mL). The reaction mixture was stirred at room temperature for 2 hours, then quenched with saturated NH4Cl aqueous solution and extracted with a MeOH:DCM mixture (9:1, 250 mL). The combined organic extracts were washed with saturated NaCl aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:hexane, 80:20). The desired fractions were combined and concentrated under reduced pressure to obtain racemic trans (5-ethoxytetrahydro-2H-pyran-2-yl)methanol (2.5 g) as a colorless oil. 1 H NMR(300MHz,DMSO-d6)δ 4.58(t,J=6.0Hz,1H),3.98-3.88(m,1H),3.52-3.30(m,2H),3.30-3.12(m,4H),2.94(t,J=1 0.5Hz,1H),2.10-2.04(m,1H),1.66-1.60(m,1H),1.26-1.12(m,2H),1.05(t,J=7.0Hz,3H).

[0311] Step c: At -78°C, 2.97 g (23.4 mmol) of oxalyl chloride in 80 mL of DCM was mixed with 2.77 mL (39.0 mmol) of DMSO in 10 mL of DCM. Racemic trans (5-ethoxytetrahydro-2H-pyran-2-yl)methanol (2.50 g, 15.6 mmol) was then added to 10 mL of DCM and 13.0 mL (93.6 mmol) of triethylamine. The reaction mixture was stirred at -78°C for 2 hours, then quenched with 25 mL of saturated NH4Cl aqueous solution and extracted with 100 mL of DCM. The combined organic extract was washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain racemic trans 5-ethoxytetrahydro-2H-pyran-2-carbaldehyde (2.5 g, crude) as a light brown oil.

[0312] Step d: At 0°C, racemic trans-5-ethoxytetrahydro-2H-pyran-2-carbaldehyde (2.44 g, 15.4 mmol) and Et3SiH (4.9 mL, 92.6 mmol) were added to 6-fluoro-2-methyl-1H-indole (2.30 g, 15.4 mmol) in DCM (100 mL). The reaction mixture was stirred for 15 minutes, after which trifluoroacetic acid (4.71 mL, 61.7 mmol) was added dropwise. The resulting reaction mixture was stirred at 0°C for 1.5 hours, then diluted with DCM (100 mL), and washed with saturated aqueous solution of NaHCO3 (100 mL), followed by saturated aqueous solution of NaCl. The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography ( Depositphotos:hexane, 30:70). The desired fractions were combined and concentrated under reduced pressure to obtain racemic trans3-((5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole (2.6 g) as a light brown solid. 1 H NMR(300MHz,DMSO-d6)δ 10.79(s,1H),7.36-7.28(m,1H),6.97(dd,J=5.4 and 9.9Hz,1H),6.76-6.70(m,1H),3.95-3.90(m,1H),3.48-3.40(m,2H),3.38-3.20(m,2H),2.91(t,J=10.5Hz,1H), 2.75-2.60(m,2H),2.25(s,3H),2.05-1.95(m,1H),1.60-1.51(m,1H),1.25-1.10(m,2H),1.03(t,J=6.6Hz,3H).

[0313] Step e: Racemic trans3-((5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole (2.6 g) was separated according to the following method for providing 3-(((2R,5S)-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole. Chiral separation: LUX AMYLOSE-1, 250 mm × 21.2 mm, 5 μm; Phase A for mobile phase CH3CN, Phase B for 0.1% DIPEA in EtOH:MeOH (1:1); Flow: 15 mL; Isocratic Phase A:Phase B = 50:50.

[0314] Peak 1 (initial elution, intermediate 25a): 1.2g; MS m / z 292.2 [M+H] + .

[0315] Peak 2 (second to elute, intermediate 25b): 1.2g; MS m / z 292.1 [M+H] + .

[0316] Intermediate 26 Ethyl(1S,4S)-4-amino-3,3-dimethylcyclohexane-1-carboxylate [ka] Step a: At room temperature under N2 conditions, benzylamine (1.31 mL, 12.0 mmol) and sodium triacetoxyborohydride (3.05 g, 14.4 mmol) were added in two parts to racemiethyl 3,3-dimethyl-4-oxocyclohexane-1-carboxylate (1.9 g, 9.58 mmol, obtained as a byproduct from step a of the pathway to intermediate 2) in anhydrous THF (25 mL). The white suspension was vigorously stirred at room temperature for 6.5 hours. The reaction mixture was quenched by adding saturated aqueous solution of NaHCO3 (50 mL), stirred for 30 minutes, and then left overnight at room temperature. The resulting mixture was partitioned between toluene (25 mL) and saturated aqueous solution of NaHCO3 (25 mL), and the aqueous phase was extracted with toluene (25 mL x 2). The combined organic extract was washed with saturated aqueous solution of NaCl (25 mL) and dried over Na2SO4. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase C18 chromatography (CH3CN:H2O (containing 0.1% NH4OH), 10:90~0:100). The desired fractions were combined, partially concentrated under reduced pressure, and then extracted with ELISA (25 mL x 3). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain racemic trans-ethyl-4-(benzylamino)-3,3-dimethylcyclohexane-1-carboxylate (1.6 g). 1 H NMR(400MHz,CDCl3)δ 7.34-6.99(m,5H),3.97(m,J=7.1Hz,2H),3.81(d,J=13.2Hz,1H),2.32(tt,J=12.6,3.5Hz,1H),2.05(dd,J=11. 6,3.7Hz,1H),1.89-1.77(m,2H),1.51(ddd,J=13.4,3.5,2.3Hz,1H),1.33-1.02(m,7H),0.81(d,J=41.0Hz,7H).

[0317] Step b: Racemic trans-ethyl-4-(benzylamino)-3,3-dimethylcyclohexane-1-carboxylate (1.6 g, 5.53 mmol) was purified by preparative chiral SFC separation: Chiralpak IG (CPC071) 21 mm x 250 mm; 5-25% MeOH and 10 mM NH3 / CO2; 125 bar for 6.2 mins; multiple runs to obtain ethyl(1S,4S)-4-(benzylamino)-3,3-dimethylcyclohexane-1-carboxylate (peak 1, first elution, 0.55 g). 1 H NMR(400MHz,CDCl3)δ 7.46-7.20(m,6H),4.12(m,J=7.1Hz,2H),3.97(d,J=13.2Hz,1H),3.72(d,J=13.2Hz,1H),2.55-2.40(m,1H),2.21(dd,J=11.5,3.7Hz,1H), 1.99(ddt,J=11.4,6.4,3.3Hz,2H),1.66(ddd,J=13.4,3.6,2.3Hz,1H),1.52-1.31(m,2H),1.26(t,J=7.1Hz,4H),1.01(s,3H),0.92(s,3H).

[0318] Step c: At room temperature under N2 pressure, Pd / C (0.202 g, 0.190 mmol) was added to ethyl (1S,4S)-4-(benzylamino)-3,3-dimethylcyclohexane-1-carboxylate (0.55 g, 1.90 mmol) in EtOH (10 mL). The vial was purged by performing two cycles from reduced pressure to N2, with the final reduced pressure purge being released with H2. The reaction mixture was vigorously stirred overnight under H2 pressure. The reaction mixture was filtered through a celite® pad while washing with EtOH and then siRNA. The filtrate was concentrated to dryness under reduced pressure, the residue was resuspended in siRNA, and the mixture was concentrated again under reduced pressure. The residue was dissolved in Et2O (50 mL), and the N2 solution was added dropwise with 2.5 M HCl solution in EtOH (1.06 mL, 2.66 mmol), thereby forming a white precipitate. Further Et2O (50 mL) was added, the resulting mixture was sonicated, and then stirred in an ice bath for 30 minutes. The solid was recovered by vacuum filtration and washed with Et2O. The solid wet cake was then dried under a stream of N2 for more than 1 hour to obtain ethyl(1S,4S)-4-amino-3,3-dimethylcyclohexane-1-carboxylate hydrochloride salt (0.324 g, crude) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ 4.14(m,J=7.1Hz,2H),2.99(dd,J=12.3,4.2Hz,1H),2.56(tt,J=12.6,3.7Hz,1H),2.14-2.04(m,1H),1.96-1.85(m,1H),1 .80(ddd,J=13.7,3.5,2.4Hz,1H),1.74-1.61(m,1H),1.61-1.40(m,2H),1.26(t,J=7.1Hz,3H),1.14(s,3H),1.02(s,3H).

[0319] Example 1 (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid [ka] Step a: At -40°C under N2, 1.5 M LHMDS solution in toluene (20.7 mL, 31.1 mmol) was added dropwise to 6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole (8.2 g, 27.0 mmol) in THF (100 mL). The reaction mixture was stirred for 10 minutes, and then 2.0 M AlMe3 solution in toluene (14.9 mL, 29.7 mmol) was added dropwise. The reaction mixture was stirred at -40°C for 40 minutes. Then, 0.5 M methyl 4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)piperidine-4-carboxylate solution in THF (64.9 mL) was rapidly added. The condenser was removed, and the solution was immediately heated to 40°C for 1 hour. The solution was then cooled to 0°C and quenched with a saturated aqueous solution of NaHCO3 (50 mL). The resulting heterogeneous mixture was diluted with DCM (150 mL) and vigorously stirred until the white aluminum salt and organic layer separated. The resulting mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (HCl:heptane, 0:100-100:0). The desired fractions were combined and concentrated under reduced pressure to obtain (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (15.1 g) as a colorless foam. 1 H NMR(400MHz,DMSO-d6)δ 7.46(dtd,J=12.0,6.4,2.7Hz,3H),7.31-7.15(m,3H),7.05-6.89(m,1H),4.11-3.45(m,6H),3.42-3.16(m,3H),2.55(s,2H),2.44(d,J =13.6Hz,1H),2.29(d,J=4.9Hz,3H),2.11(s,1H),1.87(s,3H),1.69(s,2H),1.48(s,1H),1.27(s,1H),1.04(dd,J=6.1,2.4Hz,10H).MS m / z 567.3 [M+H]+ .

[0320] Step b: (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (10.9 g, 19.2 mmol) was added to iPrOH (48.1 mL) and THF (48.1 mL) exposed to air at room temperature. 1N NaOH aqueous solution (77 mL, 77 mmol) was added. The reaction mixture was covered and stirred at 65°C for 4 hours, then cooled to room temperature and stirred overnight. The resulting mixture was acidified with formic acid (2.95 mL, 77 mmol), diluted with DCM (100 mL) and saturated NaCl aqueous solution, and vigorously stirred. The layers were separated, the organic layer was passed through a phase separator, and the filtrate was concentrated under reduced pressure to obtain 1-(6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (10.6 g, crude) as an off-white solid. MS m / z 553.7[M+H] + .

[0321] Step c: 1-(6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (15.5 g, 28.0 mmol) in CH3CN (100 mL) at room temperature was mixed with ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate hydrochloride salt (6.20 g, 28.0 mmol) and HATU (13.8 g, 36.4 mmol). The mixture was stirred for 15 minutes, after which DIPEA (24.4 mL, 140 mmol) was slowly added. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, and washed with 1N HCl aqueous solution, saturated NaHCO3 aqueous solution, and then saturated NaCl aqueous solution. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (HCl:heptane, 0:100-50:50). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl(1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (19.3 g) as a white solid. 1 H NMR(400MHz,DCM-d2)δ 7.42-7.30(m,3H),7.16-7.03(m,2H),7.01-6.82(m,2H),4.88(dd,J=17.2,8.9Hz,1H),4.06(qd,J=7.1,2.5Hz,2H),3.72-3.31( m,5H),3.22(ddt,J=14.6,10.1,4.2Hz,1H),2.54-1.72(m,18H),1.62-1.10(m,13H),1.00-0.85(m,4H),0.70(t,J=6.4Hz,3H).MS m / z 720.3 [M+H] + .

[0322] Step d: Ethyl (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (19.3 g, 26.8 mmol) was added to 2N NaOH aqueous solution (40.2 mL, 80 mmol) in THF (80 mL) and MeOH (40 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, then partially concentrated under reduced pressure and purified by reverse-phase C18 chromatography (CH3CN:H2O (containing 0.1% NH4OH), 10:90~50:50). The desired fraction was collected and partially concentrated (at a constant temperature of 30°C). The obtained solution was freeze-dried to obtain (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (sodium salt, 16.0 g) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ 7.51-7.36(m,3H),7.28(dd,J=18.1,8.7Hz,1H),7.22-7.09(m,3H),6.94( qd,J=9.3,2.4Hz,1H),3.84-3.40(m,3H),3.40-3.14(m,6H),2.71-2.52(m ,2H),2.26(d,J=4.0Hz,3H),2.04-1.51(m,10H),1.51-1.41(m,1H),1.28( qd,J=10.7,5.1Hz,1H),1.22-0.85(m,13H),0.56(dd,J=11.2,6.4Hz,3H).C 40 H 52 HRMS for F2N3O5: Calculated mass 692.3870 [M+H] + Mass measurement: 692.3900 [M+H] + Potency (μM): Biochemically suitable AC 50 :3.3E-04; NanoBiT Qualified Absolute AC 50 :0.10; Cell proliferation eligible AC 50:0.11.

[0323] The compounds listed in Table 8 below were synthesized using the corresponding functionalized piperidine, indole intermediate, and amine using the above procedure or a modification thereof. Protonated carboxylates can be obtained directly if formic acid is used to neutralize the crude sodium carboxylate salt before purification.

[0324] [Table 8-1]

[0325] [Table 8-2]

[0326] [Table 8-3]

[0327] [Table 8-4]

[0328] [Table 8-5]

[0329] Example 2 (1S,3S,4S)-4-(1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid [ka] Step a: 2-ethyl-6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-indole in THF (52.9 mL) was added dropwise to 1.0 M LHMDS solution in toluene (31.8 mL, 31.8 mmol). The reaction mixture was stirred for 10 minutes, and then 2.0 M AlMe3 solution in toluene (15.4 mL, 30.7 mmol) was added dropwise. The resulting solution was stirred at -40°C for 40 minutes. Then, 0.5 M methyl 4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)piperidine-4-carboxylate solution in THF (42.3 mL) was added dropwise. The condenser was removed, and the reaction mixture was immediately heated to 60°C for 2.5 hours. It was then cooled to 0°C and carefully quenched with a saturated aqueous solution of NaHCO3 (30 mL). The resulting mixture was diluted with DCM (100 mL) at 0°C and vigorously stirred until the white aluminum salt and organic layer were partitioned (approximately 10 minutes). The resulting mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography ( Depositphotos:heptane, 0:100-50:50). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 1-(2-ethyl-6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (8.0 g) as a colorless foam. MS m / z 581.5[M+H] + .

