Chemical compounds and uses thereof

Abstract

Disclosed herein are specific compounds of formula (I): which inhibit Wharner Syndrome ATP dependent helicase (WRN) activity, particularly WRN helicase domain activity, and thus are useful in the treatment of cancers treatable by inhibition of WRN, including cancers characterized by microsatellite instability (MSI) and / or DNA deficient mismatch repair system (dMMR). In addition, pharmaceutical compositions comprising such compounds, methods of using such compounds, and methods of making such compounds are also disclosed.

Description

Invention Field

[0001] This document discloses specific compounds that inhibit the activity of Werner syndrome helicase (WRN), particularly compounds that inhibit the activity of ATP-dependent helicase domains, and therefore may be used to treat cancers that can be treated by inhibiting WRN, including cancers characterized by microsatellite instability (MSI) and / or defective DNA mismatch repair systems (dMMR). Furthermore, pharmaceutical compositions comprising such compounds and methods for their preparation are also disclosed. sequence list

[0002] This application contains a sequence list that has been electronically submitted in XML format, and is incorporated herein by reference in its entirety. The XML file was created on May 29, 2024, named 70333WO01 Seq List XML 29May2024.xml, and has a size of 6,092 bytes. Background of the Invention

[0003] Cancer is one of the leading causes of death worldwide. A limitation of mainstream treatments (such as chemotherapy) is that their cytotoxic effects are not limited to cancer cells but can also cause adverse side effects on normal tissues. Therefore, new strategies are needed to better target cancer cells.

[0004] Synthetic lethality (SL) occurs when a combination of defects in the expression of two or more genes, or a corresponding loss of function of a related gene product protein (e.g., caused by one or more chromosomal mutations), leads to cell death, whereas a single defect / loss of function does not cause cell death. For example, one gene (or gene product) may be involved in cell proliferation, while another gene (or gene product) may be a non-essential gene. The concept of synthetic lethality originated from studies in the Drosophila model system, where a combination of mutations in two or more independent genes leads to cell death (as opposed to survival or even cell proliferation when only one gene is mutated or deleted). Recently, some studies have explored maladaptive genetic changes in cancer cells that make them vulnerable to synthetic lethal approaches. These tumor-specific gene defects can create vulnerability, allowing the use of targeted drugs with synthetic lethality against such tumor-specific genomic defects to induce tumor cell death without harming normal cells.

[0005] Disorders in DNA repair pathways make cells more susceptible to accumulating DNA damage. It is known that various types of tumors accumulate more DNA mutations during cancer development. Therefore, synthetic lethal cytotoxic therapies can target DNA repair pathways, causing the disordered repair process to attack itself, thereby inducing tumor cell death.

[0006] Identifying cancer-related SL interactions is a key area of ​​biological discovery work. In a yeast screening aimed at revealing SL interactions between tumor suppressor genes and drug targets, the gene SGS1, encoding RECQ helicases, was found to interact with multiple genes in the screening. In the same study using human cells, Bloom syndrome helicase (BLM), one of the five human RECQ helicases, interacted with checkpoint kinases (CHEK) 1 and 2 (Srivas R, et al., Mol Cell 2016; 63(3): 514-25). BLM is involved in homologous recombination (HR) during DNA damage repair (DDR). RECQ helicases are DNA-dependent ATPases that unwind 3' to 5' DNA. Altered or absent expression of three RECQ helicases (BLM, WRN (WRN), and RECQL4) can lead to syndromes in humans with overlapping but distinct symptoms (deRenty C, Ellis NA. Ageing Res Rev 2017; 33: 36-51). This suggests that they may have overlapping and distinct functions, which depend on their expression time and location in the cell, their protein-protein interactions, and post-translational modifications.

[0007] Data from another study using approximately 400 cell lines indicated that WRN is not universally essential, but MSI cell lines derived from the colon, endometrium, and stomach are sensitive to WRN shRNA (McDonald ER, 3rd, de Weck A, Schlabach MR, Billy E, Mavrakis KJ, Hoffman GR, et al., Cell 2017; 170(3): 577-92). A DepMap study, partly based on DRIVE data, also found WRN to be essential in MSI cell lines (Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al., Cell 2017; 170(3): 564-76). Other human RECQ helicases tested in this study did not exhibit this MSI SL interaction.

[0008] To confirm the findings of the DRIVE and DepMap studies, multiple laboratories have reported that knocking out the WRN gene selectively impairs the survival of cancer cells with high microsatellite instability (Behan, FM et al., Nature 2019; 568(7753): 511-16, Chan, EM et al., Nature 2019; 568 (551-556), Lieb, S. et al., eLife 2019; 8: e43333, Kategaya, L. et al., iScience 2019; 13: 488-497). WRN is an enzyme possessing both an exonuclease domain and an ATP-dependent helicase domain. Kategaya, L. et al. (above) confirmed a synthetic lethal relationship between tumor patients with high microsatellite instability and, in particular, the ATP-dependent helicase domain activity of the WRN protein. Identifying tumor patients with high microsatellite instability (reflecting high-frequency microsatellite instability) is known in the art, including, for example, as disclosed in Dudley, Jonathan C., et al., Clinical Cancer Research, 22(4): 813-820, 2016.

[0009] These results suggest that WRN inhibitors may offer a novel treatment option for cancer patients with microsatellite instability (MSI), a marker of DNA mismatch repair (dMMR), including those with tumors exhibiting high MSI. Microsatellites are repetitive DNA sequences of varying unit lengths (e.g., from one base (mononucleotide) to six bases (dinucleotide, trinucleotide, tetranucleotide, pentanucleotide, hexanucleotide)) distributed across coding and / or non-coding regions of the genome. Mutations in these microsatellites, such as alterations in the length of the repetitive sequences, may represent microsatellite instability. As is known in the art and as described in more detail herein, MSI can be detected (e.g., directly) by molecular assays (e.g., targeting certain microsatellites) or (e.g., indirectly) by immunohistochemical assessments (e.g., targeting the expression of certain MMR proteins). According to the consensus of the NCI Reference Group (Bethesda, 1998), MSI can be assessed by molecular testing of five microsatellites, including two single nucleotides (BAT25 and BAT26) and three dinucleotides (D2S123, D5S346, and D17S250). Based on the NCI Reference Group's method for molecular testing, tumors can be classified into different subtypes, including: MSI-H (MSI-H) if two or more microsatellite markers show instability; MSI-L (MSI-L) if only one microsatellite marker shows instability; and MS-Stable (MSS) if none of the five microsatellite markers show instability (i.e., each of the five microsatellite markers is determined to be stable). In some cases, such as when molecular testing or immunohistochemical assessment cannot distinguish between MSI-L and general chromosomal instability, the tumor can be classified as an MSS type tumor. Invention Overview

[0010] In a first aspect, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0011]

[0012] (Ia)

[0013] in:

[0014] Ring A is aryl, heteroaryl, or C. 3-10 A cycloalkyl ring, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0015] L 1 For -NR c -C(O)-, -OCH2-, -NR c -CH2- or -CH2-;

[0016] n is 0, 1, or 2;

[0017] R 1 It is hydrogen or C 1-3 alkyl;

[0018] R 2 It is hydrogen, halogen, or C 1-3 alkyl;

[0019] R X2 R X3 and R X4 Each is independently selected from: hydrogen, halogen, cyano, -NR d R e hydroxyl, carboxyl, phenoxy, phenyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, C 1-3 Alkoxy (C 1-3 )alkyl-, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy and L X -V;

[0020] R X5 It is hydrogen, halogen, hydroxyl, or C 1-3 Alkyl; or

[0021] R X2 R X3 R X4 Or R X5 Any two atoms in the ring, together with the carbon atoms they are attached to, form a 3- to 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S, and the ring is optionally substituted by up to three independent substituents selected from: halogens, C... 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3Alkoxy and halogen (C 1-3 )alkoxy;

[0022] L X For the bond, -CH2-, -NR d C(O)-、-NR d -(CH2) w -、-O-(CH2) w -、or -S-(CH2) w -;

[0023] V is independent of C 3-7 Cycloalkyl or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein V is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy;

[0024] Y 1 Y 2 Y 3 and Y 4 Each is independently N or CR y And Y 1 Y 2 Y 3 and Y 4 At most two of them are N;

[0025] L 2 For key, -NR f -S(O)2-、-NR f -C(O)- or -(CH2) p -;

[0026] Z represents hydrogen, halogen, cyano, hydroxyl, or -NR. g R h nitro, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, C 2-5 alkynyl or halogenated (C 2-5 ) acetylenic group; or

[0027] Z represents ring B, where ring B is aryl, heteroaryl, or C. 3-10Cycloalkyl, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0028] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0029] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)-NH-, -C(O)- and -CH2C(O)NH-;

[0030] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR m R n , carboxyl group, -CONR m R n C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C1-4 )alkyl and C 3-7 cycloalkyl;

[0031] Each R y Independently hydrogen, halogen, cyano, nitro, hydroxyl, -NR i R k , carboxyl group, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy, methoxy (C 1-3 )alkoxy, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, hydroxyl (C) 2-5 alkenyl, C 2-5 Alkyne group, halogenated (C 2-5 ) alkynyl group, hydroxyl group (C 2-5 ) an alkynyl group, or a 5- or 6-membered heteroaryl group containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is optionally surrounded by up to three C atoms. 1-3 Alkyl groups are substituted;

[0032] R a R b R c R d R f R g R h R i R k R m and R n Each independently is hydrogen, C 1-3 Alkyl, or C 3-7 cycloalkyl; or

[0033] R y and R f Together with the atoms they are attached to, they form 5- or 6-membered rings containing one or two independent heteroatoms selected from N, O, and S;

[0034] R e For hydrogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 3-7 cycloalkyl, or -C(O)C 1-3 alkyl;

[0035] Each p is independently 1 or 2; and

[0036] Each w is independently 0, 1, 2, or 3.

[0037] In a second aspect, the present invention provides a pharmaceutical composition comprising: a) a compound disclosed herein or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient.

[0038] In a third aspect, this disclosure provides compounds disclosed herein for therapeutic purposes.

[0039] In a fourth aspect, this disclosure provides compounds disclosed herein for the treatment of cancer.

[0040] In a fifth aspect, this disclosure provides a method of treating cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0041] In a sixth aspect, this disclosure provides the use of the compounds disclosed herein in the preparation of medicaments for treating cancer. Attached Figure Description

[0042] Figure 1 The efficacy study of the compound of Example 138 in a mouse model carrying a xenograft of the SW48 human colorectal cancer cell line is shown.

[0043] Figure 2 The efficacy study of the compound of Example 83 in a mouse model carrying a xenograft of the SW48 human colorectal cancer cell line is shown.

[0044] Figure 3 The efficacy study of the compound of Example 250 in a mouse model carrying a xenograft of the SW48 human colorectal cancer cell line is shown.

[0045] Figure 4 The efficacy study of the compound of Example 306 in a mouse model carrying a xenograft of the SW48 human colorectal cancer cell line is shown. Invention Details

[0046] definition:

[0047] Unless otherwise stated, the terms “a” and “an” as used herein shall be interpreted to include both the singular and the plural. For example, the phrase “pharmaceuticalally acceptable excipient” refers to one or more pharmaceutically acceptable excipients.

[0048] As used in this article, the terms “halogen” and “halogenated” refer to chlorine, fluorine, bromine, or iodine substituents.

[0049] As used in this article, the term "cyano" refers to the -CN group.

[0050] The term "nitro" as used in this article refers to the -NO2 group.

[0051] As used in this article, the term "hydroxyl" or "hydroxyl" refers to the -OH group.

[0052] The term "carboxyl group" as used in this article refers to the -COOH group.

[0053] As used herein, the term "alkyl" refers to a saturated hydrocarbon group having a specified number of carbon atoms, which may be straight-chain or branched. For example, the term "C 1-4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms, and the term "C" is used to indicate that the alkyl group has 1 to 4 carbon atoms. 1-3 "Alkyl" refers to an alkyl group having 1 to 3 carbon atoms. Exemplary groups include, but are not limited to, methyl, ethyl, propyl (n-propyl and isopropyl), and butyl (n-butyl, sec-butyl, isobutyl and tert-butyl).

[0054] When the term "alkyl" is used in combination with other substituents (e.g., "halogenated" or "C-alkyl"), 1-3 alkyl and hydroxyl (C 1-3 When referring to an alkyl group, the term "alkyl" is intended to encompass divalent straight-chain or branched hydrocarbon groups, where the connecting point is through the alkyl moiety.

[0055] The term "halogenated (C)" is used in this article. 1-3 "alkyl" refers to a group having one or more carbon atoms, which may be the same or different, on one or more carbon atoms of an alkyl moiety containing one to three carbon atoms. The group is a straight-chain or branched carbomer. Exemplary groups include, but are not limited to, -CHF2 (difluoromethyl), -CF3 (trifluoromethyl), -CCl3 (trichloromethyl), 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 2-fluoroisopropyl, and hexafluoroisopropyl.

[0056] The term "hydroxyl (C)" used in this article 1-3 "alkyl" refers to a group having one or more hydroxyl groups on one or more carbon atoms of an alkyl moiety containing one to three carbon atoms, and the group is a straight-chain or branched carbolic group. Exemplary groups include, but are not limited to, hydroxymethyl (-CH2OH), 2-hydroxyethyl (-CH2CH2OH), and hydroxy-isopropyl.

[0057] The term "cyano (C)" used in this article 1-3 "alkyl" refers to a group having one or more cyano groups on one or more carbon atoms of an alkyl moiety containing one to three carbon atoms, the group being a straight-chain or branched carbonyl group. Exemplary groups include, but are not limited to, cyanoethyl and cyanopropyl.

[0058] The term "C" used in this article 1-3"alkylsulfonyl" refers to the -SO2R group, where R is an alkyl group. Exemplary groups include, but are not limited to, methylsulfonyl (i.e., -SO2Me), ethylsulfonyl (i.e., -SO2Et), and n-propylsulfonyl (i.e., -SO2). n Pr). In this article, the term "sulfonyl (C)" is used. 1-3 )alkyl" and "C 1-3 "alkylsulfonyl" can be used interchangeably.

[0059] As used herein, the term "alkenyl" refers to a straight-chain or branched hydrocarbon group containing a specified number of carbon atoms and at least one double bond. For example, "C 2-5 "Alkenyl" has 2 to 5 carbon atoms. Exemplary groups include, but are not limited to, vinyl and propenyl.

[0060] The term "halogenated (C)" is used in this article. 2-5 "Alkenyl" refers to a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of an alkenyl moiety containing 2 to 5 carbon atoms. The group is a straight-chain or branched carbonyl group. Exemplary groups include, but are not limited to, -CH=CHF, -CH=CF2, and -CF=CF2.

[0061] The term "hydroxyl (C)" used in this article 2-5 "Alkenyl" refers to a group having one or more hydroxyl groups on one or more carbon atoms of an alkenyl moiety containing 2 to 5 carbon atoms, and the group is a straight-chain or branched carbonyl group. Exemplary groups include, but are not limited to, prop-2-enyl-1-ol, but-3-enyl-2-ol, and 2-methyl-but-3-enyl-2-ol.

[0062] As used herein, the term "alkynyl" refers to a straight-chain or branched hydrocarbon group containing a specified number of carbon atoms and at least one triple bond. For example, "C 2-5 The "alkynyl" group has 2 to 5 carbon atoms. Exemplary groups include, but are not limited to, ethynyl and propynyl.

[0063] The term "halogenated (C)" is used in this article. 2-5 "Alynyl" refers to a group having one or more halogen atoms, which may be the same or different, on one or more carbon atoms of an alkynyl moiety containing 2 to 5 carbon atoms. The group is a straight-chain or branched carbonyl group. Exemplary groups include, but are not limited to, 3-fluoro-prop-1-ynyl, 3-fluoro-but-1-ynyl, and 3-fluoro-3-methylbut-1-ynyl.

[0064] The term "hydroxyl (C)" used in this article 2-5"Alynyl" refers to a group having one or more hydroxyl groups on one or more carbon atoms of an alkynyl moiety containing 2 to 5 carbon atoms, and the group is a straight-chain or branched carbonyl group. Exemplary groups include, but are not limited to, prop-2-alkynyl-1-ol, but-3-alkynyl-2-ol, and 2-methyl-but-3-alkynyl-2-ol.

[0065] As used herein, the term "alkylene" refers to a divalent group derived from a straight-chain or branched saturated hydrocarbon group, for example, a group containing 1 to 3 carbon atoms (C1 to C2). 1-3 Alkylene groups. Exemplary groups include, but are not limited to, -CH2-, -CH2CH2- and -CH2CH2CH2-.

[0066] As used herein, the term "alkoxy" refers to an -O-alkyl group, i.e., an alkyl group linked by an oxygen atom, wherein "alkyl" is defined as described above. For example, the term "C" 1-3 "Alkoxy" refers to an alkoxy group having 1 to 3 carbon atoms. Exemplary groups include, but are not limited to, methoxy, ethoxy, n-propoxy, and isopropoxy.

[0067] As used in this article, the term "phenoxy" refers to the -O-Ph group, which is a phenyl group linked by an oxygen atom.

[0068] The term "halogenated (C)" is used in this article. 1-3 "Alkoxy" refers to a straight-chain or branched hydrocarbon group having at least one and at most three carbon atoms, to which one or more halogen atoms, which may be the same or different, are attached, and the hydrocarbon group is connected by oxygen atoms. Exemplary groups include, but are not limited to, -OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), -OCH2CHF2 (2,2-difluoroethoxy), and -OCH(CF3)2 (hexafluoroisopropoxy).

[0069] As used herein, the term "cycloalkyl" refers to a non-aromatic saturated hydrocarbon ring containing a specified number of carbon atoms, which can be monocyclic or bicyclic. Bicyclic cycloalkyl groups can be bridged, fused, or spirocyclic bicyclic groups. For example, "C 3-10 "Cycloalkyl" refers to a cycloalkyl group containing 3 to 10 carbon atoms, and the term "C" is used in conjunction with this term. 3-7 "Cycloalkyl" refers to a cycloalkyl group having 3 to 7 carbon atoms. Exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, bicyclo[1.1.1]pentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, octahydrocyclopentadienyl (e.g., (3as,6as)-octahydrocyclopentadienyl), and spirodecyl (e.g., spirodecyl[4.5]decyl).

[0070] The term "heterocyclic alkyl" refers to a saturated or unsaturated 3- to 10-membered monocyclic or bicyclic ring that must contain at least one heteroatom selected from nitrogen, oxygen, and sulfur. Heterocyclic alkyl groups may contain one or more C(O), S(O), or SO2 groups. Bicyclic heterocyclic alkyl groups may be bridged, fused, or spirocyclic bicyclic groups. However, heterocyclic alkyl groups are not aromatic. Heterocyclic alkyl groups containing more than one heteroatom may contain different heteroatoms, i.e., these heteroatoms are independently selected. For example, the term "3- to 10-membered heterocyclic alkyl" refers to a saturated or unsaturated 3- to 10-membered monocyclic or bicyclic ring that must contain one, two, or three independently selected non-carbon atoms selected from nitrogen, oxygen, and sulfur. Exemplary groups include, but are not limited to, 8-oxabicyclo[3.2.1]octyl, pyrrolyl, pyrrolyl-2-one, pyrazolyl, pyrazolinyl, imidazoyl, imidazolinyl, imidazolinyl-2-one, oxazolinyl, oxacyclobutyl, oxacycloheptyl, 1-oxa-6-azaspirooctyl (e.g., 1-oxa-6-azaspiro[2.5]octyl), thiazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxapentyl, tetrahydro-2H-pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl), morpholinyl, morpholinyl-3-one, 1,3-dioxacyclohexyl, 1,4-dioxacyclohexyl, 1,3-oxathiacyclopentyl, 1,3 -oxathionylcyclohexyl, 1,3-dithionylcyclohexyl, 1,4-oxathionylcyclopentyl, 1,4-oxathionylcyclohexyl, 1,4-dithionylcyclohexyl, piperidinyl-2-one, pyrimidinyl-2,4(1H,3H)-dione, thiomorpholinyl, 2-azaspirohepyl (e.g., 2-azaspiro[3.3]heptyl), 2,5-dihydrothiopheneyl 1,1-dioxide, tetrahydrothiopheneyl 1,1-dioxide, 3-azabicycloheptyl (e.g., 3-azabicyclo[4.1.0]heptyl, or more specifically, (1S,6S)-3-azabicyclo[4.1.0]heptyl), 6-oxaspirooctyl (e.g., 6-oxaspiro[2.5]octyl) and thiomorpholinyl 1,1-dioxide.Exemplary groups also include, but are not limited to, pyrrolidinyl, pyrrolidinyl-2-one, pyrazolyl, pyrazolinyl, imidazolinyl, imidazolinyl, imidazolinyl-2-one, oxazolinyl, oxazolidinyl, oxazolidinyl, 1-oxa-6-azaspiroctyl (e.g., 1-oxa-6-azaspiroctyl[2.5]octyl), thiazolinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, dihydrofuranyl, 1,3-dioxapentanyl, tetrahydro-2H-pyranyl, dihydropyranyl (e.g., 3,4-dihydro-2H-pyranyl), morpholinyl, morpholinyl-3-one, 1,3-dioxacyclohexyl, 1,4-dioxacyclohexyl, 1,3-oxathiacyclopentyl, 1,3-oxathiacyclohexane. 1,3-dithiacyclohexyl, 1,4-oxathiacyclopentyl, 1,4-oxathiacyclohexyl, 1,4-dithiacyclohexyl, piperidinyl-2-one, pyrimidinyl-2,4(1H,3H)-dione, thiomorpholinyl, 2-azaspirohepyl (e.g., 2-azaspiro[3.3]heptyl), 2,5-dihydrothienyl 1,1-dioxide, tetrahydrothienyl 1,1-dioxide, 3-azabicycloheptyl (e.g., 3-azabicyclo[4.1.0]heptyl, or more specifically, (1S,6S)-3-azabicyclo[4.1.0]heptyl), 6-oxaspirooctyl (e.g., 6-oxaspiro[2.5]octyl) and thiomorpholinyl 1,1-dioxide.

[0071] The term "aryl" refers to an aromatic group in monocyclic or bicyclic hydrocarbons. The term also includes bicyclic cycloalkyl-aryl groups containing an aromatic ring moiety fused to a cycloalkyl ring. Aryl groups can contain 6 to 14 carbon atoms. For example, an aryl group can contain 6 to 10 carbon atoms, referred to as C1. 6-10 Aryl groups include, for example, phenyl, naphthyl, indene, and dihydroindene.

[0072] The term "heteroaryl" refers to a group or portion comprising an aromatic monocyclic or bicyclic group containing 5 to 10 ring atoms and including at least one heteroatom independently selected from nitrogen, oxygen, and sulfur. The term also covers bicyclic heterocyclic alkyl-aryl groups containing 5 to 10 ring atoms, comprising an aromatic ring group fused with a heterocyclic alkyl group (which includes at least one heteroatom independently selected from nitrogen, oxygen, and sulfur). Alternatively, the term also includes (1) bicyclic heteroaryl-heterocyclic alkyl groups containing 5 to 10 ring atoms, comprising a heteroaryl cyclic group fused with a heterocyclic alkyl group (which includes at least one heteroatom independently selected from nitrogen, oxygen, and sulfur), and (2) bicyclic heteroaryl-cycloalkyl groups containing 5 to 10 ring atoms, comprising a heteroaryl cyclic group fused with a cycloalkyl cyclic group. Exemplary functional groups include, but are not limited to, furanyl, thiophene, pyrrolyl, imidazolyl, pyrazolyl, triazolyl (e.g., 4H-1,2,4-triazolyl), tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiazolyl (e.g., 1,3,4-thiazolyl), isothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuranyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, furanopyridazinyl (e.g., furanolyl), and furanopyridazinyl (e.g., furanolyl). (2,3-d)pyridazinyl, 1,3-benzodioxacyclopentenyl, dihydrobenzodioxacyclohexenyl, benzothiopheneyl, thienopyridyl (e.g., thieno[3,2-b]pyridyl), thienopyrimidinyl (e.g., thieno[2,3-d]pyrimidinyl), indoleazinyl, dihydroindoleyl, indoleyl, isoindoleyl, dihydroindoleyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, benzoxazolyl-2-one (e.g., benzo[d]oxazolyl-2(3H)-one), dihydrobenzoxazolyl, dihydro Benzoxazinyl (3,4-dihydro-2H-benzo[b][1,4]oxazinyl), benzothiazolyl, benzimidazolyl, benzisothiazolyl, dihydrobenzisisothiazolyl, indazole, imidazopyridyl (e.g., 3H-imidazo[4,5-c]pyridyl and 3H-imidazo[4,5-b]pyridyl), dihydropyrrolopyrazolyl (e.g., 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazolyl), imidazopyridazinyl (e.g., imidazo[1,2-b]pyridazinyl), pyrazolopyridyl, benzothiazolyl Triazolyl, tetraazolylpyridinyl (e.g., tetraazol[1,5-b]pyridinyl), purine, quinoyl, tetrahydroquinoyl, isoquinoyl, 1,2,3,4-tetrahydroisoquinoyl, 1,2,3,4-tetrahydroquinoxalinyl, tetrahydropyridopyridinyl (e.g., 5,6,7,8-tetrahydropyrido[3,4-d]pyridinyl), quinoxalinyl, cyclolinyl, phthalazinyl, quinazolinyl, 1,5-naphthidyl, 1,6-naphthidyl, 1,7-naphthidyl, 1,8-naphthidyl, and pteridyl.

[0073] The term "5- or 6-membered heteroaryl" represents a group or portion comprising an aromatic monovalent monocyclic group containing 5 or 6 ring atoms, including at least one carbon atom and containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryls contain three heteroatoms. Exemplary groups include, but are not limited to, furanyl, thiophene, pyrrole, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0074] The term "bicyclic" as used in this article may refer to a bridging, fused, or spirocyclic bicyclic group.

[0075] To avoid ambiguity, all double-ring systems can be connected at any suitable position on either ring.

[0076] The term "optionally substituted" refers to a group that may be unsubstituted or substituted by one or more substituents as defined herein. When the term "substituted" is used to refer to a group, it means that the hydrogen atom attached to a member atom in that group is replaced by one of the defined substituents. If a group can be chosen from a plurality of alternative groups, the chosen groups may be the same or different.

[0077] The term "independent selection" means selecting more than one substituent from a number of possible substituents, which may be the same or different. Therefore, each substituent is selected individually from all the listed possible substituents.

[0078] The term “pharmaceutically acceptable” refers to those compounds (including salts), materials, compositions, and dosage forms that, within reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0079] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the subject compound and exhibits minimal undesirable toxicological effects. These pharmaceutically acceptable salts can be prepared in situ during the final isolation and purification of the compound, or by reacting the purified compound, in its free acid or free base form, with its respective suitable base or acid. When the compound disclosed herein contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired base (whether pure or in a suitable inert solvent). Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary, and tertiary amines (including substituted amines, cyclic amines, and naturally occurring amines), such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. When the compounds of this disclosure contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of the compound with a sufficient amount of the desired acid (whether pure acid or acid in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrocarbonic acid, phosphoric acid, monohydrophosphoric acid, dihydrophosphoric acid, sulfuric acid, monohydrosulfuric acid, hydroiodic acid, or phosphorous acid, as well as those derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as arginine salts and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge, SM, et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). The specific compounds disclosed in this invention contain both basic and acidic functional groups, enabling these compounds to be converted into basic addition salts or acid addition salts.

[0080] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and then separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in some physical properties (e.g., solubility in polar solvents), but otherwise, for the purposes of this disclosure, these salts are equivalent to the parent form of the compound.

[0081] This invention also includes prodrugs of compounds of formula (I) or pharmaceutically acceptable salts thereof. As used herein, the term "prodrug" refers to a compound that readily undergoes a chemical change under physiological conditions to generate a pharmacologically active parent compound. The term "prodrug moiety" refers to the chemical portion of a prodrug that releases under physiological conditions to form an active parent compound. One example (but not limited to) of a prodrug is a compound administered as an ester ("prodrug") but subsequently metabolized to a carboxylic acid (the active ingredient). Furthermore, prodrugs can be converted to compounds of this disclosure by chemical or biochemical methods in an in vitro environment. For example, when a prodrug is placed in a transdermal patch reservoir along with a suitable enzyme or chemical reagent, it can be slowly converted to a compound of this disclosure.

[0082] Some compounds of formula (I) may exist in both unsolvated and solvated forms (including hydrated forms). Generally, solvated forms are equivalent to unsolvated forms and are intended to be included within the scope of this disclosure. Some compounds of formula (I) may exist in a variety of crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated in this disclosure and should be within the scope of this disclosure.

[0083] Some compounds of formula (I) have asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, regio isomers, and single isomers (e.g., isolated enantiomers) should all be included within the scope of this disclosure. When a stereochemical diagram is given, it means that the compound contains one isomer and substantially no other isomer. “Substantially no other isomer” means that the ratio of the two isomers is at least 80 / 20, more preferably 90 / 10 or 95 / 5 or higher. In some embodiments, the content of one isomer is at least 99%.

[0084] Certain compounds disclosed in this invention may exist as tautomers and / or geometric isomers. All possible tautomers, as well as cis and trans isomers (whether present individually or in mixtures thereof), are within the scope of this disclosure. For example, hydroxyl-substituted compounds of formula (I) may exist as tautomers as follows:

[0085]

[0086] The terms “compound of this disclosure” or “compound of the present invention” refer to a compound of formula (I), formula (Ia), formula (Ib), formula (Ic), formula (Id), formula (Ie), formula (II) or formula (II-a), or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or its tautomer thereof.

[0087] Compounds of formula (I) may also contain isotopes in non-natural amounts on one or more atoms constituting the compound. Non-natural amounts of isotopes can be defined as ranging from amounts found in nature to 100% of the atom in question. The difference lies only in the presence or absence of atoms enriched with one or more isotopes. Exemplary isotopes that can be incorporated into compounds of this disclosure, such as compounds of formula (I) (and any embodiments thereof disclosed herein, including specific compounds), include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine (e.g., respectively). 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and 125 I). Isotope-labeled compounds (e.g., those labeled with...) 3 H and 14 C-labeled compounds can be used for the determination of compound or substrate tissue distribution. Tritium-labeled compounds (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes have practical applications due to their ease of preparation and detection. Furthermore, heavier isotopes, such as deuterium (i.e.,...), are also used. 2 H) substitution may provide some therapeutic benefits due to greater metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In some embodiments, in the compounds disclosed herein (including those in Table 1 below), one or more hydrogen atoms are... 2 H or 3 H substitution, or one or more carbon atoms being replaced 13 C- or 14 C-enriched carbon substitution. Positron-emitting isotopes, for example... 15 O、 13 N、 11 C and 15F can be used in positron emission tomography (PET) studies to examine substrate acceptor cavitation. Isotopically labeled compounds are typically prepared by steps similar to those disclosed in the schemes and examples herein, where the isotopically labeled reagent replaces the non-isotopically labeled reagent. Therefore, in one embodiment, the invention comprises:

[0088] , , and ,

[0089] One or more hydrogen atoms bonded to carbon atoms are replaced by deuterium atoms.

[0090] The term “disease” as used in this article is generally synonymous with the terms “disorder,” “syndrome,” and “symptom” (such as medical condition) and can be used interchangeably, as all of these terms reflect an abnormal condition of the human or animal body or a part thereof that impairs normal function, usually manifested as obvious signs and symptoms, and leading to a decline in the lifespan or quality of life of the human or animal.

[0091] The term “patient” is generally synonymous with the term “subject”, and as used herein, “patient” includes all mammals, including humans. Examples of patients include humans, livestock (e.g., cattle, goats, sheep, pigs, and rabbits), and companion animals (e.g., dogs, cats, rabbits, and horses). Preferably, the patient is a human.

[0092] As used in this article, "need for treatment" refers to a judgment made by a physician or other caregiver that a patient needs treatment or will benefit from treatment. This judgment is made based on various factors within the physician's or caregiver's professional field.

[0093] For example, in the context of a patient, cell, tissue, organ, or biological fluid, "administration" and "application" mean, for example, contacting the subject, cell, tissue, organ, or biological fluid with a compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, or a diagnostic reagent. In the context of cells, administration includes contact between the reagent and the cell (e.g., in vitro or ex vivo) and contact between the reagent and a body fluid, wherein the body fluid contacts the cell.

[0094] As used herein, “therapeutic effective amount” refers to the amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof that is sufficient to elicit the desired biological response in a human body. Therapeutic effective amounts may vary depending on the compound, the disease and its severity, and the age and weight of the subject receiving treatment. Therapeutic effective amounts can be determined by measuring the relevant physiological effects and can be adjusted based on the dosing regimen and diagnostic analysis of the subject's condition. For example, measuring the serum concentration of a compound of formula (I) (or, for example, its metabolites) at a specific time after administration can indicate whether a therapeutic effective amount has been used.

[0095] The term "treatment" refers to improving or stabilizing a specific condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying the recurrence of the condition in a previously ill patient or subject.

[0096] The term "prevention" refers to preventing individuals who do not have the disease from contracting it.

[0097] The term “inhibition,” “reduction,” or any variation thereof associated with WRN, including any measurable reduction or complete inhibition to achieve the desired result. For example, the activity of the WRN helicase domain may be reduced by about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or any range thereof, compared to normal activity.

[0098] For the avoidance of doubt, any reference to compound (I) includes any one of the references to (Ia), (I-aa), (Ib), (Ic), (I-cc), (I-ccc), (Id), (I-dd), (Ie), (I-ee), (I-eee), (II), (II-a), (II-aa), (II-b), (II-bb), (II-c), and (II-cc).

[0099] compound

[0100] On the one hand, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0101]

[0102] (I)

[0103] in:

[0104] Ring A is aryl, heteroaryl, or C. 3-10A cycloalkyl ring, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0105] L 1 For -NR c -C(O)-, -OCH2-, -NR c -CH2-, -CH2-, -S-CH2-, -CH2CH2- or -S(O)2-;

[0106] n is 0, 1, or 2;

[0107] R 1 It is hydrogen or C 1-3 alkyl;

[0108] R 2 It is hydrogen, halogen, or C 1-3 alkyl;

[0109] X 1 and X 5 Each is independently either N or -CH-;

[0110] X 2 X 3 and X 4 Each independently as -NR o -、-CR X R X -、-O- or -C(O)-;

[0111] Each R X Independently selected from hydrogen, halogen, cyano, -NR d R e hydroxyl, carboxyl, phenoxy, phenyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, C 1-3Alkoxy (C 1-3 )alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy and L X -V; or

[0112] R o and R X Any two atoms in the ring, together with the atoms they are attached to, form a 3- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S, and the ring is optionally substituted by up to three independent substituents selected from: halogens, C... 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy;

[0113] L X For the bond, -CH2-, -NR d C(O)-、-NR d -(CH2) w -、-O-(CH2) w -、-S-(CH2) w -;

[0114] V is independent of C 3-7 Cycloalkyl or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein V is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy;

[0115] Y 1 Y 2 Y 3 and Y 4 Each is independently N or CR y And Y 1 Y 2 Y 3 and Y 4 At most two of them are N;

[0116] L 2 For key, -NR f -S(O)2-、-NR f -C(O)- or -(CH2) p -;

[0117] Z represents hydrogen, halogen, cyano, hydroxyl, or -NR. g R hnitro, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, C 2-5 Alkyne or halogenated (C 2-5 ) acetylenic group; or

[0118] Z represents ring B, where ring B is aryl, heteroaryl, or C. 3-10 Cycloalkyl, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0119] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0120] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)-NH-, -C(O)- and -CH2C(O)NH-;

[0121] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR m R n , carboxyl group, -CONR m R n C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0122] Each R y Independently hydrogen, halogen, cyano, nitro, hydroxyl, -NR i R k , carboxyl group, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy, methoxy (C 1-3 )alkoxy, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, hydroxyl (C) 2-5 alkenyl, C 2-5 Alkyne group, halogenated (C 2-5 ) alkynyl group, hydroxyl group (C 2-5 ) an alkynyl group, or a 5- or 6-membered heteroaryl group containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is optionally surrounded by up to three C atoms. 1-3 Alkyl groups are substituted;

[0123] R a R b R c R d R f R g R h R i R k R m and R n Each independently is hydrogen, C 1-3 Alkyl, or C 3-7 cycloalkyl; or

[0124] R y and R f Together with the atoms they are attached to, they form 5- or 6-membered rings containing one or two independent heteroatoms selected from N, O, and S;

[0125] R o For hydrogen, C 1-3 Alkyl, -C(O)C 1-3 Alkyl, or C 3-7 cycloalkyl;

[0126] R e For hydrogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 3-7 cycloalkyl or -C(O)C 1-3 alkyl;

[0127] Each p is independently 1 or 2; and

[0128] Each w is independently 0, 1, 2, or 3.