[0330] Step b: At room temperature, 1.0 g, 13.8 mmol of methyl 1-(2-ethyl-6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (8.0 g, 13.8 mmol) was added to 1N NaOH aqueous solution (27.6 mL). The reaction mixture was covered and stirred at 60°C for 5 hours, after which the reaction mixture was cooled to room temperature. The reaction mixture was diluted with DCM and saturated NaCl aqueous solution while vigorously stirring. This mixture was passed through a phase separator and concentrated under reduced pressure to obtain 1-(2-ethyl-6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (sodium salt, 8.13 g, crude) as a white solid. MS m / z 567.7[M+H] + .

[0331] Step c: At room temperature, 1.16 g, 1.97 mmol of 1-(2-ethyl-6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (sodium salt, 1.16 mL, 1.97 mmol) was added to DIPEA (1.37 mL, 7.87 mmol). Next, isopropyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate hydrochloride salt (0.510 g, 2.16 mmol), followed by HATU (1.50 g, 3.93 mmol). The reaction mixture was stirred for 30 minutes, then diluted with ELISA and poured into a separatory funnel containing saturated aqueous solution of NaHCO3 and H2O (1:1). The mixture was extracted with ELISA (20 mL x 2), and the combined organic substances were washed with saturated aqueous solution of NaCl (20 mL x 2). The resulting organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ELISA:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain isopropyl(1S,3S,4S)-4-(1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (1.13 g) as a colorless foam. MS m / z 749.0 [M+H] + .

[0332] Step d: Isopropyl(1S,3S,4S)-4-(1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (1.13 g, 1.51 mmol) was added to 1N NaOH aqueous solution (3.78 mL, 3.78 mmol) in MeOH (3.78 mL) and THF (3.78 mL) at room temperature. The reaction mixture was stirred at 55°C for 2 hours, and then cooled to room temperature. The volatile solvent was partially removed under reduced pressure, and the resulting mixture was directly purified by reverse-phase column chromatography of C18 (CH3CN:H2O (containing 0.1% NH4OH), 10:90~100:0). The desired fractions were combined and freeze-dried to obtain (1S,3S,4S)-4-(1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (sodium salt, 0.91 g) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ 7.53-7.27(m,4H),7.22-7.08(m,3H),6.95(qd,J=9.3,2.3Hz,1H),3.88-2.99(m,9H),2.87-2.53(m,3H),2 .49(s,1H),2.11(dddd,J=14.0,8.4,6.8,2.6Hz,2H),1.93-0.95(m,26H),0.59(dd,J=10.5,6.5Hz,3H).MS m / z706.3[M+H] + Potency (μM): Biochemically suitable AC 50 :<2.8E-04; NanoBiT Qualified Absolute AC 50 :0.19; Cell proliferation eligible AC 50 :0.11.

[0333] Example 3 (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid [ka] Step a: 6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole (2.7 g, 5.83 mmol) in THF (29.1 mL) was added dropwise to 1.5 M LHMDS solution in toluene (5.83 mL, 8.74 mmol). The reaction mixture was stirred for 10 minutes, and then 2.0 M AlMe3 solution in toluene (4.23 mL, 8.45 mmol) was added dropwise. The reaction mixture was stirred at -40°C for 40 minutes. Then 0.5 M methyl 4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)piperidine-4-carboxylate solution in THF (16.3 mL, 8.16 mmol) was added dropwise. The condenser was removed, and the mixture was immediately heated to 60°C for 2.5 hours. It was then cooled to 0°C and carefully quenched with a saturated aqueous solution of NaHCO3 (30 mL). The resulting heterogeneous mixture was diluted with DCM (100 mL) at 0°C and vigorously stirred until the white aluminum salt and organic layer were partitioned (approximately 10 minutes). The resulting mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 0:100-100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 1-(6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (4.0 g) as a colorless foam. MS m / z 611.5[M+H] + .

[0334] Step b: At room temperature, methyl 1-(6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (4.0 g, 4.91 mmol) was added to iPrOH (12.3 mL) and THF (12.3 mL). 1N NaOH aqueous solution (12.3 mL, 12.3 mmol) was added. The reaction mixture was covered and stirred at 40°C for 14 hours, after which the reaction mixture was cooled to room temperature. The reaction mixture was diluted with DCM and saturated NaCl aqueous solution, and then neutralized with formic acid while vigorously stirring. This mixture was passed through a phase separator and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography of C18(CH3CN:H2O (containing 0.1% NH4OH), 0:100~100:0). The desired fractions were combined and freeze-dried to obtain 1-(6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (2.41 g) as a white solid. MS m / z 597.7[M+H] + .

[0335] Step c: At room temperature, 1-(6-fluoro-3-(((1r,4r)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (700 mg, 1.17 mmol) was added to DIPEA (1.02 mL, 5.87 mmol). Next, ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate hydrochloride salt (312 mg, 1.41 mmol), followed by HATU (558 mg, 1.47 mmol) was added all at once. The reaction mixture was stirred for 30 minutes, then diluted with ELISA and poured into a separatory funnel containing saturated aqueous solution of NaHCO3 and H2O (1:1). The mixture was extracted with ELISA (20 mL x 2), and the combined organic matter was washed with saturated aqueous solution of NaCl (20 mL x 2). The resulting organic matter was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ELISA:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (896 mg) as a colorless foam. MS m / z 764.9 [M+H] + .

[0336] Step d: At room temperature, ethyl (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (870 mg, 1.14 mmol) was added to 1N NaOH aqueous solution (4.56 mL). The reaction mixture was stirred at 40°C for 30 minutes, then cooled to room temperature, and formic acid was added until the pH reached 5. The reaction mixture was partially concentrated and diluted with CH3CN, H2O, and MeOH. This mixture was purified by reverse-phase column chromatography using C18(CH3CN:H2O (containing 0.1% NH4OH), 0:100-100:0). The desired fractions were combined and lyophilized to obtain (1S,3S,4S)-4-(1-(6-fluoro-3-(((1r,4S)-4-isopropoxycyclohexyl)methyl)-2-(2-methoxyethyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (610 mg) as a white powder. 1 H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),7.54-7.27(m,4H),7.24-7.08(m,3H),6.96(qd,J=9.0,2.3Hz,1H),3.65(pd,J=6.1,2.3Hz,2H),3.47-3 .18(m,10H),3.08(s,2H),3.00(s,2H),2.59(s,2H),2.25-1.97(m,2H),1.91-1.00(m,23H),0.60(t,J=6.5Hz,3H).MS m / z736.9[M+H] + Potency (μM): Biochemically suitable AC 50 :5.0E-04; NanoBiT Qualified Absolute AC 50 :0.046; Cell proliferation eligible AC 50 :0.060.

[0337] Example 4 (1S,3S,4S)-4-((2S,4S)-1-(6-fluoro-3-((1R,4S)-4-isopropoxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid [ka] Step a: 3-((1r,4r)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline (intermediate 7b, 4.41 g, 12.7 mmol) in THF (30 mL) was added dropwise to THF (31 mL, 31.0 mmol) at -30°C under N2. The reaction mixture was stirred for 10 minutes, and then 2.0 M AlMe3 solution in toluene (14.9 mL, 29.7 mmol) was added dropwise. The resulting solution was stirred at -30°C for 40 minutes, and then 1.0 M methyl(2S,4S)-4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)-2-methylpiperidine-4-carboxylate solution in THF (16 mL) was added. The condenser was removed, and the reaction mixture was immediately heated overnight to 60°C, then cooled to 0°C, and subsequently quenched with Rochelle salt. The resulting heterogeneous mixture was diluted with ELISA (50 mL) and vigorously stirred until the white aluminum salt and organic layer were separated. The resulting two-phase mixture was transferred to a separatory funnel and separated into the organic and aqueous phases. The aqueous phase was extracted with ELISA (3x). The combined organic extracts were concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ELISA:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl(2S,4S)-1-(3-((1r,4S)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (5.33 g) as a white foam. MS m / z603.5[M+H] + .

[0338] Step b: At room temperature under N2 conditions, methyl(2S,4S)-1-(3-((1r,4S)-4-(benzyloxy)cyclohexyl)-6-fluoroindoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (5.33 g, 8.84 mmol) was added to ethyl(10 wt%, 4.71 g, 4.42 mmol) in ethyl(10 wt%), and the flask was purged with N2 (3x). The reaction mixture was placed under an H2 balloon and stirred overnight at room temperature, then filtered through celite® and rinsed thoroughly with ethyl(1). The resulting filtrate was concentrated under reduced pressure and purified by silica gel chromatography (ethyl(1):heptane, 15:85~100:0). The desired fraction was collected and concentrated under reduced pressure to obtain methyl(2S,4S)-1-((S)-6-fluoro-3-((1r,4S)-4-hydroxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (4.50 g) as a white foam. MS m / z 513.4[M+H] + .

[0339] Step c: At room temperature, methyl(2S,4S)-1-((S)-6-fluoro-3-((1r,4S)-4-hydroxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (2.00 g, 3.90 mmol) was added to DCM (40 mL), and acetone (1.13 g, 19.5 mmol) was added. The reaction mixture was cooled to -78 °C. Et3SiH (2.27 g, 19.5 mmol), followed by TMSOTf (3.82 g, 17.2 mmol), was added, and the flask was then directly heated to 0 °C and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous Na2CO3 solution, transferred to a separatory funnel, and the layers were partitioned. The aqueous phase was extracted with DCM (3x). The combined organic extracts were passed through a phase separator and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ELISA:heptane, 0:100-100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl(2S,4S)-1-(6-fluoro-3-((1r,4S)-4-isopropoxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (2.12 g) as a white foam. MS m / z 555.2[M+H] + .

[0340] Step d: Methyl (2S,4S)-1-(6-fluoro-3-((1r,4S)-4-isopropoxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (2.12 g, 3.82 mmol) was added to 2N NaOH aqueous solution (19.1 mL, 38.2 mmol) in THF (19 mL) and iPrOH (40 mL) at room temperature. The reaction mixture was stirred at room temperature for 48 hours, and then the reaction mixture was acidified to pH 3-4 with 1N HCl aqueous solution. The acidified mixture was partially concentrated under reduced pressure, diluted with ELISA (20 mL), and transferred to a separatory funnel. The layers were separated, and the aqueous phase was extracted with ELISA (3x). The combined organic extracts were washed with saturated NaCl aqueous solution and passed through a phase separator. The resulting solution was concentrated under reduced pressure to obtain (2S,4S)-1-(6-fluoro-3-((1r,4S)-4-isopropoxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (2.06 g, crude) as a white foam. MS m / z 541.2[M+H] + .

[0341] Step e: At room temperature, (2S,4S)-1-(6-fluoro-3-((1r,4S)-4-isopropoxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (2.00 g, 3.90 mmol) was added to CH3CN (40 mL), to which ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate hydrochloride salt (1.01 g, 4.57 mmol) was added. The flask was purged with N2 (3x), and DIPEA (2.46 g, 19.1 mmol) was added. The reaction mixture was stirred at room temperature for 5 minutes, and then HATU (2.90 g, 7.62 mmol) was added all at once. The reaction mixture was stirred at room temperature overnight, and then quenched with 5% NaCl aqueous solution (100 mL) and ELISA (25 mL). The separated aqueous phase was extracted with ELISA (50 mL x 3). The combined organic extract was washed with saturated NaCl aqueous solution, passed through a phase separator, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ELISA:heptane, 0:100~65:35). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl (1S,3S,4S)-4-((2S,4S)-1-(6-fluoro-3-((1r,4S)-4-isopropoxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (2.43 g) as a white foam. MS m / z 708.2[M+H] + .

[0342] Step f: Methyl (2S,4S)-1-(6-fluoro-3-((1r,4S)-4-isopropoxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (2.43 g, 3.43 mmol) was added to 2N NaOH aqueous solution (17.2 mL, 34.3 mmol) in THF (17 mL) and iPrOH (17 mL) at room temperature. The reaction mixture was stirred overnight at 50°C, and then partially concentrated under reduced pressure to remove the volatile solvent. The resulting mixture was purified by reverse-phase column chromatography of C18 (CH3CN:H2O (containing 0.1% NH4OH), 0:100~65:35). The desired fraction was collected and freeze-dried to obtain (1S,3S,4S)-4-((2S,4S)-1-(6-fluoro-3-((1r,4S)-4-isopropoxycyclohexyl)indoline-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (sodium salt, 2.19 g) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ 7.57-7.40(m,2H),7.21-7.02(m,4H),6.78(dd,J=10.3,2.4Hz,1H),6.70-6.58(m,1H),4.16(m,J=5.4Hz,1H),4. 02(dd,J=10.9,9.1Hz,1H),3.88-3.64(m,2H),3.56-3.43(m,2H),3.40-3.32(m,1H),3.25(m,J=5.2Hz,1H),3.18- 3.07(m,1H),2.79-2.56(m,2H),2.34(dd,J=13.9,5.3Hz,1H),2.09(tt,J=12.2,3.4Hz,1H),2.03-1.79(m,5H),1. 74(dt,J=12.9,3.6Hz,2H),1.61-1.36(m,4H),1.29(d,J=6.9Hz,3H),1.27-1.04(m,12H),0.71(d,J=6.4Hz,3H).C 39 H 51 HRMS for F2N3O5: Calculated mass 680.3870 [M+H] + Mass observation value: 680.3891 [M+H] +Potency (μM): Biochemically suitable AC 50 :4.7E-04; NanoBiT Qualified Absolute AC 50 :0.020; Cell proliferation eligible AC 50 :0.0030.

[0343] The following compounds in Table 9 were synthesized using the corresponding ketones with the above procedure or a modification thereof. Protonated carboxylates can be obtained directly if formic acid is used to neutralize the crude sodium carboxylate salt before purification.

[0344] [Table 9-1]

[0345] [Table 9-2]

[0346] Example 5 (1S,3S,4S)-4-(1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid [ka] Step a: 2-ethyl-6-fluoro-3-(((1r,4r)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole (5.02 g, 14.0 mmol) in THF (100 mL) was added dropwise to the mixture, and a 1.0 M LHMDS solution in toluene (21.0 mL, 21.0 mmol) was added dropwise, and the reaction mixture was stirred for 10 minutes. Next, a 2.0 M AlMe3 solution in toluene (11.2 mL, 22.3 mmol) was added dropwise, and the reaction mixture was stirred for 30 minutes. Methyl 4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)piperidine-4-carboxylate (5.09 g, 15.4 mmol) in THF (50 mL) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Subsequently, the mixture was heated to 60°C for 2 hours, cooled to -30°C, and quenched with Rochelle salt solution. The layers were separated, and the aqueous layer was extracted by DCM. The combined organic extracts were passed through a phase separator and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (HCl:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 1-(2-ethyl-6-fluoro-3-(((1R,4R)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (8.1 g) as a glassy solid. 1 H NMR(400MHz,DCM-d2)δ 7.44-7.30(m,3H),7.13-7.00(m,2H),6.99-6.84(m,2H),3.91-3.82(m,2H),3.68(d,J=21.2Hz,3H),3.61-3.51(m,1H),3.42-3.21 (m,5H),2.88-2.48(m,6H),2.06(d,J=12.0Hz,1H),1.97-1.70(m,7H),1.62-1.39(m,4H),1.34-1.20(m,2H),1.19-1.05(m,6H).MS m / z623.3[M+H] + .

[0347] Step b: Methyl 1-(2-ethyl-6-fluoro-3-(((1R,4R)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (8.1 g, 13.0 mmol) was added to methyl 1-(2-ethyl-6-fluoro-3-(((1R,4R)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (8.1 g, 13.0 mmol) in MeOH (50 mL) and THF (25.0 mL) at room temperature, to which 2N NaOH aqueous solution (32.5 mL, 65.0 mmol) was added. The resulting solution was heated to 70°C for 2 hours, and the reaction mixture was concentrated under reduced pressure and then diluted with ELISA (200 mL). The mixture was cooled to 0°C, and 1N HCl aqueous solution (130 mL, 130 mmol) and saturated NaCl aqueous solution (70 mL) were added until the pH reached 2-3. The separated aqueous fraction was extracted with ELISA. The combined organic substances were concentrated under reduced pressure to obtain 1-(2-ethyl-6-fluoro-3-(((1R,4R)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (7.9 g, crude) as a white foaming solid. MS m / z 609.2[M+H] + .

[0348] Step c: 1-(2-ethyl-6-fluoro-3-(((1R,4R)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (7.9 g, 13.0 mmol) in DMF (100 mL) at room temperature was mixed with ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate (3.17 g, 14.3 mmol) and DIPEA (11.3 mL, 64.9 mmol). The resulting mixture was stirred at room temperature for 5 minutes, after which HATU (6.42 g, 16.9 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. Further ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate (0.1 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure and diluted with ethyl(1S,3S,4S)-4-(1-(2-2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (9.4 g) was obtained as a foaming white solid. MS m / z776.3[M+H] + .

[0349] Step d: Ethyl (1S,3S,4S)-4-(1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (9.4 g, 12.1 mmol) was added to 2N NaOH aqueous solution (30.3 mL, 60.6 mmol). The reaction mixture was heated to 70°C for 1 hour, then cooled to room temperature, and directly purified by reverse-phase column chromatography of C18 (CH3CN:H2O (containing 0.1% NH4OH), 0:100~100:0). The desired fractions were combined and freeze-dried to obtain (1S,3S,4S)-4-(1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (sodium salt, 9.3g) as an off-white powder. 1 H NMR(400MHz,DMSO-d6)δ 7.52-7.08(m,7H),6.95(qd,J=9.3,2.3Hz,1H),3.75(dd,J=10.6,5.2Hz,2H),3.56(dtd,J=9.3,6.0,3 MS m / z748.6[M+H] + Potency (μM): Biochemically suitable AC 50 :7.0E-04; NanoBiT Qualified Absolute AC 50 :0.066; Cell proliferation eligible AC 50 :0.024.

[0350] Example 6 (1S,3S,4S)-4-((2S,4S)-1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid [ka] Step a: 2-ethyl-6-fluoro-3-(((1r,4r)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole (0.600 g, 1.67 mmol) in THF (20 mL) at -30°C under N2 was added dropwise to THF (2.50 mL, 2.50 mmol) with 1.0 M LHMDS solution in THF. The reaction mixture was stirred for 10 minutes. Next, 2.0 M AlMe3 solution in toluene (1.34 mL, 2.67 mmol) was added dropwise, and the reaction mixture was stirred for 1 hour. Methyl(2S,4S)-4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)-2-methylpiperidine-4-carboxylate (0.703 g, 2.04 mmol) was added to THF (10 mL), and the reaction mixture was heated to 60°C for 2.5 hours. The reaction mixture was cooled to 0°C and quenched with Rochelle salt solution. The layers were separated, and the aqueous layer was extracted with DCM (3x). The combined organic extracts were passed through a phase separator and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography of C18 (CH3CN:H2O (containing 0.1% NH4OH), 10:90~100:0). The desired fractions were combined and freeze-dried to obtain methyl(2S,4S)-1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (0.696 g) as a glassy solid. MS m / z637[M+H] + .

[0351] Step b: Methyl(2S,4S)-1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (0.696 g, 1.09 mmol) was added to 1N NaOH aqueous solution (10.9 mL, 10.9 mmol) in THF (7.3 mL) and iPrOH (3.6 mL) at 0°C. The reaction mixture was heated to 70°C. MeOH (3 mL) was added, the reaction mixture was cooled to 0°C, and acidified with 1N HCl aqueous solution (12 mL). The reaction mixture was extracted with DCM (3x). The combined organic extracts were passed through a phase separator and concentrated under reduced pressure to obtain (2S,4S)-1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (0.681 g, crude) as an off-white foam. MS m / z623[M+H] + .

[0352] Step c: (2S,4S)-1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (0.681 g, 1.09 mmol) was added to CH3CN (10.9 mL). Ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate (0.291 g, 1.31 mmol), HATU (0.624 g, 1.64 mmol), and DIPEA (1.14 mL, 6.56 mmol) were added. The reaction mixture was stirred overnight at room temperature, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (HCl:heptane, 0:100-100:0). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl(1S,3S,4S)-4-((2S,4S)-1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (740 mg) as a white solid. MS m / z 791.0[M+H] + .

[0353] Step d: Ethyl (1S,3S,4S)-4-((2S,4S)-1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (740 mg, 0.937 mmol) was added to 1N NaOH aqueous solution (4.7 mL, 4.7 mmol). The reaction mixture was stirred at 40°C for 1 hour, and then partially concentrated under reduced pressure to remove the volatile solvent. The resulting mixture was purified by reverse-phase column chromatography using C18(CH3CN:H2O (containing 0.1% NH4OH), 10:90-100:0). The desired fractions were combined and lyophilized to obtain (1S,3S,4S)-4-((2S,4S)-1-(2-ethyl-6-fluoro-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (sodium salt, 0.640 g) as a white powder. 1 H NMR(400MHz,MeOD-d4)δ 7.50-7.08(m,3H),7.05-6.67(m,4H),4.68-4.37(m,1H),3.89-3.66(m,2H),3.66-3.49(m,2H),3.49-3.27 (m,5H),2.92-2.38(m,6H),2.38-2.09(m,1H),2.09-1.21(m,19H),1.21-0.84(m,9H),0.74-0.47(m,3H).C 44 H 57 HRMS for F2N3O6: Calculated mass 762.4288 [M+H] + Mass observation value: 762.4353 [M+H] + Potency (μM): Biochemically suitable AC 50 :9.8E-04; NanoBiT Qualified Absolute AC 50 :0.072; Cell proliferation eligible AC 50:0.023.

[0354] Example 7 (1S,3S,4S)-4-(1-(3-(((1r,4S)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid [ka] Step a: At -40°C under N2, 3-(((1r,4r)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole (3.7 g, 12.8 mmol) in THF (60 mL) was added dropwise to 1.0 M LHMDS solution in toluene (16.0 mL, 16.0 mmol). The reaction mixture was stirred for 10 minutes, and then 2.0 M AlMe3 solution in toluene (7.67 mL, 15.3 mmol) was added dropwise. The reaction mixture was stirred at -40°C for 1 hour. 4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)piperidine-4-carboxylate (5.08 g, 15.3 mmol) in THF (30.7 mL) was added dropwise, and the reaction mixture was stirred for 10 minutes. The condenser was removed, the reaction mixture was heated to 40°C for 1.5 hours, then cooled to 0°C, and quenched with saturated aqueous solution of NaHCO3 (20 mL). The resulting heterogeneous mixture was diluted with DCM (60 mL) at 0°C and vigorously stirred until partition between the white aluminum salt and the organic layer occurred (approximately 10 minutes). The resulting mixture was filtered and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography ( Depositphotos:heptane, 5:95-100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 1-(3-(((1r,4r)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (4.75 g) as a colorless foam. MS m / z 553.5[M+H] + .

[0355] Step b: Methyl 1-(3-(((1r,4r)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (4.75 g, 8.59 mmol) was added to iPrOH (40 mL) and THF (40 mL) at room temperature, to which 1N NaOH aqueous solution (34.4 mL, 34.4 mmol) was added. The reaction mixture was stirred at 60°C for 1.5 hours. Volatile organic substances were partially removed under reduced pressure. The mixture was diluted with CHCl3 (100 mL) and 5% NaCl aqueous solution (100 mL), and then neutralized with formic acid while vigorously stirring. The resulting organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(3-(((1r,4r)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (4.7 g, crude) as an off-white solid. MS m / z 539.6[M+H] + .

[0356] Step c: At room temperature under N2 conditions, 1-(3-(((1r,4r)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (2.9 g, 5.38 mmol) was added to CH3CN (60 mL) and DMF (6 mL). Ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate hydrochloride salt (1.43 g, 6.46 mmol), DIPEA (5.64 mL, 32.3 mmol), and HATU (3.07 g, 8.08 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with ELISA (150 mL) and washed with 5% NaCl aqueous solution (100 mL x 2). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (HCl:heptane, 5:95-100:0). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl(1S,3S,4S)-4-(1-(3-(((1r,4S)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (3.67 g) as a white solid. MS m / z 706.7[M+H] + .

[0357] Step d: Ethyl (1S,3S,4S)-4-(1-(3-(((1r,4S)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (3.67 g, 5.20 mmol) was added to 1N NaOH aqueous solution (31.2 mL, 31.2 mmol) in MeOH (80 mL) and THF (80 mL) at room temperature. The reaction mixture was stirred at 40°C for 24 hours, then cooled to room temperature and neutralized with formic acid. The volatile organic compounds were partially concentrated under reduced pressure, the residual crude was diluted with CHCl3 (150 mL), and washed with 5% NaCl aqueous solution (120 mL). The resulting organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was suspended in EtOH and concentrated under reduced pressure to obtain (1S,3S,4S)-4-(1-(3-(((1r,4S)-4-ethoxycyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (3.50 g) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 12.09(s,1H),7.52-7.29(m,4H),7.25-7.10(m,3H),6.96(qd,J=9.4,2.3Hz,1H),3.80-3.53(m,1H),3.52-3.19(m,8H),3.15(s,1H),2.6 0-2.49(m,2H),2.27(s,3H),2.17-2.09(m,1H),1.99-1.59(m,9H),1.53-1.11(m,3H),1.23-0.97(m,9H),0.61(dd,J=10.6,6.4Hz,3H).MS m / z678.8[M+H] + Potency (μM): Biochemically suitable AC 50 :3.3E-04; NanoBiT Qualified Absolute AC 50 :0.080; Cell proliferation eligible AC 50 :0.096.

[0358] Example 8 (1S,3S,4S)-4-((2S,4S)-1-(3-((trans-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (single trans isomer) [ka] Step a: Trans-3-((5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole (intermediate 25b, 550 mg, 1.89 mmol) in THF (10 mL) at -40°C was met with dropwise addition of 1.0 M LHMDS solution in THF (2.83 mL, 2.83 mmol). The resulting mixture was stirred for 10 minutes, after which 2.0 M AlMe3 solution in toluene (1.51 mL, 3.02 mmol) was added dropwise. The resulting mixture was stirred at -40°C for 40 minutes, and then methyl(2S,4S)-4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)-2-methylpiperidine-4-carboxylate solution (700 mg, 2.03 mmol) in THF (10 mL) was added dropwise. The condenser was removed and the mixture was heated to 70°C for 2 hours. The mixture was cooled to 0°C, quenched with a saturated aqueous solution of Rochelle salt, and extracted with siRNA (50 mL x 3). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl(2S,4S)-1-(3-((trans-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (929 mg) as a beige solid. MS m / z 569[M+H] + .

[0359] Step b: Methyl(2S,4S)-1-(3-((trans-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (0.926 g, 1.63 mmol) was added to 1N NaOH aqueous solution (16.3 mL, 16.3 mmol) in THF (15 mL) and MeOH (5.0 mL) at room temperature. The reaction mixture was heated to 60°C for 5 hours. The reaction mixture was cooled to room temperature, acidified with 1N HCl aqueous solution (24.4 mL, 24.4 mmol), and extracted by DCM. The organic layer was passed through a phase separator and concentrated under reduced pressure to obtain (2S,4S)-1-(3-((trans-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (990 mg, crude) as a beige solid. MS m / z 554[M+H] + .