[0129] On the other hand, this disclosure provides compounds of formula (I) or pharmaceutically acceptable salts thereof:

[0130]

[0131] in:

[0132] Ring A is aryl, heteroaryl, or C. 3-10 A cycloalkyl ring, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0133] L 1 For -NR c -C(O)-, -OCH2-, -NR c-CH2-, -CH2-, -S-CH2-, -CH2CH2- or -S(O)2-;

[0134] n is 0, 1, or 2;

[0135] R 1 It is hydrogen or C 1-3 alkyl;

[0136] R 2 It is hydrogen, halogen, or C 1-3 alkyl;

[0137] X 1 and X 5 Each is independently either N or -CH-;

[0138] X 2 X 3 and X 4 Each independently as -NR o -、-CR X R X -or -C(O)-;

[0139] Each R X Independently selected from hydrogen, halogen, -NR d R e hydroxyl, carboxyl, phenoxy, phenyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, methoxy (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy, of which C 1-3 Alkoxy groups are optionally C 3-7 Cycloalkyl substituted; or

[0140] R o and R X Any two atoms in the ring, together with the atoms they are attached to, form a 5- or 6-membered ring, which may contain one or two heteroatoms independently selected from N, O, and S.

[0141] Y 1 Y 2 Y 3 and Y 4 Each is independently N or CR y And Y 1 Y 2 Y 3 and Y 4 At most two of them are N;

[0142] L 2 For key, -NR f-S(O)2-、-NR f -C(O)- or -(CH2) p -;

[0143] Z represents hydrogen, halogen, cyano, hydroxyl, or -NR. g R h nitro, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, C 2-5 Alkyne or halogenated (C 2-5 ) acetylenic group; or

[0144] Z represents ring B, where ring B is aryl, heteroaryl, or C. 3-10 Cycloalkyl, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0145] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0146] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)-NH-, -C(O)- and -CH2C(O)NH-;

[0147] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR m R n , carboxyl group, -CONR m R n C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0148] Each R y Independently hydrogen, halogen, cyano, nitro, hydroxyl, -NR i R k , carboxyl group, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy, methoxy (C 1-3 )alkoxy, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, hydroxyl (C) 2-5 alkenyl, C 2-5 Alkyne group, halogenated (C 2-5 ) alkynyl group, hydroxyl group (C 2-5 ) an alkynyl group, or a 5- or 6-membered heteroaryl group containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is optionally surrounded by up to three C atoms. 1-3 Alkyl-substituted; or

[0149] R y and R f Together with the atoms they are attached to, they form 5- or 6-membered rings containing one or two independent heteroatoms selected from N, O, and S;

[0150] Each p is independently 1 or 2; and

[0151] R a R b R c R d R e R f R g R h R i R k R m R n and R o Each independently is hydrogen, C 1-3 Alkyl, or C 3-7 Cycloalkyl.

[0152] When a part of a compound of formula (I) is divalent, unless otherwise stated, that part is described from left to right relative to the rest of the compound. For example, when L 2 For -NR f When -S(O)2-, L 2 The nitrogen atom is attached to the aromatic ring, L 2 The sulfur atom is bonded to Z.

[0153] On the one hand, this disclosure provides compounds of formula (I), wherein X 1 and X 5 -CH-; X 2 and X 4 It is -CH2-; n is 1; and X 3 For -NR o - and where R 1 R 2 R o Rings A, Z, L 1 L 2 Y 1 Y 2 Y 3 and Y 4 As defined in this document. See the structure shown below.

[0154]

[0155] On the one hand, this disclosure provides a compound of formula (I), wherein X 1 and X 5 -CH-; X 2 and X 4 It is -CH2-; n is 1; and X 3 It is -O-, and where R 1 R 2 Rings A, Z, L 1 L 2 Y 1 Y2 Y 3 and Y 4 As defined in this document. See the structure shown below.

[0156]

[0157] On the other hand, this disclosure provides compounds of formula (Ia) or pharmaceutically acceptable salts thereof:

[0158]

[0159] (Ia)

[0160] in:

[0161] Ring A is aryl, heteroaryl, or C. 3-10 A cycloalkyl ring, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0162] L 1 For -NR c -C(O)-, -OCH2-, -NR c -CH2- or -CH2-;

[0163] n is 0, 1, or 2;

[0164] R 1 It is hydrogen or C 1-3 alkyl;

[0165] R 2 It is hydrogen, halogen, or C 1-3 alkyl;

[0166] R X2 R X3 and R X4 Each is independently selected from: hydrogen, halogen, cyano, -NRd R e hydroxyl, carboxyl, phenoxy, phenyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, C 1-3 Alkoxy (C 1-3 )alkyl-, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy and L X -V;

[0167] R X5 It is hydrogen, halogen, hydroxyl, or C 1-3 Alkyl; or

[0168] R X2 R X3 R X4 Or R X5 Any two atoms in the ring, together with the carbon atoms they are attached to, form a 3- to 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S, and the ring is optionally substituted by up to three independent substituents selected from: halogens, C... 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy;

[0169] L X For the bond, -CH2-, -NR d C(O)-、-NR d -(CH2) w -、-O-(CH2) w -、or -S-(CH2) w -;

[0170] V is independent of C 3-7 Cycloalkyl or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein V is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy;

[0171] Y 1 Y 2 Y 3 and Y 4 Each is independently N or CR y And Y 1 Y 2 Y3 and Y 4 At most two of them are N;

[0172] L 2 For key, -NR f -S(O)2-、-NR f -C(O)- or -(CH2) p -;

[0173] Z represents hydrogen, halogen, cyano, hydroxyl, or -NR. g R h nitro, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, C 2-5 alkynyl or halogenated (C 2-5 ) acetylenic group; or

[0174] Z represents ring B, where ring B is aryl, heteroaryl, or C. 3-10 Cycloalkyl, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0175] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0176] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)-NH-, -C(O)- and -CH2C(O)NH-;

[0177] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR m R n , carboxyl group, -CONR m R n C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0178] Each R y Independently hydrogen, halogen, cyano, nitro, hydroxyl, -NR i R k , carboxyl group, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy, methoxy (C 1-3 )alkoxy, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, hydroxyl (C) 2-5 alkenyl, C 2-5 Alkyne group, halogenated (C 2-5 ) alkynyl group, hydroxyl group (C 2-5 ) an alkynyl group, or a 5- or 6-membered heteroaryl group containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is optionally surrounded by up to three C atoms. 1-3 Alkyl groups are substituted;

[0179] R a R b Rc R d R f R g R h R i R k R m and R n Each independently is hydrogen, C 1-3 Alkyl, or C 3-7 cycloalkyl; or

[0180] R y and R f Together with the atoms they are attached to, they form 5- or 6-membered rings containing one or two independent heteroatoms selected from N, O, and S;

[0181] R e For hydrogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 3-7 cycloalkyl, or -C(O)C 1-3 alkyl;

[0182] Each p is independently 1 or 2; and

[0183] Each w is independently 0, 1, 2, or 3.

[0184] In one implementation, R X2 R X3 and R X4 Each group is independently selected from: hydrogen, cyano, -NR d R e hydroxyl, phenoxy, C 1-3 Alkyl, methoxy (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy and L X -V; or

[0185] R X2 R X3 Or R X5 Any two atoms in the ring, together with the carbon atoms they are attached to, form a 5-membered ring that may contain one oxygen atom.

[0186] L X For -O-(CH2) w -;

[0187] V is selected independently from C 1-3 Alkoxy, C 3-4 Cycloalkyl, or a 3- to 7-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from N or O, wherein V is optionally composed of one heteroatom independently selected from C. 1-3 Alkyl and C 1-3Substituents of alkoxy groups; and

[0188] w is 0 or 1.

[0189] On the other hand, this disclosure provides compounds of formula (I-aa) or pharmaceutically acceptable salts thereof:

[0190]

[0191] (I-aa)

[0192] in:

[0193] Ring A is aryl, heteroaryl, or C. 3-10 A cycloalkyl ring, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0194] L 1 For -NR c -C(O)-, -OCH2-, -NR c -CH2- or -CH2-;

[0195] n is 0, 1, or 2;

[0196] R 1 It is hydrogen or C 1-3 alkyl;

[0197] R 2 It is hydrogen, halogen, or C 1-3 alkyl;

[0198] R X2 R X3 and R X4 Each is independently selected from: hydrogen, halogen, -NR d R e hydroxyl, carboxyl, phenoxy, phenyl, C 1-3 Alkyl, halogenated (C1-3 )alkyl, hydroxyl (C 1-3 )alkyl, methoxy (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy, of which C 1-3 Alkoxy groups are optionally C 3-7 Cycloalkyl substituted; or

[0199] R X2 R X3 Or R X4 Any two atoms in the ring, together with the carbon atoms to which they are attached, form a 5- or 6-membered ring, which may optionally contain one or two heteroatoms independently selected from N, O, and S.

[0200] Y 1 Y 2 Y 3 and Y 4 Each is independently N or CR y And Y 1 Y 2 Y 3 and Y 4 At most two of them are N;

[0201] L 2 For key, -NR f -S(O)2-、-NR f -C(O)- or -(CH2) p -;

[0202] Z represents hydrogen, halogen, cyano, hydroxyl, or -NR. g R h nitro, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, C 2-5 alkynyl or halogenated (C 2-5 ) acetylenic group; or

[0203] Z represents ring B, where ring B is aryl, heteroaryl, or C. 3-10 Cycloalkyl, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0204] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0205] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)-NH-, -C(O)- and -CH2C(O)NH-;

[0206] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR m R n , carboxyl group, -CONR m R n C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0207] Each R y Independently hydrogen, halogen, cyano, nitro, hydroxyl, -NR i Rk , carboxyl group, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy, methoxy (C 1-3 )alkoxy, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, hydroxyl (C) 2-5 alkenyl, C 2-5 Alkyne group, halogenated (C 2-5 ) alkynyl group, hydroxyl group (C 2-5 ) an alkynyl group, or a 5- or 6-membered heteroaryl group containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is optionally surrounded by up to three C atoms. 1-3 Alkyl-substituted; or

[0208] R y and R f Together with the atoms they are attached to, they form 5- or 6-membered rings containing one or two independent heteroatoms selected from N, O, and S;

[0209] Each p is independently 1 or 2; and

[0210] R a R b R c R d R e R f R g R h R i R k R m and R n Each independently is hydrogen, C 1-3 Alkyl, or C 3-7 Cycloalkyl.

[0211] To avoid ambiguity, for R X2 R X3 R X4 Or R X5 The reference to any two atoms in the group forming 3- to 6-membered rings together with the carbon atoms they are attached to includes the formation of fused, bridged, and spirocyclic bicyclic structures. For R... X2 R X3 Or R X4 The reference to any two atoms forming a 5- or 6-membered ring together with the carbon atoms they are attached to includes the formation of fused and bridged bicyclic structures.

[0212] For Ry and R f References to the formation of 5- or 6-membered rings together with the atoms they are attached to include the formation of fused structures. Examples include, for instance, dihydrooxazine derivatives shown below:

[0213] .

[0214] References to the formation of a 5- or 6-membered ring, optionally containing one or two heteroatoms independently selected from N, O, and S, together with two optional substituents on ring B (which may be monocyclic or bicyclic), include the formation of a fused structure with ring B. Examples include, for instance, 1,2,3,4-tetrahydrobenzimidazolidine derivatives as shown below:

[0215] .

[0216] In one embodiment, ring A is optionally substituted by up to three independent substituents selected from the following: halogen, hydroxyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl and C 3-7 Cycloalkyl.

[0217] In one implementation, ring A is C. 6-10 Aryl, 5- to 10-membered heteroaryl, C 3-10 A cycloalkyl ring, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 Cycloalkyl.

[0218] In one embodiment, ring A is phenyl, 5- or 6-membered heteroaryl, C 3-10Cycloalkyl, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and wherein ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR a R b , carboxyl group, CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 Cycloalkyl.

[0219] In one embodiment, ring A is phenyl, 5- or 6-membered heteroaryl, C 3-10 Cycloalkyl, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and wherein ring A is optionally substituted by up to three substituents independently selected from: halogen, hydroxyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl and C 3-7 Cycloalkyl.

[0220] In one embodiment, ring A is phenyl, 6-heteroaryl, or C. 3-10 Cycloalkyl, wherein ring A is monocyclic or bicyclic, wherein ring A is optionally substituted by up to three independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 Cycloalkyl.

[0221] In one embodiment, ring A is phenyl, 6-heteroaryl, or C. 3-10Cycloalkyl, wherein ring A is monocyclic or bicyclic, wherein ring A is optionally substituted by up to three independent substituents selected from the following: halogen, hydroxyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl and C 3-7 Cycloalkyl.

[0222] In one embodiment, ring A is a phenyl or C 3-10 Cycloalkyl, wherein ring A is monocyclic or bicyclic, wherein ring A is optionally substituted by up to three independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 Cycloalkyl.

[0223] In one embodiment, ring A is phenyl, bicyclo[1.1.1]pentyl, or cyclohexyl, wherein ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 Cycloalkyl.

[0224] In one embodiment, ring A is a phenyl or C 3-10 Cycloalkyl, wherein ring A is monocyclic or bicyclic, wherein ring A is optionally substituted by up to three independent substituents selected from the following: halogen, hydroxyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl and C 3-7Cycloalkyl.

[0225] In one embodiment, ring A is a phenyl group optionally substituted with up to three independent substituents selected from the following: halogen, cyano, nitro, hydroxy, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 Cycloalkyl.

[0226] In one embodiment, ring A is a phenyl group optionally substituted with one or two substituents independently selected from the following: halogen, hydroxyl, C. 1-3 Alkyl and halogenated (C 1-3 )alkyl.

[0227] In one embodiment, ring A is a phenyl group optionally substituted with up to three independent substituents selected from the following: halogen, C 1-3 Alkyl and halogenated (C 1-3 )alkyl.

[0228] In one embodiment, ring A is a phenyl group optionally substituted with up to three independent substituents selected from the following: halogenated and halogenated (C 1-3 )alkyl.

[0229] In one embodiment, ring A is a phenyl group substituted with fluorine and trifluoromethyl.

[0230] In one implementation, ring A has a structure .

[0231] To avoid ambiguity, wavy lines indicate sites that connect to the rest of the compound.

[0232] In one embodiment, ring A is phenyl, 2-azaspiro[3.3]heptyl, tetrahydropyranyl, pyridyl, bicyclo[1.1.1]pentyl, cyclohexyl, spiro[4.5]decyl, (3as,6as)-octahydrocyclopentadienyl, bicyclo[2.2.1]heptyl, or 2,3-dihydroindenyl, wherein ring A is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR a R b , carboxyl group, CONRa R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 Cycloalkyl.

[0233] In one implementation, ring A is selected from:

[0234] ,

[0235] The ring A is optionally substituted by up to three independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, -NR. a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 Cycloalkyl.

[0236] In one implementation, L 1 For -NR c -C(O)- or -OCH2-. In one implementation, L 1 For -NR c -C(O)-. In one implementation, L 1 It is -NH-C(O)-. To avoid ambiguity, divalent L 1 The left side of the part (e.g., -NR) c The N atom of -C(O)- is attached to ring A.

[0237] In one implementation, n is 1.

[0238] In one implementation, R 1 It is hydrogen.

[0239] In one implementation, R 2 It is hydrogen, fluorine, or methyl. In one embodiment, R... 2It is hydrogen.

[0240] In one implementation, L 2 For -NR f -S(O)2-. To avoid ambiguity, divalent L 2 The left side of the part (e.g., -NR) f The N atom of -S(O)2- is attached to the aromatic ring, and the right side is attached to Z.

[0241] In one implementation, R f It is H, CH3, or cyclopropane. In one embodiment, R f It is CH3.

[0242] In one implementation, L 2 It is -NCH3-S(O)2-.

[0243] In one implementation, R X2 R X3 and R X4 Each is independently selected from: hydrogen, fluorine, cyano, hydroxyl, methyl, methoxy, ethoxy, propoxy, isopropoxy, phenoxy, difluoromethoxy, cyclobutoxy, cyclobutylmethoxy, cyclopropylmethoxy, (tetrahydrofuranyl)methoxy, oxacyclobutylmethoxy, (tetrahydro-2H-pyranyl)methoxy, (8-oxabicyclo[3.2.1]octyl)methoxy, (methoxybicyclo[1.1.1]pentyl)methoxy, (methyl (1,4-dioxane-butyl)methoxy, 2,2-difluoroethoxy, (tetrahydrofuranyl)oxy, methoxyethoxy, (1,4-dioxane-hexyl)methoxy, methoxymethyl, morpholinyl, difluoropyrrolidinyl, piperidinyl, fluoropiperidinyl, difluoropiperidinyl, -NH2, -NHEt, -NMe2, -N(Me)C(O)Me, -NHC(O)Me, -NHMe and -NH(CH2CF3); or

[0244] R X5 It is hydrogen, fluorine, hydroxyl, or C 1-3 Alkyl; or

[0245] R X2 R X3 Or R X5 Any two atoms in the ring, together with the carbon atoms they are attached to, form a 5-membered ring containing oxygen.

[0246] In one implementation, R X5 It is hydrogen.

[0247] In one implementation, R X2 R X3 and R X4 Each is independently selected from: hydrogen, halogen, cyano, -NRd R e hydroxyl, carboxyl, phenoxy, phenyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, C 1-3 Alkoxy (C 1-3 )alkyl-, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy and L X -V, and R X5 It is hydrogen, halogen, hydroxyl and C 1-3 alkyl.

[0248] In one implementation, R X2 R X3 R X4 Or R X5 Any two atoms in the ring, together with the carbon atoms they are attached to, form a 3- to 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S, and the ring is optionally substituted by up to three independent substituents selected from: halogens, C... 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy.

[0249] In one implementation, R X2 R X3 and R X4 Each is independently selected from: hydrogen, -NR d R e hydroxyl, phenoxy, C 1-3 Alkyl, methoxy (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy and C 1-3 Alkoxy, where C 1-3 Alkoxy groups are optionally C 3-7 Cycloalkyl substitution; or

[0250] R X2 and R X3 Together with the carbon atoms they are attached to, they form a 5-membered ring, which may optionally contain one oxygen atom.

[0251] In one implementation, R X2 R X3 and R X4 Each is independently selected from: H, OH, Me, OMe, OEt, OPr, OPh, cyclobutylmethoxy, 2,2-difluoroethoxy, methoxymethyl, -NHEt, -NMe2, and -NHMe; or

[0252] RX2 and R X3 Together with the carbon atoms they are attached to, they form a 5-membered ring containing an oxygen atom.

[0253] In one implementation, R X2 R X3 and R X4 Each is independently selected from: hydrogen and C 1-3 Alkyl group. In another embodiment, R X2 and R X4 It is hydrogen, and R X3 Selected from C 1-3 Alkyl groups and hydrogen. In another embodiment, R X2 and R X4 It is hydrogen, and R X3 Selected from ethoxy and hydrogen. In another embodiment, R X2 R X3 and R X4 It is hydrogen. In another embodiment, R... X2 and R X4 It is hydrogen, and R X3 It is an ethoxylated compound.

[0254] In one implementation, R X2 and R X3 Together with the carbon atoms to which they are attached, they form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S, and the ring is optionally substituted by up to three independent substituents selected from: halogens, C... 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy.

[0255] In one implementation, R X2 and R X3 Together with the carbon atoms they are attached to, they form a 5- or 6-membered ring containing a heteroatom independently selected from N, O, and S, and this ring is optionally substituted by up to three independent substituents selected from: halogens, C... 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy.

[0256] In one implementation, R X3 and R X5 Together with the carbon atoms to which they are attached, they form a 3- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S, and the ring is optionally substituted by up to three independent substituents selected from: halogens, C... 1-3Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy.

[0257] In one implementation, R X2 R X4 and R X5 It is hydrogen, and R X3 Halogen, cyano, -NR d R e hydroxyl, carboxyl, phenoxy, phenyl, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, C 1-3 Alkoxy (C 1-3 )alkyl-, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy or L X -V.

[0258] In one implementation, R X2 R X4 and R X5 It is hydrogen, and R X3 Selected from hydrogen, C 1-3 Alkoxy and C 1-3 Alkoxy (C 1-3 )alkyl-. In one embodiment, R X2 R X3 R X4 and R X5 It is hydrogen. In one implementation, R X2 R X4 and R X5 It is hydrogen, and R X3 It is ethoxylated. In one embodiment, R X2 R X4 and R X5 It is hydrogen, and R X3 It is a methoxymethyl group.

[0259] In one implementation, R X2 R X4 R X5 It is hydrogen, and R X3 For L X -V.

[0260] In one implementation, L X For the bond, -CH2-, -NR d -、-NR d C(O)-、-NR d -(CH2) w-、-O-(CH2) w -、or -S-(CH2) w -; and V independently constitutes C. 3-7 Cycloalkyl or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein V is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy.

[0261] In one implementation, L X For the bond, -CH2-, -NR d -(CH2) w -、or -O-(CH2) w -; V is independently selected from C 1-3 Alkoxy, C 3-4 Cycloalkyl, or a 3- to 7-membered heterocyclic alkyl ring containing one or two heteroatoms independently selected from N or O, wherein V is optionally composed of one heteroatom independently selected from C. 1-3 Alkyl and C 1-3 The alkoxy group is substituted; and w is 0 or 1.

[0262] In one implementation, L X For bond or -O-(CH2) w -;V is C 3-7 Cycloalkyl or a 3- to 6-membered heterocyclic alkyl ring containing a heteroatom selected from N and O, wherein V is optionally substituted by up to three independent substituents selected from: halogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy group; and w is 0 or 1.

[0263] In one implementation, L X For bond or -O-(CH2) w -; V is a 3- to 6-membered heterocyclic alkyl ring containing one or two heteroatoms selected from N and O, wherein V is optionally substituted by up to three independent substituents selected from: halogen, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy group; and w is 0 or 1.

[0264] In one implementation, L X For bond or -O-(CH2) w-; V is a 3- to 6-membered heterocyclic alkyl ring containing one or two heteroatoms selected from N and O, wherein V is optionally substituted by up to three independent substituents selected from: halogen, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy group; and w is 0 or 1.

[0265] In one implementation, L X For bond or -O-(CH2) w -; V is a 5- to 6-membered heterocyclic alkyl ring containing one or two heteroatoms selected from N and O, wherein V is optionally substituted by up to three independent substituents selected from: halogen, halogenated (C 1-3 )alkyl, C 1-3 Alkoxy and halogen (C 1-3 )alkoxy group; and w is 0 or 1.

[0266] In one implementation, L X For bond or -O-(CH2) w -; V is selected from propylene-3-yl, 3,3-difluoropyrrolidone-1-yl, cyclopropyl, oxacyclopentan-3-yl, cyclobutyl, 1,4-dioxane-2-yl, 3-methoxybicyclo[1.1.1]pentan-1-yl, morpholino-4-yl, 4,4-difluoropiperidin-1-yl, 3-fluoropiperidin-1-yl, piperidin-1-yl, 3,3-difluoropiperidin-1-yl, oxane-4-yl, 8-oxabicyclo[3.2.1]oct-3-yl, 3-methylpropylene-3-yl), 3-fluoropyrrolidone-1-yl, and 4-fluoro-2-azabicyclo[2.1.1]hex-2-yl; and w is 0 or 1. In one embodiment, V is 3,3-difluoropyrrolidone-1-yl.

[0267] To avoid ambiguity, divalent L X The left side of the part (e.g., -NR) d The N atom of C(O)- is attached to the ring, and the right side is attached to V.

[0268] In one implementation, Y 1 Y 2 Y 3 and Y 4 For CR y ; or Y 1 Y 2 and Y 3 For CR y And Y 4 For N; or Y 2 and Y 4 For CR y And Y 1 and Y3 Let N be the number of elements in the array.

[0269] In one implementation, Y 1 Y 2 Y 3 and Y 4 For CR y .

[0270] In one implementation scheme, each R y Independently selected from hydrogen, halogen, cyano, C 1-3 Alkyl, C 1-3 Alkyloxy, methoxy (C 1-3 )alkoxy, hydroxyl (C 2-5 )alkyl, hydroxyl (C 2-5 ) ynyl group, C 2-5 The alkynyl group and a 5-membered heteroaryl group containing up to three heteroatoms independently selected from N, O, and S, wherein the 5-membered heteroaryl group is optionally surrounded by up to three C atoms. 1-3 Alkyl-substituted; or

[0271] R y and R f Together with the atoms they are attached to, they form 6-membered rings that optionally contain oxygen atoms.

[0272] In one implementation scheme, each R y Independently selected from hydrogen, halogen, cyano, C 1-3 Alkyloxy, methoxy (C 1-3 )alkoxy, hydroxyl (C 2-5 )alkyl, hydroxyl (C 2-5 ) ynyl group, C 2-5 The alkynyl group and a 5-membered heteroaryl group containing up to three heteroatoms independently selected from N, O, and S, wherein the 5-membered heteroaryl group is optionally surrounded by up to three C atoms. 1-3 Alkyl-substituted; or

[0273] R y and R f Together with the atoms they are attached to, they form 6-membered rings that optionally contain oxygen atoms.

[0274] In one implementation scheme, each R y Independently selected from hydrogen, halogen, cyano, methyl, methoxy, methoxyethoxy, hydroxymethyl, 2-methylbut-3-ynyl-2-ol, propyl, and 2-methyl-1,3,4-oxadiazolyl; or

[0275] R y and R f Together with the atoms they are attached to, they form a 6-membered ring containing oxygen atoms.

[0276] In one implementation scheme, each Ry Independently selected from hydrogen, halogen, cyano, methoxy, methoxyethoxy, hydroxymethyl, 2-methylbut-3-ynyl-2-ol, propyl, and 2-methyl-1,3,4-oxadiazolyl; or

[0277] R y and R f Together with the atoms they are attached to, they form a 6-membered ring containing oxygen atoms.

[0278] In one implementation scheme, each R y It is hydrogen. In other words, in one implementation, Y 1 Y 2 Y 3 and Y 4 Each is CH.

[0279] In one implementation, Z is a halogen, and C is a halogen. 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl or C 2-5 alkynyl group; or

[0280] Z represents ring B, where ring B is phenyl, benzimidazolyl, 3-azabicycloheptyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3,4-thiadiazolyl, 1,3-dihydroisobenzofuranyl, indazolyl, indolyl, 1-oxa-6-azaspirooctyl, 2,3-dihydrobenzofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophene 1,1-dioxide, 3,4-dihydrobenzoxazinyl, 3,4-dihydropyranyl, imidazopyridyl, 1,2,4-triazolyl, 5,6,7,8-tetrahydropyridinylpyridazinyl, 5,6-dihydropyrrolopyrazolyl, 6-oxaspirooctyl, benzothiazolyl Phenoyl, benzoisothiazolyl, benzoxazol-2-one, benzoxazolyl, benzothiazolyl, benzofuranyl, cyclohexyl, cyclopentyl, cyclopropyl, furanyl, furanopyridazinyl, imidazopyridazinyl, imidazoalkyl-2-one, dihydroindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxepaneyl, oxepaneyl, piperidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydrothiophene 1,1-dioxide, tetrazopyridazinyl, thiazolyl, thienopyrimidinyl, thienopyridinyl, or thienoyl, wherein ring B is optionally substituted by up to three independent substituents selected from: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0281] The two substituents of ring B, together with the atoms they are attached to, form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S; and

[0282] Where L B W, R g and R h As defined in equations (I), (Ia), and (I-aa) in this paper.

[0283] In one implementation scheme, Z is halogen, halogenated (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, or C 2-5 alkynyl group; or

[0284] Z represents ring B, where ring B is phenyl, benzimidazolyl, 3-azabicycloheptyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3,4-thiadiazolyl, 1,3-dihydroisobenzofuranyl, indazolyl, indolyl, 1-oxa-6-azaspirooctyl, 2,3-dihydrobenzofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophene 1,1-dioxide, 3,4-dihydrobenzoxazinyl, 3,4-dihydropyranyl, imidazopyridyl, 1,2,4-triazolyl, 5,6,7,8-tetrahydropyridinylpyridazinyl, 5,6-dihydropyrrolopyrazolyl, 6-oxaspirooctyl, benzothiazolyl Phenoyl, benzoisothiazolyl, benzoxazol-2-one, benzoxazolyl, benzothiazolyl, benzofuranyl, cyclohexyl, cyclopentyl, cyclopropyl, furanyl, furanopyridazinyl, imidazopyridazinyl, imidazoalkyl-2-one, dihydroindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxepaneyl, oxepaneyl, piperidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydrothiophene 1,1-dioxide, tetrazopyridazinyl, thiazolyl, thienopyrimidinyl, thienopyridinyl, or thienoyl, wherein ring B is optionally substituted by up to three independent substituents selected from: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0285] The two substituents of ring B, together with the atoms they are attached to, form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S; and

[0286] Where L B W, R g and R h As defined in equations (I), (Ia), and (I-aa) in this paper.

[0287] In one implementation, Z is a halogen, and C is a halogen. 1-3 Alkyl, halogenated (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, or C 2-5 Alkyne group.

[0288] In one implementation scheme, Z is halogen, halogenated (C 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, or C 2-5 Alkyne group.

[0289] In one implementation, L 2 For key, -NR f -S(O)2- or -NR f -C(O)-; and

[0290] Z represents halogen, halogenated (C) 1-3 )alkyl, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, or C 2-5 Alkyne group.

[0291] In one embodiment, Z is bromine, trifluoromethyl, vinyl, 1-fluorovinyl, or ethynyl.

[0292] In one implementation, L 2 For key, -NR f -S(O)2- or -NR f -C(O)-; and

[0293] Z can be bromine, trifluoromethyl, vinyl, 1-fluorovinyl, or ethynyl.

[0294] In one implementation, Z is ring B, where ring B is C. 6-10 Aryl, 3- to 10-membered heteroaryl, C 3-10 Cycloalkyl, or 3- to 10-membered heterocycloalkyl, wherein ring B is optionally substituted by up to three independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g Rh -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, where L B W, R g and R h As defined in equations (I), (Ia), and (I-aa) in this paper.

[0295] In one embodiment, Z is ring B, wherein ring B is phenyl, benzimidazolyl, 3-azabicycloheptyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3,4-thiadiazolyl, 1,3-dihydroisobenzofuranyl, indazole, indolyl, 1-oxa-6-azaspiroctyl, 2,3-dihydrobenzofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophene 1,1-dioxide, 3,4-dihydrobenzoxazinyl, 3,4-dihydropyranyl, imidazopyridyl, 1,2,4-triazolyl, 5,6,7,8-tetrahydropyridinylpyridazinyl, 5,6-dihydropyrrolopyrazolyl, 6-oxaspiroctyl Benzothiophene, benzoisothiazolyl, benzoxazolyl-2-one, benzoxazolyl, benzothiazolyl, benzofuranyl, cyclohexyl, cyclopentyl, cyclopropane, furanyl, furanopyridazinyl, imidazopyridazinyl, imidazoalkyl-2-one, dihydroindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxepaneyl, oxepaneyl, piperidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydrothiaphenyl 1,1-dioxide, tetrazopyridazinyl, thiazolyl, thienanopyrimidinyl, thienanopyridinyl, or thienyl, wherein ring B is optionally substituted by up to three independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R hand L B -W, or

[0296] The two substituents of ring B, together with the atoms they are attached to, form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S; and

[0297] Where L B W, R g and R h As defined in equations (I), (Ia), and (I-aa) in this paper.

[0298] In one implementation, ring B is selected from:

[0299]

[0300]

[0301] Each of the above groups can be replaced by up to three independent substituents selected from the following: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0302] The two substituents of ring B, together with the atoms they are attached to, form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S; and

[0303] Where L B W, R g and R h As defined in equations (I), (Ia), and (I-aa) in this paper.

[0304] In one embodiment, ring B is optionally substituted by up to three independent substituents selected from the following: halogen, cyano, hydroxyl, C 1-3 Alkyl, C1-3 Alkoxy, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, -C 2-5 alkenyl, -C 1-3 Alkylene-NR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0305] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0306] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)- and -CH2C(O)NH-;

[0307] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclic alkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl groups and -C(O)O(C) 1-4 )alkyl;

[0308] p is 1; and

[0309] Where R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0310] To avoid ambiguity, divalent L B The left side of the part (e.g., the C atom of -CH2O-) is attached to ring B, and the right side is attached to W.

[0311] In one embodiment, Z is ring B, wherein ring B is phenyl, benzimidazolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3,4-thiadiazolyl, 1,3-dihydroisobenzofuranyl, indazole, indolyl, 2,3-dihydrobenzofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophene 1,1-dioxide, 3,4-dihydrobenzoxazinyl, 3,4-dihydropyranyl, imidazopyridyl, 1,2,4-triazolyl, 5,6-dihydropyrrolopyridine. Azolyl, 6-oxaspiroctyl, benzoisothiazolyl, benzoxazol-2-one, benzoxazolyl, benzothiazolyl, benzofuranyl, cyclohexyl, cyclopentyl, furanyl, furanopyridazinyl, imidazopyridazinyl, dihydroindolyl, isothiazolyl, isoxazolyl, oxacycloheptyl, piperidinyl, pyrazolyl, pyridazinyl, pyrimidinyl, tetrahydrothiophene 1,1-dioxide, thiazolyl, or thiophene, wherein ring B is optionally substituted by up to three independent substituents selected from: halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W;

[0312] L B And W as defined in this paper for equations (I), (Ia), and (I-aa); and

[0313] Where R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0314] In one embodiment, ring B is optionally substituted by up to three independent substituents selected from the following: halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, C 2-5alkenyl, -C 1-3 Alkylene-NR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W;

[0315] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)- and -CH2C(O)NH-;

[0316] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclic alkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl groups and -C(O)O(C) 1-4 )alkyl;

[0317] p is 1; and

[0318] Where R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0319] In one implementation, L 2 It is -NCH3SO2-;

[0320] Z is C 2-5 alkenyl or C 1-3 Alkyl; or

[0321] Z is ring B, wherein ring B is aryl or heteroaryl, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted by up to three independent substituents selected from the following: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, -C 1-3 Alkylene-NR g R h -NR g R h -SO2NR g R h and L B -W, or

[0322] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0323] L B Independently selected from the bond and -C(O)-;

[0324] W is independently selected from hydrogen and C. 1-3 Alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclic alkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl groups and -C(O)O(C) 1-4 alkyl; and

[0325] R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0326] In one implementation, L 2 It is -NCH3SO2-;

[0327] Z is C 2-5 alkenyl; or

[0328] Z is ring B, wherein ring B is aryl or heteroaryl, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted by up to three independent substituents selected from the following: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, -C 1-3 Alkylene-NR g R h -NR g R h -SO2NR g R h and L B -W, or

[0329] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0330] L B Independently selected from the bond and -C(O)-;

[0331] W is independently selected from hydrogen and C. 1-3 Alkyl, C 3-7Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclic alkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl groups and -C(O)O(C) 1-4 alkyl; and

[0332] R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0333] In one implementation, L 2 It is -NCH3SO2-, and Z is a ring B;

[0334] Wherein ring B is phenyl, benzimidazolyl, 1,2,4-triazolyl, pyridyl, benzofuranyl, imidazopyridyl, benzoxazolyl-2-one, indolyl, benzothiazolyl, benzoxazolyl, dihydroindolyl, 2,3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, or 3,4-dihydrobenzoxazinyl, wherein ring B is optionally substituted by at most three independent substituents selected from the following: halogen, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, -C 1-3 Alkylene-NR g R h -NR g R h -SO2NR g R h and L B -W;

[0335] L B Independently selected from the bond and -C(O)-;

[0336] W is independently selected from hydrogen and C. 1-3 Alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclic alkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl groups and -C(O)O(C) 1-4 alkyl; and

[0337] R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0338] In one implementation, L2 For key;

[0339] Z represents a halogen or halogenated (C) 1-3 alkyl; or

[0340] Z represents ring B, where ring B is aryl, heteroaryl, or C. 3-10 Cycloalkyl, or a 3- to 10-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted by up to three substituents independently selected from: halogen, cyano, hydroxyl, C 1-3 Alkyl, C 1-3 Alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, -NR g R h and L B -W;

[0341] L B Independently selected from -(CH2) p -, -CH2O-, -C(O)- and -CH2C(O)NH-;

[0342] W is independently selected from -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclic alkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S;

[0343] p is 1; and

[0344] R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0345] In one embodiment, ring B is a single ring or a double ring. In one embodiment, ring B is a double ring.