[0360] Step c: (2S,4S)-1-(3-((trans-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (990 mg, 1.61 mmol) in DCM (20 mL) at room temperature was mixed with ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate (356 mg, 1.61 mmol), HATU (1.36 g, 3.57 mmol), and DIPEA (1.40 mL, 8.03 mmol). The reaction mixture was stirred at room temperature for 1 hour, then partially concentrated and purified by silica gel chromatography (siRNA:heptane, 0:100~60:40). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl(1S,3S,4S)-4-((2S,4S)-1-(3-((trans-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (1.1 g) as a beige solid. MS m / z722[M+H] + .

[0361] Step d: Ethyl (1S,3S,4S)-4-((2S,4S)-1-(3-((trans-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (1.1 g, 1.52 mmol) was added to 1N NaOH aqueous solution (7.62 mL, 7.62 mmol). The reaction mixture was stirred at room temperature for 18 hours, then partially concentrated under reduced pressure and purified by reverse-phase column chromatography of C18 (CH3CN:H2O (containing 0.1% NH4OH), 0:100~30:70). The desired fractions were combined and freeze-dried to obtain (1S,3S,4S)-4-((2S,4S)-1-(3-((trans-5-ethoxytetrahydro-2H-pyran-2-yl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (sodium salt, 988 mg) as a white solid. Note: The absolute stereochemistry of the trans-pyran fragment was not determined. 1 H NMR(400MHz,MeOD-d4)δ 7.47(ddt,J=20.0,11.1,5.5Hz,3H),7.26(d,J=9.9Hz,1H),7.09(td,J=8.7,5.8Hz ,2H),7.05-6.84(m,2H),4.50(d,J=51.6Hz,1H),4.07-3.97(m,1H),3.63-3.46(m, 5H),3.06(t,J=10.4Hz,1H),2.96-2.64(m,4H),2.32(dd,J=9.9,4.0Hz,4H),2.18- 2.03(m,2H),1.88(s,2H),1.74(s,3H),1.49-1.00(m,13H),0.71(m,J=7.7Hz,3H).C 39 H 49 HRMS for F2N3O6: Calculated mass 694.3662 [M+H] + Mass observation value: 694.3706 [M+H] + Potency (μM): Biochemically suitable AC50 :<2.8E-04; NanoBiT Qualified Absolute AC 50 :0.031; Cell proliferation eligible AC 50 :0.015.

[0362] The following compounds in Table 10 were synthesized using the corresponding ketones and the above procedure or a modification thereof. Protonated carboxylates can be obtained directly if formic acid is used to neutralize the crude sodium carboxylate salt before purification.

[0363] [Table 10]

[0364] Example 9 (1S,3S,4S)-4-((2S,4S)-1-(6-fluoro-2-methyl-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid [ka] Step a: 3-(((1r,4r)-4-(benzyloxy)cyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole (1.34 g, 3.82 mmol) in THF (20 mL) was added dropwise to THF (5.10 mL, 5.10 mmol) and the reaction mixture was stirred for 10 minutes. Next, 2.0 M AlMe3 solution in toluene (2.55 mL, 5.10 mmol) was added dropwise and the reaction mixture was stirred for 1 hour. Methyl(2S,4S)-4-(4-fluorophenyl)-1-(1H-imidazole-1-carbonyl)-2-methylpiperidine-4-carboxylate (1.10 g, 3.19 mmol) in THF (6.0 mL) was added and the reaction mixture was heated to 60°C for 3.5 hours. The reaction mixture was cooled to 0°C and quenched with Rochelle salt solution. The resulting mixture was extracted with DCM (25 mL x 3). The combined organic extract was passed through a phase separator and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography of C18 (CH3CN:H2O (containing 0.1% NH4OH), 10:90-100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl(2S,4S)-1-(3-(((1r,4S)-4-(benzyloxy)cyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (1.75 g) as a white foam. MS m / z 629.3 [M+H] + .

[0365] Step b: At room temperature under N2 conditions, methyl(2S,4S)-1-(3-(((1r,4S)-4-(benzyloxy)cyclohexyl)methyl)-6-fluoro-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (1.75 g, 2.79 mmol) was added all at once to SiO2 (30 mL), to which Pd / C (1.48 g, 10 wt%, 1.40 mmol) was added. The reaction mixture was stirred overnight under H2 conditions (1 atm, balloon). The flask was purged with N2 and filtered. Further Pd / C (1.00 g, 10 wt%) was added to the filtrate, and the reaction mixture was stirred under H2 conditions (1 atm, balloon) for 1 hour. The flask was purged with N2 and the reaction mixture was filtered through celite®. The filtrate was concentrated under reduced pressure to obtain methyl(2S,4S)-1-(6-fluoro-3-(((1r,4S)-4-hydroxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (1.50 g, crude) as a white foam. MS m / z 539.2[M+H] + .

[0366] Step c: Methyl(2S,4S)-1-(6-fluoro-3-(((1r,4S)-4-hydroxycyclohexyl)methyl)-2-methyl-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (1.50 g, 2.80 mmol) in DCM (30 mL) at room temperature was mixed with tetrahydro-4H-pyran-4-one (1.30 mL, 13.9 mmol) and Et3SiH (2.23 mL, 13.9 mol). The reaction mixture was placed under N2 and cooled to -78°C, after which TMSOTf (2.27 mL, 12.6 mmol) was added dropwise. The reaction mixture was stirred for 2 minutes, then stirred at 0°C for 1 hour. The reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted with DCM (30 mL x 3). The organic extract was washed with a saturated aqueous solution of NaCl and passed through a phase separator. Celite® was added, and the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl(2S,4S)-1-(6-fluoro-2-methyl-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (2.56 g) as a yellow oil. MS m / z 623.3[M+H] + .

[0367] Step d: Methyl (2S,4S)-1-(6-fluoro-2-methyl-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (1.74 g, 2.79 mmol) in THF (10 mL) and MeOH (10 mL) at room temperature was mixed with 2N NaOH aqueous solution (14.0 mL, 27.9 mmol). The reaction mixture was heated to 70°C for 2 hours, then cooled to room temperature, acidified with aqueous 1N HCl (28 mL), and extracted with DCM (40 mL x 3). The combined organic extracts were passed through a phase separator and concentrated under reduced pressure to obtain (2S,4S)-1-(6-fluoro-2-methyl-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (2.33 g, crude) as a yellow oil. MS m / z 609.3[M+H] + .

[0368] Step e: (2S,4S)-1-(6-fluoro-2-methyl-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (1.70 g, 2.79 mmol) was mixed with ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate (0.742 g, 3.35 mmol), DIPEA (2.43 mL, 14.0 mmol), and HATU (2.12 g, 5.58 mmol). The reaction mixture was stirred overnight at room temperature, and then concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse-phase column chromatography of C18(CH3CN:H2O (containing 0.1% NH4OH), 10:90-100:0). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl(1S,3S,4S)-4-((2S,4S)-1-(6-fluoro-2-methyl-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (1.48 g) as a white foam. MS m / z 776.4[M+H] + .

[0369] Step f: At room temperature under N2 conditions, ethyl (1S,3S,4S)-4-((2S,4S)-1-(6-fluoro-2-methyl-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (1.47 g, 1.9 mmol) was added to 2N NaOH aqueous solution (9.5 mL, 19.0 mmol). The reaction mixture was stirred overnight at room temperature, and then partially concentrated under reduced pressure to remove volatile organic compounds. The resulting mixture was purified by reverse-phase column chromatography using C18 (CH3CN:H2O (containing 0.1% NH4OH), 10:100~100:0). The desired fractions were combined to obtain (1S,3S,4S)-4-((2S,4S)-1-(6-fluoro-2-methyl-3-(((1r,4S)-4-((tetrahydro-2H-pyran-4-yl)oxy)cyclohexyl)methyl)-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (sodium salt, 1.21 g) as a white powder. 1 H NMR(400MHz,MeOD)δ 7.40-7.28(m,3H),7.03-6.75(m,4H),4.39(d,J=58.4Hz,1H),3.78(dt,J= 11.8,4.2Hz,2H),3.56(ttd,J=9.2,4.2,2.2Hz,1H),3.50-3.26(m,5H),2.8 0-2.56(m,2H),2.48(dd,J=7.1,4.1Hz,2H),2.29-2.10(m,4H),2.05-1.55( m,11H),1.55-1.18(m,9H),1.15-0.91(m,6H),0.60(dd,J=8.3,6.4Hz,3H). M.S. m / z748.3[M+H] + Potency (μM): Biochemically suitable AC 50 :4.4E-04; NanoBiT Qualified Absolute AC 50 :0.026; Cell proliferation eligible AC 50 :0.0059.

[0370] Example 10 (1S,3S,4S)-4-((2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (single isomer) [ka] Step a: Methyl(2S,4S)-1-(2-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-1H-indole-1-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate in DCM (40 mL) at -40°C was mixed with tetrahydro-2H-pyran-4-carbaldehyde (1.03 g, 9.04 mmol) and TMSOTf (1.63 mL, 9.04 mmol). The reaction mixture was stirred at -40°C for 1 hour, then removed from the condenser, quenched with saturated aqueous NaHCO3 solution, and stirred for 10 minutes. The resulting mixture was passed through a phase separator and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (siRNA:heptane, 0:100~50:50). The desired fractions were combined and concentrated under reduced pressure to obtain methyl(2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (2.8 g). The sample was further purified using chiral SFC:(S,S)Whelk-O1 21mm x 250mm 5μm (CPC104); flow rate: 80g / min; cosolvent: 25% 3:1 CH3CN:iPrOH (in CO2); detection: 269nm; BPR pressure: 125bar; injection volume: 46mg (23.0mg / mL in CH3CN:iPrOH, 20:1) to obtain methyl(2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate. Peak 1 (first dissolution): 879 mg. Peak 2 (second dissolution): 1.68 g.

[0371] Step b: Methyl(2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylate (peak 1, 879 mg, 1.59 mmol) was added to 1N NaOH aqueous solution (15.9 mL, 15.9 mmol) in THF (15 mL) and iPrOH (7.50 mL) at 0°C. The resulting mixture was stirred for 5 minutes, then warmed to room temperature and stirred for 30 minutes. The reaction mixture was heated to 45°C for 24 hours, and the temperature was increased to 50°C over 30 minutes. The reaction mixture was cooled to 0°C, acidified with 1N HCl aqueous solution (23.9 mL, 23.9 mmol), and extracted by DCM. The organic extract was passed through a phase separator and concentrated under reduced pressure to obtain (2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (857 mg, crude) as a beige solid. MS m / z 539.2[M+H] + .

[0372] Step c: (2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxylic acid (857 mg, 1.59 mmol) in DCM (40 mL) at room temperature was mixed with ethyl (1S,3S,4S)-4-amino-3-methylcyclohexane-1-carboxylate hydrochloride salt (353 mg, 1.59 mmol), HATU (1.21 g, 3.18 mmol), and DIPEA (1.39 mL, 7.96 mmol). The reaction mixture was stirred at room temperature for 2 hours, then partially concentrated under reduced pressure and purified by silica gel chromatography (HCl:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain ethyl(1S,3S,4S)-4-((2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (1.05 g). MS m / z 706.3[M+H] + .

[0373] Step d: At room temperature, ethyl (1S,3S,4S)-4-((2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-4-(4-fluorophenyl)-2-methylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylate (1.05 g, 1.49 mmol) was added to 1N NaOH aqueous solution (14.9 mL, 14.9 mmol). The reaction mixture was stirred at room temperature for 18 hours, and then partially concentrated under reduced pressure (at 40°C). The crude substance was purified by reverse-phase column chromatography of C18(CH3CN:H2O (containing 0.1% NH4OH), 10:90~60:40). The desired fractions were combined, partially concentrated under reduced pressure, and lyophilized to obtain (1S,3S,4S)-4-((2S,4S)-1-(7-fluoro-1-(tetrahydro-2H-pyran-4-yl)-1,3,4,5-tetrahydropyrano[4,3-b]indole-5-carbonyl)-2-methyl-4-phenylpiperidine-4-carboxamide)-3-methylcyclohexane-1-carboxylic acid (sodium salt, 879 mg) as a white solid. 1 H NMR(400MHz,MeOD-d4)δ 7.58-7.51(m,1H),7.50-7.41(m,2H),7.25(t,J=8.9Hz,1H),7.17-7.04(m,3H),6.96(tdd,J=9.0,6.6,2.4Hz,1H),4.8 5(s,1H),4.44(d,J=48.7Hz,1H),4.31-4.16(m,1H),4.04(dd,J=11.3,4.3Hz,1H),3.88(d,J=11.3Hz,1H),3.76(dtd,J =14.1,10.4,4.1Hz,1H),3.66-3.45(m,3H),2.82(ddt,J=58.7,42.4,14.1Hz,5H),2.54-2.18(m,2H),2.16-1.96(m,2H ),1.94-1.64(m,5H),1.56(qd,J=12.7,4.7Hz,1H),1.49-1.29(m,5H),1.26-0.97(m,4H),0.72(dd,J=6.4,5.0Hz,3H).C 38 H44 HRMS for F2N3O6: Calculated mass 678.3349 [M+H] + Mass observed: 678.3339 [M+H] + Potency (μM): Biochemically suitable AC 50 :<2.8E-04; NanoBiT Qualified Absolute AC 50 :0.28; Cell proliferation eligible AC 50 :0.040.

[0374] The following compounds in Table 11 were synthesized using the corresponding aldehydes and the above procedure or a modification thereof. Protonated carboxylates can be obtained directly if formic acid is used to neutralize the crude sodium carboxylate salt before purification.

[0375] [Table 11-1]

[0376] [Table 11-2]

[0377] Example 11 (R)-1-(5-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)-N-(1-methylpyrrolidine-3-yl)piperidine-4-carboxamide [ka] Step a: Methyl 4-(4-fluorophenyl)piperidine-4-carboxylate hydrochloride salt (3.72 g, 13.6 mmol) was added to DCM (50 mL) at room temperature, along with HATU (7.76 g, 20.4 mmol), 5-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid (4.60 g, 13.6 mmol), and DIPEA (8.79 g, 68.0 mmol). The reaction mixture was stirred at room temperature for 4 hours, then diluted with HCl (1.0 L) and washed with H2O (500 mL) and saturated aqueous NaCl solution (500 mL x 2). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (petroleum ether: HCl, 50:50~0:100). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 1-(5-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (5.0 g) as an off-white solid. MS m / z 559.1[M+H] + .