[0346] In one embodiment, ring B is a benzimidazole group optionally substituted by up to three independent substituents selected from the following: halogen, cyano, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, -C 1-3 Alkylene-NR g R h -NR g R h -NR g C(O)R h-SO2NR g R h and L B -W, or

[0347] The two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring that optionally contains one or two heteroatoms independently selected from N, O, and S;

[0348] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)- and -CH2C(O)NH-;

[0349] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocyclic alkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, C 1-3 Alkyl groups and -C(O)O(C) 1-4 )alkyl;

[0350] p is 1; and

[0351] R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0352] In one embodiment, ring B is a benzimidazole group optionally substituted by up to three independent substituents selected from the following: halogen, C 1-3 Alkyl, C 3-7 cycloalkyl, -C 1-3 Alkylene-NR g R h -NR g R h and a 4- to 6-membered heterocyclic alkyl ring containing one or two independent heteroatoms selected from N, O, and S, wherein the heterocyclic alkyl ring is optionally C 1-3 Alkyl substitution; and

[0353] Where R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0354] In one embodiment, ring B is a benzimidazole group optionally substituted by up to three independent substituents selected from the following: halogen, C 1-3 Alkyl, cyclopropane, -C 1-3 Alkylene-NR gR h -NR g R h and piperidine; and

[0355] Where R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0356] In one embodiment, ring B is formed by the interaction of carbon atoms with L. 2 Connected to and optionally substituted with up to three independent substituents selected from the following: halogen, C 1-3 Alkyl, cyclopropane, -C 1-3 Alkylene-NR g R h -NR g R h and piperidine; and

[0357] Where R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0358] In one embodiment, ring B is a 1H-benzo[d]imidazol-5-yl group optionally substituted with up to three independent substituents selected from the following: halogen, C 1-3 Alkyl, cyclopropane, -C 1-3 Alkylene-NR g R h -NR g R h and piperidine; and

[0359] Where R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0360] In one embodiment, when Z is cyclic B and cyclic B is a benzimidazole group, it interacts with L via a carbon atom (e.g., via the carbon atom shown in formula (II) below). 2 connect.

[0361] In one embodiment, ring B is 1,2-dimethyl-1H-benzo[d]imidazol-5-yl.

[0362] In one embodiment, the compound of formula (I) is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof:

[0363]

[0364] (Ib)

[0365] Where n, ring A, Z, L1 L 2 R 1 R 2 R X2 R X3 R X4 Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0366] In one embodiment, the compound of formula (I) is the compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

[0367]

[0368] (Ic)

[0369] Among them, rings A, Z, and R 1 R 2 R X3 R c R f Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0370] In one embodiment, the compound of formula (I) is a compound of formula (I-cc) or a pharmaceutically acceptable salt thereof:

[0371]

[0372] (I-cc)

[0373] Among them, rings A, Z, and R 1 R 2 R X2 R X3 R c R f Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0374] In one embodiment, the compound of formula (I) is a compound of formula (I-ccc) or a pharmaceutically acceptable salt thereof:

[0375]

[0376] (I-ccc)

[0377] Where X 3 For -NR o - or -O-, and where rings A, Z, R 1 R 2 R o R c R f Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0378] In one embodiment, the compound of formula (I) is the compound of formula (Id) or a pharmaceutically acceptable salt thereof:

[0379]

[0380] (Id)

[0381] Among them, rings A, Z, and R 1 R 2 R X3 R c R f Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0382] In one embodiment, the compound of formula (I) is a compound of formula (I-dd) or a pharmaceutically acceptable salt thereof:

[0383]

[0384] (I-dd)

[0385] Among them, rings A, Z, and R 1 R 2 R X2 R X3 R c R f Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0386] In one embodiment, the compound of formula (I) is the compound of formula (Ie) or a pharmaceutically acceptable salt thereof:

[0387]

[0388] (Ie)

[0389] Among them, Z and R 1 R 2 R X3 R c R f Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0390] In one embodiment, the compound of formula (I) is a compound of formula (I-ee) or a pharmaceutically acceptable salt thereof:

[0391]

[0392] (I-ee)

[0393] Among them, Z and R 1 R 2 R X2 R X3 R c R f Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0394] In one embodiment, the compound of formula (I) is a compound of formula (I-eee) or a pharmaceutically acceptable salt thereof:

[0395]

[0396] (I-eee)

[0397] Where X 3 For -NR o - or -O-, where Z, R 1 R 2 R o R c R f Y 1 Y 2 Y 3 and Y 4 As defined in equations (I), (Ia), and (I-aa) in this paper.

[0398] In one embodiment, the compound of formula (I) is the compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0399]

[0400] (II)

[0401] in:

[0402] m is an integer from 1 to 3;

[0403] q is an integer from 1 to 3;

[0404] Each R 6 Independently selected from halogen, cyano, nitro, hydroxyl, -NR a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0405] Each R 7 Independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0406] Two Rs 7 Together with the atoms they are attached to, they form 5- or 6-membered rings, which may optionally contain one or two heteroatoms independently selected from N, O, and S;

[0407] L B Independently selected from the bond, -(CH2) p -, -CH2O-, -C(O)-NH-, -C(O)- and -CH2C(O)NH-;

[0408] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR m R n , carboxyl group, -CONR m R n C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0409] p is 1 or 2;

[0410] R a R b R g R h R m and R n Each independently is hydrogen, C 1-3 Alkyl or C 3-7 cycloalkyl; and

[0411] R 1 R X3 R c and R f As defined in equations (I), (Ia), and (I-aa) in this paper.

[0412] To avoid ambiguity, R 7 It can be attached to any available atom (including two nitrogen atoms) of the benzimidazole ring of formula (II).

[0413] In one embodiment, the compound of formula (I) is the compound of formula (II) or a pharmaceutically acceptable salt thereof:

[0414]

[0415] (II)

[0416] in:

[0417] m is an integer from 1 to 3;

[0418] q is an integer from 1 to 3;

[0419] Each R 6 Independently selected from halogen, cyano, nitro, hydroxyl, -NR a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0420] Each R 7 Independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or

[0421] Two Rs 7 Together with the atoms they are attached to, they form 5- or 6-membered rings, which may optionally contain one or two heteroatoms independently selected from N, O, and S;

[0422] L B Independently selected from the bond, -(CH2) p-, -CH2O-, -C(O)-NH-, -C(O)- and -CH2C(O)NH-;

[0423] W is independently selected from hydrogen and C. 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR m R n , carboxyl group, -CONR m R n C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl;

[0424] p is 1 or 2;

[0425] R a R b R g R h R m and R n Each independently is hydrogen, C 1-3 Alkyl, or C 3-7 cycloalkyl;

[0426] R 1 It is hydrogen or C 1-3 alkyl;

[0427] R X3 It is hydrogen or C 1-3 alkoxy groups; and

[0428] R c and R f Each independently is hydrogen, C 1-3 Alkyl, or C 3-7 Cycloalkyl.

[0429] In one implementation scheme, each R 6 Independently selected from halogens, hydroxyl groups, and C 1-3 Alkyl and halogenated (C 1-3 )alkyl;

[0430] Each R 7 Independently selected from halogens, C 1-3 Alkyl, -C 1-3 Alkylene-NR g R h -NR g R h and L B -W;

[0431] L B For key;

[0432] W is C 3-7 Cycloalkyl or a 4- to 6-membered heterocyclic alkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally controlled by C. 1-3 Alkyl substitution; and

[0433] R g and R h Each is independently hydrogen or C 1-3 alkyl.

[0434] In one embodiment, the compound of formula (I) is a compound of formula (II-a) or a pharmaceutically acceptable salt thereof:

[0435]

[0436] (II-a)

[0437] Where R 1 R 6 R 7 R X3 R c R f m and q are defined as in equations (I) and (II) in this paper.

[0438] In one embodiment, the compound of formula (I) is a compound of formula (II-aa) or a pharmaceutically acceptable salt thereof:

[0439]

[0440] (II-aa)

[0441] Where X 3 For -NR o - or -O-, and where R 1 R 6 R 7 R o -、R c R f m and q are defined as in equations (I) and (II) in this paper.

[0442] In one embodiment, the compound of formula (I) is a compound of formula (II-b) or a pharmaceutically acceptable salt thereof:

[0443]

[0444] (II-b)

[0445] Where R 1 R 6 R 7 R X3 R c R f m and q are defined as in equations (I) and (II) in this paper.

[0446] In one embodiment, the compound of formula (I) is a compound of formula (II), (II-a) or (II-b), wherein:

[0447] R 1 It is hydrogen;

[0448] R c It is hydrogen;

[0449] R f Methyl; and

[0450] R X3 For hydrogen, C 1-3 Alkoxy, C 1-3 Alkoxy (C 1-3 )alkyl-, halogenated (C 1-3 Alkoxy, or a 5- or 6-membered heterocyclic alkyl ring containing a heteroatom independently selected from N, O, and S.

[0451] In one embodiment, the compound of formula (I) is a compound of formula (II), (II-a) or (II-b), wherein:

[0452] m is 2;

[0453] q is 2;

[0454] R 1 It is hydrogen;

[0455] R c It is hydrogen;

[0456] R f It is methyl;

[0457] R X3 It is hydrogen, ethoxy, methoxymethyl, or optionally substituted pyrrolidinyl;

[0458] R 6 Selected from trifluoromethyl and fluorine; and

[0459] R 7 It is a methyl group.

[0460] In one embodiment, the compound of formula (I) is selected from the compounds in Table 1 or their pharmaceutically acceptable salts.

[0461] In one embodiment, the compound of formula (I) is selected from:

[0462] , ,

[0463] and ,

[0464] Or its pharmaceutically acceptable salt.

[0465] The chemical names in this application are generated from the corresponding structures using CHEMDRAW or CHEMAXON. In some cases, chemical names generated from structures may yield different structures when using the "Convert Name to Structure" function in CHEMDRAW. For example, based on the structure of the compound in Example 83, CHEMDRAW gives the name "(1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-((N,1,2-trimethyl-1H-benzi[d]imidazole)-5-sulfonamide)phenyl)cyclohexane-1-carboxylic acid", while when using the "Convert Name to Structure" function in CHEMDRAW, this name gives a different structure. Another name, “(1R,2R,6S)-2-{[2-fluoro-4-(trifluoromethyl)phenyl]carbamoyl}-6-[4-(N-methyl-1,2-dimethyl-1H-1,3-benzodiazole-5-sulfonylamino)phenyl]cyclohexane-1-carboxylic acid”, gives the correct structure of the compound of Example 83 in CHEMDRAW. Therefore, in the event of potential ambiguity, the compounds in this application should be determined based on their structures.

[0466] In this disclosure, the designation “&” indicates the simultaneous presence of two chiral centers in the mixture. When multiple centers are designated as “&1”, their relative stereochemistry is determined. The term “rac” in the chemical name indicates a racemic mixture.

[0467] The notation "or" in the structure refers to a specific chiral center, which is a single, undefined isomer, but whose absolute stereochemistry has not yet been determined. When multiple centers are notated as "or1", what is determined is their relative stereochemistry, not their absolute stereochemistry. The term "rel" in the chemical name indicates that the relative stereochemistry has been determined, but the absolute chemistry has not yet been determined.

[0468] The marking in chemical names "This refers to the presence of undefined chiral centers in a molecule, which also contains other defined chiral centers."

[0469] Unless otherwise stated, isomer 1 refers to the first eluting isomer in the chiral chromatographic separation process, and isomer 2 refers to the second eluting isomer in the separation process.

[0470] Table 1.

[0471]

[0472]

[0473]

[0474]

[0475]

[0476]

[0477]

[0478]

[0479]

[0480]

[0481]

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500]

[0501]

[0502]

[0503] On the other hand, this disclosure provides methods for preparing the compounds disclosed herein or pharmaceutically acceptable salts thereof, as well as chemical intermediates for preparing the compounds.

[0504] On the other hand, this disclosure provides pharmaceutical compositions comprising: a) a compound disclosed herein or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable excipient. The excipient must be acceptable, i.e., compatible with other components in the composition and will not cause harm to the recipient.

[0505] On the other hand, this disclosure provides the compounds disclosed herein or pharmaceutically acceptable salts thereof for therapeutic purposes.

[0506] On the other hand, this disclosure provides the compounds disclosed herein or pharmaceutically acceptable salts thereof for the treatment of cancer.

[0507] In one embodiment, the cancer is characterized by MSI-H and / or dMMR.

[0508] In one implementation, the cancer can be treated by inhibiting WRN.

[0509] On the other hand, this disclosure provides a method for treating cancer in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0510] On the other hand, a method for treating cancer that can be treated by inhibiting a patient's WRN is provided, the method comprising administering to the patient a therapeutically effective amount of the disclosed compound or a pharmaceutically acceptable salt thereof. In one embodiment, the patient does indeed require such treatment. In one embodiment, the disclosed compound or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.

[0511] On the other hand, this disclosure provides a method for treating patients with cancers characterized by MSI-H and / or dMMR, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof. In one embodiment, the patient does indeed require such treatment. In one embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is administered in the form of a pharmaceutical composition.

[0512] In one embodiment, the cancer is characterized by MSI-L or MSI-H according to any method known in the art. For example, a cancer characterized by MSI-L or MSI-H may contain one or more MSI markers (MSI-L), or preferably two or more MSI markers (MSI-H), in each case, these markers are selected from BAT25, BAT26, D2S123, D5S346, and D17S250. In one embodiment, the cancer is characterized by dMMR and contains mutations that impair DNA mismatch repair, preferably the cancer contains mutations in the MutS homolog and / or the MutL homolog. In a sub-implementation, the MutS homolog is selected from MSH2, MSH3, and MSH6, and the MutL homolog is selected from MLH1, MLH3, PMS1, and PMS2, preferably containing mutations in MLH1, MSH2, and / or PMS2.

[0513] On the other hand, this disclosure provides pharmaceutical compositions comprising the compounds disclosed herein or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0514] On the other hand, this disclosure provides compounds disclosed herein or pharmaceutically acceptable salts thereof for the treatment of cancers that can be treated by inhibiting WRN.

[0515] On the other hand, this disclosure provides compounds disclosed herein or pharmaceutically acceptable salts thereof for treating cancers in patients characterized by high MSI and / or dMMR. In one embodiment, the patient does indeed require such treatment. In one embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are administered in the form of a pharmaceutical composition. In one embodiment, the cancer is characterized by MSI-L or MSI-H according to any method known in the art. For example, cancers characterized by MSI-L or MSI-H may contain one or more MSI markers (MSI-L), or preferably two or more MSI markers (MSI-H), in each case, these markers are selected from BAT25, BAT26, D2S123, D5S346, and D17S250. In one embodiment, the cancer is characterized by dMMR and contains mutations that impair DNA mismatch repair, preferably the cancer contains mutations in the MutS homolog and / or the MutL homolog. In one embodiment, the MutS homolog is selected from MSH2, MSH3 and MSH6, and the MutL homolog is selected from MLH1, MLH3, PMS1 and PMS2, preferably containing mutations in MLH1, MSH2 and / or PMS2.

[0516] On the other hand, this disclosure provides a method for treating cancer in a patient, the method comprising:

[0517] (i) Determine whether the cancer contains high MSI and / or dMMR; and

[0518] (ii) If the cancer contains high MSI and / or dMMR, the patient is given a therapeutically effective amount of the compound disclosed in this invention or a pharmaceutically acceptable salt thereof.

[0519] In one embodiment, this document provides a method for treating an individual with a proliferative disease using a compound of the present disclosure or a pharmaceutically acceptable salt thereof that can effectively reduce WRN helicase activity, the method comprising: determining the presence of low microsatellite instability (MSI-L) or preferably high microsatellite instability (MSI-H) in the individual's proliferating cell population, or the presence of markers associated with MSI-L or MSI-H; determining the likelihood of the individual responding to a therapy comprising administering the compound of the present invention or a pharmaceutically acceptable salt thereof to the individual, based on the determination of the presence of MSI-L or MSI-H, or the presence of markers associated with MSI-L or MSI-H, respectively, in the proliferating cell population; and administering the compound of the present disclosure or a pharmaceutically acceptable salt thereof to the individual if the individual is predicted to respond to the therapy. In some embodiments, determining the presence of MSI-L or MSI-H in a proliferating cell population includes determining the presence of one or more MSI markers (MSI-L), preferably two or more MSI markers (MSI-H), in each case of which these markers are selected from BAT25, BAT26, D2S123, D5S346, and D17S250. In some embodiments, an individual is predicted to respond to the treatment if the number of cells in the proliferating cell population identified as having at least one MSI marker (MSI-L) or preferably at least two MSI markers (MSI-H) is above a predetermined threshold for proliferative disease. In some embodiments, an individual is predicted to be unresponsive to the treatment if (a) the number of cells in the proliferating cell population identified as having at least one MSI marker (MSI-L) or preferably at least two MSI markers (MSI-H) is below a predetermined threshold for proliferative disease; or (b) the proliferating cell population is determined to have no MSI markers (e.g., considered microsatellite stable (MSS)).

[0520] In one embodiment, determining the presence of MSI-H-related markers in the proliferating cell population, according to any of the above embodiments, includes determining the presence of mutations that impair DNA mismatch repair. In some embodiments, the mutation includes mutations in the MutS homolog and / or the MutL homolog. In some embodiments, the MutS homolog is selected from MSH2, MSH3, and MSH6, and the MutL homolog is selected from MLH1, MLH3, PMS1, and PMS2. In some embodiments, the mutation includes mutations in MLH1, MSH2, and / or PMS2.

[0521] In some embodiments, determining the presence of MSI-H-related markers in the proliferating cell population, according to any of the above embodiments, includes determining the presence of one or more markers of DNA damage. In some embodiments, the one or more markers of DNA damage are selected from high p21 expression and high γH2AX expression.

[0522] In some embodiments, according to any of the above embodiments, if the number of cells in a proliferating cell population found to have (i) at least one mutation impairing DNA mismatch repair and / or (ii) at least one marker of DNA damage is higher than a predetermined threshold for proliferative disease, then the individual is predicted to respond to the treatment. In some embodiments, the at least one mutation impairing DNA mismatch repair includes mutations in MLH1, MSH2, and / or PMS2, and the at least one marker of DNA damage includes high p21 expression and / or high γH2AX expression.

[0523] In some implementations, according to any of the above implementations, the following conditions predict that the individual will not respond to the treatment: if (a) the number of cells in the proliferating cell population that are identified as having (i) at least one mutation that impairs DNA mismatch repair; and / or (ii) at least one marker of DNA damage is below a predetermined threshold for proliferative disease; or (b) the proliferating cell population is identified as having neither a mutation that impairs DNA mismatch repair nor a marker of DNA damage.

[0524] On the other hand, this article provides an in vitro method for detecting microsatellite instability (MSI-H) and helicase activity of WRN in individuals diagnosed with or suspected of having proliferative diseases. The method comprises: (a) contacting a biological sample from the individual with one or more reagents for detecting the presence of MSI and helicase activity of WRN; and (b) detecting (i) the presence of MSI-H; and (ii) the helicase activity of WRN. In some embodiments, the reagents for detecting the presence of MSI-H in the biological sample include reagents for detecting the presence of two or more MSI markers selected from BAT25, BAT26, D2S123, D5S346, and D17S250.

[0525] On the other hand, this article provides an in vitro method for detecting high microsatellite instability (MSI-H) and helicase activity of WRN in individuals diagnosed with or suspected of having proliferative diseases. The method comprises: (a) contacting a biological sample from the individual with one or more reagents for detecting the presence of MSI-H-related biomarkers and WRN helicase activity; and (b) detecting (i) the presence of MSI-H-related biomarkers; and (ii) the helicase activity of WRN helicase. In some embodiments, the reagents for detecting the presence of MSI-H-related biomarkers in the biological sample include reagents for detecting the presence of (i) one or more mutations that impair DNA mismatch repair; and / or (ii) one or more biomarkers of DNA damage. In some embodiments, the one or more mutations that impair DNA mismatch repair include mutations in MutS homologs and / or MutL homologs. In some embodiments, the MutS homologs are selected from MSH2, MSH3, and MSH6, and the MutL homologs are selected from MLH1, MLH3, PMS1, and PMS2. In some embodiments, the one or more mutations include mutations in MLH1, MSH2, and / or PMS2. In some embodiments, the one or more markers of DNA damage are selected from high p21 expression and / or high γH2AX expression.

[0526] In one embodiment of this invention, the cancer is characterized by MSI-H according to any method known in the art. For example, a cancer characterized by MSI-H may contain two or more MSI markers selected from BAT25, BAT26, D2S123, D5S346, and D17S250. In one embodiment, the cancer is characterized by dMMR and contains mutations that impair DNA mismatch repair, preferably, the cancer contains mutations in MutS homologs and / or MutL homologs. In one embodiment, the MutS homolog is selected from MSH2, MSH3, and MSH6, and the MutL homolog is selected from MLH1, MLH3, PMS1, and PMS2, preferably mutations in MLH1, MSH2, and / or PMS2. In one embodiment, the cancer contains two or more markers of DNA damage.

[0527] In one implementation, the cancer is endometrial cancer, bile duct cancer, gastric cancer, pancreatic cancer, small bowel cancer, breast cancer, prostate cancer, bladder cancer, esophageal cancer, sarcoma, retroperitoneal adenocarcinoma, small lung cancer, or renal cell carcinoma. Preferably, the cancer is uterine corpus endometrial carcinoma, gastric adenocarcinoma, colonic adenocarcinoma, rectal adenocarcinoma, prostate adenocarcinoma, adrenocortical carcinoma, esophageal cancer, liver hepatocellular carcinoma, cervical squamous cell carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, kidney clear cell carcinoma, papillary kidney carcinoma, pancreatic cancer, urothelial bladder cancer, ovarian cancer, breast cancer, glioblastoma multiforme, or low-grade glioma (see Isidro Cortes-Ciriano et al. Nature Communication DOI: 10.1038 / ncomms15180).

[0528] On the other hand, this article provides a method for identifying the WRN helicase inhibitory activity in a WRN helicase test compound, the method comprising (i) contacting the test compound with isolated WRN enzyme in an assay buffer to form a WRN reaction premix; (ii) reacting the WRN reaction premix with a mixture containing 80 µM ATP and 80 nM dT 50 (a substrate mixture containing 50 thymine bases of single-stranded DNA (ssDNA), 200 µM NADH, 4 mM PEP, 10 U / mL lactate dehydrogenase and 20 U / mL pyruvate kinase is contacted to form a WRN reaction mixture; and (iii) the absorbance of the WRN reaction mixture is measured (● = 340 nm), wherein the method further comprises performing steps (i)-(iii) using a positive control sample represented by a compound of the present disclosure.

[0529] Pharmaceutical Composition

[0530] The compounds of formula (I) or pharmaceutically acceptable salts thereof provided herein may be in the form of compositions suitable for administration to a subject. Generally, such compositions are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. Pharmaceutical compositions may be used in all the methods disclosed herein; thus, for example, pharmaceutical compositions may be administered to a subject ex vivo or in vivo to perform the treatment methods and uses described herein.

[0531] Pharmaceutical compositions may be formulated to be compatible with intended methods or routes of administration; exemplary routes of administration are described herein. Furthermore, pharmaceutical compositions may be used in combination with other therapeutically active agents or compounds described herein to treat diseases, disorders, and conditions covered by this disclosure.

[0532] Pharmaceutical compositions containing an active ingredient (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) may be in forms suitable for oral administration, such as tablets, capsules, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups, solutions, microbeads, or elixirs. Pharmaceutical compositions intended for oral administration may be prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents, such as sweeteners, flavoring agents, coloring agents, and preservatives, to provide a pharmaceutically elegant and palatable formulation. Tablets and / or capsules contain the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for manufacturing tablets and / or capsules. These excipients may be, for example, diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0533] Pharmaceutical compositions typically comprise a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients. Suitable pharmaceutically acceptable excipients include, but are not limited to, antioxidants (e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzyl alcohol, methylparaben, ethylparaben, or n-propylparaben), emulsifiers, suspending agents, dispersants, solvents, fillers, bulking agents, detergents, buffers, mediators, diluents, and / or adjuvants. For example, a suitable mediator may be an aqueous solution of physiological saline or a citrate-buffered saline solution, possibly supplemented with other materials commonly found in pharmaceutical compositions intended for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are other exemplary mediators. Those skilled in the art will readily recognize the variety of buffers that can be used in the pharmaceutical compositions and dosage forms covered herein. Typical buffers include, but are not limited to, pharmaceutically acceptable weak acids, weak bases, or mixtures thereof. As an example, the buffer component can be a water-soluble material, such as phosphoric acid, tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and their salts. Acceptable buffers include, for example, Tris buffer, N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES), 2-(N-morpholino)ethanesulfonic acid (MES), sodium 2-(N-morpholino)ethanesulfonate (MES), 3-(N-morpholino)propanesulfonic acid (MOPS), and N-tris[hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

[0534] All compounds and pharmaceutical compositions provided herein can be used in all methods described herein. For example, the compounds and pharmaceutical compositions provided herein can be used in all methods for treating and / or preventing all diseases or disorders described herein. Therefore, the compounds and pharmaceutical compositions provided herein are used as medicines.

[0535] route of administration

[0536] Compounds of formula (I) or pharmaceutically acceptable salts thereof and compositions comprising them may be administered in any suitable manner. Suitable routes of administration include oral, parenteral (e.g., intramuscular, intravenous, subcutaneous (e.g., injection or implantation), intraperitoneal, intracisional, intra-articular, intracerebral (within brain parenchyma), sublingual, intraocular, and inhalation. Long-acting injectable formulations, typically administered subcutaneously or intramuscularly, may also be used for administration of compounds of formula (I) or pharmaceutically acceptable salts thereof over a specified time period. Specific embodiments of this disclosure cover oral administration.

[0537] Treatment of patients with tumors characterized by high microsatellite instability

[0538] On the one hand, this article provides a method for reducing the proliferation of proliferating cells with microsatellite instability (MSI), which includes reducing the helicase activity of Werner syndrome ATP-dependent helicase (WRN) in the proliferating cells. In some embodiments, reducing the helicase activity of Werner syndrome ATP-dependent helicase (WRN) in the proliferating cells is achieved by administering a compound of formula (I) (or any embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof. In some embodiments, the proliferating cells are characterized by having low MSI (MSI-L). In some embodiments, the proliferating cells are characterized by having high MSI (MSI-H), with high MSI and MISH-high being interchangeable. Cells can be characterized as MSI (including MSI-L or MSI-H) or microsatellite stable (MSS) according to any method known in the art (e.g., see Dudley, Jonathan C. et al., Clinical Cancer Research, 22(4): 813-820, 2016). MSI-H is used to classify tumors as tumors with a high frequency of MSI. Tumors can be classified as MSI using polymerase chain reaction (PCR) and / or immunohistochemistry (IHC) tests, including MSI-low or MSI-high. As described by Dudley et al. (as stated above), a tumor can be classified as MSI-H by PCR detection if it meets any of the following criteria: (i) the size of at least two microsatellite sites in the tumor is offset (usually downward) relative to a reference panel of five microsatellite sites in normal tissue, where the reference panel can be the “Bethesda Panel” (also referred to herein as the “NCI-reference panel (Bethesda, 1998)”) containing two single nucleotide sites (BAT-25 and BAT-26) and three dinucleotide sites (D2S123, D5S346, and D17S250), or alternatively, the reference panel can be the MSI analysis system of Promega Corporation, which contains five single nucleotide sites (BAT-25, BAT-26, NR-21, NR-24, and MONO-27); or (ii) the size of 30% or more microsatellite sites in the tumor is offset relative to a reference panel of more than five microsatellite sites in normal tissue. The MSI-H phenotype is associated with germline defects in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, and is the predominant phenotype observed in tumors of patients with HNPCC / Lynch syndrome. In IHC assays, tumors are classified as MSI-H if they show loss of protein expression in at least one of these four mismatch repair genes. Cells can be similarly classified as MSI-H using the tumor detection method described herein.

[0539] In some embodiments, tumor tissues or cells are classified as MSI-H by PCR amplification of five microsatellite loci (BAT-25, BAT-26, D2S123, D5S346, and D17S250) of the "Bethesda Panel" in tumor tissues or cells and normal tissues or cells. A tumor tissue or cell is classified as MSI-H if at least two microsatellite loci are displaced in size relative to normal tissues or cells. In some embodiments, the displacement of the microsatellite loci is downward.

[0540] In some embodiments, tumor tissues or cells are classified as MSI-H by PCR amplification of five microsatellite loci (BAT-25, BAT-26, NR-21, NR-24, and MONO-27) from a Promega MSI analysis system in both tumor tissues or cells and normal tissues or cells. A tumor tissue or cell is classified as MSI-H if at least two microsatellite loci show a size shift relative to normal tissues or cells. In some embodiments, the size shift of the microsatellite loci is downward.

[0541] In some embodiments, IHC is used to detect the expression levels of MMR proteins MLH1, MSH2, MSH6, and / or PMS2 in tumor and normal tissues to classify tumors as MSI-H. A tumor is classified as MSI-H if the expression of at least one MMR protein is absent in the tumor tissue relative to normal tissue. In some embodiments, the absence of protein expression is defined as a decrease of at least 20% (e.g., a decrease of 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more).

[0542] Conversely, tumors are classified as MSI-L by PCR if (i) the size of a microsatellite locus in the tumor is offset relative to a reference panel of five microsatellite loci in normal tissue, where the reference panel could be the Bethesda Panel or a Promega Corporation MSI analysis system; or (ii) less than 30% of the microsatellite loci in the tumor are offset relative to a reference panel of more than five microsatellite loci in normal tissue. MSI-L tumors are considered to represent a unique mutant phenotype whose molecular etiology may differ from that of MSI-H tumors (Thibodeau, 1998; Wu et al., 1999, Am J Hum Genetics 65: 1291-1298). Cells can also be similarly classified as MSI-L using the tumor detection methods described herein.

[0543] Combination therapy

[0544] This disclosure covers the use of compounds of formula (I) or pharmaceutically acceptable salts thereof in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other preventive or therapeutic modalities (e.g., radiation). In such combination therapies, the various active agents often have different, complementary mechanisms of action. Such combination therapies can be particularly advantageous because they allow for a reduction in the dosage of one or more agents, thereby reducing or eliminating side effects associated with one or more agents. Furthermore, such combination therapies can have a synergistic therapeutic or preventive effect on underlying diseases, disorders, or conditions.

[0545] As used herein, “combination” means including therapies that can be administered separately, such as therapies formulated separately for separate administration (e.g., those that may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., “combination formulation”).

[0546] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered or given sequentially, for example, one agent is administered before one or more other agents. In other embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered simultaneously, for example, two or more agents are administered at the same time or approximately at the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a compound formulation). Whether the two or more agents are administered sequentially or simultaneously, for the purposes of this disclosure, they are considered to be administered in combination.

[0547] This disclosure provides a method for treating cancer with a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one other therapeutic or diagnostic agent.

[0548] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in combination with at least one additional therapeutic agent selected from temozolomide, pemetrexed, pegylated liposomal doxorubicin (Doxil), eribulin (Halaven), ixaprazole (Ixempra), protein-bound paclitaxel (Abraxane), oxaliplatin, irinotecan, venatoclax (a bcl2 inhibitor), 5-azacytidine, anti-CD20 therapeutic agents such as rituximab (Rituxan) and obbinutuzumab, hormonal drugs (anastrozole, exemestane, letrozole, zoladex, lupon) eligard), CDK4 / 6 inhibitors, palbociclib, abemaciclib, CPIs (avelumab, cimiplimab-rwlc, and bevacizumab).

[0549] In some embodiments, this disclosure provides a method of treating cancer comprising administering a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, in combination with a signal transduction inhibitor (STI) to achieve an additive or synergistic effect of inhibiting tumor growth. As used herein, the term “signal transduction inhibitor” refers to an agent that selectively inhibits one or more steps in a signal transduction pathway. Examples of signal transduction inhibitors (STIs) that may be used in the methods described herein include, but are not limited to: (i) bcr / abl kinase inhibitors (e.g., GLEEVEC); (ii) epidermal growth factor (EGF) receptor inhibitors, including kinase inhibitors and antibodies; (iii) HER-2 / neu receptor inhibitors (e.g., Herceptin); (iv) Akt family kinases or Akt pathway inhibitors (e.g., rapamycin); (v) cell cycle kinase inhibitors (e.g., flavopyrrol); and (vi) phosphatidylinositol kinase inhibitors. Agents involved in immunomodulation may also be used in combination with one or more compounds of formula (I) described herein, or a pharmaceutically acceptable salt thereof, to inhibit tumor growth in cancer patients.

[0550] In some embodiments, this disclosure provides a method of treating cancer, which includes the combined administration of a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof and a chemotherapeutic agent. Examples of chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, improsulfan, and piposulfan; azacyclopropanes such as benzodopa, carboquone, meturedopa, and uredopa; ethylene imines and methyl melamines, including altretamine, triethylene melamine, triethylene methylphosphamide, triethylene thiophosphamide, and trihydroxymethyl melamine; and nitrogen mustards such as chiorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, and mechlorethamine oxide. Hydrochloride, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrourea such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;Antibiotics, such as aclacinomysin, actinomycin, autramycin, azaserine, bleomycin, cactinomycin C, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, and mycophenolic acid. The following are listed as examples of antibiotics: nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, and zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); and folic acid analogues such as folate (d...). Enopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluxuridine, 5-FU.Androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; antiadrenergic drugs such as aminoglutethimide, mitotane, and trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; and aminolevulinic acid. acid); amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate nitrate); hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazine; procarbazine; razoxane; sizofiran; spirogermanium; tenuazonic acid acid); triaziquone; 2,2',2”-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa;Taxoids, such as paclitaxel and docetaxel; chlorambucil; gemcitabine; 6-thioguanine; mecaptopurine; methotrexate; platinum and platinum coordination complexes such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitomycin C. C); mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT11; topoisomerase inhibitor; difluoromethylornithine (DMFO); retinoic acid; esperamicin; capecitabine; and any of the above pharmaceutically acceptable salts, acids, or derivatives. In one specific embodiment, the compounds of this disclosure are co-administered with a cell growth inhibitory compound selected from cisplatin, doxorubicin, paclitaxel, tazocin, and mitomycin C. In one specific embodiment, the cell growth inhibitory compound is doxorubicin.

[0551] Chemotherapy agents also include anti-hormonal agents that modulate or inhibit the effects of hormones on tumors, such as anti-estrogens, including, for example, tamoxifen, raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, ketoxifen, onanasone, and toremifene; and anti-androgens, such as flutamide, nilumet, bicalutamide, enzalutamide, apalutamide, abiraterone acetate, leuprorelin, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above substances. In some embodiments, combination therapy includes administration of hormones or related hormone agents.

[0552] This disclosure also covers the use of compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, in combination with immune checkpoint inhibitors. A vast array of genetic and epigenetic alterations characteristic of all cancers provide a diverse set of antigens that the immune system can utilize to distinguish tumor cells from normal cells. For T cells, the ultimate magnitude (e.g., the level of cytokine production or proliferation) and quality (e.g., the type of immune response produced, such as the pattern of cytokine production) triggered by antigen recognition by T cell receptors (TCRs) are regulated by a balance between co-stimulatory and inhibitory signals (immune checkpoints). Under normal physiological conditions, immune checkpoints are essential for preventing autoimmunity (i.e., maintaining self-tolerance) and protecting tissues from damage when the immune system responds to pathogen infection. The expression of immune checkpoint proteins can be dysregulated by tumors as an important mechanism of immune resistance. Examples of immune checkpoint inhibitors include, but are not limited to, CTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFβ, CD73, CD39, A2AR, A2BR, IDO1, TDO2, arginase, B7-H3, and B7-H4. Cell-based anticancer immunomodulators are also included. Examples of such modulators include, but are not limited to, chimeric antigen receptor T cells, tumor-infiltrating T cells, and dendritic cells.

[0553] This disclosure covers the use of compounds of formula (I) described herein or pharmaceutically acceptable salts thereof in combination with inhibitors of the aforementioned immune checkpoint receptors and ligands (e.g., ipilimumab, abatacept, nivolumab, pembrolizumab, atezolizumab, dostarlimab, and durvalumab).

[0554] Other therapeutic modalities that may be used in combination with compounds of formula (I) disclosed herein or their pharmaceutically acceptable salts include radiotherapy, monoclonal antibodies against tumor antigens, complexes of monoclonal antibodies and toxins, T-cell adjuvants, bone marrow transplantation, or antigen-presenting cells (e.g., dendritic cell therapy).

[0555] This disclosure covers the use of compounds of formula (I) described herein, or pharmaceutically acceptable salts thereof, alone or in combination with radiation and / or temozolomide (TMZ), avastin, or lomustine, for the treatment of glioblastoma.

[0556] dose

[0557] The compounds of formula (I) or pharmaceutically acceptable salts thereof provided herein may be administered to subjects in amounts depending on factors such as: the administration target (e.g., the desired level of resolution); the age, weight, sex, and health and physical condition of the subject administering the formulation; the route of administration; and the nature of their disease, disorder, ailment, or symptom. The dosing regimen may also take into account the presence, nature, and extent of any side effects associated with the administered formulation.

[0558] The effective dose (ED) is the amount or quantity of the drug that produces a therapeutic response or desired effect in some part of a subject taking the drug. The "median effective dose" or ED of the drug is... 50 This refers to the dosage or amount of a drug that produces a therapeutic response or desired effect in 50% of the population to which it is administered. Although ED 50 It is often used as a measure of the reasonable expected effect of a drug, but considering all relevant factors, it is not necessarily the dose that clinicians deem appropriate. Therefore, in some cases, the effective dose is greater than the calculated ED. 50 In other cases, the effective quantity is less than the calculated ED. 50 Furthermore, in some cases, the effective quantity and the calculated ED 50 same. Example

[0559] The following embodiments and references (intermediates) are provided to provide a complete disclosure and description of how the invention can be made and used by those skilled in the art, and are not intended to limit the scope of the disclosure as regarded by the inventors, nor are they intended to imply that the following experiments were performed or that they are all experiments that can be performed. It should be understood that the exemplary description written in the present tense is not necessarily performed, but rather that the description can be performed to generate data for the properties described therein. Efforts have been made to ensure the accuracy of the figures used (e.g., quantities, temperatures, etc.), but some experimental errors and biases should be taken into account. Some NMR data are processed using computer analysis and may contain artifacts inherent in the process, including impurity peaks, solvent peaks, and integration errors.

[0560] The mass yield of the reactions described herein refers to the amount of substance collected from the reaction, but the millimoles and yield percentages are adjusted according to the purity of the substance. For example, if 10 grams of product are collected from the reaction (equivalent to 20 mmol if the purity is 100%), but the purity of the product is measured to be 90%, the preparation will be reported as "(10 g, 18 mmol, 54% yield)". However, when the product is used as a starting material for subsequent steps, it will be considered 100% pure for stoichiometric purposes. For example, in a subsequent reaction, 10 grams of product will be described as a starting material of "10 g, 20 mmol".

[0561] intermediate

[0562] Intermediate 1: (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0563]

[0564] Step 1: (E)-1-bromo-4-(but-1,3-dien-1-yl)benzene

[0565]

[0566] In two separate, equivalent reactions: NaH (32.4 g, 811 mmol) was added to a mixture of allyl phosphate (144 g, 811 mmol) in THF (3000 mL) at 0 °C. After 50 minutes, 4-bromobenzaldehyde (0.100 kg, 0.540 mol) was added, and the mixture was heated to 25 °C for 4 hours. The two separate reactions were combined, cooled to 0 °C, quenched with an aqueous solution of NH4Cl (500 mL), and extracted with EtOAc (500 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated. The residue was dissolved in petroleum ether (500 mL) and 300 g of silica gel (100-200 mesh) was added. The resulting mixture was concentrated at 40 °C to obtain a dry, flowing solid, which was loaded onto a Biotage column (homemade column chromatography, 100-200 mesh silica gel) using 1,500 g of silica gel and eluted with a petroleum ether solution of 0-10% ethyl acetate to give (E)-1-bromo-4-(but-1,3-dien-1-yl)benzene (90 g, 410 mmol, 38% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4Hz, 2H), 6.76 (dd, J = 15.6 Hz, 10.4 Hz, 1H), 6.53 - 6.44 (m, 2H), 5.36 (d, J= 17.2 Hz, 1H), 5.21 (d, J = 10.0 Hz, 1H).

[0567] Step 2: A 1:1 mixture of (3aS,4S,7aR)-4-(4-bromophenyl)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione

[0568]

[0569] In two separate, equivalent reactions: at 25 °C, furan-2,5-dione (65.7 g, 0.670 mol) was added to a mixture of (E)-1-bromo-4-(but-1,3-dien-1-yl)benzene (140 g, 670 mmol) in toluene (1400 mL). The mixture was stirred at 120 °C for 12 hours. The two reactions were combined, concentrated, and ground at 20 °C with a 2:1 hexane:ethyl acetate mixture for 30 minutes. The mixture was filtered and washed with hexane (200 mL x 3) to give a 1:1 mixture (189 g, 599 mmol, 44.5% yield) of (3aS,4S,7aR)-4-(4-bromophenyl)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione as a white solid. 1 H NMR(400 MHz, DMSO-d6) δ 7.52 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 6.22(m, 1H), 6.17 - 6.15 (m, 1H), 3.83 (d, J = 2.0 Hz, 1H), 3.77 - 3.72 (m, 2H), 2.66 - 2.60 (m, 1H), 2.50 - 2.40 (m, 1H).

[0570] Step 3: A 1:1 mixture of (3aS,4S,7aR)-4-(4-bromophenyl)hexahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)hexahydroisobenzofuran-1,3-dione

[0571]

[0572] In three separate, equivalent reactions: at 25 °C under nitrogen, platinum (8.00 g, 2.05 mmol) was added to a 1:1 mixture (63.0 g, 205 mmol) of (3aS,4S,7aR)-4-(4-bromophenyl)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione in 1000 mL of THF. The mixture was placed under a hydrogen atmosphere (2 atm). The reaction was degassed by vacuum and then filled with hydrogen (3X). The mixture was stirred at 25 °C for 40 min under hydrogen. The three reactions were combined, filtered, and the filter cake was washed with THF (1 L x 3). The combined filtrates were concentrated, ground at 20°C with 5:1 hexane:ethyl acetate (500 mL) for 30 minutes, filtered, washed with hexane (100 mL x 3), and dried under reduced pressure at 40°C to provide a 1:1 mixture (164 g, 477 mmol, 78%) of (3aS,4S,7aR)-4-(4-bromophenyl)hexahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)hexahydroisobenzofuran-1,3-dione as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 3.99 (t, J = 6.8Hz, 1H), 3.35 - 3.29 (m, 1H), 3.16 - 3.10 (m, 1H), 2.09 - 2.04 (m, 1H), 1.91- 1.86 (m, 1H), 1.81 - 1.76 (m, 1H), 1.67 - 1.44 (m, 3H).

[0573] Step 4: A 1:1 mixture of (3aS,4S,7aR)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (3aR,4R,7aS)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid

[0574]

[0575] At 0 °C, NaBH4 (40.1 g, 1.06 mol) was added in portions to a 1:1 mixture (164 g, 0.530 mol) of (3aS,4S,7aR)-4-(4-bromophenyl)hexahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)hexahydroisobenzofuran-1,3-dione in 1500 mL of THF. The reaction was stirred for 1 hour, quenched with 2 N HCl (1.00 L) to pH < 3, and then extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to give a 1:1 mixture (135 g, 346 mmol, 65.2% yield) of (3aS,4S,7aR)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (3aR,4R,7aS)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid as a white solid, which was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 11.6 (br.s, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 3.34 - 3.30 (m, 1H), 3.23 - 3.18 (m, 1H), 2.88 (t, J = 4.4 Hz, 1H), 2.85- 2.79 (m, 1H), 2.35 - 2.24 (m, 1H), 1.90 - 1.75 (m, 2H), 1.56 - 1.44 (m,3H), 1.41 - 1.31 (m, 1H).

[0576] Step 5: A 1:1 mixture of (3aR,7S,7aS)-7-(4-bromophenyl)hexahydroisobenzofuran-1(3H)-one and (3aS,7R,7aR)-7-(4-bromophenyl)hexahydroisobenzofuran-1(3H)-one

[0577]

[0578] At 25 °C, 4-methylbenzenesulfonic acid (7.42 g, 43.1 mmol) was added to a 1:1 mixture (135 g, 431 mmol) of (3aS,4S,7aR)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (3aR,4R,7aS)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid in toluene (1300 mL). The reaction was stirred at 110 °C for 1 hour, cooled to 25 °C, diluted with water (300 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with 200 mL of NaHCO3 (aqueous solution) and 200 mL of brine, dried over Na2SO4, filtered, and concentrated to give a 1:1 mixture (118 g, 375 mmol, 87% yield) of (3aR,7S,7aS)-7-(4-bromophenyl)hexahydroisobenzofuran-1(3H)-one and (3aS,7R,7aR)-7-(4-bromophenyl)hexahydroisobenzofuran-1(3H)-one as a white solid, which was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 4.15 (q, J = 4.4 Hz, 1H), 3.84 (d, J = 8.4 Hz, 1H), 3.26 (t, J = 5.6 Hz,1H), 3.02 – 2.98 (m, 1H), 2.61 – 2.54 (m, 1H), 1.83 (d, J = 9.6 Hz, 3H), 1.49- 1.34 (m, 2H), 1.12 – 1.06 (m, 1H).

[0579] Step 6: A 1:1 mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid

[0580]

[0581] At 25 °C, KOH (112 g, 2.00 mol) was added to a 1:1 mixture (118 g, 0.400 mol) of (3aR,7S,7aS)-7-(4-bromophenyl)hexahydroisobenzofuran-1(3H)-one and (3aS,7R,7aR)-7-(4-bromophenyl)hexahydroisobenzofuran-1(3H)-one in methanol (1.18 L). The reaction was stirred at 75 °C for 3 hours, cooled to 0 °C, quenched with 2N HCl (1.00 L) to pH < 3, and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated to give a 1:1 mixture (105 g, 287 mmol, 71.9% yield) of (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid as a white solid, which was used directly without further purification. 1 H NMR (400MHz, DMSO-d6) δ 11.8 (s, 1H), 7.46 - 7.41 (m, 2H), 7.18 - 7.15 (m, 2H), 4.50 (s, 1H), 3.40 - 3.36 (m, 1H), 3.20 - 3.16 (m, 1H), 2.71 - 2.64 (m, 1H), 2.25(t, J = 10.8 Hz, 1H), 1.94 - 1.90 (m, 1H), 1.80 - 1.63 (m, 3H), 1.43 - 1.37(m, 2H), 1.12 - 1.08 (m, 1H).

[0582] Step 7: A 1:1 mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester.

[0583]

[0584] At 0 °C, K₂CO₃ (139 g, 1.01 mol) and (bromomethyl)benzene (86 g, 0.50 mol) were added to a 1:1 mixture (105 g, 335 mmol) of (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid in DMF (1050 mL). The reaction was stirred at 25 °C for 3 hours, diluted with water (500 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, concentrated, and ground at 20 °C with 5:1 hexane:ethyl acetate (300 mL) for 30 minutes. The mixture was filtered, washed with hexane (100 mL x 3), and dried under reduced pressure at 40 °C to provide a 1:1 mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester (98.0 g, 237 mmol, 70.7% yield) as a white solid. 1 H NMR(400 MHz, DMSO-d6) δ 7.41 (d, J = 8.4 Hz, 2H), 7.25 - 7.23 (m, 3H), 7.13 (d,J = 8.4 Hz, 2H), 6.87 - 6.85 (m, 2H), 4.87 (d, J = 12.4 Hz, 1H), 4.69 (d, J =12.8 Hz, 1H), 4.53 (t, J = 4.8 Hz, 1H), 3.30 - 3.27 (m, 1H), 3.23 - 3.18 (m,1H), 2.73 - 2.67 (m, 1H), 2.43 (t, J = 10.8 Hz, 1H), 1.88 - 1.85 (m, 1H), 1.81 - 1.70 (m, 3H), 1.52 - 1.36 (m, 2H), 1.18 - 1.09 (m, 1H).

[0585] Step 8: A 1:1 mixture of (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid and (1S,2S,3R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid

[0586]

[0587] At 0 °C, sodium periodate (151 g, 707 mmol) and ruthenium(III) chloride (4.89 g, 23.6 mmol) were added to a 1:1 mixture (95 g, 0.24 mol) of (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylate and (1S,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylate in acetonitrile (950 mL) and water (30 mL). The reaction was stirred at 25 °C for 3 h, diluted with water (500 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, concentrated, and ground at 20 °C with a 3:1 hexane:ethyl acetate mixture (200 mL) for 30 minutes. The mixture was filtered, washed with hexane (50 mL x 3), and dried under reduced pressure at 40 °C to provide a 1:1 mixture of (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid and (1S,2S,3R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid (88 g, 0.21 mol, 88% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.4 (s, 1H), 7.42 (d, J = 8.4Hz, 2H), 7.25 - 7.23 (m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 4.4 Hz, 2H), 4.69 (q, J = 12.8 Hz, 2H), 2.77 - 2.74 (m, 1H), 2.66 - 2.64 (m, 2H), 2.22 - 2.10 (m, 1H), 1.78 - 1.74 (m, 2H), 1.54 - 1.47 (m, 3H). ES-LCMS m / z439.0 [M+Na] + .

[0588] Step 9: A 1:1 mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester.

[0589]

[0590] To acetonitrile (850 mL), a 1:1 mixture (85 g, 0.20 mol) of (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid and (1S,2S,3R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid was added with 2-fluoro-4-(trifluoromethyl)aniline (73.0 g, 407 mmol) and 1-methyl-1H-imidazolium (33.4 g, 407 mmol). After approximately 2 minutes, N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (86 g, 0.31 mol) was added in portions. After 12 hours at 25 °C, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, concentrated, dissolved in EtOAc (500 mL), and combined with silica gel (300 g, 100-200). The resulting mixture was concentrated at 40 °C and loaded onto a silica gel column (300 g, 100-200 mesh silica gel). Elution was performed with a 10:1 to 5:1 solution of EtOAc in n-heptane to give a 1:1 mixture (87 g, 0.15 mol, 73% yield) of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester, as a white solid. 1 ¹H NMR (400 MHz, chloroform-d) δ 8.43 (t, J = 8.1 Hz, 1H), 7.60 – 7.52 (m, 1H), 7.41 – 7.30 (m, 4H), 7.21 – 7.10 (m, 3H), 7.08 – 7.00 (m, 2H), 6.87 – 6.78 (m, 2H), 4.81 – 4.69 (m, 2H), 3.01– 2.92 (m, 1H), 2.86 – 2.72 (m, 2H), 2.13 – 2.06 (m, 1H), 2.05 – 1.98 (m, 1H), 1.99 – 1.85 (m, 2H), 1.85 – 1.73 (m, 1H), 1.66 – 1.53 (m, 2H).

[0591] Step 10: (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester

[0592]

[0593] A 1:1 mixture (35.0 g, 60.5 mmol) of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester was chirally purified by a preparative chiral SFC (column: DAICEL CHIRALPAK AD [250 mm X 50 mm, 10 µm]; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 100 g / min; gradient: isogradient 40% B; 220 nm) to obtain

[0594] First eluted isomer: Isomer 1: (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester (15.5 g, 25.1 mmol, 41.5% yield). Analytical chiral chromatography: Column: Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: MeOH (0.1% IPA, v / v); Gradient: 5-50% B for 1.2 min, then 50% B for 1 min; Retention time = 1.07 min, white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.16 (t, J = 8.1 Hz, 1H), 7.72 (dd, J = 11.0, 1.5 Hz, 1H), 7.55 (br d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.26 – 7.12 (m, 5H), 6.81 (d, J = 6.7 Hz, 2H), 4.77 – 4.62 (m, 2H), 3.13– 3.03 (m, 1H), 2.96 (t, J = 11.2 Hz, 1H), 2.74 (td, J = 11.6, 3.4 Hz, 1H),2.07 (br d, J = 8.6 Hz, 1H), 1.95 – 1.84 (m, 1H), 1.82 – 1.73 (m, 1H), 1.72 –1.47 (m, 3H).

[0595] Second eluted isomer: Isomer 2: (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester (15.3 g, 26.2 mmol, 43.4% yield). Analytical chiral chromatography: Column: Chiralpak AD-3, 50 × 4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: MeOH (0.1% IPA, v / v); Gradient: 5-50% B for 1.2 min, then 50% B for 1 min; Retention time = 1.36 min, white solid. Absolute stereochemistry was determined by subsequent co-crystal structure of the final compound and WRN protein, then traced back to the corresponding enantiomeric pure intermediate.

[0596] 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 8.16 (t, J = 8.1 Hz, 1H), 7.72 (dd, J = 10.9, 1.4 Hz, 1H), 7.55 (br d, J = 8.4 Hz, 1H), 7.45 (d, J =8.3 Hz, 2H), 7.27 – 7.09 (m, 5H), 6.81 (d, J = 6.7 Hz, 2H), 4.77 – 4.64 (m,2H), 3.14 – 3.03 (m, 1H), 2.96 (t, J = 11.1 Hz, 1H), 2.78 – 2.70 (m, 1H),2.12 – 2.02 (m, 1H), 1.93 – 1.84 (m, 1H), 1.81 – 1.73 (m, 1H), 1.71 – 1.45 (m, 3H).

[0597] Step 11: (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0598]

[0599] At 0 °C, benzyl cyclohexane-1-carboxylate (0.40 g, 0.69 mmol) in a mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (1.38 mL, 1.38 mmol) was added to dichloromethane (10 mL). After 3 hours, the reaction was quenched with cold water (2 mL) and concentrated. The resulting residue was purified by reverse-phase reaction (70% MeCN in H2O solution containing 10 mM ammonium bicarbonate modifier) ​​to give (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (0.27 g, 0.51 mmol, 74% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.80 (br s,1H), 10.13 (s, 1H), 8.21 (t, J = 8.0 Hz, 1H), 7.72 (dd, J = 10.8, 1.6 Hz,1H), 7.55 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz,2H), 2.97 - 2.95 (m, 1H), 2.78 (t, J = 10.8 Hz, 1H), 2.68 - 2.66 (m, 1H),2.02-2.00 (m, 1H), 1.90 - 1.87 (m, 1H), 1.76 - 1.73 (m, 1H), 1.51 - 1.48 (m,3H). ES-LCMS m / z 486.5, 488.5 [MH] - .

[0600] Intermediate 2: (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)cyclohexane-1-carboxylic acid

[0601]

[0602] A mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid, intermediate 1 (3.08 g, 6.31 mmol), potassium acetate (2.48 g, 25.2 mmol), PdCl2(dppf)-DCM adduct (0.438 g, 0.536 mmol), and bis(pinacol)diborane (1.92 g, 7.57 mmol) was washed with three alternating vacuum and nitrogen purging cycles. 1,4-Dioxane (50 mL) was added, and the reaction was heated to 100 °C. After 2.5 hours, the mixture was cooled to room temperature, diluted with water and ethyl acetate, and filtered through diatomaceous earth. The filtrate layer was separated, and the organic layer was washed with brine, concentrated, and purified by normal-phase silica gel chromatography (DCM solution of ethyl acetate, 0-20%) to give (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)cyclohexane-1-carboxylic acid (1.58 g, 44% yield) as an orange solid.1 H NMR (400 MHz, chloroform-d) δ 8.51 (br t, J = 8.1 Hz, 1H), 7.79 (d, J =8.3 Hz, 2H), 7.63 (br d, J = 3.4 Hz, 1H), 7.42 (br d, J = 8.8 Hz, 1H), 7.37(dd, J = 11.0, 1.7 Hz, 1H), 7.27 (d, J = 7.8 Hz, 2H), 3.11 - 3.04 (m, 1H), 2.82 (tt, J = 11.5, 3.2 Hz, 2H), 2.15 (br dd, J = 13.2, 2.9 Hz, 1H), 2.08 -2.02 (m, 1H), 2.01 - 1.95 (m, 1H), 1.88 - 1.77 (m, 1H), 1.74 - 1.59 (m, 2H), 1.37 (s, 12H). ES-LCMS m / z 536.1 [M+H] + .

[0603] Intermediate 3: A 1:1 mixture of (1R,2S,6S)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2R,6R)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0604]

[0605] Step 1: A 1:1 mixture of (1R,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and benzyl(1S,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0606]

[0607] A 1:1 mixture of (3aS,4S,7aR)-4-(4-bromophenyl)hexahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)hexahydroisobenzofuran-1,3-dione, intermediate 1 (step 3) (10.0 g, 32.3 mmol) and 4-isopropylaniline (8.75 g, 64.7 mmol) in THF (150 mL) was stirred at 25 °C for 2 hours and concentrated. The residue was ground with ethyl acetate to give a 1:1 mixture of (1R,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and benzyl(1S,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid (11.2 g, 25.1 mmol, 78.0% yield), as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 11.53 (br, 1H), 9.76 (s, 1H), 7.53 – 7.43 (m, 4H), 7.21 (d, J= 8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 3.14 – 3.12 (m, 1H), 2.93 – 2.73 (m,3H), 2.43 – 2.29 (m, 1H), 2.18 – 2.04 (m, 1H), 1.98 – 1.95 (m, 1H), 1.70 –1.67 (m, 1H), 1.60 – 1.57 (m, 1H), 1.51 – 1.43 (m, 1H), 1.17 (d, J = 6.8 Hz,6H). ES-LCMS m / z 442.2 [MH] - .

[0608] Step 2: A 1:1 mixture of (1R,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylate and (1S,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylate.

[0609]

[0610] At 0 °C, TMSCHN2 (1.1 mL, 2.2 mmol) was added to a 1:1 mixture (0.500 g, 1.13 mmol) of (1R,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and benzyl(1S,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid in DCM (10 mL) and MeOH (1 mL). The reaction was stirred at 22 °C for 16 hours and concentrated to give a 1:1 mixture (455 mg, 0.993 mmol, 88.0% yield) of methyl (1R,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylate and methyl (1S,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylate, which was a white solid and used directly without purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H),7.54 -7.38 (m, 4H), 7.22 -7.08 (m, 4H), 3.25 (s, 3H), 3.12 (t, J = 4.5 Hz,1H), 2.93 (dt, J = 13.1, 4.0 Hz, 1H), 2.88 -2.77 (m, 2H), 2.40 -2.21 (m, 1H), 2.12 (qd, J = 13.0, 3.8 Hz, 1H), 2.05 -1.93 (m, 1H), 1.76 (dd, J = 12.8, 3.7Hz, 1H), 1.59 (dd, J = 13.1, 3.1 Hz, 1H), 1.55 -1.41 (m, 1H), 1.17 (d, J =6.9 Hz, 6H).

[0611] Step 3: A 1:1 mixture of (1R,2S,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid.

[0612]

[0613] Sodium methoxide (30% w / w, 4.05 g, 22.5 mmol) was added to a 1:1 mixture (1.03 g, 2.25 mmol) of (1R,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylate in methanol (20 mL) at 22 °C. The resulting reaction mixture was heated at 75 °C for 2 hours and then cooled to room temperature. At 0 °C, the mixture was added to HCl (1 M, 10 mL, 10 mmol), and then stirred at 22 °C for 30 minutes. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, dissolved in DMF (3 mL), and purified by silica gel (80 g C18 column). It was eluted with an aqueous solution of 10-60% acetonitrile (0.1% formic acid) to give a 1:1 mixture of (1R,2S,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid (231 mg, 0.447 mmol, 19.90% yield), as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 9.76 (s, 1H), 7.55 -7.45 (m, 2H), 7.45 - 7.36 (m, 2H), 7.29 -7.17 (m, 2H), 7.17 -7.05 (m, 2H), 3.61 (td, J = 12.1, 3.9 Hz, 1H), 3.22 (dq, J = 5.0, 2.4 Hz, 1H), 2.92 (dd, J = 11.6, 4.9 Hz, 1H), 2.90 - 2.76 (m, J = 6.8 Hz, 1H), 2.00 (t, J = 6.1Hz, 1H), 1.93 -1.67 (m, 3H), 1.64 -1.46 (m, 1H), 1.46 -1.27 (m, 1H), 1.18 (d,J = 6.9 Hz, 6H).

[0614] Step 4: A 1:1 mixture of (1R,2S,6S)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2R,6R)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid.

[0615]

[0616] DMF (3 mL) was added to a 1:1 mixture (230 mg, 0.518 mmol) of (1R,2S,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid, Cs₂CO₃ (337 mg, 1.04 mmol), and tBuXPhos Pd G₃ (42 mg, 0.053 mmol). The reaction mixture was degassed under vacuum and then purged three times with nitrogen. Methylamine (3.2 mL, 6.4 mmol) was added, and the mixture was heated at 65 °C for 3 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, dissolved in DMF (3 mL), and purified by silica gel (80 g C18 column). It was eluted with an aqueous solution of 10-60% acetonitrile (0.1% formic acid) to give a 1:1 mixture of (1R,2S,6S)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2R,6R)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid (82 mg, 0.18 mmol, 34% yield), as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 9.69 (s, 1H), 8.14 (s, 1H), 7.54 -7.42 (m, 2H), 7.20 -7.10 (m, 2H), 6.95 (d, J= 8.3 Hz, 2H),6.47 -6.38 (m, 2H), 3.41 (td, J= 11.7, 3.9 Hz,1H), 3.10 (q, J= 3.6, 2.2 Hz,1H), 2.94 -2.74 (m, 2H), 2.64 (s, 2H), 1.99 - 1.87 (m, 2H), 1.72 (d, J= 13.5Hz, 2H), 1.50 (d, J= 14.1 Hz, 2H), 1.43 -1.29 (m, 2H), 1.29 -1.08 (m, 9H).

[0617] Intermediate 4: A 1:1 mixture of (1R,2S,6R)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0618]

[0619] A 1:1 mixture of (1R,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and benzyl(1S,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid (intermediate 3, step 1) (500 mg, 1.13 mmol), Cs₂CO₃ (733 mg, 2.25 mmol), and tBuXPhos PdG₃ (89 mg, 0.11 mmol) was added to DMF (1 mL). The reaction mixture was degassed under vacuum and then filled with nitrogen. Methylamine (2 M THF solution, 6.0 mL, 12 mmol) was added, and the mixture was heated at 60 °C for 3 hours, followed by filtration. The filtrate was concentrated, dissolved in DMF (3 mL), and purified by silica gel (40 g C18 column). The solution was eluted with an aqueous solution of 5-80% acetonitrile (0.1% TFA) to give a 1:1 mixture of (1R,2S,6S)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2R,6R)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid (0.240 g, 0.578 mmol, 51.4% yield), as a yellowish-brown solid. 1 H NMR(400 MHz, DMSO-d6) δ 11.69 – 11.24 (br, 1H), 9.76 (s, 1H), 7.57 – 7.38 (m,2H), 7.23 – 7.02 (m, 4H), 6.88 – 6.84 (m, 2H), 3.10 (t, J = 4.6 Hz, 1H), 2.88– 2.70 (m, 6H), 2.39 – 2.35 (m, 1H), 2.19 – 2.03 (m, 1H), 1.97 – 1.94 (m,1H), 1.67 – 1.63 (m, 1H), 1.57 – 1.54 (m, 1H), 1.47 – 1.40 (m, 1H), 1.17 (d,J = 6.8 Hz, 6H).

[0620] ES-LCMS m / z 395.3 [M+H] + .

[0621] Intermediate 5: A 1:1 mixture of (1R,2R,6S)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2S,6R)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0622]

[0623] Step 1: A 1:1 mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester.

[0624]

[0625] To a 1:1 mixture (1 g, 0.240 mol) of (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid and (1S,2S,3R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid (intermediate 1, step 8) in DMF (10 mL), HATU (1.09 g, 2.88 mmol), DIEA (1.26 mL, 7.19 mmol), and 4-isopropylaniline (0.389 g, 2.88 mmol) were added. After 12 hours at 25 °C, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give a 1:1 mixture (1.5 g, 2.3 mmol, 95% yield) of (1R,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester, which was a yellow solid and used directly without further purification. 1H NMR (400 MHz, DMSO-d6) δ 9.92(s, 1H), 7.96 (s, 1H), 7.46 (ddd, J = 10.9, 6.5, 2.2 Hz, 4H), 7.22 (s, 1H),7.20 (td, J = 6.5, 2.9 Hz, 2H), 7.14 (td, J = 8.5, 2.4 Hz, 4H), 6.84 - 6.77(m, 2H), 4.68 (d, J = 3.0 Hz, 2H), 3.01 - 2.86 (m, 4H), 2.89 - 2.80 (m, 1H),2.72 (d, J= 16.7 Hz, 6H), 2.69 (s, 1H), 2.01 (dd, J= 10.2, 4.8 Hz, 1H), 1.89 (d, J= 10.0 Hz, 1H), 1.77 (d, J= 12.3 Hz,1H), 1.64 (dd, J = 25.8, 13.1 Hz,1H), 1.54 (d, J = 10.2 Hz, 1H), 1.18 (dd, J = 7.0, 2.3 Hz, 7H), 1.15 (s, 1H), 1.13 (d, J = 6.9 Hz, 1H).

[0626] Step 2: A 1:1 mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid.

[0627]

[0628] At 0 °C, a 1:1 mixture (1.3 g, 2.4 mmol) of (1R,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester was added to BCl3 (1 M DCM solution, 4.86 mL, 4.86 mmol). After 1 hour, the reaction was quenched with ice and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, dissolved in DMF (3 mL), and purified by silica gel (80 g C18 column). It was eluted with an aqueous solution of 5-60% acetonitrile (0.1% formic acid) to give a 1:1 mixture (0.480 g, 1.07 mmol, 44.1% yield) of (1R,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid as a white solid. 1 H NMR(400 MHz, DMSO-d6) δ 11.73 (s, 1H), 9.85 (s, 1H), 7.56 – 7.38 (m, 4H), 7.22(d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 2.92 – 2.63 (m, 4H), 1.94 –1.87 (m, 2H), 1.76 – 1.73 (m, 1H), 1.64 – 1.38 (m, 2H), 1.17 (d, J = 6.8 Hz,6H).

[0629] ES-LCMS m / z 444.0 [M+H] + .

[0630] Step 3: A 1:1 mixture of (1R,2R,6S)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2S,6R)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid.

[0631]

[0632] Cs₂CO₃ (0.440 g, 1.35 mmol) and tBuXPhos Pd G₃ (54 mg, 0.068 mmol) were added to a 1:1 mixture (0.200 g, 0.450 mmol) of (1R,2S,6R)-2-(4-bromophenyl)-6-((4-isopropylphenyl)carbamoyl)cyclohexane-1-carboxylic acid in DMF (1 mL). Methylamine (2.25 mL, 4.50 mmol, in 2 M THF solution) was added, and the mixture was heated at 60 °C for 3 hours. The mixture was then purified by silica gel (40 g C18 column) and eluted with an aqueous solution of 5-55% acetonitrile (0.1% TFA) to give a 1:1 mixture (0.080 g, 0.20 mmol, 45% yield) of (1R,2S,6S)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2R,6R)-2-((4-isopropylphenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid as a white solid. 1 H NMR(400 MHz, DMSO-d6) δ 11.55 (br, 1H), 9.81 (s, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.6 Hz, 2H), 6.44 (d, J = 8.6 Hz, 2H),5.40 (br, 1H), 2.85 – 2.80 (m, 1H), 2.72 – 2.62 (m, 5H), 2.53 – 2.52 (m, 1H),1.92 – 1.84 (m, 2H), 1.71 – 1.69 (m, 1H), 1.54 – 1.50 (m, 3H), 1.17 (d, J =6.8 Hz, 6H). ES-LCMS m / z 395.2 [M+H] + .

[0633] Intermediate 6: A 1:1 mixture of (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2S,6R)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0634]

[0635] Step 1: A 1:1 mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid.

[0636]

[0637] At 0 °C, a 1:1 mixture (intermediate 1, step 9) of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester (896 mg, 1.55 mmol) was added to BCl3 (1 M DCM solution, 3.10 mL, 3.10 mmol). After 1 hour, the reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, dissolved in DMF (1.5 mL), and purified by silica gel (40 g C18 column). The solution was eluted with an aqueous solution of 5-100% acetonitrile to give a 1:1 mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (340 mg, 0.689 mmol, 44.5% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.76(s, 1H), 10.09 (s, 1H), 8.20 (t, J = 8.0 Hz, 1H), 7.71 (d, J = 11.2 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 2.99 (t, J = 11.2 Hz, 1H), 2.76 – 2.67 (m, 2H), 2.03 – 2.00 (m, 1H), 1.89 –1.88 (m, 1H), 1.77 – 1.73 (m, 1H), 1.61 – 1.53 (m, 3H). ES-LCMS m / z 488.1 [M+H] + .

[0638] Step 2: A 1:1 mixture of (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2S,6R)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid.

[0639]

[0640] To a 1:1 mixture (0.339 g, 0.694 mmol) of degassed (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid, in DMF (3 mL), Cs₂CO₃ (679 mg, 2.08 mmol) and t-BuBrettPhos Palladacycle Gen. 3 (119 mg, 0.139 mmol) were added. Methylamine (2 M THF solution, 2.25 mL, 4.50 mmol) was added, and the mixture was heated at 60 °C for 2 hours, quenched with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, dissolved in DMF (2 mL), and purified by silica gel (40 g C18 column). The solution was eluted with an aqueous solution of 5-100% acetonitrile to give a 1:1 mixture (0.060 g, 0.14 mmol, 51% yield) of (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2S,6R)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.63(br, 1H), 10.11 (br, 1H), 8.22 (t, J = 7.8 Hz, 1H), 7.71 – 7.68 (m, 1H), 7.54(d, J = 8.4 Hz, 1H), 6.95 (d, J = 8.4 Hz, 2H), 6.43 (d, J = 8.4 Hz, 2H), 5.39– 5.37 (m, 1H), 3.00 – 2.93 (m, 1H), 2.70 – 2.67 (m, 2H), 2.64 (d, J = 4.0Hz, 3H), 1.99 – 1.96 (m, 1H), 1.87 – 1.84 (m, 1H), 1.73 – 1.68 (m, 1H), 1.54– 1.47 (m, 3H). ES-LCMS m / z 439.1 [M+H] + .

[0641] Intermediate 7: (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0642]

[0643] To a DMF (30 mL) solution of degassed (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid intermediate 1 (1.50 g, 3.1 mmol), Cs₂CO₃ (3.0 g, 9.2 mmol), methylamine (2 M THF solution, 30.7 mL, 61.4 mmol), and t-BuBrettPhos PalladacycleGen. 3 (525 mg, 0.614 mmol) were added. The mixture was heated at 60 °C for 2 hours, cooled to room temperature, and filtered. The filtrate was concentrated under reduced pressure, and the residue was diluted with DMF to 100 mL to give the product in DMF solution form. Two 9 mL aliquots were taken for subsequent reactions. The remaining 82 mL was concentrated under reduced pressure to obtain the substance. The substance was purified by silica gel (150 g C18 Gold column) and eluted with an aqueous solution of 30-60% MeCN (containing 10 nM ammonium bicarbonate and 0.075% ammonium hydroxide) to give (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid (953 mg, 2.17 mmol, 86% yield), as a yellowish-brown solid. 1H NMR (400 MHz, DMSO-d6) δ12.82 - 11.29 (br s, 1H), 10.24 (br s, 1H), 8.21 (t, J = 8.1 Hz, 1H), 7.65(dd, J = 10.8, 1.5 Hz, 1H), 7.51 (br d, J 2.63 (s, 3H), 1.93 (br d, J = 10.3 Hz, 1H), 1.86 - 1.75 (m,1H), 1.71 - 1.61 (m, 1H), 1.55 - 1.35 (m, 3H). ES-LCMS m / z 439.2 [M+H] + .

[0644] Intermediate 7, Alternative Synthesis: (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)cyclohexane-1-carboxylic acid

[0645]

[0646] Step 1: (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid

[0647]

[0648] A. Four reactions occur simultaneously (850 g x 4):

[0649] At 25°C, THF (25.5 L) was added in batches to a mixture of (1R)-1-(1-naphthyl)ethylamine (348 g, 2.04 mol) and (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid intermediate 1 (0.850 kg, 2.04 mol) in step 8. The reaction was heated to 65°C. After 40 minutes, the mixture was cooled to 60°C. After 2 hours, the mixture was further cooled to 50°C, and after another 2 hours, the reaction was cooled to 25°C. After 12 hours, the four reactions were combined and filtered, and the filter cake was washed with THF (5.00 L). The filter cake was vacuum dried at 40°C to obtain a white solid of unwanted salt (1.50 kg). The mother liquor (containing approximately 1.70 kg in 25.5 L THF) was used directly in the next stage.