[0378] Step b: At room temperature, methyl 1-(5-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (4.80 g, 8.61 mmol) was added all at once to MeOH (15.0 mL), H2O (3.00 mL), and THF (30.0 mL). NaOH (689 mg, 17.2 mmol) was added all at once. The mixture was stirred at 50°C for 7 hours. The solvent was concentrated under reduced pressure, and then THF (100 mL) was added. The reaction mixture was concentrated again under reduced pressure. Finally, 4.0 M HCl in 1,4-dioxane (20 mL) was added to the residue, and the resulting mixture was concentrated under reduced pressure to obtain 1-[5-bromo-1-(tetrahydropyran-4-ylmethyl)indole-3-carbonyl]-4-(4-fluorophenyl)piperidine-4-carboxylic acid (6.00 g, crude) as a white solid. MS m / z 543.1 [M+H] + .

[0379] Step c: 1.25 g, 2.30 mmol of 1-[5-bromo-1-(tetrahydropyran-4-ylmethyl)indole-3-carbonyl]-4-(4-fluorophenyl)piperidine-4-carboxylic acid (1.25 g, 4.03 mmol) was added to 20 mL of DCM under N2, and the reaction mixture was stirred for 5 minutes. Next, (3R)-1-methylpyrrolidine-3-amine (0.230 g, 2.30 mmol) in 3 mL of DCM, followed by DIPEA (1.61 mL, 9.20 mmol), was slowly added to the reaction mixture. The reaction mixture was stirred overnight, then diluted with 10 mL of H2O and stirred for 1 hour. The organic phase was separated, and the aqueous layer was extracted with DCM. The combined organic extract was washed with saturated aqueous solution of NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (DCM:MeOH, 0:100~15:85). The desired fraction was concentrated under reduced pressure. EtOH (10 mL) was added, and the mixture was concentrated again under reduced pressure. Finally, the substance was dissolved in EtOH (10 mL), concentrated under reduced pressure until almost dry, and diluted with H2O and CH3CN. The substance was freeze-dried to obtain (R)-1-(5-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)-N-(1-methylpyrrolidine-3-yl)piperidine-4-carboxamide (870 mg) as a white solid. 1H NMR(400MHz,MeOD-d4)δ 7.86(d,J=1.8Hz,1H),7.69(s,1H),7.51-7.42(m,3H),7.37(dd,J=8.8,1.9Hz,1H),7.15-7.08(m,2H),4 .40(tt,J=9.4,4.8Hz,1H),4.15(d,J=7.3Hz,4H),3.93(dd,J=11.6,2.5Hz,2H),3.59-3.44(m,2H),3.41- 3.34(m,2H),2.85(dd,J=10.1,7.5Hz,2H),2.57(d,J=9.9Hz,4H),2.43(s,3H),2.28(ddd,J=17.1,8.5,4. MS m / z625.2[M+H] + Potency (μM): Biochemically suitable AC 50 :1.8E-02; NanoBiT Qualified Absolute AC 50 :4.9; Cell proliferation eligible AC 50 :2.7.

[0380] The compounds listed in Table 11 were synthesized using the above procedure or a modification thereof, with the corresponding functionalized piperidine, indole intermediate, and amine. Where an acid was present in the final structure, saponification of the corresponding ethyl ester was carried out in the final step. Protonated acids can be obtained directly if formic acid is used to neutralize the crude sodium carboxylate salt before purification.

[0381] [Table 12-1]

[0382] [Table 12-2]

[0383] [Table 12-3]

[0384] [Table 12-4]

[0385] Example 12 1-(5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-N-((3S,4R)-4-fluoro-1-methylpyrrolidine-3-yl)-4-(4-fluorophenyl)piperidine-4-carboxamide [ka] Step a: Methyl 4-(4-fluorophenyl)piperidine-4-carboxylate (3.40 g, 14.3 mmol) in DCM (54.6 mL) at room temperature was mixed with 5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid (4.20 g, 13.7 mmol), EDC (4.71 g, 24.6 mmol), and 1-hydroxy-7-azabenzotriazole (3.71 g, 27.3 mmol). After stirring for 30 minutes, DIPEA (11.9 mL, 68.2 mmol) was added, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with HCl (300 mL) and washed with saturated aqueous solution of NaHCO3 (150 mL), H2O (150 mL), and saturated aqueous solution of NaCl (150 mL). A single aqueous layer was extracted with HCl (150 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (MeOH:DCM, 0:100~5:95). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 1-(5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (6.12 g) as a foam. MS m / z 527.3[M+H] + .

[0386] Step b: At room temperature, NaOH (4.32 g, 108 mmol) was added to methyl 1-(5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (6.12 g, 10.8 mmol) in THF (24.7 mL), MeOH (12.3 mL), and H2O (6.17 mL). The reaction mixture was stirred at 50 °C for 18 hours, and then partially concentrated. The oily residue was diluted with H2O (50 mL) and subsequently treated with 5N HCl aqueous solution to adjust the pH to approximately 1. The resulting emulsion suspension was diluted with ELISA (100 mL), the layers were separated, and the aqueous layer was extracted with ELISA (100 mL). The combined organic extracts were dried and concentrated under reduced pressure to obtain 1-(5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (5.50 g, crude) as a solid cream. MS m / z 513.2[M+H] + .

[0387] Step c: 1-(5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (800 mg, 1.56 mmol) in DCM (15.6 mL) at room temperature was mixed with (3S,4R)-4-fluoro-1-methylpyrrolidine-3-amine hydrochloride salt (358 mg, 1.871 mmol), HATU (1.19 g, 3.12 mmol), and DIPEA (1.36 mL, 7.80 mmol). The reaction mixture was stirred overnight at room temperature, then diluted with DCM (20 mL) and washed with saturated aqueous solutions of H2O and NaCl. The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (MeOH:DCM, 0:100~10:90). The desired fractions were combined and concentrated under reduced pressure. The resulting substance was dissolved in CH3CN / H2O (1 / 3, 80 mL), lyophilized, and 1-(5-chloro-2-methyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-N-((3S,4R)-4-fluoro-1-methylpyrrolidine-3-yl)-4-(4-fluorophenyl)piperidine-4-carboxamide (750 mg) was obtained as a white solid. 1 H NMR(400MHz,MeOD-d4)δ 7.53-7.32(m,4H),7.21-7.02(m,3H),5.25-4.97(m,1H),4.59-4.20(m,2H),4.10(d,J=7.3Hz,2H),3.94(d,J=11.7Hz,2H),3.8 3-3.37(m,5H),3.05-2.73(m,3H),2.57(dd,J=55.0,6.4Hz,6H),2.38(d,J=3.8Hz,3H),2.26-1.67(m,3H),1.59-1.40(m,4H).C 33 H 40 HRMS for ClF2N4O3: Mass calculation value 613.2757 [M+H] + Mass observation value: 613.2784 [M+H] + Potency (μM): Biochemically suitable AC 50 :1.3E-03; NanoBiT Qualified Absolute AC50 :0.35; Cell proliferation eligible AC 50 :0.27.

[0388] Example 13 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-N-((3S,4R)-4-fluoro-1-methylpyrrolidine-3-yl)-4-(4-fluorophenyl)piperidine-4-carboxamide [ka] Step a: Methyl 4-(4-fluorophenyl)piperidine-4-carboxylate (2.63 g, 11.1 mmol), HOAt (2.51 g, 18.5 mmol), and EDC (3.19 g, 16.6 mmol) were added to 5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid in DCM (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 45 minutes, then DIPEA (8.06 mL, 46.2 mmol) was added and stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The aqueous phase was extracted with ethyl acetate, the combined organic matter was washed with saturated aqueous NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (ethyl acetate:heptane, 0:100~100:0). The desired fractions were combined and concentrated under reduced pressure to obtain methyl 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (4.66 g) as a solid. 1H NMR(400MHz,DMSO-d6)δ 9.97(s,1H),7.85(d,J=9.1Hz,1H),7.73(d,J=2.0Hz,1H),7.50-7.33(m,3H),7.20(t,J=8.6Hz,2H),4.48 (d,J=7.2Hz,2H),3.80(d,J=11.3Hz,2H),3.63(s,3H),3.36-3.09(m,9H),1.99(s,2H),1.44-1.23(m,4H).

[0389] Step b: Methyl 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (4.41 g, 8.15 mmol) was added to 1N NaOH aqueous solution (20.4 mL, 20.4 mmol) in THF (28 mL) and MeOH (14 mL) at room temperature. The reaction mixture was stirred overnight at room temperature, followed by stirring at 50°C for 1.5 hours. The reaction mixture was partially concentrated under reduced pressure. The residue was diluted with H2O and then treated with 1N HCl aqueous solution until pH 1 was reached. The suspension was diluted with ELISA and the layers were separated. The aqueous layer was extracted with ELISA. The combined organic extracts were washed with saturated NaCl aqueous solution, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (4.17 g, crude). 1 H NMR(400MHz,DMSO-d6)δ 12.74(s,1H),9.97(s,1H),7.84(d,J=9.1Hz,1H),7.74(d,J=10.0Hz,1H),7.49-7.38(m,3H),7.19(t,J=8.7Hz,2H),4.48(d,J=7. 2Hz,3H),3.87-3.68(m,2H),3.45(s,1H),3.27-3.08(m,5H),2.33(p,J=1.9Hz,1H),1.99(s,2H),1.75(s,1H),1.46-1.22(m,4H).

[0390] Step c: At room temperature, 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (3.29 g, 6.24 mmol) was added to DCM (62.4 mL) with (3S,4R)-4-fluoro-1-methylpyrrolidine-3-amine hydrochloride salt (1.31 g, 6.87 mmol) and HATU (4.75 g, 12.5 mmol). The reaction mixture was stirred at room temperature for 15 minutes, after which DIPEA (4.36 mL, 25.0 mmol) was added. The reaction mixture was stirred at room temperature for 2.5 hours, the resulting mixture was diluted with DCM and washed with H2O, saturated aqueous solution of Na2CO3 (3x), and saturated aqueous solution of NaCl. The combined organic extract was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel chromatography (MeOH:DCM, 0:100~20:80). The desired fractions were combined and concentrated under reduced pressure. The resulting solid was dissolved in ethyl acetate and washed with saturated aqueous solution of Na2CO3 (3x). The combined organic matter was dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was dissolved in CH3CN:H2O (50:50) and freeze-dried. This substance was purified by reverse-phase column chromatography of C18 (CH3CN:H2O, 0:100~90:10). The desired fraction was concentrated under reduced pressure, CH3CN was removed, and then the mixture was partitioned between ethyl acetate and H2O. The aqueous phase was washed with ethyl acetate, and the combined organic matter was washed with saturated aqueous solution of NaCl, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained substance was dissolved in DCM / MeOH and concentrated under reduced pressure to obtain 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-N-((3S,4R)-4-fluoro-1-methylpyrrolidine-3-yl)-4-(4-fluorophenyl)piperidine-4-carboxamide (2.33 g) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 9.97(s,1H),7.85(d,J=9.1Hz,1H),7.64(m,2H),7.46(dd,J=9.0,2.1Hz,1H),7.40(s,2H) ,7.16(t,J=8.6Hz,2H),5.00(d,J=63.0Hz,1H),4.47(d,J=7.2Hz,2H),4.40-4.11(m,2H), 3.80(d,J=11.1Hz,2H),3.41(s,1H),3.27-3.08(m,4H),3.01-2.83(m,1H),2.72-2.51(m, 4H),2.49-2.35(m,1H),2.23(s,3H),2.12-1.87(m,2H),1.71(s,1H),1.41-1.22(m,4H).C 33 H 38 HRMS for ClF2N4O4: Mass calculation value 627.2550 [M+H] + Mass measurement: 627.2566 [M+H] + Potency (μM): Biochemically suitable AC 50 :4.8E-04; NanoBiT Qualified Absolute AC 50 :0.056; Cell proliferation eligible AC 50 :0.054.

[0391] Example 14 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)-N-((3S,4R)-4-fluoropyrrolidine-3-yl)piperidine-4-carboxamide [ka] Step a: 150 mg, 0.285 mmol of 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (150 mg, 0.285 mmol) was added to DCM (1.42 mL) at room temperature, along with (3S,4R)-tert-butyl 3-amino-4-fluoropyrrolidine-1-carboxylate (87 mg, 0.427 mmol), HOAT (77 mg, 0.569 mmol), and EDC (82 mg, 0.427 mmol). The reaction mixture was stirred at room temperature for 2 minutes, then DIPEA (249 μL, 1.42 mmol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, adsorbed onto silica gel, and concentrated under reduced pressure until dry. The crude product was purified by silica gel chromatography (siRNA:heptane, 0:100-100:0, followed by MeOH:DCM, 0:100-20:80). The desired fractions were combined and concentrated under reduced pressure to obtain tert-butyl(3S,4R)-3-(1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-4-fluoropyrrolidine-1-carboxylate (155 mg) as a yellow foamy solid. MS m / z 713.0[M+H] + .

[0392] Step b: At 0°C, tert-butyl(3S,4R)-3-(1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)-4-fluoropyrrolidine-1-carboxylate (24 mg, 0.034 mmol) was added to DCM (500 μL) with TFA (51.9 μL, 0.673 mmol). The reaction mixture was stirred at room temperature for 5 hours, then diluted with CH3CN (1 mL), filtered, and purified by reverse-phase HPLC (CH3CN:H2O (containing 0.1% formic acid), 25:75~50:50). The desired fraction was combined with a substance from another batch and freeze-dried together to obtain 1-(5-chloro-2-formyl-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)-N-((3S,4R)-4-fluoropyrrolidine-3-yl)piperidine-4-carboxamide (33 mg) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ 9.97(s,1H),7.85(d,J=9.1Hz,1H),7.79-7.58(m,2H),7.57-7.30(m,3H),7.28-7.08(m,2H),5.06(d,J=55.2Hz,1H),4.58-4.11(m,4H) C 32 H 36 HRMS for ClF2N4O4: Calculated mass 613.2388 [M+H] + Mass observed: 613.2362 [M+H] + Potency (μM): Biologically Qualified AC 50 :4.8E-04; Cell proliferation eligible AC 50 :0.12.

[0393] Example 15 1-(6-((R)-3-(1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)pyrrolidine-1-yl)-6-oxohexyl)-3,3-dimethyl-5-sulfo-2-((1E,3E)-5-((E)-1,3,3-trimethyl-5-sulfoindoline-2-ylidene)penta-1,3-dien-1-yl)-3H-indole-1-ium [ka] Step a: Methyl 5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (2.50 g, 8.12 mmol) was added to methyl 5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylate (2.50 g, 8.12 mmol) in THF (13.5 mL) and MeOH (6.75 mL) at room temperature. The reaction mixture was stirred to homogenize it, then equally divided into two vials and heated each at 50°C overnight. The reaction mixtures were combined and concentrated under reduced pressure. The resulting substance was diluted with H2O, washed with DCM, and the organic layer was extracted with H2O. The combined aqueous layer was acidified with 1N HCl aqueous solution, then extracted with DCM (50 mL) and siRNA (50 mL x 2). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was suspended in DCM, sonicated, and concentrated under reduced pressure. Next, the obtained substance was suspended in Et2O, sonicated, and recovered by filtration. This solid was washed with Et2O(2x) and dried to obtain 5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid (1.95 g, crude) as a white solid. 1H NMR(400MHz,DMSO-d6)δ 12.19(s,1H),8.12(s,1H),7.97(d,J=2.2Hz,1H),7.69(d,J=8.8Hz,1H),7.25(dd,J=8.8,2.2Hz,1H),4.16 (d,J=7.3Hz,2H),3.89-3.72(m,2H),3.19(td,J=11.4,2.9Hz,2H),2.14-2.00(m,1H),1.40-1.21(m,4H).MS m / z 294.0 [M+H] + .

[0394] Step b: At room temperature, 5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carboxylic acid (1.00 g, 3.40 mmol) was added to DCM (17 mL), to which EDC (979 mg, 5.11 mmol) and HOAT (927 mg, 6.81 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes, then methyl 4-(4-fluorophenyl)piperidine-4-carboxylate (889 mg, 3.74 mmol) was added, and the mixture was stirred for another 10 minutes. DIPEA (2.97 mL, 17.0 mmol) was added to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was added to a saturated aqueous solution of NaHCO3 and extracted with DCM (50 mL x 2). The combined organic extract was dried over MgSO4, filtered, adsorbed onto silica gel, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel chromatography (siRNA:heptane, 40:60-100:0). The desired fractions were combined and concentrated under reduced pressure. The substance was sonicated with MeOH (7.5 mL), at which point it became a white solid. The organic solvent was removed under reduced pressure to obtain methyl 1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (1.50 g, crude). 1H NMR(400MHz,MeOD-d4)δ 7.78-7.64(m,2H),7.53(d,J=8.8Hz,1H),7.50-7.42(m,2H),7.24(dd,J =8.8,2.1Hz,1H),7.17-7.04(m,2H),4.29(d,J=13.6Hz,2H),4.15(d,J=7 .3Hz,2H),3.99-3.89(m,2H),3.72(s,3H),3.46-3.34(m,4H),2.64(d,J= 13.5Hz,2H),2.22-2.10(m,1H),2.06-1.93(m,2H),1.54-1.35(m,4H).MS m / z 513.0 [M+H] + .

[0395] Step c: Methyl 1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (500 mg, 0.975 mmol) was added to methyl 1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylate (500 mg, 0.975 mmol) in THF (2.44 mL) and MeOH (244 mL) at room temperature. The reaction mixture was heated to 50°C for approximately 3 days, then acidified to pH 2 with 1N HCl aqueous solution and extracted with ELISA (50 mL x 3). The combined organic extract was dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (561 mg, crude). MS m / z499.0[M+H] + .

[0396] Step d: 1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxylic acid (486 mg, 0.974 mmol) in DCM (4.87 mL) at room temperature was mixed with (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (327 mg, 1.75 mmol), HOAT (265 mg, 1.95 mmol), and EDC (280 mg, 1.46 mmol). The reaction mixture was stirred at room temperature for 2 minutes, then DIPEA (851 μL, 4.87 mmol) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM, adsorbed onto silica gel, and evaporated to dryness. The crude product was purified by silica gel chromatography (MeOH:DCM, 0:100~10:90). The desired fractions were combined and concentrated under reduced pressure to obtain tert-butyl(R)-3-(1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)pyrrolidine-1-carboxylate (640 mg). MS m / z 667.0 [M+H] + .

[0397] Step e: At room temperature, tert-butyl(R)-3-(1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)pyrrolidine-1-carboxylate (640 mg, 0.959 mmol) was added to 1,4-dioxane (6.0 mL, 24.0 mmol) in 4 M HCl solution. The reaction mixture was stirred overnight at room temperature, and then concentrated under reduced pressure to obtain a brown oil. Et2O was added to the oil, and the mixture was concentrated under reduced pressure. DCM was added to the residue, and the mixture was concentrated under reduced pressure (2x) to obtain (R)-1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)-N-(pyrrolidine-3-yl)piperidine-4-carboxamide hydrochloride salt (658 mg, crude) as a light brown solid. MS m / z 565.3 [MH] - .

[0398] Step f: At room temperature, (R)-1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)-N-(pyrrolidine-3-yl)piperidine-4-carboxamide hydrochloride salt (6.4 mg, 10.6 μmol) is mixed with 1-(6-((2,5-dioxopyrrolidine-1-yl)oxy)-6-oxohexyl)-3,3-dimethyl-2-((1E,3E,5E)-5-(1,3,3-trimethyl-5-sulfonatoindolin-2-ylidene)penta-1,3-dien-1-yl)-3H-indole-1-ium-5-sulfonate potassium (sulfocyanine 5NHS ester, Lumiprobe, CAS# 2230212-27-6 (7 mg, 9.0 μmol) and DIPEA (18.5 μL, 0.106 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours while protected from light. The reaction mixture was diluted with MeOH (1 mL), filtered, and purified by reverse-phase HPLC (CH3CN:H2O (containing 0.1% formic acid), 25:75~50:50). The desired fractions were combined, lyophilized, and the resulting substance was purified again under the same conditions. The desired fractions were combined and freeze-dried to obtain 1-(6-((R)-3-(1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)pyrrolidine-1-yl)-6-oxohexyl)-3,3-dimethyl-5-sulfo-2-((1E,3E)-5-((E)-1,3,3-trimethyl-5-sulfoindoline-2-ylidene)penta-1,3-dien-1-yl)-3H-indole-1-ium (1.3 mg) as a brownish-blue powder. 1H NMR(400MHz,DMSO-d6)δ 8.36(t,J=13.1Hz,2H),7.87(d,J=2.6Hz,1H),7.84-7.75(m,3H),7.71(d,J=2.1Hz,1H),7.69-7.57(m,3H),7.39(ddd,J=9 .0,5.4,2.0Hz,2H),7.36-7.27(m,2H),7.24-7.11(m,3H),6.58(s,2H),6.29(dd,J=19.8,13.9Hz,2H),4.34-4.00(m,6H), 3.80(d,J=11.1Hz,2H),3.59(s,3H),3.48-3.39(m,1H),3.33(s,5H),3.19(dd,J=12.9,10.0Hz,4H),3.10-2.95(m,1H),2. 63-2.55(m,2H),2.23-1.93(m,4H),1.81(d,J=13.6Hz,3H),1.68(t,J=2.2Hz,12H),1.56-1.41(m,2H),1.41-1.17(m,7H). C 63 H 73 ClFN6O 10 HRMS for S2: Mass calculation value 1191.4497 [M] + Mass observation value: 1191.4431 [M] + .

[0399] Assay The practical applications of the compounds of the present invention described herein can be demonstrated by testing in the following assays. The titer is determined by a biochemical assay (eligible AC). 50 -Example 16) NanoBiT assay (qualified absolute AC 50 -Example 17), and cell proliferation assay (qualified ACAC 50 -This is demonstrated using Example 18). The compounds of the present invention are WM793 BRAF in nude mice and nude rats. V600E The antitumor activity and tolerability of tumor xenografts will be further investigated.

[0400] Biochemical assay The competitive assay was performed at room temperature in a 384-well white polystyrene flat-bottom plate (Greiner #784075) using a final reaction volume of 15 μL and the following assay buffer conditions: 50 mM MOPS, pH 7.2, 10 mM MgCl2, 0.5 mM TCEP, 0.01% Triton-X-100. 75 nL of a 10 mM compound solution in DMSO or 100% DMSO (12-stop titration, final concentration: 50 μM-300 pM; final DMSO: 0.5%) was titrated using an acoustic liquid handler (Echo, Beckman). Using a Coulter, add 7.5 μL of 1-(6-((R)-3-(1-(5-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-indole-3-carbonyl)-4-(4-fluorophenyl)piperidine-4-carboxamide)pyrrolidine-1-yl)-6-oxohexyl)-3,3-dimethyl-5-sulfo-2-((1E,3E)-5-((E)-1,3,3-trimethyl-5-sulfoindoline-2-ylidene)penta-1,3-dien-1-yl)-3H-indole-1-ium (Example 15) to a well; add 7.5 μL of 400 pM SA-Tb (Cisbio, 610SATLB) and 400 pM ERK2[2-360(p-T185 / p-Y187)]-Avi was added to a plate and incubated overnight at room temperature. HTRF signals were measured at excitation and emission wavelengths of 665 and 620 nm, respectively, using a microplate reader (PheraStar, BMG Labtech). Inhibitor dose-response curves were normalized using control-based normalization IC50. 50 The HTRF ratio signal was analyzed using regression curve fitting.

[0401] NanoBiT assay Cancer cell culture medium was prepared by adding 500 mL of RPMI (ThermoFisher catalog ##22400-089) for WM793 cells (ATCC catalog #CRL-2806, RRID:CVCL_8787) and F12K (Thermo Fisher catalog #21127-022, 500 mL; or 21127-030, 10 × 500 mL) and 10% FBS for 10% fetal bovine serum (Gibco) + PC3 (ATCC CRL-1435) cells. The entire medium, including supplements, was filtered and sterilized through a 0.4 μm bottle-top filter system. Cancer cell lines were detached from conventional cell culture flasks by washing three times with 1 × PBS, and a thin layer was formed on the cells by adding an appropriate amount of 0.25% TrypLE® Express enzyme (1 ×), phenol red-free (ThermoFisher catalog #12604013). The trypsin was neutralized with a culture medium containing serum, and then the cells were counted.

[0402] Nanobit stable cell lines were generated using WM793 cells containing nanobit-large-bit-ERK2 and nanobit-small-bit-PEA15. The cell solution concentration was set to 62.5 x 10⁻⁶. 5Cells were prepared and seeded into 384-well tissue culture-treated plates (Greiner) with a total of 5000 cells per well in 30 μL of phenol red-free RPMI1640 (ThermoFisher catalog #11835-030, 500 mL; or 11835-055, 10 × 500 mL) + 10% FBS + puromycin (1 μg / mL) + hygromycin (100 μg / mL) and MT cell viability substrate (Promega #G9711 at final dilution, final dilution at 1:3000). Cells were seeded in a biological safety cabinet using a sterile small stainless steel tip cassette on a Multi-Drop Combi. Between different cell lines, the cassette tubes were flushed with 1 × sterile PBS for 10 seconds. Alternatively, depending on the required plate volume per cell line, cells can be seeded using a Multi-Flow system located in a Hepa filtration robotic room, using either a sterile miniature sapphire jewel-tipped cassette and a peristaltic pump or an attached syringe pump. The plates were placed in an incubator set to 37°C with 5% CO2 and 95% relative humidity. Ten-point, 3-fold serial dilutions of the compound were prepared in 100% DMSO on a liquid handling robot to a maximum concentration of 10 mM. 90 nL / well was dispensed into three assay plates / one compound source plate, with a maximum concentration of 30 μM. After compound addition was complete, the plates were placed overnight in an incubator set to 37°C with 5% CO2 and 95% relative humidity. Luminescence was captured using a plate illuminometer such as Envision or View Lux, and measured at day 0 for both selected cell lines. The PheraStar reader was used with LUM plus, gain 3500, 0.1s, and focal height 12.5 mm. Raw data was extracted from the instrument, and all fields containing the test compound were normalized to the mean of all wells containing only DMSO as a neutral control. From this value, the growth inhibition percentage was calculated for each compound. The normalized data values ​​against compound concentration were graphed using either GraphPad® or Excel Fit to obtain dose-response curves and inhibitory IC scores. 50I created it.