[0650] B. Four reactions occur simultaneously (425 g x 4)

[0651] At 25°C, (1S)-1-(1-naphthyl)ethylamine (174 g, 1.02 mol) was added in batches to the mother liquor obtained from step A (containing approximately 425 g in 6.37 L, THF). The mixture was heated at 50°C for 2 hours and then cooled to 25°C. After 12 hours, the four reactions were combined and filtered, and the filter cake was washed with THF (2.00 L). The filter cake was dried under vacuum at 40°C to give (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid, (1S)-1-(1-naphthyl)ethylamine salt (1.50 kg, 3.59 mol, 99.6%), as a white solid. This substance was divided into four portions and used in four simultaneous reactions (375 g x 4).

[0652] C. At 25 °C, ethyl acetate (800 mL) was added in batches to the above (1S)-1-(1-naphthyl)ethylamine salt (375 g, 899 mmol). The pH of the mixture was adjusted to ~1 with 1 M HCl (899 mL, 899 mmol) at 0–5 °C, and the reaction became clear. The four reactions were combined for post-treatment. The organic layers were separated, and the aqueous phase was extracted with EtOAc (3.00 L x 3). The combined organic layers were washed with H₂O (2.00 L x 3), dried over Na₂SO₄, filtered, and concentrated under vacuum at 40 °C to give the crude product as a white solid. oC. The substance was ground with MTBE:EtOAc (3:1, 5 L) for 30 minutes, filtered, washed with MTBE (500 mL X 3), and dried under reduced pressure at 40 °C to give (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid (1.19 kg, 2.85 mol, 35.0% yield), as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 12.3 (s, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.25 - 7.23(m, 3H), 7.17 (d, J = 8.4 Hz, 2H), 6.83 (d, J = 7.6 Hz, 2H), 4.69 (q, J =12.8 Hz, 2H), 2.77 - 2.74 (m, 1H), 2.67 - 2.63 (m, 2H), 2.22 - 2.10 (m, 1H), 1.78 - 1.74 (m, 2H), 1.54 - 1.47 (m, 3H). ES-LCMS m / z 439.2 [M+Na] + .

[0653] Step 2: (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester

[0654]

[0655] Three reactions were carried out simultaneously (393 g x 3).

[0656] At 0 °C, 2-fluoro-4-(trifluoromethyl)aniline (337 g, 1.88 mol) and NMI (155 g, 1.88 mol) were added to a mixture of (1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)cyclohexane-1-carboxylic acid (393 g, 942 mmol) in acetonitrile (1.70 L). After approximately 2 minutes, TCFH (396 g, 1.41 mmol) was added in portions. The reaction was stirred at 25 °C for 12 hours. The three reactions were combined, concentrated at 40 °C, dissolved in DCM, loaded onto silica gel (100-200 mesh silica gel, homemade column chromatography), and eluted with EtOAc:petroleum ether at a ratio of 100:1 to 3:1 to give the crude product. The substance was ground with petroleum ether (3.00 L) for 2 hours at 25 °C, filtered, washed with petroleum ether (500 mL x 3), and dried under reduced pressure at 40 °C to provide (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester (910 g, 1.57 mol, 55.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ10.1 (s, 1H), 8.15 (t, J = 8.0 Hz, 1H), 7.70 (d, J = 11.2 Hz, 1H), 7.53 (d, J= 8.4 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.19 -7.13 (m, 3H), 6.80 (d, J = 6.8 Hz, 2H), 4.68 (q, J = 12.4 Hz, 1H), 3.09 -3.04 (m, 1H), 2.98 - 2.92 (m, 1H), 2.75 - 2.69 (m, 1H), 2.07 - 2.04 (m, 1H), 1.89 - 1.87 (m, 1H), 1.77 - 1.74 (m, 1H), 1.66 - 1.52 (m, 3H).

[0657] Step 3: (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0658]

[0659] Three reactions were carried out simultaneously (217 g x 3).

[0660] At -30 °C, BBr3 (188 g, 0.750 mol) was added to a mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester (217 g, 375 mmol) in DCM (1.20 L). After 1 hour, the three reactions were combined, cooled to 0 °C, quenched with water (3.00 L), and extracted with EtOAc (2.40 L x 3). The combined organic layers were washed with brine (2.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure at 40 °C to give a crude residue. The crude product was milled at 25°C with PE:EA (4.80 L) in a 5:1 ratio for 2 hours, filtered, washed with PE (500 mL x 3), and dried under reduced pressure at 40°C to provide (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (0.610 kg, 1.25 mol, 84.9% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.8 (s, 1H), 10.0 (s, 1H), 8.21 (t, J= 8.0 Hz, 1H), 7.70 (dd, J = 10.8, 1.6 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H),7.46 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 3.03 – 2.97 (m, 1H), 2.82- 2.76 (m, 1H), 2.71 – 2.65 (m, 1H), 2.02 – 2.00 (m, 1H), 1.87 (m, 1H), 1.76- 1.73 (m, 1H), 1.59 - 1.47 (m, 3H).

[0661] Step 4: (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)cyclohexane-1-carboxylic acid

[0662]

[0663] Two reactions occur simultaneously (100 g x 2).

[0664] At 20 °C, Cs₂CO₃ (0.200 kg, 614 mmol), t-BuBrettPhos Palladacycle Gen. 3 (35.0 g, 40.9 mmol), and methylamine (426 g, 4.12 mol) were added to a mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (0.100 kg, 204 mmol) in DMF (600 mL). The reaction was heated at 60 °C for 2 hours. The two reactions were combined, cooled to 20 °C, poured into water (2.40 L), and extracted with MTBE (800 mL x 3). The aqueous phase was adjusted to pH 6 with 1 M HCl (1.20 L) and extracted with 2-Me-THF (1.50 L x 3). The combined organic layers were washed with brine (1.00 L x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure at 30 °C to obtain a crude residue. The crude product was ground at 20 °C with a 1:1 EtOAc:MTBE mixture (600 ml) for 30 minutes, filtered, washed with PE (500 mL x 3), and dried under reduced pressure at 40 °C to give (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)phenyl)cyclohexane-1-carboxylic acid (0.120 kg, 273 mmol, 66.8% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.6 (s, 1H), 10.0 (s, 1H), 8.21 (t, J = 8.0 Hz, 1H), 7.70 (d, J =9.6 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 6.42 (d, J =8.4 Hz, 2H), 5.42 (s, 1H), 2.99 - 2.93 (m, 1H), 2.71 - 2.62 (m, 4H), 2.54 -2.50 (m, 1H), 1.98 - 1.96 (m, 1H), 1.85 - 1.853 (m, 1H), 1.71 - 1.68 (m, 1H), 1.51 - 1.46 (m, 3H).

[0665] Intermediate 8: A 1:1 mixture of (1R,2R,4R,6S)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2S,4S,6R)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0666]

[0667] Step 1: (E)-4-(4-bromophenyl)but-3-en-2-one

[0668]

[0669] Three reactions were carried out simultaneously (1.35 kg x 3): NaOH (135 g, 3.37 mol) was slowly added through a dropping funnel to a mixture of 4-bromobenzaldehyde (1.35 kg, 7.30 mol), acetone (5.4 L), and H₂O (10.8 L). The reaction mixture was stirred at 15–20 °C for 12 hours. The three batches were combined, and the reaction mixture was filtered. The filter cake was washed with water (1.00 L) and concentrated under vacuum at 45 °C to give compound (E)-4-(4-bromophenyl)but-3-en-2-one (4.60 kg, 20.0 mol, 89.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ7.68 - 7.57 (m, 5H), 6.83 (d, J = 16 Hz, 1H), 2.33 (s, 3H). ES-LCMS m / z 224.9[M+H] + .

[0670] Step 2: (E)-((4-(4-bromophenyl)but-1,3-dien-2-yl)oxy)triisopropylsilane

[0671]

[0672] Ten reactions (340 g x 10) were carried out simultaneously: a mixture of (E)-4-(4-bromophenyl)but-3-en-2-one (0.34 kg, 1.51 mol) in 2-methyltetrahydrofuran (2.04 L) was degassed and purged three times with N2. The reaction was cooled to -20 °C and TIPSOTf (451 mL, 1.66 mol) and Et3N (421 mL, 3.02 mol) were added dropwise. The mixture was stirred at 0 °C for 2 hours until the reaction was complete. These reactions were combined and poured into ice water (15.0 L), and partitioned between 2-Me-THF and water. The organic layer was dried in MgSO4 for 12 hours, filtered, and concentrated under vacuum below 30°C to give (E)-((4-(4-bromophenyl)but-1,3-dien-2-yl)oxy)triisopropylsilane (5.75 kg, 14.8 mol, quantitative yield). 1 H NMR(400 MHz, DMSO-d6) δ 7.51 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.83(d, J = 16 Hz, 1H), 6.76 (d, J = 17 Hz, 1H), 4.54 (s, 1H), 4.42 (s, 1H), 1.28- 1.33 (m, 3 H), 1.13 - 1.08 (m, 18H). ES-LCMS m / z 381.1 [M+H] + .

[0673] Step 3: A 1:1 mixture of (3aS,4S,7aR)-4-(4-bromophenyl)-6-((triisopropylsilyl)oxy)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)-6-((triisopropylsilyl)oxy)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione

[0674]

[0675] Eighteen reactions were carried out simultaneously (300 g x 18): at 15 o C. Over a period of 15 minutes, slowly add a solution of (E)-((4-(4-bromophenyl)but-1,3-dien-2-yl)oxy)triisopropylsilane (300 g, 790 mmol) in DCM (2.0 L) to a mixture of furan-2,5-dione (390 g, 3.9 mol) in DCM (2.0 L). Then, in a 25°C solution... oStir at C for 3.5 hours. Combine these reactions and mix at 30°C. o Vacuum concentration was performed at C, followed by grinding with n-heptane (5.00 L). The resulting solid product was collected by filtration and washed with n-heptane (1.00 L). Then, at 30 °C... o C. The filtrate was concentrated under vacuum, then ground with n-heptane, filtered, and washed with n-heptane to recover additional product. This recovery process was repeated three times, and the products were combined to provide a 1:1 mixture (5.60 kg, 8.25 mol, crude) of (3aS,4S,7aR)-4-(4-bromophenyl)-6-((triisopropylsilyl)oxy)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)-6-((triisopropylsilyl)oxy)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.52 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4Hz, 2H), 5.07 - 5.05 (m, 1 H), 3.92 - 3.80 (m, 3H), 2.66 - 2.53 (m, 2H), 1.08– 1.03 (m, 21H).

[0676] Step 4: A 1:1 mixture of (1S,2S,3R)-4'-bromo-3-(hydroxymethyl)-5-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid and (1R,2R,3S)-4'-bromo-3-(hydroxymethyl)-5-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid.

[0677]

[0678] A 1:1 mixture (5.50 kg, 11.5 mol) of (3aS,4S,7aR)-4-(4-bromophenyl)-6-((triisopropylsilyl)oxy)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione and (3aR,4R,7aS)-4-(4-bromophenyl)-6-((triisopropylsilyl)oxy)-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione) in THF (36.0 L) was degassed and purged three times with N2. The reaction mixture was then cooled to 0°C. o C, and in 0~3 oC. NaBH4 (521 g, 13.8 mol) was added to the mixture in portions. The mixture was then subjected to a 20°C test. o C. Stir for 1 hour, then at 0-5°C. o C. Slowly add water (962 mL) to the reaction over 10 minutes. Add HCl (1 N) to the mixture until pH = 7. Let the reaction proceed for 5-10 minutes. o Stir at C for 20 minutes and add anhydrous Na₂SO₄ (1.00 kg). Filter the mixture and concentrate under reduced pressure to give a 1:1 mixture (3.60 kg, crude) of (1S,2S,3R)-4'-bromo-3-(hydroxymethyl)-5-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid and (1R,2R,3S)-4'-bromo-3-(hydroxymethyl)-5-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid, which was a white solid and used directly without purification. ES-LCMS m / z 483.2 [M+H] + .

[0679] Step 5: A 1:1 mixture of (3aR,7S,7aS)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione and (3aS,7R,7aR)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione

[0680]

[0681] Ten reactions were carried out simultaneously (220 g x 10): A 1:1 mixture (220 g, 4.55 mol) of (1S,2S,3R)-4'-bromo-3-(hydroxymethyl)-5-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid and (1R,2R,3S)-4'-bromo-3-(hydroxymethyl)-5-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid was degassed in toluene (1.32 L) and purged three times with N2. TsOH (8.70 g, 0.455 mol) was added to the mixture at 20 °C, and the reaction was stirred at 110 °C for 12 hours. o C. Pour the mixture into H2O (1.2 L) and extract the aqueous layer with ethyl acetate (300 mL x 3). Wash the combined organic layers with saturated aqueous sodium bicarbonate solution (150 mL) and brine (150 mL), dry with sodium sulfate, filter, and concentrate under reduced pressure at 40 °C to provide the crude product.

[0682] In separate reactions, a 1:1 mixture (400 g, 827 mmol) of (1S,2S,3R)-4'-bromo-3-(hydroxymethyl)-5-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid and (1R,2R,3S)-4'-bromo-3-(hydroxymethyl)-5-((triisopropylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylic acid was degassed in toluene (2.4 L) and purged three times with N2. At 20 °C, TsOH (15.7 g, 83.0 mmol) was added to this mixture, and the reaction was stirred at 110 °C for 13 hours. o C. Pour the mixture into H2O (500 mL) and extract the aqueous layer with dichloromethane (500 mL x 2). Wash the combined organic layers with saturated aqueous sodium bicarbonate solution (500 mL) and brine (500 mL), dry with sodium sulfate, filter, and concentrate under reduced pressure to provide the crude product.

[0683] The two batches of crude products were combined and ground at 20 °C with isopropyl ether (700 mL) for 30 minutes. The mixture was filtered, washed with isopropyl ether (100 mL), and dried under reduced pressure to provide a 1:1 mixture (550 g, 1.78 mol, 33% yield) of (3aR,7S,7aS)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione and (3aS,7R,7aR)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ7.51 - 7.49 (m, 2H), 7.29 - 7.26 (m, 2H), 4.36 - 4.32 (dd, J = 5.6 Hz, J =8.8 Hz, 1H), 3.91 - 3.88 (dd, J = 2.0 Hz, J = 9.2 Hz, 1H), 3.69 - 3.63 (dt, J= 4.4 Hz, J = 14.0 Hz, 1H), 3.49 - 3.43 (m, 1H), 3.19 - 3.11 (m, 1H), 2.73 -2.64 (m, 2H), 2.48 - 2.44 (m, 1H), 2.37 - 2.30 (m, 1H). ES-LCMS m / z 310.1 [M+H] + .

[0684] Step 6: A 1:1 mixture of (3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one and (3aS,5S,7R,7aR)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one

[0685]

[0686] Solid sodium borohydride (3.37 g, 89.0 mmol) was added in portions over 5 minutes to a 1:1 mixture (11.0 g, 35.6 mmol) of (3aR,7S,7aS)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione and (3aS,7R,7aR)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione in THF (100 mL) and methanol (100 mL). The reaction was stirred at room temperature for 16 hours, quenched with water (100 mL), and extracted with EtOAc (500 mL). The EtOAc layer was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated to give a 1:1 mixture (7.00 g, 21.6 mmol, 60.7% yield) of (3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one and (3aS,5S,7R,7aR)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one as a white solid, which was used directly without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 4Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 4.86 (d, J = 4.4 Hz, 1H), 4.20-4.16 (m,1H), 3.86 (d, J = 8.4 Hz, 1H), 3.56-3.55 (m, 1H), 3.21-3.18 (m, 1H), 3.11-3.07 (m, 1H), 2.67-2.64 (m, 1H), 1.99-2.02 (m, 2H), 1.39 (q, J = 12.8 Hz,1H), 1.00 (q, J = 12.8 Hz, 1H). ES-LCMS m / z 311.1 [M+H] + .

[0687] Step 7: A 1:1 mixture of (3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-ethoxyhexahydroisobenzofuran-1(3H)-one and (3aS,5S,7R,7aR)-7-(4-bromophenyl)-5-ethoxyhexahydroisobenzofuran-1(3H)-one

[0688]

[0689] At 0 °C, solid NaH (1.29 g, 32.1 mmol) was added to a 1:1 mixture (5.00 g, 16.1 mmol) of (3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one and (3aS,5S,7R,7aR)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one in N,N-dimethylformamide (50 mL). After 30 minutes, iodoethane (13.0 mL, 161 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction was quenched with 2NHCl (~10 mL) to pH < 3 and extracted with EtOAc (100 mL, 3 times). The combined EtOAc layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated. The resulting residue was dissolved in THF (20 mL) and subjected to reverse-phase purification (MeCN H₂O solution, 10 mM ammonium bicarbonate modifier, 0-100% gradient) to give a 1:1 mixture (1.70 g, 4.56 mmol, 28.4% yield) of (3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-ethoxyhexahydroisobenzofuran-1(3H)-one and (3aS,5S,7R,7aR)-7-(4-bromophenyl)-5-ethoxyhexahydroisobenzofuran-1(3H)-one as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.51 - 7.41 (m, 2H), 7.32 - 7.20 (m, 2H), 4.19 (dd, J = 8.8, 4.3 Hz, 1H), 3.95 - 3.83 (m, 1H), 3.57 - 3.42 (m, 3H), 3.27 - 3.07 (m, 2H), 2.75 - 2.63 (m, 1H), 2.17 (dd, J = 12.3, 4.3 Hz, 2H), 1.44 - 1.21 (m, 2H), 1.14 - 1.06 (m, 3H). ES-LCMS m / z 341.0 [M+H] + .

[0690] Step 8: A 1:1 mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid

[0691]

[0692] KOH (2.23 g, 39.8 mmol) was added to a 1:1 mixture (2.70 g, 7.96 mmol) of (3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-ethoxyhexahydroisobenzofuran-1(3H)-one and (3aS,5S,7R,7aR)-7-(4-bromophenyl)-5-ethoxyhexahydroisobenzofuran-1(3H)-one in methanol (30 mL), and the reaction mixture was stirred at 75 °C for 16 hours. The reaction was quenched with 2N HCl (~15 mL) to pH < 3, resulting in the precipitation of a solid precipitate. The solid was filtered, washed with water (5 mL, 4 times), washed with petroleum ether (5 mL, 4 times), and dried to give a 1:1 mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid (2.40 g, 5.71 mmol, 71.7% yield). 1 H NMR(400 MHz, DMSO-d6) δ 11.85 (br s, 1H), 7.46 - 7.42 (m, 2H), 7.22 - 7.14 (m,2H), 4.58 (br s, 1H), 3.55 - 3.38 (m, 4H), 3.23 - 3.12 (m, 1H), 2.83 - 2.68(m, 1H), 2.28 - 2.17 (m, 2H), 1.98 (d, J = 12.5 Hz, 1H), 1.80 - 1.68 (m, 1H),1.47 - 1.24 (m, 1H), 1.15 - 1.00 (m, 4H). ES-LCMS m / z 357.0 [M+H] + .

[0693] Step 9: A 1:1 mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester.

[0694]

[0695] At 0 °C, benzyl bromide (0.799 mL, 6.72 mmol) was added dropwise over 1 minute to a 1:1 mixture (2.40 g, 6.72 mmol) of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid in N,N-dimethylformamide (25 mL). After 3 hours, ice water (20 mL) was added, and the reaction was extracted with EtOAc (50 mL x 3). The combined EtOAc layers were washed with water (10 mL) and brine (20 mL), dried over sodium sulfate, and evaporated to give the crude substance. The crude substance was purified by normal-phase purification (ethyl acetate in petroleum ether solution, 0-100% gradient, run for 50 min) to give a 1:1 mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester (2.30 g, 4.63 mmol, 68.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.47 -7.37 (m, 2H), 7.29 - 7.22 (m, 3H), 7.19 - 7.11 (m, 2H), 6.86 (dd, J = 7.5,2.0 Hz, 2H), 4.87 (d, J = 12.5 Hz, 1H), 4.70 (d, J = 12.5 Hz, 1H), 4.60 (t, J= 5.0 Hz, 1H), 3.49 - 3.41 (m, 3H), 3.35 - 3.32 (m, 1H), 3.31 - 3.19 (m, 2H), 2.89 - 2.74 (m, 1H), 2.42 (t, J = 11.0 Hz, 1H), 2.21 - 1.95 (m, 2H), 1.90 -1.77 (m, 1H), 1.42 (q, J = 12.0 Hz, 1H), 1.07 (t, J = 6.8 Hz, 3H). ES-LCMS m / z shows poor ionization performance.

[0696] Step 10: A 1:1 mixture of (1R,2R,3S,5R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-ethoxycyclohexane-1-carboxylic acid and (1S,2S,3R,5S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-ethoxycyclohexane-1-carboxylic acid.

[0697]

[0698] At 0 °C, sodium periodate (3.30 g, 15.4 mmol) and ruthenium(III) chloride (1.07 g, 5.14 mmol) were added to a 1:1 mixture (2.30 g, 5.14 mmol) of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-(hydroxymethyl)cyclohexane-1-carboxylate in acetonitrile (10 mL) and water (20 mL). After 1 hour, water (100 mL) was added, and the mixture was extracted with EtOAc (500 mL). The EtOAc layer was washed with water (100 mL) and brine (100 mL), dried over sodium sulfate, and concentrated by evaporation to give a 1:1 mixture (1.60 g, 2.95 mmol, 57.3% yield) of (1R,2R,3S,5R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-ethoxycyclohexane-1-carboxylic acid and (1S,2S,3R,5S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-ethoxycyclohexane-1-carboxylic acid as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ12.54 (br s, 1H), 7.53 - 7.36 (m, 2H), 7.31 - 7.14 (m, 5H), 6.92 - 6.79 (m,2H), 4.81 - 4.62 (m, 2H), 3.57 - 3.43 (m, 2H), 3.24 - 3.05 (m, 1H), 2.96 -2.83 (m, 1H), 2.79 - 2.70 (m, 2H), 2.43 - 2.18 (m, 1H), 1.99 (dd, J = 6.8,5.8 Hz, 1H), 1.62 - 1.49 (m, 1H), 1.45 - 1.30 (m, 1H), 1.08 (t, J = 7.0 Hz, 3H). ES-LCMS m / z 461.0 [M+H] + .

[0699] Step 11: A 1:1 mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester.

[0700]

[0701] To acetonitrile (10 mL), a 1:1 mixture (1.50 g, 3.25 mmol) of (1R,2R,3S,5R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-ethoxycyclohexane-1-carboxylic acid and (1S,2S,3R,5S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-ethoxycyclohexane-1-carboxylic acid was added sequentially with 1-methyl-1H-imidazolium (0.518 mL, 6.50 mmol) and 2-fluoro-4-(trifluoromethyl)aniline (582 mg, 3.25 mmol), followed by the addition of chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (1.83 g, 6.50 mmol). Two hours later, the mixture was concentrated and purified in a normal phase (petroleum ether solution of ethyl acetate, 0-80% gradient) to give a 1:1 mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester (1.20 g, 1.79 mmol, 55.1% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.17(s, 1H), 8.17 (t, J = 8.0 Hz, 1H), 7.73 (dd, J = 11.0, 1.5 Hz, 1H), 7.56 (d,J = 9.0 Hz, 1H), 7.46 (d, J = 7.7 Hz, 2H), 7.27 - 7.14 (m, 5H), 6.81 (s, 1H), 6.79 (d, J = 1.5 Hz, 1H), 4.74 - 4.64 (m, 2H), 3.58 - 3.46 (m, 3H), 3.21 -3.05 (m, 1H), 2.96 (t, J = 11.3 Hz, 1H), 2.82 (td, J = 12.0, 3.0 Hz, 1H), 2.39 - 2.34 (m, 1H), 2.12 - 1.97 (m, 1H), 1.69 - 1.53 (m, 1H), 1.52 - 1.40(m, 1H), 1.10 (t, J = 7.0 Hz, 3H). ES-LCMS m / z 622.0 [M+H]+ .

[0702] Step 12: A 1:1 mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid.

[0703]

[0704] At 0 °C, a 1:1 mixture (0.600 g, 0.964 mmol) of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester) in DCM (12 mL) was added to a solution of boron trichloride (1.93 mL, 1.93 mmol, 1 M DCM solution). After 1 hour, ice water (2 mL) was added, and the mixture was concentrated. The resulting residue was dissolved in THF (5 mL) and purified by reverse-phase (MeCN H2O solution, 0.1% ammonium bicarbonate modifier, 0-100% gradient) to give a 1:1 mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (350 mg, 0.638 mmol, 66.2% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.27 (br s, 1H), 8.23 ​​(t, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.68 (s,1H), 7.53 (d, J = 9.0 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.0 Hz,2H), 3.54 - 3.47 (m, 2H), 3.02 - 2.95 (m, 1H), 2.84 - 2.72 (m, 1H), 2.39 -2.24 (m, 2H), 2.13 - 1.91 (m, 2H), 1.56 - 1.33 (m, 2H), 1.09 (t, J = 7.0 Hz,3H). ES-LCMS m / z 532.0 [M+H] + .

[0705] Step 13: A 1:1 mixture of (1R,2R,4R,6S)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2S,4S,6R)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid.

[0706]

[0707] A 1:1 mixture (550 mg, 1.03 mmol) of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and sodium tert-butoxide (298 mg, 3.10 mmol) was stirred in 1,4-dioxane (5 mL) for 5 minutes. tBuXPhos Pd G3 (82.0 mg, 0.103 mmol) was added, and the mixture was degassed for 5 minutes. Add methylamine (2M THF solution, 10.3 mL, 20.7 mmol) and heat the reaction at 100 °C in a Biotage Initiator (microwave) for 1 hour. The mixture was concentrated, and the resulting residue was purified by reverse-phase reaction (MeCN in H2O solution, 10 nM ammonium bicarbonate modifier, 0-100% gradient) to give a 1:1 mixture of (1R,2R,4R,6S)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid and (1S,2S,4S,6R)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid (305 mg, 0.601 mmol, 58.1% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (br s, 1H), 10.10 (br s, 1H), 8.21 (t, J = 8.0 Hz, 1H), 7.72 (d, J = 9.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H),6.99 - 6.95 (m, 2H), 6.46 - 6.42 (m, 2H), 5.50 - 5.36 (m, 1H), 3.54 - 3.47(m, 3H), 3.32 - 3.27 (m, 1H), 3.06 - 2.98 (m, 1H), 2.71 - 2.66 (m, 1H), 2.63(s, 3H), 2.33 - 2.25 (m, 1H), 2.06 - 1.94 (m, 1H), 1.51 - 1.32 (m, 2H), 1.10(t, J = 7.0 Hz, 3H). ES-LCMS m / z 483.2 [M+H] + .

[0708] Intermediate 9: (1R,2R,4R,6S)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0709]

[0710] Step 1: (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0711]

[0712] A 1:1 mixture (intermediate 8, step 12) of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid and (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (intermediate 8, step 12) (4.50 g, 8.45 mmol) was chirally purified by a preparative chiral SFC (column: YMC Cellulose-SA 250 X 30 mm, 5 μm; mobile phase: 75:25 CO2: [MeOH containing 0.5% isopropylamine]) to obtain:

[0713] First eluting isomer (1S,2R,4S,6S)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (1.20 g, 2.05 mmol, 24.3% yield). 1H NMR (400MHz, DMSO-d6) δ 10.27 (br s, 1H), 8.29 (t, J = 8.3 Hz, 1H), 7.73 - 7.64 (m,1H), 7.52 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.21 (d, J = 8.5 Hz,2H), 3.50 - 3.47 (m, 2H), 3.09 - 3.02 (m, 1H), 2.98 - 2.90 (m, 1H), 2.81 -2.71 (m, 1H), 2.52 (br d, J = 2.0 Hz, 1H), 2.24 (d, J = 12.5 Hz, 1H), 2.04 -1.94 (m, 1H), 1.40 (qd, J = 12.0, 7.0 Hz, 2H), 1.08 (t, J = 7.0 Hz, 3H). ES-LCMS m / z 532.0 [M+H] + .

[0714] Second eluting isomer (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (1.60 g, 2.92 mmol, 34.5% yield) 1 H NMR (400MHz, DMSO-d6) δ 10.35 (br s, 1H), 8.28 (t, J = 8.0 Hz, 1H), 7.68 (dd, J =11.0, 1.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.5 Hz, 2H), 7.21(d, J = 8.5 Hz, 2H), 3.51 - 3.46 (m, 2H), 3.04 (dt, J = 12.6, 6.4 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.81 - 2.72 (m, 1H), 2.57 - 2.53 (m, 1H), 2.25 (d, J =11.5 Hz, 1H), 2.02 - 1.95 (m, 1H), 1.47 - 1.34 (m, 2H), 1.09 (t, J = 7.0 Hz, 3H). ES-LCMS m / z 532.0 [M+H] + .

[0715] Absolute stereochemistry is determined by the co-crystal structure of the final compound and the WRN protein, and then traced back to the corresponding enantiomeric pure intermediate.

[0716] Step 2: (1R,2R,4R,6S)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0717]

[0718] A mixture of (1R,2S,4R,6R)-2-(4-bromophenyl)-4-ethoxy-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (450 mg, 0.845 mmol) and sodium tert-butoxide (244 mg, 2.54 mmol) in 1,4-dioxane (4.5 mL) was stirred for 5 minutes. tBuXPhos Pd G3 (67 mg, 0.085 mmol) was added, and the mixture was degassed for 5 minutes. Methylamine (2 M THF solution, 8.45 mL, 16.9 mmol) was added, and the reaction was heated at 100 °C in a Biotage Initiator (microwave) for 1 hour. The mixture was concentrated, and the resulting residue was purified by reverse-phase reaction (MeCN in H2O solution, 10 nM ammonium bicarbonate modifier, 10-100% gradient) to give (1R,2R,4R,6S)-4-ethoxy-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid (360 mg, 0.709 mmol, 84.0% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.55(br s, 1H), 8.29 (t, J = 8.0 Hz, 1H), 7.65 (dd, J = 11.0, 1.5 Hz, 1H), 7.51(d, J = 8.0 Hz, 1H), 6.94 (d, J = 8.5 Hz, 2H), 6.39 (d, J = 8.5 Hz, 2H), 5.32(br s, 1H), 3.47 (qd, J = 7.0, 1.5 Hz, 2H), 3.42 - 3.37 (m, 1H), 2.84 (t, J =10.8 Hz, 1H), 2.69 - 2.58 (m, 4H), 2.44 - 2.35 (m, 1H), 2.23 (d, J = 12.5 Hz,1H), 1.92 (d, J = 12.0 Hz, 1H), 1.37 - 1.25 (m, 2H), 1.08 (t, J = 7.0 Hz,3H). ES-LCMS m / z 483.2 [M+H] + .

[0719] Intermediate 10: rac-(1R,2S,4S,6R)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxy-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0720]

[0721] Step 1: rac-(1R,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-oxocyclohexane-1-carboxylic acid

[0722]

[0723] In step 5 of a 1:1 mixture intermediate 8 (9.1 g, 29 mmol) of (3aR,7S,7aS)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione and (3aS,7R,7aR)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione in methanol (100 mL), KOH (8.26 g, 147 mmol) was added, and the reaction mixture was stirred at 75 °C for 3 hours. The reaction was quenched with 2N HCl (~50 mL) to pH < 3, and a solid precipitate formed. The solid was filtered, washed with water (25 mL, 4 times), washed with petroleum ether (25 mL, 4 times), and dried to give rac-(1R,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-oxocyclohexane-1-carboxylic acid (9.5 g, 26 mmol, 89% yield). 1 H NMR (400MHz, DMSO-d6) δ 12.54 - 11.83 (m, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.22 (d, J =8.5 Hz, 2H), 3.36 - 3.25 (m, 5H), 3.01 (t, J = 4.0 Hz, 1H), 2.64 - 2.54 (m,1H), 2.30 - 2.21 (m, 3H). ES-LCMS m / z 327.0 [M+H] + .

[0724] Step 2: rac-(1R,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester

[0725]

[0726] At 0 °C, benzyl bromide (3.45 mL, 29.0 mmol) was added dropwise over 1 minute to a mixture of rac-(1R,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-oxocyclohexane-1-carboxylic acid (9.5 g, 29 mmol) and potassium carbonate (12.0 g, 87.0 mmol) in N,N-dimethylformamide (100 mL). After 3 hours, ice water (20 mL) was added, and the reaction was extracted with EtOAc (200 mL x 2). The combined EtOAc layers were washed with water (100 mL) and brine (50 mL), dried over sodium sulfate, and evaporated to give the crude substance. The resulting residue was purified in normal phase (petroleum ether solution of ethyl acetate, 5-75% gradient) to give rac-(1R,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester (8.70 g, 19.4 mmol, 66.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.46 (d,J = 8.5 Hz, 2H), 7.32 - 7.12 (m, 5H), 6.98 - 6.89 (m, 2H), 4.96 (d,J = 12.5Hz, 1H), 4.83 - 4.71 (m, 2H), 3.49 (dt, J = 14.0, 4.3 Hz, 1H), 3.40 - 3.33(m, 2H), 3.17 (t, J = 4.3 Hz, 1H), 2.74 - 2.58 (m, 1H), 2.44 - 2.13 (m, 4H).ES-LCMS m / z 417.0 [M+H] + .

[0727] Step 3: rac-(1R,2S,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-oxocyclohexane-1-carboxylic acid

[0728]

[0729] At 0 °C, sodium periodate (16.8 g, 78.0 mmol) and ruthenium(III) chloride (542 mg, 2.61 mmol) were added to a mixture of rac-(1R,2R,6S)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester (10.9 g, 26.1 mmol) in acetonitrile (19.3 mL) and water (4.8 mL). After 2 hours, water (100 mL) was added, and the mixture was extracted with EtOAc (500 mL x 2). The EtOAc layer was washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, concentrated, and purified by reverse-phase (MeCN H2O solution, 0.1% formic acid modifier, 10-90% gradient) to give rac-(1R,2S,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-oxocyclohexane-1-carboxylic acid (6.9 g, 15 mmol, 57% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.77 (br s, 1H), 7.57 - 7.40 (m,2H), 7.34 - 7.10 (m, 5H), 6.96 - 6.84 (m, 2H), 4.89 - 4.77 (m, 2H), 3.58 (dt,J = 14.4, 4.1 Hz, 1H), 3.39 (t, J = 4.5 Hz, 1H), 3.34 (br s, 1H), 3.07 (td, J= 14.3, 11.0 Hz, 2H), 2.47 (br d, J = 5.5 Hz, 1H), 2.36 - 2.24 (m, 1H). ES-LCMS m / z 429.0 [MH] - .

[0730] Step 4: rac-(1R,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester

[0731]

[0732] Add 1-methyl-1H-imidazolium (2.55 mL, 32.0 mmol), 2-fluoro-4-(trifluoromethyl)aniline (2.87 g, 16.0 mmol), and chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (8.98 g, 32.0 mmol) to a mixture of rac-(1R,2S,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-oxocyclohexane-1-carboxylic acid (6.9 g, 16 mmol) in acetonitrile (35 mL). Sixteen hours later, the mixture was concentrated and purified in normal phase (petroleum ether solution of ethyl acetate, 0-50% gradient) to give rac-(1R,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester (6.6 g, 11 mmol, 68% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.15 (t, J = 8.0 Hz, 1H), 7.73 (dd, J= 11.0, 2.0 Hz, 1H), 7.58 - 7.46 (m, 3H), 7.27 - 7.10 (m, 5H), 6.90 - 6.83(m, 2H), 4.94 - 4.72 (m, 2H), 3.64 - 3.47 (m, 3H), 3.39 - 3.32 (m, 1H), 3.11(t, J = 14.3 Hz, 1H), 2.47 - 2.33 (m, 2H).ES-LCMS m / z 592.0 [M+H] + .

[0733] Step 5: rac-(1R,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid

[0734]

[0735] At 0 °C, a boron trichloride solution (13.50 mL, 1 M DCM solution) was added to a mixture of rac-(1R,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester (4.00 g, 6.75 mmol) in DCM (40 mL). After 1 hour, water (30 mL) was added, and the mixture was extracted with DCM (50 mL x 4). The combined organic layers were washed with water (25 mL x 4) and brine (25 mL), dried over sodium sulfate, concentrated, and purified by reverse-phase (MeCN H2O solution, 0.1% formic acid modifier, 10-90% gradient) to give rac-(1R,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid (2.5 g, 4.6 mmol, 68% yield). 1 H NMR (400 MHz, DMSO-d6) δ 12.25 (br s,1H), 10.24 (s, 1H), 8.22 (t, J = 8.3 Hz, 1H), 7.74 (dd, J = 11.0, 1.5 Hz,1H), 7.59 - 7.50 (m, 3H), 7.24 (d, J = 8.5 Hz, 2H), 3.53 (dt, J = 13.5, 4.5Hz, 1H), 3.49 - 3.41 (m, 2H), 3.18 - 3.02 (m, 2H), 2.43 - 2.32 (m, 2H). ES-LCMS m / z 504.0 [M+H] + .