[0403] Cell proliferation assay After counting the cells, the cell solution concentration was adjusted, and a total of 750 cells per well were seeded in 50 μL of complete medium in a 384-well tissue culture processing plate. Cells were seeded using a sterile miniature stainless steel tip cassette on a Multi-Drop Combi in a biological safety cabinet. Between different cell lines, the cassette tubes were flushed with 1× sterile PBS for 10 seconds. Alternatively, depending on the required plate volume per cell line, cells could be seeded using a Multi-Flow located in a Hepa filtration robot room, using either a sterile miniature sapphire jewel tip cassette and either a peristaltic pump or an attached syringe pump. The plates were placed in an incubator set to 37°C with 5% CO2 and 95% relative humidity. Ten point, 3-fold serial dilutions of the compound in 100% DMSO were prepared at a maximum concentration of 10 mM on a liquid handling robot. Three assay plates were prepared, with 100 nL / well of one compound dispensed into the source plate, resulting in a maximum concentration of 20 μM. After compound addition was complete, the plates were placed in an incubator set to 37°C with 5% CO2 and 95% relative humidity for 3 days. A sufficient volume of CellTiter-Glo® (Promega #G7571) detection reagent was pre-warmed at room temperature or in an H2O bath at 37°C. 25 μL of reagent was added to each well using either Multi-Drop Combi or MultiFlo, and incubated at room temperature for at least 15 minutes. Luminescence was captured using a plate illuminometer such as Envision or View Lux, and measured at day 0 for both selected cell lines. PheraStar reader settings were LUM plus, gain 3500, 0.1 s, focal height 12.5 mm. On day 3, a sufficient volume of CellTiter-Glo® detection reagent was pre-warmed at room temperature or in an H2O bath at 37°C. A total of 25 μL of reagent was added to each well using either Multi-Drop Combi or MultiFlo, and incubated at room temperature for at least 15 minutes. Luminescence was captured using a plate illuminometer such as Envision or View Lux, and measured at day 3 for both selected cell lines.The PheraStar reader was set to LUM plus, gain 3500, 0.1s, and focal height 12.5 mm. Raw data was extracted from the instrument and normalized all fields containing the test compound to the mean value of all wells containing only DMSO from day 3 onwards as a neutral control, and to the starting value on day 0. From these values, the growth inhibition percentage for each compound was calculated. The normalized data values ​​against compound concentration were graphed using a program such as GraphPad® or Excel Fit to obtain dose-response curves and growth inhibition ICs. 50 I created it.

[0404] WM793 BRAF in nude mice V600E Antitumor activity and tolerability of tumor xenografts. SCID beige female mice (Charles River, 8-9 weeks old) were adapted to the animal facility and administered 20-40 mg of WM793 from previous generations using sterilization techniques under isoflurane anesthesia in a 10-gauge trocar (n=8 / group). V600E A tumor fragment was subcutaneously transplanted to the right flank. Body weight was monitored at least once a week and calculated as (BWcurrent-BWinitial) / (BWinitial)×100%. Tumor volume was monitored at least once a week by caliper measurement 1-3 weeks after the onset of a palpable tumor. Tumor volume (mm 3 The tumor size (200-250 mm) was calculated as (length × width × width) / 2. Mice were randomized, and tumor size (200-250 mm) was determined. 3 Animals were selected for the study based on their health condition and other factors. Compound I of formula 1, formulated in 0.1% Tween80 + 0.5% MC at concentrations of 3, 7.5, 15, and 30 mg / mL, was administered at a rate of 10 mL / kg per OS. Animals were selected based on their poor health condition and 1500 mm 3 Euthanasia was performed based on tumor volume exceeding a certain threshold or reaching the end of the trial. T / C% was calculated as 100 × ΔT / ΔC if ΔT > 0, where ΔT is the change in tumor volume after drug treatment and ΔC is the change in tumor volume in the vehicle control group. Regression% was calculated as 100 × ΔT / Tinal if ΔT < 0, where ΔT is the change in tumor volume.

[0405] Figure 1 shows WM793 BRAF in nude mice. V600E This shows the antitumor activity and tolerability of Example 13, a tumor xenograft. A) When Example 13 was administered to mice with tumors at 30 mg / kg twice daily (orange line), 75 mg / kg twice daily (blue line), 150 mg / kg twice daily (red line), and 300 mg / kg twice daily for 2 days followed by a 1-day rest period (green line) for 14 days, dose-dependent antitumor activity was obtained, and tumor regression was achieved at the highest dose. B) From the percentage change in body weight after the first dose, Example 13 was shown to have minimal weight loss and high tolerability. One mouse in the highest dose group was sacrificed on day 11 due to increased weight loss.

[0406] WM793 BRAF in Nude Rat V600E Antitumor activity and tolerability of tumor xenografts. Female RNU rats (Charles River, 4-5 weeks old) were acclimated to the animal facility and pretreated with 100 mg / kg cyclophosphamide IP at 10 mL / kg 24 hours prior to tumor transplantation. Nude rats were subjected to WM793 from previous generations using sterilization techniques under isoflurane anesthesia in 10-gauge trocars (n=4 / group). V600E Tumor fragments (20-40 mg) were subcutaneously transplanted into the right flank. Body weight was monitored at least once a week and calculated as (BWcurrent-BWinitial) / (BWinitial) × 100%. Tumor volume was monitored at least once a week by caliper measurement 1-3 weeks after the onset of a palpable tumor. Tumor volume (mm 3 The tumor size was calculated as (length × width × width) / 2. Rats were randomized, and tumor size (100-200 mm) was used. 3 Animals were selected for the study based on their health condition and other factors. They were administered a compound of formula I, formulated as either 20% HPBCD (5 mg / mL) or 20% HPBCD (2.5 mg / mL), at a rate of 10 mL / kg per 1 os. Animals with poor health conditions were selected, and were 2500 mm 3Euthanasia was performed based on tumor volume exceeding a certain threshold or reaching the end of the trial. The regression percentage was calculated as 100 × ΔT / Tinial if ΔT < 0, where ΔT is the change in tumor volume.

[0407] Figure 2 shows WM793 BRAF in nude rats. V600E The antitumor activity and tolerability of tumor xenografts in Examples 5 and 4 are shown. A) When Example 5 was administered to rats with tumors at a dose of 50 mg / kg twice daily for 22 days (red line), tumor regression was observed, and this was maintained even after a 2-day rest period (administered at 50 mg / kg twice daily for 5 days with a 2-day rest period - orange line). Similarly, treatment of rats with tumors with Example 4 for 22 days resulted in regression (blue line). B) The percentage change in body weight after the first dose indicates that all compounds were well tolerated.

Claims

1. Equation (I): 【Chemistry 1】 [In the formula, X is N and CR ６ (In the formula, R ６ (Selected from hydrogen and halo); R １ This is selected from hydrogen and halo; R ２ is, -X １ -R ２ａ and R ２ａ Selected from; X １ is C １ to C ４ alkylene and C ２ to C ４ selected from haloalkylene; R ２ａ i) hydrogen, and ii) 0 to 3 substituents R ２ｂ A ring is selected from those substituted with, where the ring is selected from a) a 3-6 member saturated or partially unsaturated carbon ring, b) a 5-6 member heteroaryl, c) phenyl, and d) a 4-6 member heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen; Each R ２ｂ These are independently halo, hydroxyl, and C. １ ~C ３ Alkyl, C ３ ~C ４ Cycloalkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Hydroxyalkyl, O-C １ ~C ３ Alkyl, C １ ~C ３ Alkylene-OC １ ~C ３ Alkyl, cyano, -CO ２ R １１ , -CO ２ N(R) １１ ) ２ , -X ２ -CO ２ R １１ , and -X ２ -CO ２ N(R) １１ ) ２ Selected from; X ２ C １ ~C ５ Alkylene and C ３ ~C ６ Selected from cycloalkylenes; Each R １１ These are, independently, hydrogen, C １ ~C ５ Alkyl, C ３ ~C ５ Cycloalkyl, C １ ~C ５ Haloalkyl and C ３ ~C ５ Selected from cyclohaloalkyls, or two R １１ The groups bond together with the nitrogen atoms they are connected to, forming a 4- to 6-membered heterocycle containing one nitrogen heteroatom; R ３ is hydrogen, C １ ~C ３ Alkyl and C １ ~C ３ Selected from haloalkyls, and R ４ is hydrogen, or R ３ and R ４ R ３ and R ４ It bonds with the piperidinyl ring of formula (I) to which it is connected, forming a seven- or eight-membered bridge or fused heterocycle; R ５ teeth, 【Chemistry 2】 (In the formula, R ８ is selected from hydrogen, halo, C １ to C ６ alkyl, C ３ to C ４ cycloalkyl, C １ to C ６ haloalkyl, C １ to C ６ alkylene-O-C １ to C ４ alkyl, C １ to C ６ haloalkylene-O-C １ to C ４ alkyl, C １ to C ６ hydroxyalkyl, C １ to C ６ haloalkylene-O-C １ to C ４ haloalkyl, C １ to C ６ alkylene-O-C １ to C ４ haloalkyl, C(=O)H and cyano, and R ９ is selected from -X ３ -R ９ａ and R ９ａ ; or or R ８ and R ９ together with the carbon atom to which R ８ and R ９ are bonded form a ring substituted with 0 to 3 R ９ｂ groups, wherein said ring is: a) a 5- to 6-membered saturated or partially unsaturated carbocyclic ring, or b) a 5- to 6-membered heterocyclyl containing one heteroatom which is O; X ３ C １ ~C ２ Alkylene and C ３ ~C ５ Selected from cycloalkylenes; R ９ａ i) hydrogen and ii) 0 to 3 R ９ｂ A ring is selected from rings substituted with a group, where the ring is a) phenyl, b) a 5-6 member heteroaryl, c) C ３ ~C ７ Cycloalkyl, d) C ７ ~C ９ spiroalkyl, e) a 4- to 7-membered heterocycline containing one or two heteroatoms, each being oxygen, or f) a 7- to 9-membered spiroheterocycline containing one or two heteroatoms, each being oxygen; Each R ９ｂ These are independently halo, hydroxyl, and C. １ ~C ４ Alkyl, C １ ~C ４ Haloalkyl, O-C １ ~C ４ Alkyl, O-C １ ~C ４ Haloalkyl, C １ ~C ４ Alkylene-OC １ ~C ４ Alkyl, C １ ~C ４ Haloalkilene-OC １ ~C ４ Alkyl, C １ ~C ４ Alkylene-OC １ ~C ４ Haloalkyl, C １ ~C ４ Haloalkilene-OC １ ~C ４ Haloalkyl, 0-2 R ９ｃ C substituted with a group ３ ~C ７ Cycloalkyl, 0 to 2 R ９ｃ C substituted with a group ３ ~C ７ Cyclohaloalkyl, 0 to 2 R ９ｃ O-C substituted with a group ３ ~C ７ Cycloalkyl, 0 to 2 R ９ｃ O-C substituted with a group ３ ~C ７ Cyclohaloalkyl, 0 to 2 R ９ｃ A 3- to 7-membered heterocycline containing one heteroatom, which is oxygen, substituted with a group, and 0-2 R groups. ９ｃ O-3 to 7 membered heterocyclyl containing one heteroatom, which is oxygen, substituted with a group, and 0 to 2 R ９ｃ Phenyl groups substituted with R groups, 0-2 R groups ９ｃ Pyridinyl substituted with a group, 0 to 2 R ９ｃ O-C substituted with a group １ ~C ３ Alkylene-C ３ ~C ７ Cycloalkyl, 0 to 2 R ９ｃ O-C substituted with a group １ ~C ３ Alkylene-C ３ ~C ７ Cyclohaloalkyl and 0 to 2 R ９ｃ O-C containing one heteroatom of oxygen substituted with a group. １ ~C ３ Alkilen-3 to 7-membered heterocyclines are selected; or two R ９ｂ The groups, in combination with the carbon atoms to which they are connected, form 0 to 2 R groups. ９ｃ A ring is formed by substitution with a group, where the ring is i) C ３ ~C ６ A cycloalkyl or ii) 4-6 membered heterocycline containing one heteroatom which is oxygen; Each R ９ｃ These are independently of halo (e.g., fluoro), CH ３ and OCH ３ Selected from; Each R １０ It is a halo; m is selected from integers between 0 and 2. A compound of or a pharmaceutically acceptable salt thereof.

2. The aforementioned compound is of formula (Ia): 【Transformation 3】 [In the formula, X is N and CR ６ (In the formula, R ６ (Selected from hydrogen and halo); R １ This is selected from hydrogen and halo; R ２ is, -X １ -R ２ａ and R ２ａ Selected from; X １ C １ ~C ２ Alkylene and C ２ Selected from haloalkylenes; R ２ａ i) hydrogen, and ii) 0 to 3 substituents R ２ｂ A ring is selected from those substituted with, where the ring is selected from a) a 3-6 member saturated or partially unsaturated carbon ring, b) a 5-6 member heteroaryl, c) phenyl, and d) a 4-6 member heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen; Each R ２ｂ These are independently halo, hydroxyl, and C. １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Hydroxyalkyl, O-C １ ~C ３ Alkyl, C １ ~C ３ Alkylene-OC １ ~C ３ Alkyl, cyano, -CO ２ R １１ , -CO ２ N(R) １１ ) ２ , -X ２ -CO ２ R １１ , and -X ２ -CO ２ N(R) １１ ) ２ Selected from; X ２ C １ ~C ５ Alkylene and C ３ ~C ６ Selected from cycloalkylenes; Each R １１ These are, independently, hydrogen and C １ ~C ５ Alkyl and C ３ ~C ６ Selected from cycloalkyl groups, R ３ is selected from hydrogen and methyl; R ５ teeth, 【Chemistry 4】 (In the formula, R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ OCH ２ CH ３ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano, R ９ is, X ３ -R ９ａ and R ９ａ Selected from; or R ８ and R ９ R ８ and R ９ Together with the connected carbon atom, 0 to 1 R ９ｂ A ring is formed by substitution with a group, where the ring is a 5-6 membered heterocycline containing one heteroatom which is oxygen; X ３ C １ ~C ２ It is alkylene; R ９ａ i) hydrogen, ii) 0 to 3 R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ４ ~C ６ a) a cycloalkyl, a) a 6-membered heterocycline containing one heteroatom which is O, c) a 7- to 9-membered spiroheterocycline each containing one or two heteroatoms which are O; Each R ９ｂ It is independent, Haro, C １ ~C ３ Alkyl, O-C １ ~C ３ Alkyl, 0-2 R ９ｃ O-4 to 6 membered heterocyclyl containing one heteroatom, which is oxygen, substituted with a group, and 0 to 2 R ９ｃ Pyridinyl substituted with a group, and 0 to 2 R groups ９ｃ O-C containing one heteroatom of oxygen substituted with a group. １ ~C ３ Alkilen-4 to 6-membered heterocyclines are selected; or two R ９ｂ The groups, in combination with the carbon atoms to which they are connected, form 0 to 2 R groups. ９ｃ A ring is formed by substitution with a group, where the ring is i) C ３ ~C ６ A cycloalkyl or ii) 4-6 membered heterocycline containing one heteroatom which is oxygen; Each R ９ｃ These are independently of halo (e.g., fluoro), CH ３ and OCH ３ Selected from; Each R １０ It is a halo; m is selected from integers between 0 and 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein X is CH or CF.

4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein X is CH.

5. R ２ However, R ２ａ The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. R ２ａ However, 0 to 3 substituents R ２ｂ A ring substituted with, where the ring is a) C ４ ~C ６ A compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, selected from cycloalkyls and a) a 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen.

7. R ２ａ However, 1 to 3 substituents R ２ｂ A ring substituted with, where the ring is a) C ５ ~C ６ The compound according to claim 6 or a pharmaceutically acceptable salt thereof, selected from cycloalkyls and b) 4- to 6-membered heterocyclines (e.g., fully saturated heterocyclines) containing one or two heteroatoms independently selected from oxygen and nitrogen.

8. Each R ２ｂ However, they became independent, Hello, C １ ~C ３ Alkyl and CO ２ A compound according to any one of claims 1 to 7, selected from H, or a pharmaceutically acceptable salt thereof.

9. Each R ２ｂ However, independently, fluoro, chloro, methyl, and CO ２ A compound according to any one of claims 1 to 8, selected from H, or a pharmaceutically acceptable salt thereof.

10. R ３ A compound according to any one of claims 1 to 9, wherein H is present, or a pharmaceutically acceptable salt thereof.

11. R ５ but, 【Transformation 5】 A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, selected from among.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.

13. R ５ but, 【Transformation 6】 A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, selected from among.

14. Each R １０ However, independently selected from fluoro, chloro, and bromo, the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. R ２ａ However, 1 to 3 substituents R ２ｂ C replaced by ５ ~C ６ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

16. R ２ａ However, 1 to 3 substituents R ２ｂ C replaced by ６ A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl compound.

17. One R ２ｂ However, CO ２ H and 0 to 2 other R ２ｂ The compound according to claim 15 or claim 16, or a pharmaceutically acceptable salt thereof, wherein each group is independently selected from methyl, fluoro, and chloro.

18. The aforementioned compound is of formula (Ib): 【Transformation 7】 (In the formula, X, R １ , R ３ , R ５ , and each R ２ｂ A compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein the compound is as defined in any one of claims 1 to 16.

19. Each R ２ｂ However, independently selected from methyl, fluoro, and chloro, the compound according to claim 18 or a pharmaceutically acceptable salt thereof.

20. R ２ａ However, 0 to 3 substituents R ２ｂ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is a 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with .

21. R ２ａ However, 0 to 2 substituents R ２ｂ The compound according to claim 20 or a pharmaceutically acceptable salt thereof, which is a 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one heteroatom that is nitrogen, substituted with .

22. R ２ａ However, one or two substituents R ２ｂ A 4-6 membered heterocycline (e.g., a fully saturated heterocycline) containing one heteroatom, which is nitrogen, substituted with R, and each R ２ｂ The compound according to claim 20 or claim 21, or a pharmaceutically acceptable salt thereof, wherein the substituent is independently selected from methyl and halo (e.g., fluoro).

23. R ８ However, hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ A compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, selected from C(=O)H and cyano.

24. R ９ However, X ３ -R ９ａ The compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof.

25. X ３ However, CH ２ The compound according to claim 24 or a pharmaceutically acceptable salt thereof.

26. R ９ａ However, there are 0 to 2 R ９ｂ A ring substituted with a group, where the ring is a) C ５ ~C ６ A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, which is a cycloalkyl or a six-membered heterocycline containing one heteroatom that is b)O.

27. R ９ａ However, 0 or 1 R ９ｂ A ring substituted with a group, where the ring is a) C ６ The compound according to claim 26 or a pharmaceutically acceptable salt thereof, which is a cycloalkyl or a six-membered heterocycline containing one heteroatom that is b)O.

28. Each R ９ｂ However, O-C became independent. １ ~C ３ A compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, selected from an O-6 membered heterocyclyl containing an alkyl and one heteroatom that is oxygen.

29. R ８ and R ９ However, R ８ and R ９ Together with the connected carbon atom, 0 to 1 R ９ｂ A compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein a ring is formed by substitution with a group, the ring being a 5- to 6-membered heterocycline containing one heteroatom which is oxygen.

30. R ８ and R ９ However, R ８ and R ９ Together with the connected carbon atom, R ９ｂ A ring is formed by substitution with a group, where the ring is a six-membered heterocyclyl containing one heteroatom which is O, and R ９ｂ However, there are 0 to 2 (for example, 0) R ９ｃ O-4 to 6 membered heterocyclyl containing one heteroatom that is oxygen, substituted with a group, and 0 to 2 (e.g., 0) R ９ｃ A compound according to claim 29 or a pharmaceutically acceptable salt thereof, selected from phenyls substituted with a group.

31. Formula (Ic) or (Id): 【Transformation 8】 (In the formula, X, R １ , R ２ , R ３ , R ９ｂ , and each R １０ A compound or a pharmaceutically acceptable salt thereof according to claim 29 or claim 30, which is independently defined as in claim 29 or claim 30.

32. Formula (Ic-1) or (Id-1): 【Chemistry 9】 (In the formula, X, R １ , R ２ , R ３ , R ９ｂ , and each R １０ The compound according to claim 31 or a pharmaceutically acceptable salt thereof, which is independently defined as in claim 31.

33. Formula (Ic-2) or (Id-2): 【Chemistry 10】 (In the formula, R １ , each R ２ｂ R is independent of R ３ , R ６ , R ９ｂ , and each R １０ The compound according to claim 32 or a pharmaceutically acceptable salt thereof, which is independently defined as in claim 32.

34. R ９ｂ The compound according to claim 32 or claim 33 or a pharmaceutically acceptable salt thereof, selected from an O-6 membered heterocyclyl containing one heteroatom which is O, and phenyl.

35. The aforementioned compound is of formula (II): 【Chemistry 11】 [wherein, X, R １ , R ３ , each R ２ｂ These are independent and each R １０ This is independently defined as any one of claims 1 to 14; R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano; R ９ is, X ３ -R ９ａ And; X ３ CH ２ And; R ９ａ i) hydrogen and ii) 0 to 2 (e.g., 0 to 1) R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ５ ~C ６ A six-membered heterocycline containing one heteroatom that is a cycloalkyl or b)O; each R ９ｂ This is as defined in any one of claims 1 to 16 (for example, each R ９ｂ O-C １ ~C ３ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a six-membered heterocycline containing one heteroatom that is alkyl and one that is oxygen.

36. The aforementioned compound is of formula (III): 【Chemistry 12】 [wherein, X, R １ , R ３ , and each R １０ This is independently defined as any one of claims 1 to 14; R ２ R ２ａ And; R ２ａ is a substituent R of 0 to 3 ２ｂ A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R ２ｂ The substituents are independently selected from methyl and halo (e.g., fluoro); R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano; R ９ is, X ３ -R ９ａ And; X ３ CH ２ And; R ９ａ i) hydrogen and ii) 0 to 2 (e.g., 0 to 1) R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ５ ~C ６ A six-membered heterocycline containing one heteroatom that is a cycloalkyl or b)O; each R ９ｂ This is as defined in any one of claims 1 to 16 (for example, each R ９ｂ O-C １ ~C ３ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a six-membered heterocycline containing one heteroatom that is alkyl and one that is oxygen.

37. The aforementioned compound is of formula (IV): 【Chemistry 13】 (In the formula, X, R １ , R ３ , each R ２ｂ Each R is independent. ９ｂ These are independent and each R １０ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein ( is independently defined as in any one of claims 1 to 14).

38. The aforementioned compound is of formula (V): 【Chemistry 14】 [wherein, X, R １ , R ３ , each R ９ｂ These are independent and each R １０ This is independently defined as any one of claims 1 to 14; R ２ R ２ａ And; R ２ａ is a substituent R of 0 to 3 ２ｂ A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R ２ｂ The substituent is independently selected from methyl and halo (e.g., fluoro) in the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof.

39. The aforementioned compound is of formula (VI): 【Chemistry 15】 [In the formula, X, R １ , R ３ , each R ２ｂ These are independent and each R １０ This is independently defined as any one of claims 1 to 14; R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano; R ９ is, X ３ -R ９ａ And; X ３ CH ２ And; R ９ａ i) hydrogen and ii) 0 to 2 R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ５ ~C ６ A six-membered heterocycline containing one heteroatom that is a cycloalkyl or b)O; each R ９ｂ This is as defined in any one of claims 1 to 16 (for example, each R ９ｂ O-C １ ~C ３ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a six-membered heterocycline containing one heteroatom that is alkyl and one that is oxygen.

40. The aforementioned compound is of formula (VII): 【Chemistry 16】 [In the formula, X, R １ , R ３ , and each R １０ This is independently defined as any one of claims 1 to 14; R ２ R ２ａ And; R ２ａ is a substituent R of 0 to 3 ２ｂ A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R ２ｂ The substituents are independently selected from methyl and halo (e.g., fluoro); R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano; R ９ is, X ３ -R ９ａ And; X ３ CH ２ And; R ９ａ i) hydrogen and ii) 0 to 2 R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ５ ~C ６ A six-membered heterocycline containing one heteroatom that is a cycloalkyl or b)O; each R ９ｂ This is as defined in any one of claims 1 to 16 (for example, each R ９ｂ O-C １ ~C ３ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a six-membered heterocycline containing one heteroatom that is alkyl and one that is oxygen.

41. The aforementioned compound is of formula (VIII): 【Chemistry 17】 [In the formula, X, R １ , R ３ , each R ２ｂ These are independent and each R １０ This is independently defined as any one of claims 1 to 14; R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano; R ９ is, X ３ -R ９ａ And; X ３ CH ２ And; R ９ａ i) hydrogen and ii) 0 to 2 R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ５ ~C ６ A six-membered heterocycline containing one heteroatom that is a cycloalkyl or b)O; each R ９ｂ This is as defined in any one of claims 1 to 16 (for example, each R ９ｂ O-C １ ~C ３ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a six-membered heterocycline containing one heteroatom that is alkyl and one that is oxygen.

42. The aforementioned compound is of formula (IX): [Chemistry 18] [In the formula, X, R １ , R ３ , and each R １０ This is independently defined as any one of claims 1 to 14; R ２ R ２ａ And; R ２ａ is a substituent R of 0 to 3 ２ｂ A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R ２ｂ The substituents are independently selected from methyl and halo (e.g., fluoro); R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano; R ９ is, X ３ -R ９ａ And; X ３ CH ２ And; R ９ａ i) hydrogen and ii) 0 to 2 R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ５ ~C ６ A six-membered heterocycline containing one heteroatom that is a cycloalkyl or b)O; each R ９ｂ This is as defined in any one of claims 1 to 16 (for example, each R ９ｂ O-C １ ~C ３ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a six-membered heterocycline containing one heteroatom that is alkyl and one that is oxygen.

43. The aforementioned compound is given by formula (X): 【Chemistry 19】 [In the formula, X, R １ , R ３ , each R ２ｂ These are independent and each R １０ This is independently defined as any one of claims 1 to 14; R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano; R ９ R ９ａ or X ３ -R ９ａ (Especially R ９ａ ) and; X ３ CH ２ And; R ９ａ i) hydrogen and ii) 0 to 2 R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ５ ~C ６ A six-membered heterocycline containing one heteroatom that is a cycloalkyl or b)O; each R ９ｂ This is as defined in any one of claims 1 to 16 (for example, each R ９ｂ O-C １ ~C ３ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a six-membered heterocycline containing one heteroatom that is alkyl and one that is oxygen.

44. The aforementioned compound is of formula (XI): 【Chemistry 20】 [In the formula, X, R １ , R ３ , and each R １０ This is independently defined as any one of claims 1 to 14; R ２ R ２ａ And; R ２ａ is a substituent R of 0 to 3 ２ｂ A 4- to 6-membered heterocycline (e.g., a fully saturated heterocycline) containing one or two heteroatoms independently selected from oxygen and nitrogen, substituted with; Each R ２ｂ The substituents are independently selected from methyl and halo (e.g., fluoro); R ８ It is hydrogen, methyl, ethyl, CHF ２ ,CH ２ CH ２ OCH ３ Selected from C(=O)H and cyano; R ９ R ９ａ or X ３ -R ９ａ (Especially R ９ａ ) and; X ３ CH ２ And; R ９ａ i) hydrogen and ii) 0 to 2 R ９ｂ A ring is selected from those substituted with a group, where the ring is a) C ５ ~C ６ A six-membered heterocycline containing one heteroatom that is a cycloalkyl or b)O; each R ９ｂ This is as defined in any one of claims 1 to 16 (for example, each R ９ｂ O-C １ ~C ３ A compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, which is selected from a six-membered heterocycline containing one heteroatom that is alkyl and one that is oxygen. 【Request Item 45】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 A compound selected from or a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising a compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

47. A combination comprising a compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, and one or more further therapeutically active agents.

48. A method for regulating ERK activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 46.

49. A method for treating a patient having a disease associated with abnormal activity of the MAP kinase pathway, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 45 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 46.

50. The method according to claim 49, wherein the disease associated with abnormal activity of the MAP kinase pathway is cancer.

51. The method according to claim 50, wherein the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

52. The method according to claim 50 or claim 51, wherein the cancer contains a BRAF and / or RAS mutation.

53. A compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

54. A compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer.

55. The compound for use according to claim 54 or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

56. The compound for use according to claim 54 or claim 55, or a pharmaceutically acceptable salt thereof, wherein the cancer contains a BRAF and / or RAS mutation.

57. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 46 in the manufacture of a pharmaceutical product for the treatment of cancer.

58. The use according to claim 57, wherein the cancer is selected from melanoma, lung cancer, colorectal cancer (CRC), pancreatic cancer, and thyroid cancer.

59. The use according to claim 57 or 58, wherein the cancer contains BRAF and / or RAS mutations.

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