[0736] Step 6: rac-(1R,2R,4S,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxycyclohexane-1-carboxylic acid

[0737]

[0738] At 0 °C, solid sodium borohydride (377 mg, 9.96 mmol) was added to a mixture of rac-(1R,2R,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid (0.500 g, 0.996 mmol) in THF (15 mL) and methanol (15 mL). The reaction was stirred at room temperature for 16 hours, concentrated, and purified by reverse-phase (MeCN in H2O solution [10 mM ammonium bicarbonate], 10-90% gradient) to give rac-(1R,2R,4S,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxycyclohexane-1-carboxylic acid (0.300 g, 0.563 mmol, 56.5% yield). 1 H NMR (400 MHz, DMSO-d6) δ 13.58 (br s, 1H), 8.40 (t,J = 8.3 Hz, 1H), 7.62 (dd, J = 11.3, 1.8 Hz, 1H), 7.51 - 7.46 (m, 1H), 7.40 -7.33 (m, 2H), 7.31 - 7.22 (m, 2H), 4.67 (br d, J = 4.0 Hz, 1H), 3.69 - 3.51(m, 1H), 3.17 (d, J = 3.0 Hz, 2H), 2.94 (t, J = 3.3 Hz, 1H), 2.80 - 2.62 (m,2H), 2.02 (br d, J = 11.5 Hz, 1H), 1.87 (q, J = 11.7 Hz, 1H), 1.69 (br d, J =10.5 Hz, 1H). ES-LCMS m / z 503.9 [M+H] + .

[0739] Step 7: rac-(1R,2S,4S,6R)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxy-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0740]

[0741] A mixture of rac-(1R,2R,4S,6S)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxycyclohexane-1-carboxylic acid (0.300 g, 0.595 mmol) and sodium tert-butoxide (172 mg, 1.79 mmol) in 1,4-dioxane (10 mL) was stirred for 5 minutes. tBuXPhos Pd G3 (47 mg, 0.059 mmol) was added, and the mixture was degassed for 5 minutes. Methylamine (2 M THF solution, 5.95 mL, 11.9 mmol) was added, and the reaction was heated at 100 °C in a Biotage Initiator (microwave) for 1.5 hours. The mixture was concentrated, and the resulting residue was purified by reverse-phase reaction (MeCN in H2O solution, 10 nM ammonium bicarbonate modifier, 10-80% gradient) to give rac-(1R,2S,4S,6R)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxy-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid (0.20 g, 0.41 mmol, 69% yield). 1 H NMR (400 MHz, DMSO-d6) δ 13.10 (br s, 1H), 8.38 (t, J = 8.3 Hz, 1H), 7.62 (dd, J = 11.0, 2.0 Hz, 1H), 7.48 (br d, J =8.0 Hz, 1H), 7.05 (d, J = 8.5 Hz, 2H), 6.39 (d, J = 8.5 Hz, 2H), 5.24 (q, J =5.3 Hz, 1H), 4.59 (br s, 1H), 3.57 (br s, 1H), 3.20 - 3.08 (m, 1H), 2.91 -2.75 (m, 2H), 2.67 - 2.54 (m, 4H), 2.05 - 1.82 (m, 2H), 1.61 (br d, J = 11.5Hz, 1H), one proton is masked by the solvent. ES-LCMS m / z 455.1 [M+H] + .

[0742] Intermediate 11: rac-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxy-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0743]

[0744] Step 1: rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-4-hydroxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid

[0745]

[0746] KOH (2.88 g, 51.4 mmol) was added to intermediate 8 (3.20 g, 10.3 mmol) of a 1:1 mixture of (3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one and (3aS,5S,7R,7aR)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one in step 6. The reaction was stirred at 75 °C for 3 hours, quenched with 2NHCl (~20 mL) to pH < 3, concentrated, and then purified by reversed-phase chromatography (MeCN H2O solution, 0.1% ammonium bicarbonate modifier, 0-100% gradient) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-4-hydroxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid (2.30 g, 6.92 mmol, 67.0% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ δ 7.41 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 3.58 - 3.53 (m, 1H),3.41 - 3.38 (m, 1H), 3.24 - 3.21 (m, 1H), 2.78 - 2.71 (m, 1H), 2.15 - 2.10(m, 1H), 2.05 (d, J = 12.4 Hz, 1H), 1.83 (d, J = 12.0 Hz, 1H), 1.73 - 1.68(m, 1H), 1.29 (q, J = 12.4 Hz, 1H), 1.05 (q, J = (12.4 Hz, 1H), two proton peaks are masked by the solvent. ES-LCMS m / z 329.0 [M+H] + .

[0747] Step 2: rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-4-hydroxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester

[0748]

[0749] At 0 °C, benzyl bromide (0.83 mL, 7.0 mmol) was added dropwise over 1 minute to a mixture of rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-4-hydroxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid (2.30 g, 6.99 mmol) and potassium carbonate (2.90 g, 20.9 mmol) in N,N-dimethylformamide (20 mL). The reaction was stirred at room temperature for 3 hours, diluted with ice water (30 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, concentrated, and purified by reversed-phase chromatography (MeCN H2O solution, 0.1% ammonium bicarbonate modifier, 0-100% gradient) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-4-hydroxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester (2.10 g, 4.51 mmol, 65.0% yield), as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.45 - 7.41 (m, 2H), 7.27 - 7.22 (m, 3H), 7.16 -7.12 (m, 2H), 6.89 - 6.85 (m, 2H), 4.88 (d, J = 12.8 Hz, 1H), 4.74 - 4.69 (m,1H), 4.59 - 4.57 (m, 1H), 3.61 (s, 1H), 3.32 - 3.20 (m, 1H), 2.90 (s, 2H),2.79 - 2.74 (m, 1H), 2.38 (t, J = 11.2 Hz, 1H), 2.04 - 1.09 (m, 4H). ES-LCMS m / z: poor ionization performance in MS.

[0750] Step 3: rac-(1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-oxocyclohexane-1-carboxylic acid

[0751]

[0752] At -20 °C, sodium periodate (3.21 g, 15.0 mmol) and ruthenium(III) chloride (1.04 g, 5.01 mmol) were added to a mixture of rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-4-hydroxy-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester (2.10 g, 5.01 mmol) in acetonitrile (31 mL) and water (15 mL). After 1 hour, the reaction was diluted with water (35 mL) and extracted with ethyl acetate (4 x 50 mL). The combined organic layers were washed with water (20 mL) and brine (25 mL), dried over sodium sulfate, concentrated, and then purified by reversed-phase chromatography (MeCN H2O solution, 0.1% ammonium bicarbonate modifier, 0-100% gradient) to give rac-(1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-oxocyclohexane-1-carboxylic acid (1.1 g, 2.4 mmol, 49% yield) as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ7.48 (d, J = 1.6 Hz, 2H), 7.28 - 7.23 (m, 5H), 6.88 (dd, J = 6.6, 4.0 Hz, 2H), 4.77 (d, J = 12.4 Hz, 1H), 4.69 (d, J = 12.8 Hz, 1H), 3.25 (t, J = 11.2Hz, 1H), 3.16 - 2.84 (m, 4H), 2.68 (t, J = 13.6 Hz, 1H), 2.55 - 2.53 (m, 1H), 2.26 - 2.21 (m, 1H). ES-LCMS m / z 429.0 [MH] + .

[0753] Step 4: rac-(1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester

[0754]

[0755] Add 1-methyl-1H-imidazolium (0.111 mL, 1.39 mmol) and 2-fluoro-4-(trifluoromethyl)aniline (125 mg, 0.690 mmol) to a suspension of rac-(1R,2R,3S)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-oxocyclohexane-1-carboxylic acid (0.30 g, 0.69 mmol) in acetonitrile (1.5 mL), followed by the addition of chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (390 mg, 1.39 mmol). Two hours later, the reaction was concentrated and purified by normal-phase chromatography (petroleum ether solution of ethyl acetate, 0-50% gradient) to give rac-(1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester (0.26 g, 0.40 mmol, 57% yield), as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.15 (t, J =8.0 Hz, 1H), 7.75 (d, J = 2.0 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.50 (d, J =8.4 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.23 - 7.15 (m, 3H), 6.84 (d, J = 6.4Hz, 2H), 4.73 (q, J = 12.8 Hz, 2H), 3.54 - 3.46 (m, 2H), 3.20 - 3.17 (m, 1H),3.01 (t, J = 13.6 Hz, 1H), 2.83 (t, J = 13.2 Hz, 1H), 2.68 - 2.60 (m, 1H), 2.37 - 2.33 (m, 1H). ES-LCMS m / z 592.0 [MH] + .

[0756] Step 5: rac-(1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid

[0757]

[0758] At 0 °C, boron trichloride solution (1 M DCM solution, 0.878 mL, 0.878 mmol) was added dropwise over 2 minutes to a mixture of rac-(1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester (0.26 g, 0.44 mmol) in dichloromethane (5 mL). One hour later, the reaction was quenched with ice water (2 mL), concentrated, and purified by reversed-phase chromatography (MeCN H2O solution, 0.1% ammonium bicarbonate modifier, 10-100% gradient) to give rac-(1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid (0.14 g, 0.26 mmol, 60% yield) as a white solid. 1 HNMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.23 ​​(t, J = 8.0 Hz, 1H), 7.73 (d, J= 9.2 Hz, 1H), 7.57 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.32 (d, J= 8.4 Hz, 2H), 3.42 - 3.41 (m, 1H), 3.29 - 3.23 (m, 1H), 3.13 (t, J = 4.0,Hz, 1H), 2.92 (t, J = 13.6 Hz, 1H), 2.80 (t, J = 13.6 Hz, 1H), 2.55 - 2.52(m, 1H), 2.46-2.29 (m, 1H). ES-LCMS m / z 499.8 [MH] - .

[0759] Step 6: rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxycyclohexane-1-carboxylic acid

[0760]

[0761] Sodium borohydride (26.4 mg, 0.697 mmol) was added to a mixture of rac-(1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid (0.14 g, 0.28 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) over a period of 1 minute at 0 °C. Three hours later, the reaction was concentrated and then purified by reversed-phase chromatography (MeCN in H2O solution, 0.1% ammonium bicarbonate modifier, 0-100% gradient) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxycyclohexane-1-carboxylic acid (70 mg, 0.14 mmol, 49% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ10.19 (s, 1H), 8.21 (t, J = 8.0 Hz, 1H), 7.71 (dd, J = 11.2, 1.6 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 4.90 (s, 1H), 3.69 - 3.33 (m, 1H), 3.08 - 3.01 (m, 1H), 2.80 - 2.65 (m, 2H), 2.15 (d, J = 12.0 Hz, 1H), 2.09 (d, J = 4.8 Hz, 1H), 1.91 - 1.47 (m, 2H). ES-LCMS m / z 504.0 [M+H] + .

[0762] Step 7: rac-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxy-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid

[0763]

[0764] In a 10 mL microwave-safe vial, solid tBuXPhos Pd G3 (11.03 mg, 0.0140 mmol) and methylamine (1.39 mL, 2.78 mmol) were added to a mixture of rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxycyclohexane-1-carboxylic acid (70.0 mg, 0.140 mmol) and sodium tert-butoxide (40.0 mg, 0.420 mmol) in 1,4-dioxane (2 mL). The reaction was heated in an Anton microwave initiator at 100 °C for 1 hour. The reaction was concentrated and then purified by reversed-phase chromatography (MeCN in H2O solution, 0.1% ammonium bicarbonate modifier, 0-100% gradient) to give rac-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-hydroxy-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid (35.0 mg, 0.0800 mmol, 54% yield) as a white solid. 1 H-NMR (400 MHz, DMSO-d6): δ 10.30 (s, 1H), 8.24 (t, J = 8.0Hz, 1H), 7.69 (d, J = 10.8 Hz, 1H), 7.54 (d, J = 7.6 Hz, 1H), 6.94 (d, J =8.4 Hz, 2H), 6.42 (d, J = 8.4 Hz, 2H), 5.40 (s, 1H), 4.77 (d, J = 4.0 Hz,2H), 3.61 (s, 1H), 2.95 (t, J = 12.8 Hz, 1H), 2.68 - 2.58 (m, 5H), 2.11 (d, J= 10.0 Hz, 1H), 1.84 (d, J = 11.2 Hz, 1H), 1.38 (q, J = 12.4 Hz, 1H). ES-LCMSm / z 455.0 [M+H] + .

[0765] Intermediate 12: rel-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid, isomer 1

[0766]

[0767] Step 1: rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)cyclohexane-1-carboxylic acid benzyl ester

[0768]

[0769] At 0 °C, trifluoromethanesulfonic acid (0.150 mL, 1.69 mmol) and triethylsilane (1.35 mL, 8.44 mmol) were added to a mixture of intermediate 11 (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-oxocyclohexane-1-carboxylic acid benzyl ester intermediate 11 (0.500 g, 0.844 mmol) and methyl-d3-ol-d (304 mg, 8.44 mmol) in acetonitrile (5 mL). The reaction was stirred overnight at room temperature, quenched with water (100 mL), and extracted with ethyl acetate (100 mL x 3). The organic layer was washed with saturated sodium bicarbonate solution (100 mL) and brine (100 mL), dried over sodium sulfate, filtered, concentrated, and purified in normal phase (petroleum ether solution of ethyl acetate, 0-20% gradient) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)cyclohexane-1-carboxylic acid benzyl ester (150 mg, 0.23 mmol, 27% yield), as a white solid.

[0770] 1HNMR (400 MHz, DMSO-d6): δ 10.19 (s, 1H), 8.17 (t, J = 8.0 Hz, 1H), 7.74 (dd, J = 10.8, 1.6 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.19 - 7.14 (m, 4H), 6.79 (d, J = 1.6 Hz, 1H), 4.69 (ab q, J = 12.8 Hz, 2H), 3.44 - 3.40 (m, 1H), 3.33 - 3.10 (m, 1H),2.97 (t, J = 11.2 Hz, 1H), 2.85 - 2.78 (m, 1H), 2.50 - 2.41 (m, 1H), 2.34 -2.07 (m, 1H), 1.60 - 1.57 (m, 1H), 1.45 - 1.42 (m, 1H), δ 1.24 - 0.83 (m,1H). ES-LCMS m / z 611.0, 613 / 0 [M+H] + .

[0771] Step 2: rel-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)cyclohexane-1-carboxylic acid, isomer 1

[0772]

[0773] At 0 °C, boron trichloride (1.31 mL, 1.31 mmol in 1 M DCM solution) was added to a mixture of rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)cyclohexane-1-carboxylic acid benzyl ester (0.40 g, 0.65 mmol) in dichloromethane (5 mL). The reaction was stirred at 0 °C for 10 min and then warmed to room temperature over 1 hour. The mixture was quenched with methanol at 0 °C, concentrated, and purified by reverse-phase purification (MeCN in H2O solution, 10 mM formic acid modifier, 95-98% gradient) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)cyclohexane-1-carboxylic acid (200 mg, 0.37 mmol, 56% yield) as a grayish-white solid. The racemic compound was separated by a chiral preparative SFC (column: LuxAmylose-1 [250 X 30] mm, 5 μm; CO2: IPA 60:40) to give rel-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)cyclohexane-1-carboxylic acid, isomer 1 (0.10 g, 0.18 mmol, 48% yield), as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 10.20(s, 1H), 8.23 ​​(t, J = 8.0 Hz, 1H), 7.71 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.8Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 3.41 - 3.36 (m,1H), 3.18 - 3.02 (m, 1H), 2.75 - 2.56 (m, 2H), 2.34 - 2.33 (m, 1H), 2.07 -2.04 (m, 1H), 1.51 - 1.39 (m, 2H), 1.13 - 1.11 (m, 1H). ES-LCMS m / z 521.0,523.0 [M+H] + .

[0774] Step 3: rel-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid, isomer 1

[0775]

[0776] To a mixture of rel-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)cyclohexane-1-carboxylic acid, isomer 1 (0.090 g, 0.17 mmol) in 1,4-dioxane (2 mL), sodium tert-butoxide (16.6 mg, 0.173 mmol) was added, followed by a single addition of tBuXPhos PdG3 (137 mg, 0.173 mmol). After degassing for 5 minutes, methylamine (2 M THF solution, 0.86 mL, 0.173 mmol) was added, and the reaction vessel was sealed and heated at 100 °C in a Biotage Initiator (microwave) for 1 hour. The reaction was stirred at room temperature for 3 hours, concentrated, and purified by reverse-phase reaction (MeCN in H2O solution, 0.1% formic acid, 10-55% gradient) to give rel-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid, isomer 1 (40 mg, 0.080 mmol, 46% yield), as a white solid. 1 H NMR (400 MHz, DMSO-d6): δ 11.73 (br.s, 1H), 10.11 (s, 1H), 8.22 (t, J = 8.0Hz, 1H), 7.73 (dd, J = 11.0, 1.6 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 6.97 (d,J = 8.8 Hz, 2H), 6.44 (d, J = 8.8 Hz, 2H), 5.46 (br.s, 1H), 3.39 - 3.36 (m,1H), 3.05 - 3.00 (m, 1H), 2.70 - 2.61 (m, 5H), 2.34 - 2.29 (m, 1H), 2.34 -2.29 (m, 1H), 1.44 - 1.35 (m, 2H). ES-LCMS m / z 472.2 [M+H] + .

[0777] Intermediates 13 and 14: rel-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 1 and isomer 2

[0778]

[0779] Step 1: rac-(3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-phenoxyhexahydroisobenzofuran-1(3H)-one

[0780]

[0781] To an intermediate 8 (2.0 g, 6.4 mmol) of a 1:1 mixture of (3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one and (3aS,5S,7R,7aR)-7-(4-bromophenyl)-5-hydroxyhexahydroisobenzofuran-1(3H)-one in acetonitrile (20 ml), 2-(trimethylsilyl)phenyltrifluoromethanesulfonate (2.3 g, 7.7 mmol), potassium fluoride (1.87 g, 32.1 mmol), and 18-crown ether-6 (4.25 g, 16.1 mmol) were added. After 16 hours, the reaction was quenched with water (50 ml) and extracted with ethyl acetate (50 mL x 3). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, concentrated, and purified by reverse-phase purification (MeCN H2O solution, 10 mM formic acid modifier, 95-98% gradient) to give rac-(3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-phenoxyhexahydroisobenzofuran-1(3H)-one (870 mg, 1.8 mmol, 28% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.44 (m,2H), 7.32 - 7.23 (m, 4H), 7.03 - 6.96 (m, 2H), 5.01 - 4.78 (m, 1H), 4.52 (tt,J = 11.0, 3.8 Hz, 1H), 4.27 - 4.15 (m, 1H), 3.91 - 3.67 (m, 1H), 3.55 - 3.44(m, 1H), 2.86 (dt, J = 12.0, 6.0 Hz, 1H), 2.39 - 2.23 (m, 2H), 1.90 - 1.49(m, 2H), 1.18 (q, J = 12.5 Hz, 1H). ES-LCMS has poor m / z ionization performance.

[0782] Step 2: rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-phenoxycyclohexane-1-carboxylic acid

[0783]

[0784] To a mixture of rac-(3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-phenoxyhexahydroisobenzofuran-1(3H)-one (0.870 g, 2.25 mmol) in methanol (15 mL), KOH (0.630 g, 11.3 mmol) was added. The reaction was stirred at 75 °C for 16 h and quenched with 2N HCl (~20 mL) to pH < 3. The resulting solid was collected by filtration and washed with water (5 mL x 4) and petroleum ether (5 mL x 4) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-phenoxycyclohexane-1-carboxylic acid (0.730 g, 1.44 mmol, 64.0% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 8.5 Hz, 2H), 7.32 - 7.10 (m, 5H), 6.99 - 6.94 (m, 2H), 4.62 - 4.40 (m, 1H), 3.90 - 3.70 (m, 1H), 3.42 (dd, J =10.5, 3.5 Hz, 2H), 3.06 - 2.87 (m, 1H), 2.39 - 2.23 (m, 2H), 2.06 (d, J =11.5 Hz, 1H), 1.96 - 1.83 (m, 1H), 1.65 - 1.51 (m, 1H), 1.32 - 1.22 (m, 1H),0.84 (dd, J = 8.8, 2.3 Hz, 1H). ES-LCMS m / z 405.0 [MH] - .

[0785] Step 3: rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-phenoxycyclohexane-1-carboxylic acid benzyl ester

[0786]

[0787] At 0 °C, potassium carbonate (0.747 g, 5.40 mmol) and benzyl bromide (0.321 mL, 2.70 mmol) were added to a mixture of rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-phenoxycyclohexane-1-carboxylic acid (0.730 g, 1.80 mmol) in N,N-dimethylformamide (10 mL). The reaction was stirred at room temperature for 16 hours, diluted with water (50 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, concentrated, and purified by normal-phase chromatography (petroleum ether solution of EtOAc, 0-50% gradient) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-phenoxycyclohexane-1-carboxylic acid benzyl ester (0.400 g, 0.686 mmol, 38.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.49 - 7.38 (m, 2H), 7.32 - 7.13 (m, 7H), 7.03 - 6.83 (m, 5H), 4.93 - 4.70 (m, 2H), 4.66 (t, J =5.0 Hz, 1H), 4.63 - 4.49 (m, 1H), 3.30 - 3.17 (m, 1H), 3.09 - 2.94 (m, 1H), 2.71 - 2.56 (m, 1H), 2.31 - 1.96 (m, 3H), 1.77 - 1.60 (m, 1H), 1.44 - 1.18(m, 1H). ES-LCMS Poor m / z ionization effect.

[0788] Step 4: rac-(1R,2R,3S,5R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-phenoxycyclohexane-1-carboxylic acid

[0789]

[0790] At 0 °C, sodium periodate (518 mg, 2.42 mmol) and ruthenium(III) chloride (16.8 mg, 0.0810 mmol) were added to a mixture of rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)-4-phenoxycyclohexane-1-carboxylic acid benzyl ester (0.400 g, 0.807 mmol) in acetonitrile (50 mL) and water (10 mL). After 2 hours, the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, concentrated, and then purified by reversed-phase chromatography (MeCN in H2O solution, 10 mM formic acid modifier, 95-98% gradient) to give rac-(1R,2R,3S,5R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-phenoxycyclohexane-1-carboxylic acid (0.290 g, 0.529 mmol, 65.6% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.59(br s, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.34 - 7.13 (m, 7H), 7.07 - 6.81 (m,5H), 4.81 - 4.59 (m, 3H), 3.01 - 2.81 (m, 3H), 2.42 (d, J = 11.5 Hz, 1H), 2.07 (d, J = 10.5 Hz, 1H), 1.80 (q, J = 12.0 Hz, 1H), 1.68 - 1.53 (m, 1H).ES-LCMS m / z 509.0 [M+H] + .

[0791] Step 5: rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-phenoxycyclohexane-1-carboxylic acid benzyl ester

[0792]

[0793] To a suspension of rac-(1R,2R,3S,5R)-2-((benzyloxy)carbonyl)-3-(4-bromophenyl)-5-phenoxycyclohexane-1-carboxylic acid (0.290 g, 0.569 mmol) in acetonitrile (0.2 mL), 1-methyl-1H-imidazolium (0.272 mL, 3.42 mmol) and 2-fluoro-4-(trifluoromethyl)aniline (153 mg, 0.854 mmol) were added, followed by the addition of chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (799 mg, 2.85 mmol). Sixteen hours later, the reaction was concentrated and purified by reversed-phase chromatography (MeCN in H2O solution, 10 mM formic acid modified, 95-98% gradient) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-phenoxycyclohexane-1-carboxylic acid benzyl ester (0.280 g, 0.405 mmol, 71.2% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.17 (t, J = 8.0 Hz, 1H), 7.74 (dd, J = 11.3, 1.8Hz, 1H), 7.47 (d, J = 8.5 Hz, 2H), 7.31 - 7.27 (m, 4H), 7.23 - 7.14 (m, 4H), 7.04 (d, J = 7.5 Hz, 2H), 6.93 (t, J = 7.3 Hz, 1H), 6.85 - 6.80 (m, 2H), 4.80- 4.65 (m, 2H), 4.63 - 4.50 (m, 1H), 3.33 - 3.22 (m, 1H), 3.11 - 2.98 (m,2H), 2.47 (br s, 1H), 2.20 - 2.09 (m, 1H), 1.89 (q, J = 11.5 Hz, 1H), 1.71(q, J = 11.7 Hz, 1H). ES-LCMS m / z 670.0 [M+H] + .

[0794] Step 6: rel-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 1 and isomer 2

[0795]

[0796] At 0 °C, boron trichloride (1.31 mL, 1.31 mmol in 1 M DCM solution) was added to a mixture of rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-(methoxy-d3)cyclohexane-1-carboxylic acid benzyl ester (0.40 g, 0.65 mmol) in dichloromethane (5 mL). The reaction was stirred at 0 °C for 10 min and then warmed to room temperature over 1 hour. The mixture was quenched with methanol at 0 °C, concentrated, and purified by reverse-phase purification (MeCN in H2O solution, 10 mM formic acid modifier, 95-98% gradient) to give rac-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-phenoxycyclohexane-1-carboxylic acid (230 mg, 0.39 mmol, 94% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 10.15 (s, 1H), 8.20 (t, J = 8.0 Hz, 1H), 7.73 (dd, J = 11.0, 2.0 Hz, 1H), 7.55 (d,J = 8.0 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.33 – 7.24 (m, 4H), 7.06 – 6.99(m, 2H), 6.96 – 6.87 (m, 1H), 4.62 – 4.47 (m, 1H), 3.25 – 3.14 (m, 1H), 3.04– 2.79 (m, 2H), 2.46 – 2.36 (m, 1H), 2.13 (br d, J = 13.0 Hz, 1H), 1.86 –1.59 (m, 2H). ES-LCMS m / z 577.7 [MH] - .

[0797] The racemic compound was prepared by chiral preparation of a type SFC (column: Chiralpak IG

[250] ).

[30] mm, 5 μm; mobile phase: CO2:IPA 60:40) separation, yielding:

[0798] The first eluted isomer, rel-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 1 (110 mg, 0.17 mmol, 43% yield), is a white solid.

[0799] and

[0800] The second eluted isomer, rel-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 2 (110 mg, 0.17 mmol, 43% yield), is a white solid.

[0801] Step 7: rel-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 1 and isomer 2

[0802]

[0803] To a mixture of rel-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 1 (0.0900 g, 0.155 mmol) and sodium tert-butoxide (37.3 mg, 0.388 mmol) in 1,4-dioxane (2 mL), tBuXPhos Pd G3 (24.6 mg, 0.0310 mmol) was added. After degassing for 5 minutes, methylamine (2 M THF solution, 1.55 mL, 3.10 mmol) was added, and the reaction vessel was sealed and heated at 100 °C in a Biotage Initiator (microwave) for 1 hour. The reaction was purified by reverse-phase reaction (MeCN in H2O solution, 10 nM ammonium bicarbonate, 95-98% gradient) to give rel-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 1 (0.070 g, 0.12 mmol, 78% yield), as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (br s,1H), 10.12 (s, 1H), 8.20 (t, J = 8.0 Hz, 1H), 7.72 (dd, J = 11.0, 1.5 Hz,1H), 7.55 (d, J = 8.5 Hz, 1H), 7.31 - 7.25 (m, 2H), 7.05 - 6.99 (m, 4H), 6.95- 6.88 (m, 1H), 6.43 (d, J = 9.0 Hz, 2H), 5.47 (br s, 1H), 4.59 - 4.45 (m,1H), 3.23 - 3.09 (m, 1H), 2.84 - 2.71 (m, 2H), 2.63 (s, 3H), 2.39 (d, J =12.0 Hz, 1H), 2.09 (d, J = 12.0 Hz, 1H), 1.77 - 1.56 (m, 2H). ES-LCMS m / z531.0 [M+H] + .

[0804] In a separate reaction, tBuXPhos Pd G3 (27.4 mg, 0.0340 mmol) was added to a mixture of rel-(1R,2S,4R,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 2 (0.100 g, 0.172 mmol) and sodium tert-butoxide (41.4 mg, 0.431 mmol) in 1,4-dioxane (5 mL). After degassing for 5 minutes, methylamine (1.72 mL, 3.45 mmol, 2 M THF solution) was added, and the reaction vessel was sealed and heated at 100 °C in a Biotage Initiator (microwave) for 1 hour. The reaction was purified by reverse-phase reaction (MeCN in H2O solution, 10 nM ammonium bicarbonate, 10-100% gradient) to give rel-(1R,2R,4R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)-4-phenoxycyclohexane-1-carboxylic acid, isomer 2 (75 mg, 0.13 mmol, 76% yield), as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.84(br s, 1H), 10.13 (s, 1H), 8.21 (t, J = 8.0 Hz, 1H), 7.72 (dd, J = 11.0, 1.5Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 8.5, 7.5 Hz, 2H), 7.05 -6.98 (m, 4H), 6.95 - 6.88 (m, 1H), 6.43 (d, J = 8.5 Hz, 2H), 5.47 (d, J = 4.5Hz, 1H), 4.66 - 4.38 (m, 1H), 3.22 - 3.09 ES-LCMS m / z 531.0 [M+H] + .

[0805] Intermediate 15: rac-(3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-(cyclobutylmethoxy)hexahydroisobenzofuran-1(3H)-one

[0806]

[0807] Triethylsilane (3.9 mL, 24 mmol) and trifluoromethanesulfonic acid (1.4 mL, 16 mmol) were added to a mixture of rac-(3aR,7S,7aS)-7-(4-bromophenyl)tetrahydroisobenzofuran-1,5(3H,4H)-dione intermediate 8 (5.0 g, 16 mmol) and cyclobutylmethanol (3.05 mL, 32.3 mmol) in acetonitrile (50 mL). After 16 hours, the reaction was quenched with ice water (10 mL) and extracted with EtOAc (50 mL x 3). The combined EtOAc layers were washed with water (50 mL) and brine (50 mL), dried over sodium sulfate, concentrated, and purified by normal-phase purification (petroleum ether solution of ethyl acetate, 0-100% gradient) to give rac-(3aR,5R,7S,7aS)-7-(4-bromophenyl)-5-(cyclobutylmethoxy)hexahydroisobenzofuran-1(3H)-one (1.8 g, 4.4 mmol, 27% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.47(d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.5 Hz, 2H), 4.20 (dd, J = 8.5, 4.5 Hz,1H), 3.90 (d, J = 9.0 Hz, 1H), 3.52 - 3.35 (m, 3H), 3.25 (t, J = 5.5 Hz, 1H), 3.17 - 3.06 (m, 1H), 2.76 - 2.63 (m, 1H), 2.49 - 2.41 (m, 1H), 2.24 - 2.13(m, 2H), 2.01 - 1.94 (m, 2H), 1.89 - 1.78 (m, 2H), 1.74 - 1.65 (m, 2H), 1.39- 1.28 (m, 1H), 1.02 - 0.90 (m, 1H). ES-LCMS m / z 379.0 [M+H] + .

[0808] Intermediate 16: rac-(3aR,4S,5S,6R,7aS)-4-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-((N,1,2-trimethyl-1H-benzo[d]imidazole)-5-sulfonylamino)phenyl)octahydrobenzofuran-5-carboxylic acid methyl ester

[0809]

[0810] Step 1: (E / Z)-2-(4-bromostyryl)furan

[0811]

[0812] At 0 °C, potassium 2-methylprop-2-oxide (1 M, 229 mL, 229 mmol) was added to a mixture of (4-bromobenzyl)triphenylphosphine bromide (96.0 g, 187 mmol) in tetrahydrofuran (200 mL). After 10 minutes, a furan-2-carboxaldehyde solution (20.0 g, 208 mmol) was added dropwise over 5 minutes. After 4 hours, the reaction was quenched with water (100 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified in a normal phase (eethyl acetate in petroleum ether solution, 0-20% gradient) to give (E / Z)-2-(4-bromostyryl)furan (33 g, 0.11 mmol, 51% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 7.60 (d, J =1.5 Hz, 1H), 7.56 - 7.51 (m, 3H), 7.43 - 7.35 (m, 2H), 6.50 - 6.47 (m, 1H),6.46 - 6.41 (m, 2H). ES-LCMS m / z 249.9 [M+H] + .

[0813] Step 2: rac-(4R,5S,6R)-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4,5-dicarboxylic acid dimethyl ester

[0814]

[0815] A mixture of (E / Z)-2-(4-bromostyryl)furan (33.0 g, 132 mmol) and dimethyl fumarate (38.2 g, 265 mmol) was stirred at 140 °C for 1 week and then purified in normal phase (ethyl acetate to petroleum ether, 0-100% gradient) to give rac-(4R,5S,6R)-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4,5-dicarboxylic acid dimethyl ester (8.0 g, 16 mmol, 12% yield) as a yellow oil. 1¹H NMR (400 MHz, DMSO-d⁶) δ 7.56 (d, J = 1.9 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.5 Hz, 2H), 6.42 (d, J = 1.9 Hz, 1H), 3.99 – 3.92 (m, 1H), 3.67 (s, 3H), 3.27 – 3.19 (m, 5H), 3.04 – 2.91 (m, 1H), 2.90 – 2.79 (m, 1H). NMR analysis of the major isomers in diastereomer mixtures. ES-LCMS m / z 393.0 [M] + .

[0816] Step 3: rac-(4R,5S,6R)-6-(4-(methylamino)phenyl)-4,5,6,7-tetrahydrobenzofuran-4,5-dicarboxylic acid dimethyl ester

[0817]

[0818] To a mixture of rac-(4R,5S,6R)-6-(4-bromophenyl)-4,5,6,7-tetrahydrobenzofuran-4,5-dicarboxylate (8.00 g, 20.3 mmol) and cesium carbonate (19.9 g, 61.0 mmol) in N,N-dimethylformamide (80 mL) (degassed for 10 min), tBuBrettPhos Pd G3 (0.869 g, 1.02 mmol) was added. After 5 min, methylamine (2 M THF solution, 153 mL, 305 mmol) was added. The reaction was stirred at 60 °C for 16 h, quenched with water (100 mL), and extracted with EtOAc (100 mL x 4). The combined EtOAc layers were washed with water (100 mL x 2) and brine (100 mL), dried over sodium sulfate, concentrated, and purified in normal phase (petroleum ether solution of ethyl acetate, 0-20% gradient) to give rac-(4R,5S,6R)-6-(4-(methylamino)phenyl)-4,5,6,7-tetrahydrobenzofuran-4,5-dicarboxylic acid dimethyl ester (5.5 g, 14 mmol, 68% yield) as a yellow oil.

[0819] 1H NMR (400 MHz, DMSO-d6) δ 7.54 (d, J = 1.8 Hz, 1H), 7.02 (d, J = 8.5Hz, 2H), 6.45 (d, J = 8.5 Hz, 2H), 6.39 (d, J = 2.0 Hz, 1H), 5.58 – 5.47 (m,1H), 3.92 (dd, J = 7.8, 2.1 Hz, 1H), 3.66 (s, 3H), 3.25 (s, 3H), 3.06 (dd, J= 7.6, 2.8 Hz, 2H), 2.96 – 2.85 (m, 1H), 2.84 – 2.73 (m, 1H), 2.65 (d, J =5.1 NMR analysis of the major isomers in diastereomer mixtures (m / z, 3H). ES-LCMS m / z 344.2 [M+H] + .

[0820] Step 4: rac-(3aS,4R,5R,6S,7aR)-6-(4-(methylamino)phenyl)octahydrobenzofuran-4,5-dicarboxylic acid dimethyl ester

[0821]

[0822] A rhodium-carbon catalyst (6.89 g, 3.35 mmol) was added to a mixture of rac-(4R,5S,6R)-6-(4-(methylamino)phenyl)-4,5,6,7-tetrahydrobenzofuran-4,5-dicarboxylate (11.5 g, 33.5 mmol) in methanol (200 mL), and the reaction was carried out under a hydrogen atmosphere with a gas chamber (1 atm). The mixture was degassed by vacuum and then backfilled with hydrogen; this process was repeated three times. Sixteen hours later, the reaction was filtered through diatomaceous earth, concentrated, and purified in a normal phase (ethyl acetate in petroleum ether solution, 0-100% gradient) to give rac-(4R,5R,6S)-6-(4-(methylamino)phenyl)octahydrobenzofuran-4,5-dicarboxylic acid dimethyl ester (0.650 g, 1.60 mmol, 5.00% yield), as a brown oil. 1H NMR (400 MHz, DMSO-d6) δ 6.90 (d, J = 8.5 Hz, 2H), 6.41 (d, J = 8.5Hz, 2H), 5.45 (br d, J = 4.5 Hz, 1H), 4.17 (dt, J = 10.6, 6.4 Hz, 1H), 3.97 -3.87 (m, 1H), 3.77 - 3.63 (m, 1H), 3.60 - 3.54 (m, 2H), 3.33 (s, 3H), 3.23(dd, J = 6.3, 5.3 Hz, 1H), 2.77 (t, J = 11.5 Hz, 1H), 2.70 - 2.57 (m, 4H),2.46 - 2.39 (m, 1H), 2.08 - 2.00 (m, 1H), 1.96 - 1.84 (m, 1H), 1.67 - 1.51 (m, 2H), One proton is masked by the residual DMSO / H2O peak. ES-LCMS m / z 348.0 [M+H] + .

[0823] Step 5: rac-(3aR,4S,5S,6R,7aS)-5-(methoxycarbonyl)-6-(4-(methylamino)phenyl)octahydrobenzofuran-4-carboxylic acid.

[0824]

[0825] At 0 °C, lithium hydroxide (0.258 g, 10.79 mmol) was added to a mixture of rac-(4R,5R,6S)-6-(4-(methylamino)phenyl)octahydrobenzofuran-4,5-dicarboxylic acid dimethyl ester (2.50 g, 7.20 mmol) in tetrahydrofuran (55 mL), methanol (55.0 mL), and water (55 mL). The reaction was stirred at 60 °C for 16 h, concentrated, and purified by reverse-phase (MeCN in H2O solution, 0.1% ammonium bicarbonate modifier, 0-100% gradient) to give rac-(3aR,4S,5S,6R,7aS)-5-(methoxycarbonyl)-6-(4-(methylamino)phenyl)octahydrobenzofuran-4-carboxylic acid (1.5 g, 4.2 mmol, 59% yield) as a grayish-white solid. 1¹H NMR (400 MHz, DMSO-d⁶) δ 6.89 - 6.81 (m, 2H), 6.40 (m, 2H), 5.39 (br s, 1H), 3.81 - 3.62 (m, 2H), 3.61 - 3.47 (m, 1H), 3.19 - 3.06 (m, 3H), 2.77 - 2.66 (m, 1H), 2.62 (s, 3H), 2.37 - 2.25 (m, 1H), 2.21 - 2.05 (m, 1H), 1.94 - 1.64 (m, 3H), 1.56 - 1.45 (m, 1H). Two protons are masked by the residual DMSO / H₂O peak. ES-LCMS m / z 334.2 [M+H] + .

[0826] Step 6: rac-(3aR,4S,5S,6R,7aS)-5-(methoxycarbonyl)-6-(4-((N,1,2-trimethyl-1H-benzo[d]imidazole)-5-sulfonylamino)phenyl)octahydrobenzofuran-4-carboxylic acid

[0827]

[0828] Add pyridine (1.5 mL, 18.00 mmol) to a suspension of rac-(3aR,4S,5S,6R,7aS)-5-(methoxycarbonyl)-6-(4-(methylamino)phenyl)octahydrobenzofuran-4-carboxylic acid (1.50 g, 4.50 mmol) and 1,2-dimethyl-1H-benzo[d]imidazolium-5-sulfonyl chloride (2.64 g, 10.80 mmol) in dichloromethane (20 mL). One hour later, the reaction was concentrated and purified in normal phase (DCM solution of MeOH, 2-25% gradient) to give rac-(3aR,4S,5S,6R,7aS)-5-(methoxycarbonyl)-6-(4-((N,1,2-trimethyl-1H-benzo[d]imidazole)-5-sulfonamide)phenyl)octahydrobenzofuran-4-carboxylic acid (2.2 g, 3.3 mmol, 72% yield) as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.91 - 8.89 (m, 3H), 8.54 - 8.49 (m, 2H), 8.02 - 7.97 (m, 3H), 7.17 (d, J = 8.5 Hz, 1H), 7.01 - 6.94 (m, 1H), 4.18 (dt, J = 10.5, 6.3 Hz,1H), 3.90 (s, 3H), 3.80 - 3.69 (m, 1H), 3.16 (s, 3H), 3.15 - 3.10 (m, 3H),2.76 (s, 3H), 2.71 - 2.63 (m, 1H), 2.62 - 2.54 (m, 1H), 2.47 - 2.38 (m, 1H), 2.10 - 2.00 (m, 1H), 1.78 - 1.54 (m, 2H), one proton is masked by the DMSO / H2O peak. ES-LCMS m / z 542.3 [M+H] + .

[0829] Step 7: rac-(3aR,4S,5S,6R,7aS)-4-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-((N,1,2-trimethyl-1H-benzo[d]imidazole)-5-sulfonylamino)phenyl)octahydrobenzofuran-5-carboxylic acid methyl ester

[0830]

[0831] At 25°C, TCFH (3.89 g, 13.9 mmol), 2-fluoro-4-(trifluoromethyl)aniline (0.719 mL, 5.54 mmol), and finally NMI (2.21 mL, 27.7 mmol) were added sequentially to a mixture of rac-(3aR,4S,5S,6R,7aS)-5-(methoxycarbonyl)-6-(4-((N,1,2-trimethyl-1H-benzo[d]imidazole)-5-sulfonamide)phenyl)octahydrobenzofuran-4-carboxylic acid (1.5 g, 2.8 mmol) in acetonitrile (5 mL). Sixteen hours later, the reaction was concentrated and purified in normal phase (MeOH solution in DCM, 2-10% gradient) to give rac-(3aR,4S,5S,6R,7aS)-4-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-((N,1,2-trimethyl-1H-benzo[d]imidazole)-5-sulfonamide)phenyl)octahydrobenzofuran-5-carboxylic acid methyl ester (0.25 g, 0.35 mmol, 13% yield) as a white solid.1 H NMR (400MHz, DMSO-d6) δ 10.20 (s, 1H), 8.10 (t, J = 8.3 Hz, 1H), 7.77 - 7.63 (m, 2H), 7.60 - 7.51 (m, 2H), 7.32 (dd, J = 8.3, 1.8 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 4.23 - 4.13 (m, 1H), 3.99 - 3.89 (m, 1H), 3.84- 3.68 (m, 4H), 3.51 (dd, J = 11.8, 5.8 Hz, 2H), 3.17 (s, 3H), 3.12 - 3.06(m, 3H), 2.99 (t, J = 11.5 Hz, 1H), 2.87 - 2.72 (m, 2H), 2.57 (s, 3H), 2.17 -2.07 (m, 1H), 1.70 - 1.58 (m, 2H). ES-LCMS m / z 703.2 [M+H] + .

[0832] Intermediates 17 and 18: rel-(1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(5-(methylamino)pyridin-2-ylcyclohexane-1-carboxylic acid, isomer 1 and isomer 2

[0833]

[0834] Step 1: 1-(5-bromopyridin-2-yl)but-3-en-1-ol

[0835]

[0836] At -5°C, allyl magnesium bromide (1 M ether solution, 53.8 mL, 53.8 mmol) was added dropwise over 10 minutes to a mixture of 5-bromopyridinecarboxaldehyde (10.0 g, 53.8 mmol) in tetrahydrofuran (150 mL). The reaction was warmed to room temperature and stirred for 1 hour. The mixture was cooled to 0°C, and another 10.75 mL of allyl magnesium bromide (1 M ether solution, 10.75 mmol) was added over 5 minutes. The reaction was stirred at room temperature for 2.5 hours, quenched with cold water, and concentrated. The resulting residue was washed with 1N HCl (100 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give a dark brown gelatinous substance, 1-(5-bromopyridin-2-yl)but-3-en-1-ol (14.1 g, 39.6 mmol, 74.0% yield), which was used directly as the crude product in the next step. ES-LCMS m / z 228.2 [M+H] + .

[0837] Step 2: 1-(5-bromopyridin-2-yl)but-3-en-1-yl methanesulfonate

[0838]

[0839] At 0 °C, triethylamine (19.3 mL, 138 mmol) was added to a mixture of 1-(5-bromopyridin-2-yl)but-3-en-1-ol (14.0 g, 39.5 mmol) in dichloromethane (100 mL), followed by the addition of methanesulfonyl chloride (4.61 mL, 59.2 mmol). After 2.5 hours, the reaction was quenched with ammonium chloride solution (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to normal-phase chromatography (0-50% EtOAc in petroleum ether solution) to give 1-(5-bromopyridin-2-yl)but-3-en-1-yl methanesulfonic acid (16.8 g, 46.3 mmol, quantitative yield) as a pale brown gel. 1H NMR (400 MHz, DMSO-d6) δ 8.74 (dd, J = 2.6, 0.8 Hz,1H), 8.14 (dd, J = 8.4, 2.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 5.76 - 5.66(m, 2H), 5.13 - 5.06 (m, 1H), 3.16 (s, 3H), 3.11 - 3.09 (m, 1H), 2.75 (t, J =6.0 Hz, 2H). ES-LCMS m / z 306.0 [M+H] + .

[0840] Step 3: (E)-5-bromo-2-(but-1,3-dien-1-yl)pyridine

[0841]

[0842] DBU (19.9 mL, 132 mmol) was added to a mixture of 1-(5-bromopyridin-2-yl)but-3-en-1-yl methanesulfonic acid (16.0 g, 44.0 mmol) in dichloromethane (100 mL). After 2 hours, another 5.00 mL (33.2 mmol) of DBU was added, and the reaction was stirred for another 4 hours. DBU (10.0 mL, 66.3 mmol) was added again, and the mixture was stirred for 18 hours. The mixture was concentrated and subjected to normal-phase chromatography, eluting with 0-20% EtOAc in petroleum ether, to give (E)-5-bromo-2-(but-1,3-dien-1-yl)pyridine (4.22 g, 17.5 mmol, 40.0% yield) as a pale yellow liquid. 1 HNMR (400 MHz, DMSO-d6) δ 8.64 (d, J = 2.4 Hz, 1H), 8.01 (dd, J = 8.4, 2.4 Hz,1H), 7.46 (d, J = 8.4 Hz, 1H), 7.34 - 7.27 (m, 1H), 6.72 - 6.64(m, 1H), 6.61- 6.54 (m, 1H), 5.56-5.51 (m, 1H), 5.36-5.33 (m, 1H). ES-LCMS m / z 210.0 [M+H] + .

[0843] Step 4: Dimethyl rac-(1R,2R,3R)-3-(5-bromopyridin-2-yl)cyclohexyl-4-ene-1,2-dicarboxylate and dimethyl rac-(1R,2R,3S)-3-(5-bromopyridin-2-yl)cyclohexyl-4-ene-1,2-dicarboxylate

[0844]

[0845] Dimethyl fumarate (5.83 g, 40.5 mmol) was added to a mixture of (E)-5-bromo-2-(but-1,3-dien-1-yl)pyridine (8.50 g, 40.5 mmol) and o-xylene (75 mL). The reaction was heated at 140 °C for 16 h, concentrated, and subjected to normal-phase chromatography, eluting with 0-30% EtOAc in petroleum ether to give rac-(1R,2R,3R)-3-(5-bromopyridin-2-yl)cyclohex-4-ene-1,2-dicarboxylate dimethyl ester and rac-(1R,2R,3S)-3-(5-bromopyridin-2-yl)cyclohex-4-ene-1,2-dicarboxylate dimethyl ester (13.0 g, 16.3 mmol, 40.0% yield) as a brown liquid. 1 H NMR (400MHz, DMSO-d6) δ 8.61 (dd, J = 5.3, 1.8 Hz, 1H), 7.98 (ddd, J = 9.8, 8.3, 2.5Hz, 1H), 7.22 (dd, J = 18.5, 8.0 Hz, 1H), 5.95 - 5.75 (m, 1H), 5.58 (dd, J =9.8, 1.8 Hz, 1H), 3.81 - 3.71 (m, 1H), 3.58 (d, J = 9.0 Hz, 3H), 3.39 (d, J =5.0 Hz, 3H), 3.17 - 3.05 (m, 1H), 3.01 - 2.88 (m, 1H), 2.32 - 2.21 (m, 1H),2.17 - 2.03 (m, 1H). ES-LCMS m / z 354.0 [M+H] + .

[0846] Step 5: rac-(1S,5S,6S)-5-(5-bromopyridin-2-yl)-6-(methoxycarbonyl)cyclohex-3-en-1-carboxylic acid reacts with rac-(1R,5S,6R)-5-(5-bromopyridin-2-yl)-6-(methoxycarbonyl)cyclohex-3-en-1-carboxylic acid

[0847]

[0848] Dimethyl rac-(1R,2R,3R)-3-(5-bromopyridin-2-yl)cyclohex-4-ene-1,2-dicarboxylate was added to a mixture of rac-(1R,2R,3S)-3-(5-bromopyridin-2-yl)cyclohex-4-ene-1,2-dicarboxylate (13.0 g, 36.8 mmol) in tetrahydrofuran (25 mL), water (25 mL), and methanol (25 mL). After 16 hours, the reaction was concentrated, diluted with cold water (200 mL), acidified with 1.5 N HCl, and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by SFC achiral purification (column: YMC EP2; mobile phase 85:15 CO2: [0.5% isopropylamine in MeOH solution]). The product was diluted with EtOAc (200 mL) and washed with water (150 mL), 0.5N HCl (50 mL), and brine (50 mL). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give rac-(1S,5S,6S)-5-(5-bromopyridin-2-yl)-6-(methoxycarbonyl)cyclohex-3-en-1-carboxylic acid and (1R,5S,6R)-5-(5-bromopyridin-2-yl)-6-(methoxycarbonyl)cyclohex-3-en-1-carboxylic acid (6.0 g, 8.3 mmol, 23% yield) as colorless colloids. 1 H NMR (400 MHz, DMSO-d6) δ12.44 (br s, 1H), 8.67 - 8.58 (m, 1H), 8.06 - 7.94 (m, 1H), 7.25 - 7.11 (m,1H), 5.99 - 5.53 (m, 2H), 3.75 - 3.65 (m, 1H), 3.42 - 3.35 (m, 3H), 3.09 -2.79 (m, 2H), 2.29 - 2.16 (m, 1H), 2.15 - 2.03 (m, 1H). ES-LCMS m / z 340.0 [M+H] + .

[0849] Step 6: methyl rac-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenylcarbamoyl)cyclohex-3-ene-1-carboxylate

[0850]

[0851] Add 2-fluoro-4-(trifluoromethyl)aniline (1.74 g, 9.70 mmol), NMI (2.11 mL, 26.5 mmol), and N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (2.47 g, 8.82 mmol) to a mixture of rac-(1R,5S,6R)-5-(5-bromopyridin-2-yl)-6-(methoxycarbonyl)cyclohexane-3-en-1-carboxylic acid (6.00 g, 8.82 mmol) in acetonitrile (100 mL) and DMF (10 mL). Sixteen hours later, the reaction mixture was diluted with EtOAc (300 mL), washed with water (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to normal-phase chromatography. The mixture was eluted with 0-25% EtOAc in petroleum ether to give methyl rac-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenylcarbamoyl)cyclohex-3-ene-1-carboxylate (4.60 g, 8.83 mmol, 100% yield), as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 8.63 (dd, J = 0.40, 2.40 Hz, 1H), 8.16 (t, J = 8.00 Hz, 1H), 8.00 (dd, J = 2.40, 6.20 Hz, 1H), 7.73 (dd, J= 2.00, 11.00 Hz, 1H), 7.55 (d, J = 8.40 Hz, 1H), 7.27 (dd, J = 0.40, 8.40Hz, 1H), 5.92 - 5.87 (m, 1H), 5.64 - 5.61 (m, 1H), 3.76 - 3.72 (m, 1H), 3.29–3.25 (m, 1H), 3.06 (t, J = 11.20 Hz, 1H), 2.55–2.54 (m, 1H), 2.33–2.27 (m, 1H); three protons are masked by the DMSO-d6 / H2O peak. ES-LCMS m / z 501.0 [M+H] + .

[0852] Step 7: rac-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid methyl ester

[0853]

[0854] Add Crabtree's catalyst (0.80 g, 1.0 mmol) to a mixture of rac-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohex-3-ene-1-carboxylate (2.50 g, 4.99 mmol) in DCM (100 mL). The reaction was stirred under a hydrogen atmosphere (1 kg gasbag pressure) for 16 hours, concentrated, and subjected to normal-phase chromatography. The product was eluted with 0-25% EtOAc in petroleum ether to give rac-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylate (1.7 g, 3.3 mmol, 66% yield), as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ10.13 (s, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.16 (t, J = 8.0 Hz, 1H), 7.96 (dd,J = 8.4, 2.4 Hz, 1H), 7.72 (dd, J = 11.0, 1.6 Hz, 1H), 7.55 (d, J = 8.4 Hz,1H), 7.28 (d, J = 8.4 Hz, 1H), 3.21 (s, 3H), 3.06 - 3.01 (m, 2H), 2.95 - 2.88(m, 1H), 2.05 (d, J = 7.6 Hz, 1H), 1.90 - 1.85 (m, 2H), 1.71 - 1.63 (m, 1H), 1.56 - 1.48 (m, 2H). ES-LCMS m / z 503.0 [M+H] + .

[0855] Step 8: rel-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid, isomer 1 and isomer 2

[0856]

[0857] TMS-I (2.70 mL, 19.87 mmol) was added to a mixture of methyl rac-(1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylate (0.500 g, 0.993 mmol) in acetonitrile (25 mL). The reaction was heated at 90 °C for 16 h, concentrated, diluted with EtOAc (100 mL), washed with 10% sodium thiosulfate solution (25 mL x 3) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by reverse-phase (0-100% MeCN in H2O solution containing 0.1% formic acid modifier) ​​to give the racemic compound. The substance (200 mg) was purified by ChiralPrep SFC (column: [R,R] Whelk; mobile phase 80:20 CO2: 0.5% isopropylamine in IPA solution) to obtain:

[0858] The first eluted isomer was dissolved in water (25 mL) and acidified with 1.5 N HCl. The resulting solid was collected by filtration and dried under vacuum to give rel-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid, isomer 1 (65 mg, 0.13 mmol, 13% yield), as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 10.11 (s, 1H), 8.61 (d, J =2.4 Hz, 1H), 8.22 (t, J = 8.0 Hz, 1H), 7.95 (dd, J = 2.4, 8.4 Hz, 1H), 7.71(dd, J = 10.8, 1.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.29 (d, J = 8.0 Hz,1H), 3.03 - 2.86 (m, 3H), 2.02 (d, J = 8.4 Hz, 1H), 1.89 - 1.82 (m, 2H), 1.65- 1.55 (m, 1H), 1.49 - 1.47 (m, 2H). ES-LCMS m / z 489.0 [M+H] + .

[0859] The second eluted isomer was dissolved in water (25 mL) and acidified with 1.5 N HCl. The resulting solid was collected by filtration and dried under vacuum to give rel-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid, isomer 2 (55 mg, 0.11 mmol, 11% yield), as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.09 (s, 1H), 8.61 (d, J = 2.0Hz, 1H), 8.22 (t, J = 8.0 Hz, 1H), 7.95 (dd, J = 8.2, 2.4 Hz, 1H), 1.89 - 1.82 (m, 2H), 1.79 -1.62 (m, 1H), 1.52 - 1.45 (m, 2H). ES-LCMS m / z 489.0 [M+H] + .

[0860] Step 9: rel-(1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(5-(methylamino)pyridin-2-ylcyclohexane-1-carboxylic acid, isomer 1 and isomer 2

[0861]

[0862] A mixture of rel-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid isomer 1 (0.070 g, 0.14 mmol) and sodium tert-butoxide (27.5 mg, 0.290 mmol) in dioxane (2.0 mL) was purged with N2 for 2 min. tBuXPhos Pd G3 (22.7 mg, 0.0300 mmol) and methylamine (2 M THF solution, 1.43 mL, 2.86 mmol) were added, and the reaction was sealed and heated to 100 °C in a Biotage Initiator for 2 h. The mixture was filtered through diatomaceous earth filter media, washed with dioxane (25 mL), and the filtrate was concentrated and purified by reverse-phase purification (0-100% MeCN in H2O solution containing 0.1% formic acid modifier) ​​to give rel-(1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(5-(methylamino)pyridin-2-ylcyclohexane-1-carboxylic acid isomer 1 (35 mg, 0.080 mmol, 56% yield) as a grayish-white solid. 1 H NMR (400MHz, DMSO-d6) δ 10.06 (s, 1H), 8.23 ​​- 8.17 (m, 2H), 7.84 (d, J = 2.8 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.55 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 8.4, 2.8 Hz, 1H), 5.67 (s, 1H), 2.98 - 2.95 (m, 1H), 2.88 (t, J= 11.2 Hz, 1H), 2.74 - 2.70 (m, 1H), 2.67 (s, 3H), 1.98 (d, J = 7.6 Hz, 2H), 1.86 (d, J = 5.6 Hz, 2H), 1.74 - 1.62 (m, 2H), 1.59 - 1.50 (m, 2H). ES-LCMSm / z 440.2 [M+H] + .

[0863] The rel-(1R,2S,6R)-2-(5-bromopyridin-2-yl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid isomer 2 was reacted according to the above steps to give rel-(1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(5-(methylamino)pyridin-2-ylcyclohexane-1-carboxylic acid isomer 2 (25 mg, 0.060 mmol, 42% yield), as a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H),8.23 - 8.18 (m, 2H), 7.84 (d, J = 2.8 Hz, 1H), 7.70 (d, J = 1.2 Hz, 1H), 7.55(d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.78 (dd, J = 8.4, 2.8 Hz,1H), 5.67 (s, 1H), 2.98 - 2.95 (m, 1H), 2.87 (t, J = 11.2 Hz, 1H), 2.74 -2.70 (m, 1H), 2.67 (s, 3H), 1.98 (d, J = 8.0 Hz, 1H), 1.86 (d, J = 6.0 Hz, 1H), 1.74 - 1.62 (m, 2H), 1.59 - 1.50 (m, 2H).

[0864] ES-LCMS m / z 440.2 [M+H] + .

[0865] Intermediate 19: rac-(1R,2S,6R)-2-(3-carbamoyl-4-((N,1,2-trimethyl-1H-benzimidazole)-5-sulfonylamino)phenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0866]

[0867] Step 1: (E)-2-bromo-5-(3-oxoprop-1-en-1-yl)benzylnitrile

[0868]

[0869] Add 2-(triphenyl-λ) to a mixture of 2-bromo-5-formylbenzylnitrile (9.50 g, 45.2 mmol) in DMSO (230 mL).5 (E)-phosphine-containing acetaldehyde (15.14 g, 49.8 mmol) was reacted with stirring at 120 °C. After 16 hours, the reaction was quenched with water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to normal-phase chromatography (0-10% EtOAc in petroleum ether) to give (E)-2-bromo-5-(3-oxoprop-1-en-1-yl)benzyl nitrile (4.5 g, 14 mmol, 32% yield). 1 ¹H NMR (400 MHz, DMSO-d⁶) δ 9.69 (d, J = 7.5 Hz, 1H), 8.40 (s, 1H), 7.99 (s, 2H), 7.72 (d, J = 16.0 Hz, 1H), 7.03 (dd, J = 16.0, 7.5 Hz, 1H). ES-LCMS m / z unionized.

[0870] Step 2: (E)-2-bromo-5-(but-1,3-dien-1-yl)benzylnitrile

[0871]

[0872] At 0 °C, potassium tert-butoxide (1M, 19.06 mL, 19.06 mmol) was added dropwise over 5 minutes with stirring to a mixture of methyltriphenylphosphine bromide (7.49 g, 21.0 mmol) in THF (45 mL). After 10 minutes, a solution of (E)-2-bromo-5-(3-oxoprop-1-en-1-yl)benzyl nitrile (4.50 g, 19.1 mmol) in THF (45 mL) was added dropwise over 5 minutes. The reaction was heated at 25 °C for 2 hours, quenched with saturated NH4Cl solution (100 mL), and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and subjected to normal-phase chromatography (0-10% EtOAc in petroleum ether solution) to obtain (E)-2-bromo-5-(but-1,3-dien-1-yl)benzyl nitrile (3.13 g, 9.27 mmol, 48.6% yield), as a pale yellow liquid. 1H NMR (400 MHz, DMSO-d6) δ 8.10 (d, J = 2.0Hz, 1H), 7.85 - 7.81 (m, 1H), 7.76 - 7.70 (m, 1H), 7.13 (dd, J = 15.8, 10.8Hz, 1H), 6.63 (d, J = 16.0 Hz, 1H), 6.58 - 6.45 (m, 1H), 5.46 (dd, J = 17.0,1.0 Hz, 1H), 5.31 (dd, J = 10.0, 1.5 Hz, 1H). ES-LCMS m / z Not ionized.

[0873] Step 3: Dimethyl rac-(1R,2R,3R)-4'-bromo-3'-cyano-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2,3-dicarboxylate reacts with dimethyl rac-(1R,2R,3S)-4'-bromo-3'-cyano-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2,3-dicarboxylate

[0874]

[0875] Dimethyl fumarate (1.909 g, 13.24 mmol) was added to a mixture of (E)-2-bromo-5-(but-1,3-dien-1-yl)benzyl nitrile (3.10 g, 13.2 mmol) in o-xylene (30 mL). The reaction was heated at 140 °C for 8 hours, concentrated, and subjected to normal-phase chromatography, eluting with 30-50% EtOAc in petroleum ether solution to give rac-(1R,2R,3R)-4'-bromo-3'-cyano-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2,3-dicarboxylic acid dimethyl ester and rac-(1R,2R,3S)-4'-bromo-3'-cyano-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2,3-dicarboxylic acid dimethyl ester (3.10 g, 3.51 mmol, 26.5% yield), as pale yellow liquids. 1H NMR (400 MHz, DMSO-d6) δ 7.80 (td, J = 8.9, 2.8 Hz, 4H), 7.65 (d, J = 2.0 Hz, 1H), 7.44 (dd, J = 8.3, 2.3 Hz, 1H), 7.36 (dd, J = 8.5, 2.0 Hz, 1H), 6.04 - 5.97 (m, 1H), 5.93 - 5.85 (m, 1H), 5.74 - 5.65 (m, 1H), 5.51 (dd, J = 10.0, 2.0 Hz, 1H), 3.97 (t, J = 5.8 Hz, 1H), 3.72 - 3.64 (m,1H), 3.59 (s, 3H), 3.56 (s, 3H), 3.44 (s, 3H), 3.40 (s, 4H), 3.16 (dd, J = 12.3, 6.3 Hz, 1H), 2.92 (dd, J = 11.0, 5.5 Hz, 1H), 2.86 - 2.72 (m, 3H), 2.44 - 2.39 (m, 1H). ES-LCMS m / z unionized.

[0876] Step 4: Dimethyl rac-(1R,2R,3R)-3-(4-bromo-3-cyanophenyl)cyclohexane-1,2-dicarboxylate and dimethyl rac-(1R,2R,3S)-3-(4-bromo-3-cyanophenyl)cyclohexane-1,2-dicarboxylate

[0877]

[0878] Pd / C (1.29 g, 0.330 mmol) was added to a mixture of rac-(1R,2R,3R)-4'-bromo-3'-cyano-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2,3-dicarboxylate and rac-(1R,2R,3S)-4'-bromo-3'-cyano-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2,3-dicarboxylate (5.00 g, 6.61 mmol) in THF (50 mL). The reaction was stirred at 25°C under a hydrogen atmosphere (2 atm gas chamber pressure) for 2 hours, filtered through diatomaceous earth and concentrated to give rac-(1R,2R,3R)-3-(4-bromo-3-cyanophenyl)cyclohexane-1,2-dicarboxylate dimethyl ester and rac-(1R,2R,3S)-3-(4-bromo-3-cyanophenyl)cyclohexane-1,2-dicarboxylate dimethyl ester (5.10 g, 6.09 mmol, 92.0% yield), as pale yellow liquids.1 H NMR (400 MHz, DMSO-d6) δ 7.92 (d, J = 2.0 Hz, 1H), 7.82 - 7.75 (m,3H), 7.54 - 7.47 (m, 2H), 3.66 (s, 2H), 3.61 - 3.54 (m, 4H), 3.38 (s, 2H),3.30 - 3.27 (m, 1H), 3.25 (s, 3H), 3.13 - 3.03 (m, 1H), 2.85 (d, J = 11.0 Hz,1H), 2.82 - 2.70 (m, 2H), 2.45 (br s, 1H), 2.04 - 2.00 (m, 1H), 1.96 - 1.88 (m, 1H), 1.85 - 1.76 (m, 2H), 1.74 - 1.59 (m, 4H), 1.56 - 1.42 (m, 3H). ES-LCMS m / z unionized.

[0879] Step 5: rac-(1R,2R,3R)-3-(4-bromo-3-cyanophenyl)-2-(methoxycarbonyl)cyclohexane-1-carboxylic acid reacts with rac-(1R,2R,3S)-3-(4-bromo-3-cyanophenyl)-2-(methoxycarbonyl)cyclohexane-1-carboxylic acid

[0880]

[0881] Add a 10 mL solution of lithium hydroxide monohydrate (828 mg, 19.7 mmol) to a mixture of dimethyl rac-(1R,2R,3R)-3-(4-bromo-3-cyanophenyl)cyclohexane-1,2-dicarboxylate and dimethyl rac-(1R,2R,3S)-3-(4-bromo-3-cyanophenyl)cyclohexane-1,2-dicarboxylate (5.00 g, 6.57 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL). After 20 hours, the reaction was concentrated and purified by reverse-phase extraction, eluting with an aqueous solution of 80-100% MeCN (0.1% formic acid) to give rac-(1R,2R,3R)-3-(4-bromo-3-cyanophenyl)-2-(methoxycarbonyl)cyclohexane-1-carboxylic acid and rac-(1R,2R,3S)-3-(4-bromo-3-cyanophenyl)-2-(methoxycarbonyl)cyclohexane-1-carboxylic acid (3.70 g, 2.26 mmol, 34.4% yield), as colorless gels. 1H NMR (400 MHz, DMSO-d6) δ 8.37 (s, 1H), 7.88 (d, J = 2.5 Hz, 2H), 7.77 (d, J = 8.5 Hz, 2H), 7.54 - 7.43 (m, 3H), 3.37 (s,1H), 3.30 (d, J = 5.0 Hz, 1H), 3.17 (s, 1H), 3.08 - 2.99 (m, 1H), 2.86 - 2.60 (m, 5H), 2.01 - 1.89 (m, 2H), 1.85 - 1.74 (m, 3H), 1.72 - 1.54 (m, 5H), 1.50- 1.36 (m, 5H). ES-LCMS m / z 365.8 [M+H] +

[0882] Step 6: Methyl rac-(1R,2S,3S)-4'-bromo-3'-cyano-3-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylate

[0883]

[0884] To a mixture of rac-(1R,2R,3R)-3-(4-bromo-3-cyanophenyl)-2-(methoxycarbonyl)cyclohexane-1-carboxylic acid and rac-(1R,2R,3S)-3-(4-bromo-3-cyanophenyl)-2-(methoxycarbonyl)cyclohexane-1-carboxylic acid (1.00 g, 1.37 mmol) in acetonitrile (10 mL), 2-fluoro-4-(trifluoromethyl)aniline (0.269 g, 1.50 mmol) and NMI (336 mg, 4.10 mmol) were added. After 10 minutes, N-(chloro(dimethylamino)methylene)-N-methylmethylammonium hexafluorophosphate (V) (498 mg, 1.78 mmol) was added, and the reaction was stirred at 25 °C. Sixteen hours later, the reaction was concentrated and subjected to normal-phase chromatography, eluting with 10% EtOAc in petroleum ether to give methyl rac-(1R,2S,3S)-4'-bromo-3'-cyano-3-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylate (0.670 g, 0.854 mmol, 62.5% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s,1H), 8.16 – 8.12 (m, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.73 (d, J = 2.5 Hz, 1H), 7.55 (td, J = 5.8, 3.0 Hz, 2H), 3.19 (s, 3H), 3.08- 3.00 (m, 2H), 2.79 (td, J = 11.1, 4.3 Hz, 1H), 2.05 (d, J = 10.5 Hz, 1H), 1.92 - 1.86 (m, 1H), 1.73 (d, J = 9.0 Hz, 1H), 1.58 - 1.41 (m, 3H). ES-LCMSm / z 525.0 [M+H] + .

[0885] Step 7: rac-(1R,2S,6R)-2-(4-bromo-3-cyanophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0886]

[0887] TMS-I (1.28 mL, 9.10 mmol) was added to a mixture of methyl rac-(1R,2S,3S)-4'-bromo-3'-cyano-3-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-1,2,3,4-tetrahydro-[1,1'-biphenyl]-2-carboxylate (0.480 g, 0.910 mmol) in acetonitrile (2.5 mL). The reaction was heated at 70 °C for 16 hours, concentrated, diluted with THF (10 mL), and purified by reverse phase (90-100% MeCN in H2O solution containing 0.1% formic acid modifier) ​​to give rac-(1R,2S,6R)-2-(4-bromo-3-cyanophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (408 mg, 0.793 mmol, 87.0% yield), as a grayish-white solid. 1H NMR (400 MHz, DMSO-d6) δ11.89 (s, 1H), 10.12 (s, 1H), 8.20 (t, J = 8.0 Hz, 1H), 7.94 (d, J = 2.0 Hz,1H), 7.80 (d, J = 8.5 Hz, 1H), 7.71 (dd, J = 11.0, 1.5 Hz, 1H), 7.58 (dd, J =8.5, 2.0 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 3.05 - 2.95 (m, 1H), 2.91 - 2.83(m, 1H), 2.83 - 2.73 (m, 1H), 2.06 - 2.00 (m, 1H), 1.92 - 1.82 (m, 1H), 1.78- 1.71 (m, 1H), 1.66 (d, J = 12.0 Hz, 1H), 1.59 - 1.44 (m, 2H). ES-LCMS m / z512.8 [M+H] + .

[0888] Step 8: rel-(1R,2S,6R)-2-(3-carbamoyl-4-(methylamino)phenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0889]

[0890] Add tBuXPhos Pd G3 (22.7 mg, 0.0300 mmol) to a mixture of rac-(1R,2S,6R)-2-(4-bromo-3-cyanophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (0.200 g, 0.390 mmol) and sodium tert-butoxide (94 mg, 0.97 mmol) in dioxane (2.0 mL). Degas the reaction for 5 minutes and then add methylamine (3.90 mL, 7.79 mmol). The mixture was heated to 100 °C for 1 hour in a Biotage Initiator, dissolved in THF (3 mL), and purified by reverse phase (20-55% MeCN in H2O solution containing 0.1% formic acid modifier) ​​to give rel-(1R,2S,6R)-2-(3-carbamoyl-4-(methylamino)phenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (0.170 g, 0.224 mmol, 57.4% yield), as a grayish-white solid.1 ¹H NMR (400 MHz, DMSO-d⁶) δ 8.37 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 5.0 Hz, 1H), 7.64 (br d, J = 11.5 Hz, 1H), 7.49 (s, 2H), 6.45 (d, J = 8.5 Hz, 1H), 2.79 - 2.66 (m, 4H), 2.65 - 2.55 (m, 1H), 2.44 - 2.35 (m, 1H), 1.97 - 1.61 (m, 3H), 1.53 - 1.36 (m, 3H). Five protons were obscured. ES-LCMS m / z 480.0 [M+H] + .

[0891] Step 9: rac-(1R,2S,6R)-2-(3-carbamoyl-4-((N,1,2-trimethyl-1H-benzi[d]imidazole)-5-sulfonylamino)phenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0892]

[0893] At 0 °C, 1,2-dimethyl-1H-benzo[d]imidazolium-5-sulfonyl chloride (137 mg, 0.561 mmol) was added to a mixture of rel-(1R,2S,6R)-2-(3-carbamoyl-4-(methylamino)phenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (0.150 g, 0.312 mmol) and pyridine (0.076 mL, 0.94 mmol) in dichloromethane (3.5 mL). The reaction was stirred at room temperature for 1 hour, concentrated, and purified by reverse phase (50-75% MeCN in H2O solution containing 0.1% formic acid modifier) ​​to give rac-(1R,2S,6R)-2-(3-carbamoyl-4-((N,1,2-trimethyl-1H-benzi[d]imidazole)-5-sulfonylamino)phenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (0.100 g, 0.132 mmol, 42.4% yield), as a grayish-white solid. 1H NMR (400MHz, DMSO-d6) δ 11.99 (s, 1H), 10.11 (s, 1H), 8.22 (t, J = 8.00 Hz, 1H), 7.73- 7.69 (m, 3H), 7.57 - 7.40 (m, 5H), 7.21 (dd, J = 8.00, 2.00 Hz, 1H), 6.54(d, J = 8.40 Hz, 1H), 3.82 (s, 3H), 3.10 (s, 3H), 3.01 - 2.85 (m, 1H), 2.82 -2.74 (m, 2H), 2.59 (s, 3H), 2.01 - 1.79 (m, 3H), 1.77 - 1.52 (m, 3H). ES-LCMSm / z 687.8 [M+H] + .

[0894] Intermediate 20: (1R,2S,6R)-2-(3-bromo-4-(methylamino)phenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid

[0895]

[0896] At 0 °C, N-bromosuccinimide (128 mg, 0.718 mmol) dissolved in acetonitrile (5 mL) was added to a mixture of (1R,2R,6S)-2-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid intermediate 7, alternative route, step 3 (0.350 g, 0.798 mmol) in acetonitrile (21 mL). Two hours later, the reaction was filtered, concentrated, and purified by reverse-phase (0-100% MeCN in H2O solution containing 0.1% formic acid modifier) ​​to give (1R,2S,6R)-2-(3-bromo-4-(methylamino)phenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid (0.120 g, 0.222 mmol, 27.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.73 (br s, 1H), 10.07 (s, 1H), 8.20 (t, J = 8.3 Hz, 1H), 7.71 (dd, J = 10.8, 1.8 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.07 (dd, J = 8.5, 2.0 Hz, 1H), 6.52 (d, J = 8.5 Hz, 1H), 5.14 (q, J =4.8 Hz, 1H), 3.17 (d, J = 5.0 Hz, 1H), 3.03 - 2.91 (m, 1H), 2.77 ES-LCMS m / z 516.8 [MH] - .

[0897] The following compounds were synthesized using a similar method to the preparation method described below (Example 83, the second preparation method), using the relevant alkylamine precursor and omitting the debenzylation step:

[0898]

[0899] Intermediate 22: rac-(1R,2R,6S)-2-(((4-isopropylphenyl)amino)methyl)-6-(4-((N,1,2-trimethyl-1H-benzimidazole)-5-sulfonylamino)phenyl)cyclohexane-1-carboxylic acid benzyl ester

[0900]

[0901] Step 1: rac-(1R,2S,6R)-2-(4-bromophenyl)-6-formylcyclohexane-1-carboxylic acid benzyl ester

[0902]

[0903] At 0 °C, the intermediate 1 of rac-(1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester (1.251 g, 3.102 mmol) from step 4 was slowly added to a mixture in dichloromethane (15 ml) with Dess-Martin periodinane (1.973 g, 4.653 mmol). After 2 hours, the reaction was warmed to room temperature. After 4 hours, the reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted with dichloromethane (3 x 10 ml). The combined organic layers were dried over anhydrous Na2SO4, concentrated, and purified by silica gel column chromatography. The elution with 0-10% EtOAc in hexane yielded rac-(1R,2S,6R)-2-(4-bromophenyl)-6-carboxyylcyclohexane-1-carboxylic acid benzyl ester (0.92 g, 2.3 mmol, 75%), a white solid. 1 H NMR (400 MHz, DMSO-d6) δ (400 MHz, CDCl3) δ9.71 - 9.56 (m, 1H), 7.40 - 7.30 (m, 3H), 7.03 (dq, J = 9.1, 2.6 Hz, 2H), 6.97 - 6.80 (m, 2H), 4.93 - 4.82 (m, 1H), 4.82 - 4.72 (m, 1H), 2.99 - 2.62(m, 4H), 2.32 - 2.16 (m, 1H), 2.16 - 1.99 (m, 2H), 1.99 - 1.83 (m, 2H), 1.70- 1.40 (m, 5H), 1.40 - 1.18 (m, 2H).

[0904] Step 2: rac-(1R,2S,6R)-2-(4-bromophenyl)-6-(((4-isopropylphenyl)amino)methyl)cyclohexane-1-carboxylic acid benzyl ester

[0905]

[0906] To a mixture of 4-isopropylaniline (0.342 g, 2.53 mmol) in 1,2-dichloroethane (12 ml), rac-(1R,2S,6R)-2-(4-bromophenyl)-6-carboxycyclohexane-1-carboxylic acid benzyl ester (0.922 g, 2.29 mmol) and glacial acetic acid (0.152 g, 2.53 mmol) were added. After 15 minutes, sodium triacetoxyborohydride (0.730 g, 3.45 mmol) was added. After 1 hour, the reaction mixture was poured into dichloromethane (25 ml) and washed with saturated aqueous solution of NaHCO3 (25 ml) and brine (25 ml). The organic layer was dried over anhydrous MgSO4, concentrated, and purified by silica gel column chromatography (gradient eluent: 10-50% EtOAc in hexane) to obtain rac-(1R,2S,6R)-2-(4-bromophenyl)-6-(((4-isopropylphenyl)amino)methyl)cyclohexane-1-carboxylic acid benzyl ester, which is a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.51 -7.38 (m, 2H), 7.31 - 7.09 (m, 5H), 6.96 - 6.81 (m, 4H), 6.48 - 6.37 (m, 2H),5.41 (t, J = 5.9 Hz, 1H), 4.86 (d, J = 12.5 Hz, 1H), 4.72 (d, J = 12.5 Hz, 1H), 3.01 - 2.85 (m, 1H), 2.85 - 2.63 (m, 3H), 1.98 (d, J = 11.7 Hz, 2H), 1.87 - 1.66 (m, 2H), 1.62 - 1.29 (m, 2H), 1.13 (d, J = 6.9 Hz, 7H).

[0907] Step 3: rac-(1R,2R,6S)-2-(((4-isopropylphenyl)amino)methyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid benzyl ester

[0908]

[0909] A mixture of rac-(1R,2S,6R)-2-(4-bromophenyl)-6-(((4-isopropylphenyl)amino)methyl)cyclohexane-1-carboxylic acid benzyl ester (63 mg, 0.12 mmol), DMF (1 ml), Cs₂CO₃ (79 mg, 0.24 mmol), tBuXPhos Pd G₃ (9.6 mg, 0.012 mmol), and methylamine (2 M THF solution, 0.24 ml, 0.48 mmol) was stirred at 80 °C. After 18 hours, the reaction mixture was diluted with water and extracted with EtOAc (3 x 10 ml). The organic layer was dried over anhydrous MgSO4, concentrated, and purified by silica gel column chromatography (gradient eluent: 10-100% EtOAc in hexane solution) to obtain rac-(1R,2R,6S)-2-(((4-isopropylphenyl)amino)methyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid benzyl ester (36 mg, 0.076 mmol, 63%), as a grayish-white solid. ES-LCMS m / z 471.3 [M+H] + .

[0910] Step 4: rac-(1R,2R,6S)-2-(((4-isopropylphenyl)amino)methyl)-6-(4-((N,1,2-trimethyl-1H-benzimidazole)-5-sulfonylamino)phenyl)cyclohexane-1-carboxylic acid benzyl ester

[0911]

[0912] At 0 °C, 1,2-dimethyl-1H-benzo[d]imidazolium-5-sulfonyl chloride (22.5 mg, 0.0920 mmol) was added to a mixture of rac-(1R,2R,6S)-2-(((4-isopropylphenyl)amino)methyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid benzyl ester (36 mg, 0.076 mmol) and pyridine (0.5 ml) in dichloromethane (0.2 ml), and the resulting solution was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography (gradient eluent: 0-5% MeOH in DCM solution) to give rac-(1R,2R,6S)-2-(((4-isopropylphenyl)amino)methyl)-6-(4-(((N,1,2-trimethyl-1H-benzimidazole)-5-sulfonylamino)phenyl)cyclohexane-1-carboxylic acid benzyl ester (29 mg, 0.043 mmol, 56%), as a grayish-white solid. ES-LCMS m / z 679.3 [M+H] + .

[0913] Intermediate 23: (1R,2R,6S)-2-((4-(trifluoromethyl)phenoxy)methyl)-6-(4-((N,1,2-trimethyl-1H-benzimidazole)-5-sulfonamide)phenyl)cyclohexane-1-carboxylic acid benzyl ester

[0914]

[0915] Step 1: (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester

[0916]

[0917] Intermediate 1 of rac-(1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester (20.2 g, 50.1 mmol) was purified by chiral chromatography (column: Chiralpak IA; mobile phase: 4:4:2 heptane:MTBE:MeCN) to give the first eluting isomer (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester (8.2 g, 0.020 mol, 41% yield). 1 H NMR (400 MHz, DMSO-d6) δ 7.46 -7.39 (m, 2H), 7.29 - 7.22 (m, 3H), 7.19 - 7.12 (m, 2H), 6.91 - 6.85 (m, 2H),4.93 - 4.63 (m, 2H), 4.54 (t, J = 5.1 Hz, 1H), 3.31 - 3.27 (m, 1H), 3.25 -3.17 (m, 1H), 2.72 (td, J = 11.5, 3.4 Hz, 1H), 2.44 (t, J = 11.0 Hz, 1H), 1.92 - 1.68 (m, 4H), 1.56 - 1.35 (m, 2H), 1.23 - 1.06 (m, 1H). ES-LCMS m / z403.1 [M+1] + .

[0918] Step 2: (1R,2S,6R)-2-(4-bromophenyl)-6-((4-(trifluoromethyl)phenoxy)methyl)cyclohexane-1-carboxylic acid benzyl ester

[0919]

[0920] At 0 °C, DIAD (8.222 g, 7.906 mL, 40.66 mmol) was added to a mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid benzyl ester (8.2000 g, 20.331 mmol), 4-(trifluoromethyl)phenol (9.8877 g, 60.994 mmol), and triphenylphosphine (10.665 g, 40.663 mmol) in THF (200 mL), and the reaction was warmed to room temperature. After stirring over the weekend, the mixture was concentrated and purified by ISCO silica gel column chromatography, eluting with a heptane solution of 40-100% EtOAc, to provide (1R,2S,6R)-2-(4-bromophenyl)-6-((4-(trifluoromethyl)phenoxy)methyl)cyclohexane-1-carboxylic acid benzyl ester (7.60 g, 13.9 mol, 68.3% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 8.3 Hz, 2H), 7.48 - 7.40 (m,2H), 7.26 - 7.14 (m, 5H), 7.03 (d, J = 8.3 Hz, 2H), 6.87 - 6.78 (m, 2H), 4.93- 4.63 (m, 2H), 4.04 - 3.84 (m, 2H), 2.79 (td, J = 11.4, 3.2 Hz, 1H), 2.70 -2.61 (m, 1H), 2.26 - 2.10 (m, 1H), 1.98 - 1.88 (m, 1H), 1.88 - 1.80(m, 1H),1.79 - 1.70 (m, 1H), 1.61 - 1.44 (m, 2H), 1.41 - 1.26 (m, 1H). ES-LCMS m / z547.1 [M+1] + .

[0921] Step 3: (1R,2S,6R)-2-(4-(methylamino)phenyl)-6-((4-(trifluoromethyl)phenoxy)methyl)cyclohexane-1-carboxylic acid benzyl ester

[0922]

[0923] A mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-((2-fluoro-4-(trifluoromethyl)phenyl)carbamoyl)cyclohexane-1-carboxylic acid benzyl ester (7.60 g, 13.9 mmol) in DMF (140 ml) was degassed with nitrogen and then treated with Cs₂CO₃ (13.00 g, 39.90 mmol), methylamine (2 M THF solution, 140 ml, 280.0 mmol), and tBuXPhos PdG₃ (2.36 g, 2.76 mmol). The reaction was stirred at 60 °C for 2 h, filtered, diluted with water, and extracted with EtOAc (3x). The organic layer was washed with brine, dried over anhydrous MgSO4, concentrated, and purified by silica gel column chromatography. Elution with 50-100% EtOAc in heptane yielded (1R,2S,6R)-2-(4-(methylamino)phenyl)-6-((4-(trifluoromethyl)phenoxy)methyl)cyclohexane-1-carboxylic acid benzyl ester (6.07 g, 0.0122 mol, 87.8% yield), a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.62 (d, J = 8.8 Hz, 2H), 7.24 - 7.13 (m, 3H), 7.02 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.3 Hz, 2H), 6.87 - 6.81 (m, 2H), 6.44(d, J = 8.8 Hz, 2H), 5.48 (q, J = 4.9 Hz, 1H), 4.91 - 4.66 (m, 2H), 3.96 -3.84 (m, 2H), 2.66 (d, J = 4.9 Hz, 3H), 2.61 (br dd, J = 11.2, 3.4 Hz,1H),2.55 (d, J = 10.8 Hz, 1H), 2.21 - 2.08 (m, 1H), 1.95 - 1.86 (m, 1H), 1.86 -1.79 (m, 1H), 1.72 (br d, J = 8.3 Hz, 1H), 1.56 - 1.42 (m, 2H), 1.39 - 1.20 (m, 1H). ES-LCMS m / z 498.2 [M+1] + .

[0924] Step 4: (1R,2R,6S)-2-((4-(trifluoromethyl)phenoxy)methyl)-6-(4-((N,1,2-trimethyl-1H-benzimidazole)-5-sulfonamide)phenyl)cyclohexane-1-carboxylic acid benzyl ester

[0925]

[0926] 1,2-Dimethyl-1H-benzo[d]imidazolium-5-sulfonyl chloride (1.020 g, 4.169 mmol) was added to a mixture of (1R,2S,6R)-2-(4-(methylamino)phenyl)-6-((4-(trifluoromethyl)phenoxy)methyl)cyclohexane-1-carboxylic acid benzyl ester (1.50 g, 3.01 mmol) and pyridine (0.5 ml) in DMF (30 ml), and the reaction was stirred at 23 °C for 4 h. The reaction mixture was diluted with water and extracted with EtOAc (3 x). The organic layer was washed with brine, dried over anhydrous MgSO4, concentrated, and purified by silica gel column chromatography. The solution was eluted with 0-100% EtOAc in heptane and then with 20% MeOH in DCM to give (1R,2R,6S)-2-((4-(trifluoromethyl)phenoxy)methyl)-6-(4-((N,1,2-trimethyl-1H-benzi[d]imidazole)-5-sulfonamide)phenyl)cyclohexane-1-carboxylic acid benzyl ester (1.100 g, 1.559 mmol, 51.78%), a grayish-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.71 – 7.47 (m, 4H), 7.32 – 7.26 (m, 1H), 7.25 – 7.11 (m, 5H), 7.03 – 6.90 (m, 6H), 4.89 – 4.57 (m, 2H), 3.90 (br dd, J= 5.1, 3.2 Hz, 2H), 3.73 (s, 3H), 3.08 (s, 3H), 2.83 – 2.74 (m, 1H), 2.67 –2.58 (m, 1H), 2.24 – 2.09 (m, 1H), 1.97 – 1.68 (m, 3H), 1.60 – 1.44 (m, (2H), 1.41 – 1.26 (m, 1H). One of the methyl peaks was masked by the solvent. ES-LCMS m / z 706.1 [M+H] + .

[0927] Intermediate 24: (1R,2R,6S)-2-((2-(benzyloxy)-4-(trifluoromethyl)phenoxy)methyl)-6-(4-((N,1,2-trimethyl-1H-benzimidazole)-5-sulfonamide)phenyl)cyclohexane-1-carboxylic acid benzyl ester

[0928]

[0929] Step 1: (1R,2S,6R)-2-(4-bromophenyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylic acid benzyl ester

[0930]

[0931] At 0 °C, DMAP (0.327 g, 2.68 mmol), triethylamine (1.493 mL, 10.71 mmol), and tert-butyldimethylchlorosilane (2.83 g, 18.7 mmol) were added to a mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-(hydroxymethyl)cyclohexane-1-carboxylic acid intermediate 23 (3.60 g, 8.93 mmol) in DCM (50 mL). After 16 hours, the reaction was diluted with saturated sodium bicarbonate (30 mL) at 25 °C and extracted with DCM (3 x 30 mL). The combined organic layers were washed with water (30 ml) and brine (30 ml), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography. The eluent was 0-20% EtOAc in petroleum ether to give (1R,2S,6R)-2-(4-bromophenyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylic acid benzyl ester (4.0 g, 7.2 mmol, 81% yield). 1HNMR (400 MHz, DMSO-d6) 7.42 (d, J = 8.5 Hz, 2H), 7.29 - 7.22 (m, 3H), 7.13 (d, J = 8.5 Hz, 2H), 6.89 (dd, J = 7.5, 2.0 Hz, 2H), 4.85 - 4.80 (m, 1H),4.75 - 4.68 (m, 1H), 3.46 - 3.35 (m, 2H), 2.77 - 2.65 (m, 1H), 2.47 - 2.41(m, 1H), 1.89 - 1.68 (m, 4H), 1.53 - 1.39 (m, 2H), 1.24 - 1.11 (m, 1H), 0.84(s, 8H), 0.87 - 0.80 (m, 1H), -0.03 (d, J = 2.5 Hz, 6H). ES-LCMS m / z 518.8 [M+1] + .

[0932] Step 2: (1R,2S,6R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-6-(4-(methylamino)phenyl)cyclohexane-1-carboxylic acid benzyl ester

[0933]

[0934] A mixture of (1R,2S,6R)-2-(4-bromophenyl)-6-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-carboxylic acid benzyl ester (4.0 g, 7.7 mmol) and Cs₂CO₃ (7.55 g, 23.2 mmol) in DMF (80 mL) was degassed with nitrogen for 10 min, treated with tBuXPhos Pd G₃ (0.200 g, 0.541 mmol), degassed with nitrogen for 5 min, and then treated with methylamine (2 M THF solution, 77.0 mL, 155 mmol). The reaction was stirred at 60 °C for 16 h, diluted with water (100 mL), and extracted with EtOAc (4 x 50 mL). The organic layer was washed with water (2 x 50 mL) and brine, dried over sodium sulfate, concentrated, and purifi...

Claims

1. A compound of Formula (I-a) or a pharmaceutically acceptable salt thereof: (I-a) wherein: A is aryl, heteroaryl, C 3-10 cycloalkyl, or a 3- to 10-membered heterocycloalkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring A is monocyclic or bicyclic, and ring A is optionally substituted with up to three substituents independently selected from halo, cyano, nitro, hydroxy, -NR a R b , carboxy, -CONR a R b , C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, cyano(C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl, and C 3-7 cycloalkyl; L 1 -NR c -C(O)-, -OCH2-, -NR c -CH2-, or -CH2-; n is 0, 1, or 2; R 1 is hydrogen or C 1-3 alkyl; R 2 is hydrogen, halogen, or C 1-3 alkyl; R X2 , R X3 and R X4 are each independently selected from the group consisting of hydrogen, halogen, cyano, -NR d R e , hydroxyl, carboxyl, phenoxy, phenyl, C 1-3 alkyl, halo(C 1-3 )alkyl, hydroxy(C 1-3 )alkyl, C 1-3 alkoxy(C 1-3 )alkyl-, C 1-3 alkoxy, halo(C 1-3 )alkoxy and L X -V; R X5 hydrogen, halogen, hydroxyl, or C 1-3 alkyl; or R X2 , R X3 , R X4 or R X5 any two of which, together with the carbon atom to which they are attached, form a 3- to 6-membered ring optionally containing one or two heteroatoms independently selected from N, O and S, and which ring is optionally substituted with up to three substituents independently selected from halo, C 1-3 alkyl, halo(C 1-3 )alkyl, C 1-3 alkoxy and halo(C 1-3 )alkoxy; L X is a bond, -CH2-, -NR d C(O)-, -NR d -(CH2) w -, -O-(CH2) w -, or -S-(CH2) w -; V is independently C 3-7 cycloalkyl or a 3- to 10-membered heterocycloalkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein V is optionally substituted with up to three substituents independently selected from the group consisting of halogen, C 1-3 alkyl, halo(C 1-3 )alkyl, C 1-3 alkoxy, and halo(C 1-3 )alkoxy; Y 1 Y 2 Y 3 and Y 4 Each is independently N or CR y And Y 1 Y 2 Y 3 and Y 4 At most two of them are N; L 2 is a bond, -NR f -S(O)2-, -NR f -C(O)-, or -(CH2) p -; Z is hydrogen, halogen, cyano, hydroxyl, -NR g R h , nitro, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, cyano(C 1-3 )alkyl, C 2-5 alkenyl, halo(C 2-5 )alkenyl, C 2-5 alkynyl, or halo(C 2-5 )alkynyl; or Z is a ring B, wherein ring B is aryl, heteroaryl, C 3-10 cycloalkyl, or a 3- to 10-membered heterocycloalkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein ring B is monocyclic or bicyclic, and ring B is optionally substituted with up to three substituents independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl, -C 1-3 alkylene-NR g R h , -CONR g R h , -NR g R h , -NR g C(O)R h , -SO2NR g R h , and L B -W, or the two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S; L B is independently selected from the group consisting of a bond, -(CH2) p -, -CH2O-, -C(O)-NH-, -C(O)-, and -CH2C(O)NH-; W is independently selected from the group consisting of hydrogen, C 1-3 alkyl, -0(C 1-4 )alkyl, C 3-7 ycloalkyl, 5- or 6-membered heteroaryl and 4- to 6-membered heterocycloalkyl ring containing one, two or three heteroatoms independently selected from N, O and S, wherein W is optionally substituted with up to three substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, -NR m R n , carboxyl, -CONR m R n , C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, cyano(C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 ycloalkyl; Each R y Independently hydrogen, halogen, cyano, nitro, hydroxyl, -NR i R k , carboxyl group, C 1-3 Alkyl, halogenated (C 1-3 )alkyl, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkoxy, methoxy (C 1-3 )alkoxy, C 2-5 alkenyl, halogenated (C 2-5 alkenyl, hydroxyl (C) 2-5 alkenyl, C 2-5 Alkyne group, halogenated (C 2-5 ) alkynyl group, hydroxyl group (C 2-5 ) an alkynyl group, or a 5- or 6-membered heteroaryl group containing one, two, or three heteroatoms independently selected from N, O, and S, wherein the heteroaryl group is optionally surrounded by up to three C atoms. 1-3 Alkyl groups are substituted; R a , R b , R c , R d , R f , R g , R h , R i , R k , R m , and R n are each independently hydrogen, C 1-3 alkyl, or C 3-7 cycloalkyl; or R y and R f with the atom to which they are attached form a 5- or 6-membered ring containing one or two heteroatoms independently selected from N, O, and S; R e is hydrogen, C 1-3 alkyl, halo(C 1-3 )alkyl, C 3-7 cycloalkyl, or -C(O)C 1-3 alkyl; each p is independently 1 or 2; and each w is independently 0, 1, 2, or 3.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, 2-azaspiro[3.3]heptyl, tetrahydropyranyl, pyridinyl, bicyclo[l. l. l]pentyl, cyclohexyl, spiro[4.5]decyl, (3as,6as)-octahydropentalenyl, bicyclo[2.2.1]heptyl, or 2,3-dihydroindenyl, wherein ring A is optionally substituted with up to three substituents independently selected from halo, cyano, nitro, hydroxy, -NR a R b , carboxyl, -CONR a R b , C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, cyano(C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl, and C 3-7 cycloalkyl.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, bicyclo[l. l. l]pentyl or cyclohexyl, wherein ring A is optionally substituted with up to three substituents independently selected from halo, cyano, nitro, hydroxy, -NR a R b , carboxy, -CONR a R b , C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, cyano(C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl.

4. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with up to three substituents independently selected from halogen, hydroxy, C 1-3 alkyl, halo(C 1-3 )alkyl, hydroxy(C 1-3 )alkyl, and C 3-7 cycloalkyl.

5. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl optionally substituted with one or two substituents independently selected from halogen, hydroxy, C 1-3 alkyl and halo(C 1-3 )alkyl.

6. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl substituted with fluoro and trifluoromethyl.

7. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L 1 is -NR c -C(O)- or -OCH2-.

8. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L 1 is -NH-C(O)-.

9. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 1.

10. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.

11. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

12. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L 2 is -NR f -S(O)2-.

13. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L 2 is -N(CH3)-S(O)2-.

14. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R X2 , R X3 , and R X4 are each independently selected from the group consisting of hydrogen, cyano, -NR d R e , hydroxy, phenoxy, C 1-3 alkyl, methoxy(C 1-3 )alkyl, halo(C 1-3 )alkoxy, and L X -V; or R X2 , R X3 , or R X5 any two of which, together with the carbon atom to which they are attached, form a 5-membered ring optionally containing one O; L X -CH2-; -O-(CH2) w -; V is independently selected from C 1-3 alkyl, C 3-4 cycloalkyl, or a 3- to 7-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N or O, wherein V is optionally substituted with one substituent independently selected from C 1-3 alkyl and C 1-3 alkoxy; and w is 0 or 1.

15. A compound according to any one of the preceding claims, wherein R X5 is hydrogen.

16. The compound according to any one of the preceding claims, wherein R X2 R X3 and R X4 Each is independently selected from: hydrogen, C 1-3 Alkoxy, C 1-3 Alkoxy (C 1-3 )alkyl- and L X -V; where L X is a bond, -CH2-, -NR d -(CH2) w - or -O-(CH2) w -; and V is C 3-7 cycloalkyl or a 3- to 6-membered heterocycloalkyl ring containing one heteroatom selected from N and O, wherein V is optionally substituted with up to three substituents independently selected from halo, C 1-3 alkyl, halo(C 1-3 )alkyl, C 1-3 alkoxy and halo(C 1-3 )alkoxy.

17. The compound according to any one of the preceding claims, wherein R X2 R X4 and R X5 It is hydrogen, and R X3 Selected from hydrogen, C 1-3 Alkoxy and C 1-3 Alkoxy (C 1-3 )alkyl-.

18. A compound according to any one of claims 1-16, wherein R X2 , R X4 , and R X5 are hydrogen, and R X3 is L X -V; wherein L X is a bond or -0-(CH2) w -; and V is C 3-7 cycloalkyl or a 3- to 6-membered heterocycloalkyl ring containing one heteroatom selected from N and O, wherein V is optionally substituted with up to three substituents independently selected from halo, C 1-3 alkyl, halo(C 1-3 )alkyl, C 1-3 alkoxy and halo(C 1-3 )alkoxy.

19. The compound according to any one of the preceding claims, wherein R X2 , R X3 , R X4 and R X5 are hydrogen.

20. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 , and Y 4 are CR y .

21. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each R y is independently selected from hydrogen, halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, methoxy(C 1-3 )alkoxy, hydroxy(C 2-5 )alkyl, hydroxy(C 2-5 )alkynyl, C 2-5 alkynyl, and 5-membered heteroaryl containing up to three heteroatoms independently selected from N, O, and S, wherein the 5-membered heteroaryl is optionally substituted with up to three C 1-3 alkyl; or R y and R f together with the atoms on which they are attached form a 6-membered ring optionally containing an oxygen atom.

22. The compound or pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein each R y is hydrogen.

23. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Z is halogen, C 1-3 alkyl, halo(C 1-3 )alkyl, C 2-5 alkenyl, halo(C 2-5 )alkenyl, or C 2-5 alkynyl.

24. The compound according to any one of claims 1-22, wherein Z is ring B, wherein ring B is phenyl, benzimidazolyl, 3-azabicycloheptyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3,4-thiadiazolyl, 1,3- dihydroisobenzofuranyl, indazolyl, indolyl, 1-oxa-6-azaspirooctyl, 2,3- dihydrobenzofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl 1,1-dioxide, 3,4- dihydrobenzoxazinyl, 3,4-dihydropyranyl, imidazopyridinyl, 1,2,4-triazolyl, 5,6,7,8- tetrahydropyridopyridazinyl, 5,6-dihydropyrrolopyrazolyl, 6-oxaspirooctyl, benzothiophenyl, benzoisothiazolyl, benzoxazolyl-2-one, benzoxazolyl, benzothiazolyl, benzofuranyl, cyclohexyl, cyclopentyl, cyclopropyl, furanyl, furopyridazinyl, imidazopyridazinyl, imidazolidinyl-2-one, indolinyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxepanyl, oxetanyl, piperidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrofuranyl, tetrahydrothiophenyl 1,1-dioxide, tetrazolopyridazinyl, thiazolyl, thienopyrimidinyl, thienopyridinyl, or thienyl, wherein ring B is optionally substituted with up to three substituents independently selected from the group consisting of halogen, cyano, nitro, hydroxy, carboxy, C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl, -C 1-3 alkylene-NR g R h , -CONR g R h , -NR g R h , -NR g C(O)R h , -SO2NR g R h , and L B -W, or the two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S.

25. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B is optionally substituted with up to three substituents independently selected from halogen, cyano, hydroxy, C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, hydroxy(C 1-3 )alkyl, C 2-5 alkenyl, -C 1-3 alkylene-NR g R h , -NR g R h , -NR g C(O)R h , -SO2NR g R h and L B -W, or two substituents of ring B, together with the atoms to which they are attached, form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O and S; L B is independently selected from the group consisting of a bond, -(CH2) p -, -CH2O-, -C(O)-, and -CH2C(O)NH-; W is independently selected from the group consisting of hydrogen, C 1-3 alkyl, -O(C 1-4 )alkyl, C 3-7 ycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl ring containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted with up to three substituents independently selected from the group consisting of halogen, C 1-3 alkyl, and -C(O)O(C 1-4 )alkyl; p is 1; and R g and R h each independently is hydrogen or C 1-3 alkyl.

26. A compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein Z is ring B, wherein ring B is phenyl, benzimidazolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3,4-thiadiazolyl, 1,3-dihydroisobenzofuranyl, indazolyl, indolyl, 2,3-dihydrobenzofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl 1,1-dioxide, 3,4-dihydrobenzoxazinyl, 3,4-dihydropyranyl, imidazopyridinyl, 1,2,4-triazolyl, 5,6-dihydropyrrolopyrazolyl, 6-oxaspirocyclooctyl, benzisothiazolyl, benzoxazolyl-2-one, benzoxazolyl, benzothiazolyl, benzofuranyl, cyclohexyl, cyclopentyl, furanyl, furopyridazinyl, imidazopyridazinyl, indolinyl, isothiazolyl, isoxazolyl, oxepanyl, piperidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrothiophenyl 1,1-dioxide, thiazolyl, or thiophenyl, wherein ring B is optionally substituted with up to three substituents independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl, -C 1-3 alkylene-NR g R h , -CONR g R h , -NR g R h , -NR g C(O)R h , -SO2NR g R h , and L B -W; and 27. A compound according to claim 23, or a pharmaceutically acceptable salt thereof, wherein Z is ring B, wherein ring B is phenyl, benzimidazolyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1,3,4-thiadiazolyl, 1,3-dihydroisobenzofuranyl, indazolyl, indolyl, 2,3-dihydrobenzofuranyl, 2,5-dihydrofuranyl, 2,5-dihydrothiophenyl 1,1-dioxide, 3,4-dihydrobenzoxazinyl, 3,4-dihydropyranyl, imidazopyridinyl, 1,2,4-triazolyl, 5,6-dihydropyrrolopyrazolyl, 6-oxaspirocyclooctyl, benzisothiazolyl, benzoxazolyl-2-one, benzoxazolyl, benzothiazolyl, benzofuranyl, cyclohexyl, cyclopentyl, furanyl, furopyridazinyl, imidazopyridazinyl, indolinyl, isothiazolyl, isoxazolyl, oxepanyl, piperidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, tetrahydrothiophenyl 1,1-dioxide, thiazolyl, or thiophenyl, wherein ring B is optionally substituted with up to three substituents independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, halo(C 1-3 )alkyl, halo(C 1-3 )alkoxy, hydroxy(C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl, -C 1-3 alkylene-NR g R h , -CONR g R h , -NR g R h , -NR g C(O)R h , -SO2NR g R h , and L B -W; and R g and R h each independently is hydrogen or C 1-3 alkyl.

27. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein ring B is benzimidazolyl optionally substituted with up to three substituents independently selected from halo, C 1-3 alkyl, C 3-7 cycloalkyl, -C 1-3 alkylene-NR g R h , -NR g R h and a 4- to 6-membered heterocycloalkyl ring containing one or two heteroatoms independently selected from N, O and S, wherein said heterocycloalkyl ring is optionally substituted with C 1-3 alkyl; and wherein R g and R h each independently is hydrogen or C 1-3 alkyl.

28. The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I-b): (I-b).

29. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II): (II) wherein: m is an integer from 1 to 3; q is an integer from 1 to 3; Each R 6 Independently selected from halogen, cyano, nitro, hydroxyl, -NR a R b , carboxyl group, -CONR a R b C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl; Each R 7 Independently selected from halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, C 2-5 alkenyl, C 2-5 alkynyl group, -C 1-3 Alkylene-NR g R h -CONR g R h -NR g R h -NR g C(O)R h -SO2NR g R h and L B -W, or two R 7 with the atom to which they are attached form a 5- or 6-membered ring optionally containing one or two heteroatoms independently selected from N, O, and S; L B is independently selected from the group consisting of a bond, -(CH2) p -, -CH2O-, -C(O)-NH-, -C(O)-, and -CH2C(O)NH-; W is independently selected from: hydrogen, C 1-3 Alkyl, -O(C) 1-4 )alkyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted by up to three substituents independently selected from: halogen, cyano, nitro, hydroxyl, -NR m R n , carboxyl group, -CONR m R n C 1-3 Alkyl, C 1-3 Alkoxy, halogenated (C 1-3 )alkyl, halogenated (C 1-3 )alkoxy, hydroxyl (C 1-3 )alkyl, cyano (C 1-3 )alkyl, C 1-3 alkylsulfonyl, -C(O)O(C 1-4 )alkyl and C 3-7 cycloalkyl; p is 1 or 2; R a , R b , R g , R h , R m , and R n are each independently hydrogen, C 1-3 alkyl, or C 3-7 cycloalkyl; R 1 is hydrogen or C 1-3 alkyl; R X3 is hydrogen, C 1-3 alkyl, C 1-3 alkoxy(C 1-3 )alkyl- or L X -V; R c and R f each independently is hydrogen, C 1-3 alkyl, or C 3-7 cycloalkyl; L X is a bond or -O-(CH2) w -; and V is C 3-7 cycloalkyl or a 3- to 6-membered heterocycloalkyl ring containing one heteroatom selected from N and O, wherein V is optionally substituted with up to three substituents independently selected from halo, C 1-3 alkyl, halo(C 1-3 )alkyl, C 1-3 alkoxy and halo(C 1-3 )alkoxy; and w is 0 or 1.

30. The compound according to claim 29, or a pharmaceutically acceptable salt thereof, wherein: Each R 6 Independently selected from halogens, hydroxyl groups, and C 1-3 Alkyl and halogenated (C 1-3 )alkyl; each R is independently selected from the group consisting of halogen, C 7 halogen, C 1-3 alkyl, -C 1-3 alkylene-NR g R h , -NR g R h and L B -W; L B is a bond; W is independently selected from C 3-7 cycloalkyl and 4- to 6-membered heterocycloalkyl rings containing one, two, or three heteroatoms independently selected from N, O, and S, wherein W is optionally substituted with C 1-3 alkyl; and R g and R h each independently is hydrogen or C 1-3 alkyl.

31. The compound according to claim 29 or 30, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II-b): (II-b).

32. The compound according to claim 31, or a pharmaceutically acceptable salt thereof, wherein m is 2; q is 2; R 1 is hydrogen; R c is hydrogen; R f is methyl; R 6 selected from trifluoromethyl and fluoro; and R 7 is methyl.

33. A compound selected from the compounds of Table 1, or a pharmaceutically acceptable salt thereof.

34. A compound selected from the group consisting of: , , , and , or a pharmaceutically acceptable salt thereof.

35. A compound selected from the group consisting of: , , , and .

36. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

37. A compound according to any one of claims 1-35, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36, for use in therapy.

38. A compound according to any one of claims 1-35, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36, for use in the treatment of cancer.

39. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-35, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 36.

40. The method of treating cancer according to claim 39, wherein the cancer is characterized by MSI-H and / or dMMR.

41. The method of treating cancer according to claim 39, wherein the cancer is treatable by inhibition of WRN.

42. Use of a compound according to any one of claims 1-35, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 36, for the manufacture of a medicament for the treatment of cancer.

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